Renal Function and Outcomes With Use of Left Ventricular Assist Device Implantation and Inotropes in End-Stage Heart Failure: A Retrospective Single Center Study.

PubMed

Verma, Sean; Bassily, Emmanuel; Leighton, Shane; Mhaskar, Rahul; Sunjic, Igor; Martin, Angel; Rihana, Nancy; Jarmi, Tambi; Bassil, Claude

2017-07-01

Left ventricular assist device (LVAD) and inotrope therapy serve as a bridge to transplant (BTT) or as destination therapy in patients who are not heart transplant candidates. End-stage heart failure patients often have impaired renal function, and renal outcomes after LVAD therapy versus inotrope therapy have not been evaluated. In this study, 169 patients with continuous flow LVAD therapy and 20 patients with continuous intravenous inotrope therapy were analyzed. The two groups were evaluated at baseline and at 3 and 6 months after LVAD or inotrope therapy was started. The incidence of acute kidney injury (AKI), need for renal replacement therapy (RRT), BTT rate, and mortality for 6 months following LVAD or inotrope therapy were studied. Results between the groups were compared using Mann-Whitney U test and Chi-square with continuity correction or Fischer's exact at the significance level of 0.05. Mean glomerular filtration rate (GFR) was not statistically different between the two groups, with P = 0.471, 0.429, and 0.847 at baseline, 3 and 6 months, respectively. The incidence of AKI, RRT, and BTT was not statistically different. Mortality was less in the inotrope group (P < 0.001). Intravenous inotrope therapy in end-stage heart failure patients is non-inferior for mortality, incidence of AKI, need for RRT, and renal function for 6-month follow-up when compared to LVAD therapy. Further studies are needed to compare the effectiveness of inotropes versus LVAD implantation on renal function and outcomes over a longer time period.

Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations.

PubMed

Vahlensieck, U; Bokník, P; Gombosová, I; Huke, S; Knapp, J; Linck, B; Lüss, H; Müller, F U; Neumann, J; Deng, M C; Scheld, H H; Jankowski, H; Schlüter, H; Zidek, W; Zimmermann, N; Schmitz, W

1999-02-01

Diadenosine tetraphosphate (AP4A) is an endogenous compound and exerts diverse physiological effects in animal systems. However, the effects of AP4A on inotropy in ventricular cardiac preparations have not yet been studied. The effects of AP4A on force of contraction (FOC) were studied in isolated electrically driven guinea pig and human cardiac preparations. Furthermore, the effects of AP4A on L-type calcium current and [Ca]i were studied in isolated guinea pig ventricular myocytes. In guinea pig left atria, AP4A (0.1-100 microM) reduced FOC maximally by 36.5 +/- 4.3%. In guinea pig papillary muscles, AP4A (100 microM) alone was ineffective, but reduced isoproterenol-stimulated FOC maximally by 29.3 +/- 3.4%. The negative inotropic effects of AP4A in atria and papillary muscles were abolished by the A1-adenosine receptor antagonist 1, 3-dipropyl-cyclopentylxanthine. In guinea pig ventricular myocytes, AP4A (100 microM) attenuated isoproterenol-stimulated L-type calcium current and [Ca]i. In human atrial and ventricular preparations, AP4A (100 microM) alone increased FOC to 158.3 +/- 12.4% and 167.5 +/- 25.1%, respectively. These positive inotropic effects were abolished by the P2-purinoceptor antagonist suramin. On the other hand, AP4A (100 microM) reduced FOC by 27.2 +/- 7.4% in isoproterenol-stimulated human ventricular trabeculae. The latter effect was abolished by 1,3-dipropyl-cyclopentylxanthine. In summary, after beta adrenergic stimulation AP4A exerts negative inotropic effects in animal and human ventricular preparations via stimulation of A1-adenosine receptors. In contrast, AP4A alone can exert positive inotropic effects via P2-purinoceptors in human ventricular myocardium. Thus, P2-purinoceptor stimulation might be a new positive inotropic principle in the human myocardium.

The Positive Inotropic Effect of Pyruvate Involves an Increase in Myofilament Calcium Sensitivity

PubMed Central

Torres, Carlos A. A.; Varian, Kenneth D.; Canan, Cynthia H.; Davis, Jonathan P.; Janssen, Paul M. L.

2013-01-01

Pyruvate is a metabolic fuel that is a potent inotropic agent. Despite its unique inotropic and antioxidant properties, the molecular mechanism of its inotropic mechanism is still largely unknown. To examine the inotropic effect of pyruvate in parallel with intracellular calcium handling under near physiological conditions, we measured pH, myofilament calcium sensitivity, developed force, and calcium transients in ultra thin rabbit heart trabeculae at 37 °C loaded iontophoretically with the calcium indicator bis-fura-2. By contrasting conditions of control versus sarcoplasmic reticulum block (with either cyclopiazonic acid and ryanodine or with thapsigargin) we were able to characterize and isolate the effects of pyruvate on sarcoplasmic reticulum calcium handling and developed force. A potassium contracture technique was subsequently utilized to assess the force-calcium relationship and thus the myofilament calcium sensitivity. Pyruvate consistently increased developed force whether or not the sarcoplasmic reticulum was blocked (16.8±3.5 to 24.5±5.1 vs. 6.9±2.6 to 12.5±4.4 mN/mm2, non-blocked vs. blocked sarcoplasmic reticulum respectively, p<0.001, n = 9). Furthermore, the sensitizing effect of pyruvate on the myofilaments was demonstrated by potassium contractures (EC50 at baseline versus 20 minutes of pyruvate infusion (peak force development) was 701±94 vs. 445±65 nM, p<0.01, n = 6). This study is the first to demonstrate that a leftward shift in myofilament calcium sensitivity is an important mediator of the inotropic effect of pyruvate. This finding can have important implications for future development of therapeutic strategies in the management of heart failure. PMID:23691074

Renal Function and Outcomes With Use of Left Ventricular Assist Device Implantation and Inotropes in End-Stage Heart Failure: A Retrospective Single Center Study

PubMed Central

Verma, Sean; Bassily, Emmanuel; Leighton, Shane; Mhaskar, Rahul; Sunjic, Igor; Martin, Angel; Rihana, Nancy; Jarmi, Tambi; Bassil, Claude

2017-01-01

Background Left ventricular assist device (LVAD) and inotrope therapy serve as a bridge to transplant (BTT) or as destination therapy in patients who are not heart transplant candidates. End-stage heart failure patients often have impaired renal function, and renal outcomes after LVAD therapy versus inotrope therapy have not been evaluated. Methods In this study, 169 patients with continuous flow LVAD therapy and 20 patients with continuous intravenous inotrope therapy were analyzed. The two groups were evaluated at baseline and at 3 and 6 months after LVAD or inotrope therapy was started. The incidence of acute kidney injury (AKI), need for renal replacement therapy (RRT), BTT rate, and mortality for 6 months following LVAD or inotrope therapy were studied. Results between the groups were compared using Mann-Whitney U test and Chi-square with continuity correction or Fischer’s exact at the significance level of 0.05. Results Mean glomerular filtration rate (GFR) was not statistically different between the two groups, with P = 0.471, 0.429, and 0.847 at baseline, 3 and 6 months, respectively. The incidence of AKI, RRT, and BTT was not statistically different. Mortality was less in the inotrope group (P < 0.001). Conclusion Intravenous inotrope therapy in end-stage heart failure patients is non-inferior for mortality, incidence of AKI, need for RRT, and renal function for 6-month follow-up when compared to LVAD therapy. Further studies are needed to compare the effectiveness of inotropes versus LVAD implantation on renal function and outcomes over a longer time period. PMID:28611860

Possible mechanism of the negative inotropic effect of α1-adrenoceptor agonists in rat isolated left atria after exposure to free radicals

PubMed Central

Peters, Stephan L M; Batink, Harry D; Michel, Martin C; Pfaffendorf, Martin; van Zwieten, Pieter A

1998-01-01

This study was designed to investigate the mechanism(s) of the negative inotropic effects of α1-adrenoceptor agonists observed in rat isolated left atria after exposure to free radicals.Ouabain and calphostin C were used in contraction experiments to block the sodium pump and protein kinase C. Methoxamine-induced phospholipase C and Na+/K+ ATPase activities were measured.Methoxamine (300 μM) increased contractile force by 1.6±0.2 mN in control atria but decreased contractile force in electrolysis-treated atria by 2.0±0.1 mN (P<0.05), as determined 10 min after methoxamine addition. In contrast, the positive inotropic effects of endothelin-1 (30 nM) and isoprenaline (10 μM) were reduced from 2.6±0.3 to 1.3±0.1 mN and from 2.6±0.3 to 1.7±0.2 mN, respectively, by electrolysis treatment (P<0.05), but not converted into a negative inotropic action.In an inositol phosphate assay we observed that the stimulation of phospholipase C by methoxamine was attenuated by electrolysis when the (electrolyzed) medium from the organ bath was used, but the phospholipase C responses were restored by the use of fresh medium. However, fresh medium did not counteract the negative inotropic effect of methoxamine. Accordingly, the negative inotropic effect of methoxamine is not directly related to the impaired phospholipase C responses seen in atria subjected to electrolysis.Ouabain (10 μM) and the protein kinase C inhibitor calphostin C (50 nM), completely prevented the negative inotropic effect of 300 μM methoxamine in electrolysis-treated atria.Measurement of the Na+/K+ ATPase activity, revealed that in control atria, α1-adrenoceptor stimulation with 300 μM methoxamine, decreased the Na+/K+ ATPase activity by 14.4±7.7%. In contrast, methoxamine increased the Na+/K+ ATPase activity by 48.8±8.9% (P<0.05) in electrolysis-treated atria. Interestingly, this increase in Na+/K+ ATPase activity was completely counteracted by calphostin C (1.4±0.1% over basal).These results indicate that the negative inotropic effects of α1-adrenoceptor agonists, observed in rat isolated left atria exposed to free radicals, are likely to be caused by protein kinase C-mediated phosphorylation and subsequent activation of the Na+/K+ ATPase. PMID:9535025

Role of N-type calcium channels in autonomic neurotransmission in guineapig isolated left atria

PubMed Central

Serone, Adrian P; Angus, James A

1999-01-01

Calcium entry via neuronal calcium channels is essential for the process of neurotransmission. We investigated the calcium channel subtypes involved in the operation of cardiac autonomic neurotransmission by examining the effects of selective calcium channel blockers on the inotropic responses to electrical field stimulation (EFS) of driven (4 Hz) guineapig isolated left atria. In this tissue, a previous report (Hong & Chang, 1995) found no evidence for N-type channels involved in the vagal negative inotropic response and only weak involvement in sympathetic responses. The effects of cumulative concentrations of the selective N-type calcium channel blocker, ω-conotoxin GVIA (GVIA; 0.1–10 nM) and the nonselective N-, P/Q-type calcium channel blocker, ω-conotoxin MVIIC (MVIIC; 0.01–10 nM) were examined on the positive (with atropine, 1 μM present) and negative (with propranolol, 1 μM and clonidine, 1 μM present) inotropic responses to EFS (eight trains, each train four pulses per punctate stimulus). GVIA caused complete inhibition of both cardiac vagal and sympathetic inotropic responses to EFS. GVIA was equipotent at inhibiting positive (pIC50 9.29±0.08) and negative (pIC50 9.13±0.17) inotropic responses. MVIIC also mediated complete inhibition of inotropic responses to EFS and was 160 and 85 fold less potent than GVIA at inhibiting positive (pIC50 7.08±0.10) and negative (pIC50 7.20±0.14) inotropic responses, respectively. MVIIC was also equipotent at inhibiting both sympathetic and vagal responses. Our data demonstrates that N-type calcium channels account for all the calcium current required for cardiac autonomic neurotransmission in the guinea-pig isolated left atrium. PMID:10433500

Inotropes and cardiorenal syndrome in acute heart failure - A retrospective comparative analysis.

PubMed

Madeira, Marta; Caetano, Francisca; Almeida, Inês; Fernandes, Andreia; Reis, Liliana; Costa, Marco; Gonçalves, Lino

2017-09-01

Cardiorenal syndrome (CRS) is common in acute heart failure (AHF), and is associated with dire prognosis. Levosimendan, a positive inotrope that also has diuretic effects, may improve patients' renal profile. Published results are conflicting. We aimed to assess the incidence of CRS in AHF patients according to the inotrope used and to determine its predictors in order to identify patients who could benefit from the most renoprotective inotrope. In a retrospective study, 108 consecutive patients with AHF who required inotropes were divided into two groups according to the inotrope used (levosimendan vs. dobutamine). The primary endpoint was CRS incidence. Follow-up for mortality and readmission for AHF was conducted. Seventy-one percent of the study population were treated with levosimendan and the remainder with dobutamine. No differences were found in heart failure etiology or chronic kidney disease. At admission, the dobutamine group had lower blood pressure; there were no differences in estimated glomerular filtration rate or cystatin C levels. The levosimendan group had lower left ventricular ejection fraction. CRS incidence was higher in the dobutamine group, and they more often had incomplete recovery of renal function at discharge. In multivariate analysis, cystatin C levels predicted CRS. The dobutamine group had higher in-hospital mortality, of which CRS and the inotrope used were predictors. Levosimendan appears to have some renoprotective effect, as it was associated with a lower incidence of CRS and better recovery of renal function at discharge. Identification of patients at increased risk of renal dysfunction by assessing cystatin C may enable more tailored therapy, minimizing the incidence of CRS and its negative impact on outcome in AHF. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of the cardiac inotropic drug, OPC 8212, on pituitary-thyroid function in the rat.

PubMed

Lueprasitsakul, W; Fang, S L; Alex, S; Braverman, L E

1991-06-01

3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-1 piperaznyl]-2(1H)-quinolinone (OPC 8212) is a new synthetic quinolinone with potent cardiac inotropic action in man. Long term oral administration of OPC induces goiter and thyroid tumor formation in rats, associated with decreases in serum T4 and increases in serum TSH concentrations. Studies were carried out to explore the mechanisms responsible for these drug induced abnormalities. OPC 8212, administered for 1 week at doses of 500 and 2000 mg/kg.day mixed with the diet, resulted in an increase in thyroid weight, a decrease in circulating T4 and free T4 concentrations and an increase in serum TSH concentrations. OPC decreased the 5'-deiodinase (5'-D) activity in liver homogenates and increased the 5'-D activity in pituitary homogenates, consistent with hypothyroidism. OPC 8212 did not affect thyroid iodine metabolism and hormone synthesis or the binding of T4 to serum binding proteins. The hepatic uptake of 125 I-T4 4 h after T4 administration was significantly increased in OPC 8212 treated rats. The biliary excretion of administered 125 I-T4 was increased in OPC 8212-treated rats and most of the increase was due to an increase in the excretion of T4-glucuronide. Hepatic T4-glucuronyltransferase activity measured in vitro in OPC 8212 treated rats was increased as compared to that of controls. It is concluded that the effect of OPC 8212 on lowering serum T4 with a compensatory rise in TSH leading to goiter formation is due to a drug-induced increase in hepatic T4 disposal. The induction of T4-glucuronyl-transferase appears to play an important role in the increased biliary excretion of T4 in OPC 8212-treated rats.

Studies on the cardiac actions of flosequinan in vitro.

PubMed Central

Gristwood, R. W.; Beleta, J.; Bou, J.; Cardelús, I.; Fernández, A. G.; Llenas, J.; Berga, P.

1992-01-01

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity. PMID:1324061

The influence of hormonal and neuronal factors on rat heart adrenoceptors

PubMed Central

Kunos, George; Mucci, Lucia; O'Regan, Seana

1980-01-01

1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective α- and β-adrenoceptor antagonists. The numbers and affinities of α- and β-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments. 2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria. 3 The decreased β- and increased α-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days). 4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [3H]-dihydroalprenolol ([3H]-DHA) binding sites from 27.5 ± 2.7 to 45.5 ± 5.7 fmol/mg protein and decreased the density of [3H]-WB-4101 binding sites from 38.7 ± 3.1 to 18.7 ± 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of α1- and β-receptors remained the same. 5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [3H]-DHA binding sites was higher and that of [3H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [3H]-DHA and [3H]-WB-4101 binding sites. 6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac α1- and β-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of α1- and β-adrenoceptors. Reciprocal regulation of cardiac α1- and β-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter. PMID:7470752

PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

PubMed Central

Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

2013-01-01

Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle. Linked Article This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168 PMID:23489141

Studies on the positive inotropic effect of phenylephrine: a comparison with isoprenaline.

PubMed

Ledda, F; Marchetti, P; Mugelli, A

1975-05-01

1. The effects of phenylephrine and isoprenaline on the isometric contraction of guinea-pig ventricle were compared over the whole range of their respective dose-response curves. 2. In preparations driven at 2.5 Hz the increase in contractile force induced by either isoprenaline of phenylephrine was linearly correlated to an increase in maximum velocity of force development. The relaxation time was shortened by isoprenaline but not by phenylephrine. 3. The negative inotropic effect induced by delta [N-(3,4-dimethoxyphenethyl)-N-methyl-amino]-alpha-(3,4,5-trimethoxyphenyl)alpha-isopropylvaleronitrile hydrochloride (D(600)) was reversed by isoprenaline, but little influenced by phenylephrine. 4. The study of the interval-force relationship shows that the increase in contractile force induced by phenylephrine (3 X 10(-5) M) was relatively greater at low frequencies of stimulation, and that the maximum effect was reached at the frequency of 1 Hz. 5. The positive inotropic effect of phenylephrine (10-4 M) was significantly higher at a frequency of 1 Hz than at 2.5 Hz; the effect of isoprenaline (3 x 10-8 M) was not significantly different at the two driving frequencies. 6. In preparations driven at 1 Hz the inotropic effect of the lower concentrations of phenylephrine was due to an increase in the time to peak tension without any change of the maximum velocity of force development; however an increase of this parameter became evident only after higher concentrations of the amine (10-5 M or more), associated with a progressive shortening of the time to peak. 7. A correlation between mechanical and electrophysiological effects of phenylephrine is attempted; the suggestion is advanced that the prolongation of the action potential and of the active state duration may be an important factor in the inotropic effect of phenylephrine.

Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart.

PubMed

Holmboe, Sarah; Andersen, Asger; Jensen, Rebekka V; Kimose, Hans Henrik; Ilkjær, Lars B; Shen, Lei; Clapp, Lucie H; Nielsen-Kudsk, Jens Erik

2017-01-01

Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium.

[Levosimendan as a treatment for acute renal failure associated with cardiogenic shock after hip fracture].

PubMed

Hinojosa, Fabiola Quinteros; Revelo, Margarita; Salazar, Alexander; Maggi, Genaro; Schiraldi, Renato; Brogly, Nicolas; Gilsanz, Fernando

Inotropic drugs are part of the treatment of heart failure; however, inotropic treatment has been largely debated due to the increased incidence of adverse effects and increased mortality. Recently levosimendan, an inotropic positive agent, has been proved to be effective in acute heart failure, reducing the mortality and improving cardiac and renal performance. We report the case of a 75-year-old woman with history of heart and renal failure and hip fracture. Levosimendan was used in preoperative preparation as an adjuvant therapy, to improve cardiac and renal function and to allow surgery. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Levosimendan as a treatment for acute renal failure associated with cardiogenic shock after hip fracture.

PubMed

Hinojosa, Fabiola Quinteros; Revelo, Margarita; Salazar, Alexander; Maggi, Genaro; Schiraldi, Renato; Brogly, Nicolas; Gilsanz, Fernando

Inotropic drugs are part of the treatment of heart failure; however, inotropic treatment has been largely debated due to the increased incidence of adverse effects and increased mortality. Recently levosimendan, an inotropic positive agent, has been proved to be effective in acute heart failure, reducing the mortality and improving cardiac and renal performance. We report the case of a 75-year-old woman with history of heart and renal failure and hip fracture. Levosimendan was used in preoperative preparation as an adjuvant therapy, to improve cardiac and renal function and to allow surgery. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Functional β2-adrenoceptors in rat left atria: effect of foot-shock stress.

PubMed

Moura, André Luiz de; Hyslop, Stephen; Grassi-Kassisse, Dora M; Spadari, Regina C

2017-09-01

Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the β 1 /β 2 -adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and β-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective β 2 -receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective β 1 -receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that β 2 -adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.

[Inotropic effect of a new probiotic product on myocardial contractility. Comparison with diazoxide].

PubMed

Sobol', K V; Korotkov, S M; Nesterov, V P

2014-01-01

The inotropic effect of a new probiotic product on myocardial contractility of the frog Rana ridibunda and the effect of probiotic product on the rat cardiac mitochondria swelling were studied. In both cases, the comparison with known cardioprotector diazoxide was done. Probiotic product and diazoxide were shown to cause a dual effect on the maximum force induced by the muscle sample during spontaneous atrial contraction. Addition of agents caused a negative impact, while washing out exerted a positive inotropic effect. At the same time probiotic product has virtually no effect on the amplitude of contraction induced by electrical stimulation of the ventricle fragments. Probiotic product decreases both proton passive permeability in the inner mitochondrial membrane, and potassium active transport in mitochondria caused by activation of K(+)-uniporter of cardiomyocytes. A possible mechanism of action of probiotic product is discussed.

Effects of the new imidazopyridine CL 86-02-01 on isolated papillary muscle of guinea-pig hearts.

PubMed

Studenik, C; Lemmens-Gruber, R; Heistracher, P

1998-06-01

Inotropic activity and the effect of CL 86-02-01 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo[4,5-c]pyridine hydrochloride, CAS 109 792-24-7) on membrane resting and action potentials were studied in isolated guinea-pig papillary muscles. Membrane resting potential and action potential parameters were not significantly changed, while CL 86-02-01 exerted a concentration-dependent inotropic effect by increasing the maximum rate of force development and maximum rate of force relaxation. Time to peak force, relaxation time and total contraction time were reduced. These effects are similar to those of beta-adrenergic drugs and phosphodiesterase inhibitors, but markedly differ from those described for other positive inotropic agents like cardiac glycosides, calcium agonists, alpha-adrenergic drugs or increased extracellular calcium concentration.

Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure.

PubMed

Ishihara, Shiro; Gayat, Etienne; Sato, Naoki; Arrigo, Mattia; Laribi, Said; Legrand, Matthieu; Placido, Rui; Manivet, Philippe; Cohen-Solal, Alain; Abraham, William T; Jessup, Mariell; Mebazaa, Alexandre

2016-12-01

Acute heart failure (AHF) with reduced left-ventricular ejection fraction (LVEF) is often a biventricular congested state. The comparative effect of vasodilators and inotropes on the right- and/or left-sided congestion is unknown. A systematic review, meta-analysis, and meta-regression of AHF studies using pulmonary artery catheter were performed using PubMed, Embase, and Cochrane library. Data from 35 studies, including 3016 patients, were studied. Included patients had a weighted mean age of 60 years, left-ventricular ejection fraction (LVEF) of 24 %, and plasma B-type natriuretic peptide (BNP) of 892 pg/ml. Both the left- and right-ventricular filling pressures were elevated: weighted mean pulmonary artery wedge pressure (PAWP) was 25 mmHg (range 17-31 mmHg) and right atrial pressure (RAP) 12 mmHg (range 7-18 mmHg). Vasodilators and inotropes had similar beneficial effects on PAWP [-6.3 mmHg (95 % CI -7.4 to -5.2 mmHg) and -5.8 mmHg (95 % CI -7.6 to -4.0 mmHg), respectively] and RAP [-2.9 mmHg (95 % CI -3.8 to -2.1 mmHg) and -2.8 mmHg (95 % CI -3.8 to -1.7 mmHg), respectively]. Among inotropes, inodilators, such as levosimendan, have greater beneficial effect on the left-ventricular filling pressure than dobutamine. Drug-induced improvement of PAWP tightly paralleled that of RAP with all studied drugs (r 2  = 0.90, p < 0.001). Vasodilators and inotropes had no short-term effect of renal function. The left- and right-sided filling pressures are similarly improved by vasodilators or inotropes, in AHF with reduced LVEF.

Calcium influx through L-type channels attenuates skeletal muscle contraction via inhibition of adenylyl cyclases.

PubMed

Menezes-Rodrigues, Francisco Sandro; Pires-Oliveira, Marcelo; Duarte, Thiago; Paredes-Gamero, Edgar Julian; Chiavegatti, Tiago; Godinho, Rosely Oliveira

2013-11-15

Skeletal muscle contraction is triggered by acetylcholine induced release of Ca(2+) from sarcoplasmic reticulum. Although this signaling pathway is independent of extracellular Ca(2+), L-type voltage-gated calcium channel (Cav) blockers have inotropic effects on frog skeletal muscles which occur by an unknown mechanism. Taking into account that skeletal muscle fiber expresses Ca(+2)-sensitive adenylyl cyclase (AC) isoforms and that cAMP is able to increase skeletal muscle contraction force, we investigated the role of Ca(2+) influx on mouse skeletal muscle contraction and the putative crosstalk between extracellular Ca(2+) and intracellular cAMP signaling pathways. The effects of Cav blockers (verapamil and nifedipine) and extracellular Ca(2+) chelator EGTA were evaluated on isometric contractility of mouse diaphragm muscle under direct electrical stimulus (supramaximal voltage, 2 ms, 0.1 Hz). Production of cAMP was evaluated by radiometric assay while Ca(2+) transients were assessed by confocal microscopy using L6 cells loaded with fluo-4/AM. Ca(2+) channel blockers verapamil and nifedipine had positive inotropic effect, which was mimicked by removal of extracellular Ca(+2) with EGTA or Ca(2+)-free Tyrode. While phosphodiesterase inhibitor IBMX potentiates verapamil positive inotropic effect, it was abolished by AC inhibitors SQ22536 and NYK80. Finally, the inotropic effect of verapamil was associated with increased intracellular cAMP content and mobilization of intracellular Ca(2+), indicating that positive inotropic effects of Ca(2+) blockers depend on cAMP formation. Together, our results show that extracellular Ca(2+) modulates skeletal muscle contraction, through inhibition of Ca(2+)-sensitive AC. The cross-talk between extracellular calcium and cAMP-dependent signaling pathways appears to regulate the extent of skeletal muscle contraction responses. © 2013 Published by Elsevier B.V.

[Effects of genistein on contractility of isolated right ventricular muscles in guinea pig].

PubMed

Wu, Jin-xia; Li, Hong-fang; Liu, Chong-bin; Tian, Zhi-feng

2008-11-01

To study the effect of genistein (GEN) on contractility of isolated right ventricular muscles in guinea pig and its mechanisms. Isolated guinea pig ventricular muscles were suspended in organ baths containing K-H solution.After an equilibration period, the effect of GEN on contraction of myocardium was observed. GEN and isoprenaline hydrochloride had the positive inotropic effects on contractity of myocardium. Meanwhile, the effect of GEN (1-100 micromol x L(-1)) was in dose-dependent manner. Propranolol (1 micromol x L(-1)) and verapamil hydrochloride (0.5 micromol x L(-1)) attenuated the positive inotropic effect of isoprenaline hydrochloride (1 micromol x L(-1)), but did not change the effect of GEN (50 micromol x L(-1)). Further more, the enhancement of the contraction induced by elevation of extracellular Ca2+ concentration in ventricular muscles had no change after pretreatment with GEN (1.10 micromol x L(-1)). In addition,the positive inotropic effect of GEN was inhibited partially by tamoxifen (1 micromol x L(-1)) and SQ22536 (1 micromol x L(-1)), also, could be attenuated by bpV (1 micromol x L(-1)). GEN has the positive inotropic effect on guinea pig ventricular muscles, which is not related to the activation of beta adrenoceptor, Ca2+ channel on cell membrane,but may involve in cAMP of intracellular signal transduction and tyrosine kinase pathway.

A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects.

PubMed

Trân, Kien; Murza, Alexandre; Sainsily, Xavier; Coquerel, David; Côté, Jérôme; Belleville, Karine; Haroune, Lounès; Longpré, Jean-Michel; Dumaine, Robert; Salvail, Dany; Lesur, Olivier; Auger-Messier, Mannix; Sarret, Philippe; Marsault, Éric

2018-03-22

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, K i 0.15 nM and t 1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.

Inotropic effects of diadenosine tetraphosphate in isolated canine cardiac preparations.

PubMed

Neumann, J; Meissner, A; Bokník, P; Gombosová, I; Knapp, J; Lüss, H; Müller, F U; Schlüter, H; Zidek, W; Rolf, N; Van Aken, H; Vahlensieck, U; Schmitz, W

1999-01-01

We studied the effects of diadenosine tetraphosphate (AP4A) on the force of contraction in canine preparations. The force of contraction was measured in isolated electrically driven (1 Hz) atrial and ventricular cardiac trabeculae from adult dogs. AP4A (100 microM) alone and after prestimulation with 10 nM isoproterenol reduced force of contraction in atrial preparations by approximately 24%. Moreover, AP4A (100 microM) alone and after prestimulation with 10 nM isoproterenol reduced the force of contraction in ventricular preparations by 29 and 29%, respectively. The negative inotropic effects of AP4A were abolished by the A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX). In summary, in canine myocardium, AP4A alone and after prestimulation with a beta-adrenoceptor agonist exerts negative inotropic effects, which are probably mediated via A1-adenosine receptors.

Negative inotropism of terpenes on guinea pig left atrium: structure-activity relationships.

PubMed

Vasconcelos, Carla M L; Oliveira, Ingrid S N; Santos, José N A; Souza, Américo A; Menezes-Filho, José E R; Silva Neto, Júlio A; Lima, Tamires C; de Sousa, Damião P

2018-06-01

The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC 50 and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism.

Putative β4-adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (−)-[3H]-CGP 12177 binding

PubMed Central

Sarsero, Doreen; Molenaar, Peter; Kaumann, Alberto J; Freestone, Nicholas S

1999-01-01

We identified putative β4-adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (−)-CGP 12177 and (±)-cyanopindolol and demonstrated increased Ca2+ transients by (−)-CGP 12177 in rat cardiomyocytes.(−)-[3H]-CGP 12177 labelled 13–22 fmol mg−1 protein ventricular β1, β2-adrenoceptors (pKD ∼9.0) and 50–90 fmol mg−1 protein putative β4-adrenoceptors (pKD ∼7.3). The affinity values (pKi) for (β1,β2-) and putative β4-adrenoceptors, estimated from binding inhibition, were (−)-propranolol 8.4, 5.7; (−)-bupranolol 9.7, 5.8; (±)-cyanopindolol 10.0,7.4.In left ventricular papillary muscle, in the presence of 30 μM 3-isobutyl-1-methylxanthine, (−)-CGP 12177 and (±)-cyanopindolol caused positive inotropic effects, (pEC50, (−)-CGP 12177, 7.6; (±)-cyanopindolol, 7.0) which were antagonized by (−)-bupranolol (pKB 6.7–7.0) and (−)-CGP 20712A (pKB 6.3–6.6). The cardiostimulant effects of (−)-CGP 12177 in papillary muscle, left and right atrium were antagonized by (±)-cyanopindolol (pKP 7.0–7.4).(−)-CGP 12177 (1 μM) in the presence of 200 nM (−)-propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 μM 3-isobutyl-1-methylxanthine and 200 nM (−)-propranolol, 1 μM (−)-CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (−)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes.Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1-methylxanthine facilitates the inotropic function of ventricular putative β4-adrenoceptors, suggesting coupling to Gs protein-adenylyl cyclase. The receptor-mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation through putative β4-adrenoceptors labelled with (−)-[3H]-CGP 12177. PMID:10602323

Use of Inotropic Agents in Treatment of Systolic Heart Failure.

PubMed

Tariq, Sohaib; Aronow, Wilbert S

2015-12-04

The most common use of inotropes is among hospitalized patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and with signs of end-organ dysfunction in the setting of a low cardiac output. Inotropes can be used in patients with severe systolic heart failure awaiting heart transplant to maintain hemodynamic stability or as a bridge to decision. In cases where patients are unable to be weaned off inotropes, these agents can be used until a definite or escalated supportive therapy is planned, which can include coronary revascularization or mechanical circulatory support (intra-aortic balloon pump, extracorporeal membrane oxygenation, impella, left ventricular assist device, etc.). Use of inotropic drugs is associated with risks and adverse events. This review will discuss the use of the inotropes digoxin, dopamine, dobutamine, norepinephrine, milrinone, levosimendan, and omecamtiv mecarbil. Long-term inotropic therapy should be offered in selected patients. A detailed conversation with the patient and family shall be held, including a discussion on the risks and benefits of use of inotropes. Chronic heart failure patients awaiting heart transplants are candidates for intravenous inotropic support until the donor heart becomes available. This helps to maintain hemodynamic stability and keep the fluid status and pulmonary pressures optimized prior to the surgery. On the other hand, in patients with severe heart failure who are not candidates for advanced heart failure therapies, such as transplant and mechanical circulatory support, inotropic agents can be used for palliative therapy. Inotropes can help reduce frequency of hospitalizations and improve symptoms in these patients.

SR Ca2+-leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure.

PubMed

Mustroph, Julian; Wagemann, Olivia; Lebek, Simon; Tarnowski, Daniel; Ackermann, Jasmin; Drzymalski, Marzena; Pabel, Steffen; Schmid, Christof; Wagner, Stefan; Sossalla, Samuel; Maier, Lars S; Neef, Stefan

2018-03-01

Ethanol has acute negative inotropic and arrhythmogenic effects. The underlying mechanisms, however, are largely unknown. Sarcoplasmic reticulum Ca 2+ -leak is an important mechanism for reduced contractility and arrhythmias. Ca 2+ -leak can be induced by oxidative stress and Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII). Therefore, we investigated the influence of acute ethanol exposure on excitation-contraction coupling in atrial and ventricular cardiomyocytes. Isolated human atrial and murine atrial or ventricular cardiomyocytes were preincubated for 30 min and then superfused with control solution or solution containing ethanol. Ethanol had acute negative inotropic and positive lusitropic effects in human atrial muscle strips and murine ventricular cardiomyocytes. Accordingly, Ca 2+ -imaging indicated lower Ca 2+ -transient amplitudes and increased SERCA2a activity, while myofilament Ca 2+ -sensitivity was reduced. SR Ca 2+ -leak was assessed by measuring Ca 2+ -sparks. Ethanol induced severe SR Ca 2+ -leak in human atrial cardiomyocytes (calculated leak: 4.60 ± 0.45 mF/F 0 vs 1.86 ± 0.26 in control, n ≥ 80). This effect was dose-dependent, while spontaneous arrhythmogenic Ca 2+ -waves increased ~5-fold, as investigated in murine cardiomyocytes. Delayed afterdepolarizations, which can result from increased SR Ca 2+ -leak, were significantly increased by ethanol. Measurements using the reactive oxygen species (ROS) sensor CM-H 2 DCFDA showed increased ROS-stress in ethanol treated cells. ROS-scavenging with N-acetylcysteine prevented negative inotropic and positive lusitropic effects in human muscle strips. Ethanol-induced Ca 2+ -leak was abolished in mice with knockout of NOX2 (the main source for ROS in cardiomyocytes). Importantly, mice with oxidation-resistant CaMKII (Met281/282Val mutation) were protected from ethanol-induced Ca 2+ -leak. We show for the first time that ethanol acutely induces strong SR Ca 2+ -leak, also altering excitation-contraction coupling. Acute negative inotropic effects of ethanol can be explained by reduced systolic Ca 2+ -release. Mechanistically, ROS-production via NOX2 and oxidative activation of CaMKII appear to play central roles. This provides a mechanism for the arrhythmogenic and negative inotropic effects of ethanol and suggests a druggable target (CaMKII). Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery.

PubMed

Shahin, Jason; DeVarennes, Benoit; Tse, Chun Wing; Amarica, Dan-Alexandru; Dial, Sandra

2011-07-07

Acute haemodynamic complications are common after cardiac surgery and optimal perioperative use of inotropic agents, typically guided by haemodynamic variables, remains controversial. The aim of this study was to examine the relationship of inotrope use to hospital mortality and renal dysfunction. A retrospective cohort study of 1,326 cardiac surgery patients was carried out at two university-affiliated ICUs. Multivariable logistic regression analysis and propensity matching were performed to evaluate whether inotrope exposure was independently associated with mortality and renal dysfunction. Patients exposed to inotropes had a higher mortality rate than those not exposed. After adjusting for differences in Parsonnet score, left ventricular ejection fraction, perioperative intraaortic balloon pump use, bypass time, reoperation and cardiac index, inotrope exposure appeared to be independently associated with increased hospital mortality (adjusted odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.2 to 4.5) and renal dysfunction (adjusted OR 2.7, 95% CI 1.5 to 4.6). A propensity score-matched analysis similarly demonstrated that death and renal dysfunction were significantly more likely to occur in patients exposed to inotropes (P = 0.01). Postoperative inotrope exposure was independently associated with worse outcomes in this cohort study. Further research is needed to better elucidate the appropriate use of inotropes in cardiac surgery.

The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery

PubMed Central

2011-01-01

Introduction Acute haemodynamic complications are common after cardiac surgery and optimal perioperative use of inotropic agents, typically guided by haemodynamic variables, remains controversial. The aim of this study was to examine the relationship of inotrope use to hospital mortality and renal dysfunction. Material and methods A retrospective cohort study of 1,326 cardiac surgery patients was carried out at two university-affiliated ICUs. Multivariable logistic regression analysis and propensity matching were performed to evaluate whether inotrope exposure was independently associated with mortality and renal dysfunction. Results Patients exposed to inotropes had a higher mortality rate than those not exposed. After adjusting for differences in Parsonnet score, left ventricular ejection fraction, perioperative intraaortic balloon pump use, bypass time, reoperation and cardiac index, inotrope exposure appeared to be independently associated with increased hospital mortality (adjusted odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.2 to 4.5) and renal dysfunction (adjusted OR 2.7, 95% CI 1.5 to 4.6). A propensity score-matched analysis similarly demonstrated that death and renal dysfunction were significantly more likely to occur in patients exposed to inotropes (P = 0.01). Conclusions Postoperative inotrope exposure was independently associated with worse outcomes in this cohort study. Further research is needed to better elucidate the appropriate use of inotropes in cardiac surgery. PMID:21736726

Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morton, M.J., E-mail: michael.morton@astrazeneca.com; Armstrong, D.; Abi Gerges, N.

2014-09-01

Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity inmore » the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. - Highlights: • The L-type calcium channel is a significant safety liability during drug discovery. • Radioligand-binding to the L-type calcium channel can be measured in vitro. • The assay can be run at a single test concentration as part of a screening cascade. • This measurement is highly predictive of changes in cardiac myocyte contractility.« less

Rational use of inotropic therapy in heart failure.

PubMed

Felker, G M; O'Connor, C M

2001-03-01

Despite their theoretic appeal, agents that increase cardiac contractility (positive inotropes) have consistently been shown to increase mortality when given chronically to patients with heart failure. The routine use of inotropes as heart failure therapy in either the acute or the chronic setting is not supported by the available data. Some appropriate uses of inotropes are as temporary treatment of diuretic-refractory acute heart failure decompensations, or as a bridge to definitive treatment such as revascularization or cardiac transplantation. Although controversial, the use of inotropes as a palliative measure in the small subset of patients with truly end-stage heart failure may be appropriate. An understanding of the appropriate goals of therapy is important for both patients and physicians if rational decisions about the use of inotropes are to be made.

Low-frequency blood pressure oscillations and inotrope treatment failure in premature infants.

PubMed

Vesoulis, Zachary A; Hao, Jessica; McPherson, Christopher; El Ters, Nathalie M; Mathur, Amit M

2017-07-01

The underlying mechanism as to why some hypotensive preterm infants do not respond to inotropic medications remains unclear. For these infants, we hypothesize that impaired vasomotor function is a significant factor and is manifested through a decrease in low-frequency blood pressure variability across regulatory components of vascular tone. Infants born ≤28 wk estimated gestational age underwent prospective recording of mean arterial blood pressure for 72 h after birth. After error correction, root-mean-square spectral power was calculated for each valid 10-min data frame across each of four frequency bands ( B1 , 0.005-0.0095 Hz; B2 , 0.0095-0.02 Hz; B3 , 0.02-0.06 Hz; and B4 , 0.06-0.16) corresponding to different components of vasomotion control. Forty infants (twenty-nine normotensive control and eleven inotrope-exposed) were included with a mean ± SD estimated gestational age of 25.2 ± 1.6 wk and birth weight 790 ± 211 g. 9.7/11.8 Million (82%) data points were error-free and used for analysis. Spectral power across all frequency bands increased with time, although the magnitude was 20% less in the inotrope-exposed infants. A statistically significant increase in spectral power in response to inotrope initiation was noted across all frequency bands. Infants with robust blood pressure response to inotropes had a greater increase compared with those who had limited or no blood pressure response. In this study, hypotensive infants who require inotropes have decreased low-frequency variability at baseline compared with normotensive infants, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure. NEW & NOTEWORTHY In this study, we examine patterns of low-frequency oscillations in blood pressure variability across regulatory components of vascular tone in normotensive and hypotensive infants exposed to inotropic medications. We found that hypotensive infants who require inotropes have decreased low-frequency variability at baseline, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure. Copyright © 2017 the American Physiological Society.

[Alpha but not beta-adrenergic stimulation has a positive inotropic effect associated with alkalinization of intracellular pH].

PubMed

Gambassi, G; Lakatta, E G; Capogrossi, M C

1991-01-01

There is increasing evidence that alpha-adrenoceptors also exist in the myocardium and that an increase in force of contraction may be produced by stimulation of these sites. This positive inotropism seems to be dependent either on an increased amount of Ca++ released into the cytosol with each action potential or on increased myofilament responsiveness. In contrast, beta-adrenergic stimulation reduces the sensitivity of the contractile proteins and the positive inotropic effect is due to the activation of L-type calcium channels on the sarcolemma. We used single, isolated, enzymatically dissociated, adult rat ventricular myocytes. Cells were loaded either with the ester derivative of the Ca++ probe Indo-1 or with the intracellular pH probe Snarf-1 and at the same time we measured the contractile parameters and monitored the fluorescence as an index of intracellular calcium concentration or pH value. The single cells (bicarbonate buffer continuously gassed with O2 95%, CO2 5%, Ca++ 1.5 mM, field stimulation 0.5 Hz) were exposed to phenylephrine (50 microM) and nadolol (1 microM). Alpha-adrenergic stimulation increased twitch amplitude (delta ES = 1.93 +/- 0.77, n = 8; p less than 0.05) and showed only a slight increase in Ca++ transient. On the other end, the positive inotropic effect (delta ES = 2.84 +/- 0.86, n = 4; p less than 0.02) obtained with beta-adrenergic stimulation (isoproterenol 50 nM, bicarbonate buffer, Ca++ 0.5 mM, field stimulation 0.2 Hz) was always associated with a large increase in intracellular Ca++ concentration. Isoproterenol did not change intracellular pH (delta pH = 0.006 +/- 0.006, n = 4; NS) while phenylephrine increased it significantly (delta pH = 0.055 +/- 0.011, n = 8; p less than 0.002). Moreover, there was a statistically significant correlation between delta ES and delta pH (R2 = 0.532; p less than 0.05) when phenylephrine was present. This alkalinization as well as the increased contractility was antagonized by treatment with ethyl isopropyl-amiloride (10 microM), a selective Na+/H+ inhibitor (delta ES = 0.09 +/- 0.07, n = 6; NS and delta pH = -0.001 +/- 0.011, n = 6; NS). Thus, alpha-adrenergic stimulation in isolated cardiac cells exerts a positive inotropic effect and this is associated with a significant intracellular pH alkalinization. In contrast, the marked inotropic action of beta-stimulation does not involve any intracellular pH modulation. Therefore, it seems likely that, in myocardial cells, an increased myofilament responsiveness due to the alkalinization could represent a possible mechanism for the positive inotropic effect mediated by alpha-adrenergic stimulation.

[Positive inotropic and lusitropic effect of RP 62719, a new class III antiarrhythmia agent].

PubMed

Beregi, J P; Escande, D; Coudray, N; Chemla, D; Mestre, M; Péry, N; Lecarpentier, Y

1994-02-01

Antiarrhythmic drugs, especially the Class I family, exert a negative inotropic effect on the myocardium which is particularly undesirable in patients with depressed left ventricular function. Therefore, research has been directed to the development of new, more specific molecules of the Class III family. The authors studies the mechanical effects of RP 62719 on guinea pig left ventricular papillary muscle. This new molecule is a pure Class III antiarrhythmic, known to lengthen the duration of the cardiac action potential by selectively blocking the potassium current iK1 (inward rectifier K+ current). The mechanical parameters were determined during the phases of contraction and relaxation under isotonic and isometric conditions. At 0.2 and 2 microM concentrations, RP 62719 improved cardiac contraction under both isotonic and isometric conditions with an increase of about 30% of Vmax (p < 0.001), the maximum unloaded shortening velocity delta 1 (p < 0.001), the peak isometric active force normalized per cross-sectional area [AF/S (p < 0.001)]. At these two concentrations, a positive lusitropic effect (improved relaxation) was demonstrated by an increase in negative peak of derivative per mm2-dF/s and maximum lengthening velocity VR max (p < 0.01). At higher concentrations (20 microM), the inotropic and lusitropic effects were less marked with a bell-shaped form of the dose-effect curve. This study indicates that RP 62719 has moderate but significant positive inotropic and lusitropic effects. These actions could provide significant therapeutic advantages especially in patients cardiac failure.

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy.

PubMed

Carillion, Aude; Feldman, Sarah; Na, Na; Biais, Matthieu; Carpentier, Wassila; Birenbaum, Aurélie; Cagnard, Nicolas; Loyer, Xavier; Bonnefont-Rousselot, Dominique; Hatem, Stéphane; Riou, Bruno; Amour, Julien

2017-01-01

In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their "pleiotropic" effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes. β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD. Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response. Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway.

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

PubMed Central

Carillion, Aude; Feldman, Sarah; Na, Na; Biais, Matthieu; Carpentier, Wassila; Birenbaum, Aurélie; Cagnard, Nicolas; Loyer, Xavier; Bonnefont-Rousselot, Dominique; Hatem, Stéphane; Riou, Bruno

2017-01-01

Background In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their “pleiotropic” effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD. Results Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response. Conclusions Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway. PMID:28727746

The utility of levosimendan in the treatment of heart failure.

PubMed

Lehtonen, Lasse; Põder, Pentti

2007-01-01

Calcium sensitizers are a new group of inotropic drugs. Levosimendan is the only calcium sensitizer in clinical use in Europe. Its mechanism of action includes both calcium sensitization of contractile proteins and the opening of adenosine triphosphate (ATP)-dependent potassium channels as mechanism of vasodilation. The combination of K-channel opening with positive inotropy offers potential benefits in comparison to currently available intravenous inotropes, since K-channel opening protects myocardium during ischemia. Due to the calcium-dependent binding of levosimendan to troponin C, the drug increases contractility without negative lusitropic effects. In patients with heart failure levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. Since levosimendan has an active metabolite OR-1896 with a half-life of some 80 hours, the duration of the hemodynamic effects significantly exceeds the 1-hour half-life of the parent compound. The hemodynamic effects of the levosimendan support its use in acute and postoperative heart failure. Several moderate-size trials (LIDO, RUSSLAN, CASINO) have previously suggested that the drug might even improve the prognosis of patients with decompensated heart failure. These trials were carried out in patients with high filling pressures. Recently two larger trials (SURVIVE and REVIVE) in patients who were hospitalized because of worsening heart failure have been finalized. These trials did not require filling pressures to be measured. The two trials showed that levosimendan improves the symptoms of heart failure, but does not improve survival. The results raise the question whether a 24-hour levosimendan infusion can be used without invasive hemodynamic monitoring.

Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart.

PubMed

Lim, Yi-Cheng; Budin, Siti Balkis; Othman, Faizah; Latip, Jalifah; Zainalabidin, Satirah

2017-07-01

Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dt max , suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca 2+ channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

Ginseng-Aconite Decoction elicits a positive inotropic effect via the reverse mode Na+/Ca2+ exchanger in beating rabbit atria.

PubMed

Cui, Hao Zhen; Kim, Hye Yoom; Kang, Dae Gill; Lee, Ho Sub

2013-07-09

Ginseng-Aconite Decoction (GAD), a traditional oriental medicine composed of Panax ginseng C.A. Mey. (Araliaceae) and Aconitum carmichaeli Debx. (Ranunculaceae) has been used as treatment for cardiovascular diseases from Song Dynasty of China. The purpose of the present study was to elucidate the possible mechanisms of GAD-induced positive inotropic effect. GAD-induced changes in atrial dynamics and cAMP efflux were determined in isolated perfused beating rabbit atria. GAD significantly increased atrial dynamics such as stroke volume, pulse pressure and augmented cAMP efflux in beating rabbit atria. The inotropic effect was significantly attenuated by pre-treatment with KB-R7943, a reverse mode Na(+)/Ca(2+) exchanger blocker. The GAD-induced increase in atrial dynamics was also markedly inhibited by staurosporine, a non-selective protein kinase inhibitor, and partly blocked by KT5720, a selective PKA inhibitor. The effect of GAD on atrial dynamics was not altered by pre-treatment with propranolol, a β-adrenergic receptor inhibitor, or diltiazem, an L-type Ca(2+)channel blocker. The phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) failed to modulate the GAD-induced increase in atrial dynamics, but markedly attenuated cAMP efflux in the beating atria. These results suggest that the GAD-induced positive inotropic effect in beating rabbit atria may be attributable to stimulation of the reverse mode Na(+)/Ca(2+) exchanger, while PKA activity would, at least in part, be participated in the course. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis.

PubMed

McIntosh, Amanda M; Tong, Suhong; Deakyne, Sara J; Davidson, Jesse A; Scott, Halden F

2017-08-01

To assess the validity of Vasoactive-Inotropic Score as a scoring system for cardiovascular support and surrogate outcome in pediatric sepsis. Secondary retrospective analysis of a single-center sepsis registry. Freestanding children's hospital and tertiary referral center. Children greater than 60 days and less than 18 years with sepsis identified in the emergency department between January 2012 and June 2015 treated with at least one vasoactive medication within 48 hours of admission to the PICU. None. Vasoactive-Inotropic Score was abstracted at 6, 12, 24, and 48 hours post ICU admission. Primary outcomes were ventilator days and ICU length of stay. The secondary outcome was a composite outcome of cardiac arrest/extracorporeal membrane oxygenation/in-hospital mortality. One hundred thirty-eight patients met inclusion criteria. Most common infectious sources were pneumonia (32%) and bacteremia (23%). Thirty-three percent were intubated and mortality was 6%. Of the time points assessed, Vasoactive-Inotropic Score at 48 hours showed the strongest correlation with ICU length of stay (r = 0.53; p < 0.0001) and ventilator days (r = 0.52; p < 0.0001). On multivariable analysis, Vasoactive-Inotropic Score at 48 hours was a strong independent predictor of primary outcomes and intubation. For every unit increase in Vasoactive-Inotropic Score at 48 hours, there was a 13% increase in ICU length of stay (p < 0.001) and 8% increase in ventilator days (p < 0.01). For every unit increase in Vasoactive-Inotropic Score at 12 hours, there was a 14% increase in odds of having the composite outcome (p < 0.01). Vasoactive-Inotropic Score in pediatric sepsis patients is independently associated with important clinically relevant outcomes including ICU length of stay, ventilator days, and cardiac arrest/extracorporeal membrane oxygenation/mortality. Vasoactive-Inotropic Score may be a useful surrogate outcome in pediatric sepsis.

Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening.

PubMed

Carosati, Emanuele; Budriesi, Roberta; Ioan, Pierfranco; Ugenti, Maria P; Frosini, Maria; Fusi, Fabio; Corda, Gaetano; Cosimelli, Barbara; Spinelli, Domenico; Chiarini, Alberto; Cruciani, Gabriele

2008-09-25

With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.

PubMed Central

Crane, J; Burgess, C; Beasley, R

1989-01-01

The cardiovascular and hypokalaemic effects of equal doses of inhaled fenoterol, isoprenaline and salbutamol were compared in eight healthy male volunteers, in a double blind, placebo controlled study. Increasing doses of 400, 600, and 800 micrograms were given from a metered dose inhaler at 15 minute intervals, followed by measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, and plasma potassium concentration. After repeated inhalation, fenoterol resulted in significantly greater chronotropic, electrocardiographic, and hypokalaemic effects than either isoprenaline or salbutamol. The maximum inotropic effect of fenoterol was similar to that of isoprenaline. PMID:2928998

A cardioactive peptide from the southern armyworm, Spodoptera eridania.

PubMed

Furuya, K; Hackett, M; Cirelli, M A; Schegg, K M; Wang, H; Shabanowitz, J; Hunt, D F; Schooley, D A

1999-01-01

A cardioactive peptide was isolated from extracts of whole heads of the southern armyworm, Spodoptera eridania. This peptide has the sequence ENFAVGCTPGYQRTADGRCKPTF (Mr = 2516.8), determined from both Edman sequencing and tandem mass spectrometry in combination with off-line micropreparative capillary liquid chromatography. This peptide, termed Spoer-CAP23, has excitatory effects on a semi-isolated heart from larval Manduca sexta, causing an inotropic effect at low concentrations of peptide and chronotropic and inotropic effects at high doses. The threshold concentration for stimulatory effects of the synthetic peptide on the semi-isolated heart was about 1 nM, suggesting a physiological role as a neuropeptide.

Pharmacological and physiological assessment of serotonin formation and degradation in isolated preparations from mouse and human hearts.

PubMed

Gergs, Ulrich; Jung, Franziska; Buchwalow, Igor B; Hofmann, Britt; Simm, Andreas; Treede, Hendrik; Neumann, Joachim

2017-12-01

Using transgenic (TG) mice that overexpress the human serotonin (5-HT) 4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT 4a receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias. NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT. Copyright © 2017 the American Physiological Society.

Scaffold evaluation of liguzinediol analogs as novel cardiotonic agents.

PubMed

Liu, Z; Li, W; Qin, K; Wen, K; Zhu, C J; Li, N G; Bian, H M; Wen, H M; Chen, L

2013-12-01

Liguzinediol (LZDO) could mediate the positive inotropic effects through sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism without the risk of arrhythmia. However, the pharmacophore of LZDO contributed to the activities was not clear. The aim of this work was to explore the relationship between positive inotropic effect and scaffold of LZDO as well as to check whether the pharmacophore of LZDO on anti-heart failure activity was located at the pyrazine ring. A series of LZDO analogs (3a-b, 4a-b, 9-19) were designed and synthesised, and their activities were evaluated on isolated heart contractility by Langendorff perfusion. The results showed that the efficacy of LZDO was reduced when the hydroxyl, carboxyl or ester moieties at the side chain position of LZDO were induced, and the para-dihydroxy in LZDO was necessary for its activity. Thus, the pharmacophore of the positive inotropic effect might be located at the whole scaffold of LZDO, but not at the pyrazine ring. The finding may provide an important clue of the pharmacophore for the development of novel cardiotonic agents.

Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart

PubMed Central

Mazza, Rosa; Gattuso, Alfonsina; Mannarino, Cinzia; Brar, Bhawanjit K.; Barbieri, Sandra Francesca; Tota, Bruno; Mahata, Sushil K.

2008-01-01

The catecholamine release-inhibitory catestatin [Cts; human chromogranin (Cg) A352-372, bovine CgA344-364] is a vasoreactive and anti-hypertensive peptide derived from CgA. Using the isolated avascular frog heart as a bioassay, in which the interactions between the endocardial endothelium and the subjacent myocardium can be studied without the confounding effects of the vascular endothelium, we tested the direct cardiotropic effects of bovine Cts and its interaction with β-adrenergic (isoproterenol, ISO) and endothelin-1 (ET-1) signaling. Cts dose-dependently decreased stroke volume and stroke work, with a threshold concentration of 11 nM, approaching the in vivo level of the peptide. Cts reduced contractility by inhibiting phosphorylation of phospholamban (PLN). Furthermore, the Cts effect was abolished by pretreatment with either nitric oxide synthase (NG-monomethyl-l-arginine) or guanylate cyclase (ODQ) inhibitors, or an ETB receptor (ETBR) antagonist (BQ-788). Cts also noncompetitively inhibited the positive inotropic action of ISO. In addition, Cts inhibited the positive inotropic effect of ET-1, mediated by ETA receptors, and did not alter the negative inotropic ET-1 influence mediated by ETBR. Cts action through ETBR was further suggested when, in the presence of BQ-788, Cts failed to inhibit the positive inotropism of both ISO and ET-1 stimulation and PLN phosphorylation. We concluded that the cardiotropic actions of Cts, including the β-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic and ET-1 stimuli. PMID:18469147

Digoxin and bepridil: pharmacokinetic and pharmacodynamic interactions.

PubMed

Belz, G G; Wistuba, S; Matthews, J H

1986-01-01

The influence of bepridil on steady-state serum digoxin concentrations (SDCs) and the pharmacodynamic actions of both drugs were tested in 48 healthy subjects in a randomized, double-blind study. Subjects were assigned to one of two groups of 24 subjects each: One group received placebo 1, while the other received digoxin, 0.375 mg/day, loaded with doubled doses on days 1 and 2, for 14 days. After 7 days the groups were subdivided into four groups of 12 subjects each and received concurrent dosing of digoxin with either placebo 2 or bepridil, 300 mg/day, loaded with 900 mg on day 8. Mean (+/- SD) SDCs rose during concurrent bepridil dosing from 0.93 +/- 0.22 to 1.25 +/- 0.25 ng/ml (P less than 0.001). Noninvasive cardiovascular parameters from ECG, systolic time intervals, and electrical impedance cardiography were not influenced by the placebos. Digoxin and bepridil reduced heart rate and prolonged the PQ interval because of negative chronotropic and dromotropic properties. Positive inotropism from digoxin shortened the corrected electromechanical systole (QS2c) and the preejection period and increased impedance cardiography [(dZ/dt)/RZ index]; the opposite effects occurred after bepridil, indicating negative inotropism. The QT interval corrected for heart rate (QTc) showed a similar pattern of changes, as did QS2c for each drug. Concurrent dosing of both drugs resulted in an addition of their chronotropic effects, whereas the dromotropic effects of each drug alone was not intensified. The strengthened digoxin effect from the increased SDC diminished the negative inotropic effect of bepridil. Overall, drug coadministration resulted in a nearly unchanged digoxin-induced positive inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)

Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis*

PubMed Central

Tong, Suhong; Deakyne, Sara J.; Davidson, Jesse A.; Scott, Halden F.

2017-01-01

Objectives: To assess the validity of Vasoactive-Inotropic Score as a scoring system for cardiovascular support and surrogate outcome in pediatric sepsis. Design: Secondary retrospective analysis of a single-center sepsis registry. Setting: Freestanding children’s hospital and tertiary referral center. Patients: Children greater than 60 days and less than 18 years with sepsis identified in the emergency department between January 2012 and June 2015 treated with at least one vasoactive medication within 48 hours of admission to the PICU. Interventions: None. Measurements and Main Results: Vasoactive-Inotropic Score was abstracted at 6, 12, 24, and 48 hours post ICU admission. Primary outcomes were ventilator days and ICU length of stay. The secondary outcome was a composite outcome of cardiac arrest/extracorporeal membrane oxygenation/in-hospital mortality. One hundred thirty-eight patients met inclusion criteria. Most common infectious sources were pneumonia (32%) and bacteremia (23%). Thirty-three percent were intubated and mortality was 6%. Of the time points assessed, Vasoactive-Inotropic Score at 48 hours showed the strongest correlation with ICU length of stay (r = 0.53; p < 0.0001) and ventilator days (r = 0.52; p < 0.0001). On multivariable analysis, Vasoactive-Inotropic Score at 48 hours was a strong independent predictor of primary outcomes and intubation. For every unit increase in Vasoactive-Inotropic Score at 48 hours, there was a 13% increase in ICU length of stay (p < 0.001) and 8% increase in ventilator days (p < 0.01). For every unit increase in Vasoactive-Inotropic Score at 12 hours, there was a 14% increase in odds of having the composite outcome (p < 0.01). Conclusions: Vasoactive-Inotropic Score in pediatric sepsis patients is independently associated with important clinically relevant outcomes including ICU length of stay, ventilator days, and cardiac arrest/extracorporeal membrane oxygenation/mortality. Vasoactive-Inotropic Score may be a useful surrogate outcome in pediatric sepsis. PMID:28486385

Cardiac and Vascular Synergic Protective Effect of Olea europea L. Leaves and Hibiscus sabdariffa L. Flower Extracts.

PubMed

Micucci, Matteo; Malaguti, Marco; Toschi, Tullia Gallina; Di Lecce, Giuseppe; Aldini, Rita; Angeletti, Andrea; Chiarini, Alberto; Budriesi, Roberta; Hrelia, Silvana

2015-01-01

This study was aimed at investigating the cardiovascular effects of an Olea europea L. leaf extract (OEE), of a Hibiscus sabdariffa L. flower extract (HSE), and of their 13 : 2 w/w mixture in order to assess their cardiac and vascular activity. Both extracts were fully characterized in their bioactive compounds by HPLC-MS/MS analysis. The study was performed using primary vascular endothelial cells (HUVECs) to investigate the antioxidant and cytoprotective effect of the extracts and their mixture and isolated guinea-pig left and right atria and aorta to evaluate the inotropic and chronotropic activities and vasorelaxant properties. In cultured HUVECs, OEE and HSE reduced intracellular reactive oxygen species formation and improved cell viability, following oxidative stress in dose-dependent manner. OEE and HSE exerted negative inotropic and vasorelaxant effects without any chronotropic property. Interestingly, the mixture exerted higher cytoprotective effects and antioxidant activities. Moreover, the mixture exerted an inotropic effect similar to each single extract, while it revealed an intrinsic negative chronotropic activity different from the single extract; its relaxant activity was higher than that of each single extract. In conclusion OEE and HSE mixture has a good potential for pharmaceutical and nutraceutical application, thanks to the synergistic effects of the single phytochemicals.

Cardiac and Vascular Synergic Protective Effect of Olea europea L. Leaves and Hibiscus sabdariffa L. Flower Extracts

PubMed Central

Micucci, Matteo; Gallina Toschi, Tullia; Di Lecce, Giuseppe; Aldini, Rita; Angeletti, Andrea; Chiarini, Alberto

2015-01-01

This study was aimed at investigating the cardiovascular effects of an Olea europea L. leaf extract (OEE), of a Hibiscus sabdariffa L. flower extract (HSE), and of their 13 : 2 w/w mixture in order to assess their cardiac and vascular activity. Both extracts were fully characterized in their bioactive compounds by HPLC-MS/MS analysis. The study was performed using primary vascular endothelial cells (HUVECs) to investigate the antioxidant and cytoprotective effect of the extracts and their mixture and isolated guinea-pig left and right atria and aorta to evaluate the inotropic and chronotropic activities and vasorelaxant properties. In cultured HUVECs, OEE and HSE reduced intracellular reactive oxygen species formation and improved cell viability, following oxidative stress in dose-dependent manner. OEE and HSE exerted negative inotropic and vasorelaxant effects without any chronotropic property. Interestingly, the mixture exerted higher cytoprotective effects and antioxidant activities. Moreover, the mixture exerted an inotropic effect similar to each single extract, while it revealed an intrinsic negative chronotropic activity different from the single extract; its relaxant activity was higher than that of each single extract. In conclusion OEE and HSE mixture has a good potential for pharmaceutical and nutraceutical application, thanks to the synergistic effects of the single phytochemicals. PMID:26180582

The role of urocortins in the cardiovascular system.

PubMed

Walczewska, J; Dzieza-Grudnik, A; Siga, O; Grodzicki, T

2014-12-01

Urocortins (Ucn) 1, 2 and 3 are a group of endogenous peptide hormones belonging to the corticotropin-releasing hormone (CRH) family of peptides. The presence of urocortins has been detected in the central nervous system as well as in peripheral tissues. They play an important role in a stress response (with respect to its duration, intensity and restoration of homeostasis). They also act as regulatory factors of the cardiovascular, gastrointestinal, reproductive and immune systems. Urocortins act by binding to G-protein-coupled receptors (GPCR). The "central" effects of urocortins are mediated mainly by activation of CRH receptor 1 (CRH-R1), and the "peripheral" effects by activation of CRH-R2. Ucn2 and Ucn3 are selective CRH-R2 agonists and have much higher binding affinity to this receptor than CRH and Ucn1. Recent studies have shown that urocortins exert various biological effects in the cardiovascular system, such as vasodilation, positive inotropic and lusitropic effects, as well as cardioprotection against ischemia-reperfusion injury. They also suppress the renin-angiotensin system and may have an impact on the sympathetic nervous system. Urocortins and CRH-R2 may be a potential therapeutic target in coronary heart disease, congestive heart failure and hypertension. This review summarizes the data published to date on the role of urocortins in the cardiovascular system.

First report on an inotropic peptide activating tetrodotoxin-sensitive, "neuronal" sodium currents in the heart.

PubMed

Kirchhof, Paulus; Tal, Tzachy; Fabritz, Larissa; Klimas, Jan; Nesher, Nir; Schulte, Jan S; Ehling, Petra; Kanyshkova, Tatayana; Budde, Thomas; Nikol, Sigrid; Fortmueller, Lisa; Stallmeyer, Birgit; Müller, Frank U; Schulze-Bahr, Eric; Schmitz, Wilhelm; Zlotkin, Eliahu; Kirchhefer, Uwe

2015-01-01

New therapeutic approaches to improve cardiac contractility without severe risk would improve the management of acute heart failure. Increasing systolic sodium influx can increase cardiac contractility, but most sodium channel activators have proarrhythmic effects that limit their clinical use. Here, we report the cardiac effects of a novel positive inotropic peptide isolated from the toxin of the Black Judean scorpion that activates neuronal tetrodotoxin-sensitive sodium channels. All venoms and peptides were isolated from Black Judean Scorpions (Buthotus Hottentotta) caught in the Judean Desert. The full scorpion venom increased left ventricular function in sedated mice in vivo, prolonged ventricular repolarization, and provoked ventricular arrhythmias. An inotropic peptide (BjIP) isolated from the full venom by chromatography increased cardiac contractility but did neither provoke ventricular arrhythmias nor prolong cardiac repolarization. BjIP increased intracellular calcium in ventricular cardiomyocytes and prolonged inactivation of the cardiac sodium current. Low concentrations of tetrodotoxin (200 nmol/L) abolished the effect of BjIP on calcium transients and sodium current. BjIP did not alter the function of Nav1.5, but selectively activated the brain-type sodium channels Nav1.6 or Nav1.3 in cellular electrophysiological recordings obtained from rodent thalamic slices. Nav1.3 (SCN3A) mRNA was detected in human and mouse heart tissue. Our pilot experiments suggest that selective activation of tetrodotoxin-sensitive neuronal sodium channels can safely increase cardiac contractility. As such, the peptide described here may become a lead compound for a new class of positive inotropic agents. © 2014 American Heart Association, Inc.

The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion.

PubMed

Nieminen, Markku S; Buerke, Michael; Cohen-Solál, Alain; Costa, Susana; Édes, István; Erlikh, Alexey; Franco, Fatima; Gibson, Charles; Gorjup, Vojka; Guarracino, Fabio; Gustafsson, Finn; Harjola, Veli-Pekka; Husebye, Trygve; Karason, Kristjan; Katsytadze, Igor; Kaul, Sundeep; Kivikko, Matti; Marenzi, Giancarlo; Masip, Josep; Matskeplishvili, Simon; Mebazaa, Alexandre; Møller, Jacob E; Nessler, Jadwiga; Nessler, Bohdan; Ntalianis, Argyrios; Oliva, Fabrizio; Pichler-Cetin, Emel; Põder, Pentti; Recio-Mayoral, Alejandro; Rex, Steffen; Rokyta, Richard; Strasser, Ruth H; Zima, Endre; Pollesello, Piero

2016-09-01

Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thal, David M.; Homan, Kristoff T.; Chen, Jun

2012-08-10

G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. In this paper we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2·paroxetine–Gβγ complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice withmore » paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.« less

Deletion of thioredoxin-interacting protein improves cardiac inotropic reserve in the streptozotocin-induced diabetic heart.

PubMed

Myers, Ronald B; Fomovsky, Gregory M; Lee, Samuel; Tan, Max; Wang, Bing F; Patwari, Parth; Yoshioka, Jun

2016-06-01

Although the precise pathogenesis of diabetic cardiac damage remains unclear, potential mechanisms include increased oxidative stress, autonomic nervous dysfunction, and altered cardiac metabolism. Thioredoxin-interacting protein (Txnip) was initially identified as an inhibitor of the antioxidant thioredoxin but is now recognized as a member of the arrestin superfamily of adaptor proteins that classically regulate G protein-coupled receptor signaling. Here we show that Txnip plays a key role in diabetic cardiomyopathy. High glucose levels induced Txnip expression in rat cardiomyocytes in vitro and in the myocardium of streptozotocin-induced diabetic mice in vivo. While hyperglycemia did not induce cardiac dysfunction at baseline, β-adrenergic challenge revealed a blunted myocardial inotropic response in diabetic animals (24-wk-old male and female C57BL/6;129Sv mice). Interestingly, diabetic mice with cardiomyocyte-specific deletion of Txnip retained a greater cardiac response to β-adrenergic stimulation than wild-type mice. This benefit in Txnip-knockout hearts was not related to the level of thioredoxin activity or oxidative stress. Unlike the β-arrestins, Txnip did not interact with β-adrenergic receptors to desensitize downstream signaling. However, our proteomic and functional analyses demonstrated that Txnip inhibits glucose transport through direct binding to glucose transporter 1 (GLUT1). An ex vivo analysis of perfused hearts further demonstrated that the enhanced functional reserve afforded by deletion of Txnip was associated with myocardial glucose utilization during β-adrenergic stimulation. These data provide novel evidence that hyperglycemia-induced Txnip is responsible for impaired cardiac inotropic reserve by direct regulation of insulin-independent glucose uptake through GLUT1 and plays a role in the development of diabetic cardiomyopathy. Copyright © 2016 the American Physiological Society.

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

PubMed Central

Jaski, B E; Fifer, M A; Wright, R F; Braunwald, E; Colucci, W S

1985-01-01

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects. Images PMID:3973022

Cholesterol regulates contractility and inotropic response to β2-adrenoceptor agonist in the mouse atria: Involvement of Gi-protein-Akt-NO-pathway.

PubMed

Odnoshivkina, Yulia G; Sytchev, Vaycheslav I; Petrov, Alexey M

2017-06-01

Majority of cardiac β2-adrenoceptors is located in cholesterol-rich microdomains. Here, we have investigated the underlying mechanisms by which a slight to moderate cholesterol depletion with methyl-β-cyclodextrin (MβCD, 1 and 5mM) interferes with contractility and inotropic effect of β2-adrenergic agonist (fenoterol, 50μM) in the mouse atria. Treatment with MβCD itself increased amplitude of Ca 2+ transient but did not change the contraction amplitude due to a clamping action of elevated NO. Cholesterol depletion significantly attenuated the positive inotropic response to fenoterol which is accompanied by increase in NO generation and decrease in Ca 2+ transient. Influence of 1mM MβCD on the fenoterol-driven changes in both contractility and NO level was strongly attenuated by inhibition of G i -protein (pertussis toxin), Akt (Akt 1/2 kinase inhibitor) or NO-synthase (L-NAME). After exposure to 5mM MβCD, pertussis toxin or Akt inhibitor could recover the β2-agonist effects on contractility, NO production and Ca 2+ transient, while L-NAME only reduced NO level. An adenylyl cyclase activator (forskolin, 50nM) had no influence on the MβCD-induced changes in the β2-agonist effects. Obtained results suggest that slight cholesterol depletion upregulates G i -protein/Akt/NO-synthase signaling that attenuates the positive inotropic response to β2-adrenergic stimulation without altering the Ca 2+ transient. Whilst moderate cholesterol depletion additionally could suppress the enhancement of the Ca 2+ transient amplitude caused by the β2-adrenergic agonist administration in G i -protein/Akt-dependent but NO-independent manner. Copyright © 2016 Elsevier Ltd. All rights reserved.

N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress

PubMed Central

Chen, Fangping; Hadfield, Jessalyn M.; Berzingi, Chalak; Hollander, John M.; Miller, Diane B.; Nichols, Cody E.

2013-01-01

Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77–82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca2+ concentration responses to extracellular Ca2+ (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10−3 M) normalized calcium handling in response to ISO and extracellular Ca2+ concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca2+ (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy. PMID:23722706

Treatment with inotropes and related prognosis in acute heart failure: contemporary data from the Italian Network on Heart Failure (IN-HF) Outcome registry.

PubMed

Mortara, Andrea; Oliva, Fabrizio; Metra, Marco; Carbonieri, Emanuele; Di Lenarda, Andrea; Gorini, Marco; Midi, Paolo; Senni, Michele; Urso, Renato; Lucci, Donata; Maggioni, Aldo P; Tavazzi, Luigi

2014-10-01

In the recent Italian Network on Heart Failure (IN-HF) Outcome registry, including 1,855 patients with acute heart failure (AHF), we reviewed the use of inotropes and their prognostic implication on in-hospital and 12-month mortality. IN-HF Outcome is a prospective, multicenter, observational, study involving 61 Italian cardiology centers. AHF patients have been enrolled over a 2-year period and followed-up for 1 year. Inotropes were used in 360 patients (19.4%). Patients who received inotropes had a more severe clinical and hemodynamic profile than those who did not and exhibited a significantly higher rate of in-hospital (21.4% vs 2.7%, p < 0.01) and 1-year (50.6% vs 17.7%, p < 0.01) mortality. At entry, systolic blood pressure (SBP) was ≤ 110 mm Hg in 58%, 111 to 130 mm Hg in 24.5%, and > 130 mm Hg in 17.5%. Multivariable analyses showed use of inotropes was the strongest predictor of all-cause death. These data were confirmed by propensity score analyses. According to SBP at entry, the 2 groups with SBP > 110 mm Hg who took inotropes, despite a more favorable clinical profile, exhibited a similar worse prognosis, particularly at 1 year: 56.3% (≤ 110 mm Hg), 43.7% (111-130 mm Hg), and 40.3% (>130 mm Hg) vs 17.7%. Inotropes were used in nearly 20% of the patient admitted for AHF, and this treatment was associated with a short-term to medium-term poor prognosis. An inappropriate use of inotropes in patients with normal to high SBP, and presumably preserved cardiac output, may have significantly contributed to affect the all-group outcome. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Negative Inotropic Effects of High Mobility Box Group 1 Protein in Isolated Contracting Cardiac Myocytes

PubMed Central

Tzeng, Huei-Ping; Fan, Jinping; Vallejo, Jesus G.; Dong, Jian Wen; Chen, Xiongwen; Houser, Steven R.; Mann, Douglas L.

2013-01-01

HMGB1 released from necrotic cells or macrophages functions as a late inflammatory mediator, and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients using fluo-3, and L-type calcium currents using whole cell perforate configuration of the patch clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca++ transient within 5 min (p <0.01). The immediate negative inotropic effects HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward L-type calcium currents also was documented by the patch clamp technique. HMGB1 induced the PKCε translocation and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx, and suggest that HMGB1 maybe act as a novel myocardial depressant factor during cardiac injury. PMID:18223193

[Pharmacologic action profile of crataegus extract in comparison to epinephrine, amirinone, milrinone and digoxin in the isolated perfused guinea pig heart].

PubMed

Joseph, G; Zhao, Y; Klaus, W

1995-12-01

Using isolated perfused guinea pig hearts experiments were performed to investigate the influence of crataegus extract LI 132 (Faros 300, CRA) in comparison to other inotropic drugs--epinephrine (adrenaline, ADR), amrinone (AM), milrinone (MIL) and digoxin (DIG)--on different functional parameters, with special emphasis on the effective refractory period of the myocardium. The simultaneous registration of appropriate parameters allowed to relate the effect on the refractory period to the inotropic, chronotropic, dromotropic and coronary actions of these compounds at each concentration level. All substances--with the exception of CRA--shortened the effective refractory period concentration-dependently besides their known other functional effects (max.: 1 x 10(-5) mol/l ADR by 38%, 7 x 10(-7) mol/l DIG by 26%, 1 x 10(-4) mol/l MIL by 13% and 5 x 10(-4) mol/l AM by 1.6%). Related to the positive inotropy the shortening was most effective under MIL (1.32 ms/mN), followed by AM (0.65 ms/mN), DIG (0.40 ms/mN) and ADR (0.28 ms/mN). On the contrary, CRA produced a prolongation of the effective refractory period by maximally 10% resp. by 2.54 ms/mN. Thus, the pharmacologic profile of CRA differs from that of other inotropic compounds mainly in this parameter (with potentially reduced arrhythmogenic risk).

Antagonist effects of seglitide (MK 678) at somatostatin receptors in guinea-pig isolated right atria.

PubMed Central

Dimech, J.; Feniuk, W.; Humphrey, P. P.

1993-01-01

Somatostatin (SS) exerts a negative inotropic effect in isolated atria. Here we report that in guinea-pig isolated right atria, seglitide, a potent cyclic hexapeptide somatostatin agonist, behaves as a competitive somatostatin receptor antagonist with pA2 values against SS14, SS25 and SS28, of 6.50 +/- 0.40, 6.24 +/- 0.08 and 6.09 +/- 0.06, respectively. Seglitide had little or no effect on the negative inotropic action of carbachol or N6-cyclohexyladenosine. Our findings indicate that the receptor-response coupling characteristics of guinea-pig atria are such that in this preparation seglitide has low intrinsic activity and behaves specifically as a somatostatin receptor antagonist. PMID:8104651

Oxysterol, 5α-cholestan-3-one, modulates a contractile response to β2-adrenoceptor stimulation in the mouse atria: Involvement of NO signaling.

PubMed

Sytchev, Vaycheslav I; Odnoshivkina, Yulia G; Ursan, Roman V; Petrov, Alexey M

2017-11-01

Atrial β2-adrenoceptors provide an important mechanism for regulation of cardiac function and changes in their downstream signaling are involved in processes underlying heart disorders. We have investigated the mechanism by which the cholesterol metabolite 5α-cholestan-3-one (5ɑCh3) modulates inotropic effect of β2-adrenoceptor agonist fenoterol. Atria from mice were electrically stimulated and changes in contraction amplitude in response to fenoterol were studied in 5ɑCh3-pretreated samples. Intracellular Ca 2+ and NO levels were estimated using fluorescent dyes Fluo-4 and DAF-FM, respectively. By itself 5αCh3 that appears in the circulation under some pathological conditions had a negligible influence on contraction, Ca 2+ -transient and NO production. However, pretreatment with 5αCh3 markedly attenuated the positive inotropic effect of fenoterol which was accompanied by an increase in the NO synthesis. Unexpectedly, the oxysterol also augmented an enhancement of Ca 2+ -transient amplitude in response to fenoterol. Under conditions of a pharmacological inhibition of G i -protein/Akt/NO synthase/protein kinase G signaling, 5αCh3 augmented the inotropic effect of fenoterol. Herein, Akt antagonist suppressed the increase in NO production, while inhibition of NO synthesis did not modify the increased amplitude of the Ca 2+ -transient. Along similar lines, enrichment of plasma membranes with cholesterol reduced the stimulatory effect of 5αCh3 on β2-adrenoceptor-evoked NO production, but not on the Ca2+-transient amplitude, leading to an elevation of the positive inotropic response to fenoterol. These data suggest that 5ɑCh3 potentiates the effect of pharmacological β2-adrenoceptor activation on both NO production and Ca 2+ transient via independent mechanisms, thereby affecting the positive inotropy. Copyright © 2017 Elsevier Inc. All rights reserved.

Influence of pyruvate on economy of contraction in isolated rabbit myocardium.

PubMed

Keweloh, Boris; Janssen, Paul M L; Siegel, Ulf; Datz, Nicolin; Zeitz, Oliver; Hermann, Hans-Peter

2007-08-01

Treatment of acute heart failure frequently requires positive-inotropic stimulation. However, there is still no inotropic agent available, which combines a favourable haemodynamic profile with low expenditure for energy metabolism. Pyruvate exhibits positive inotropic effects in vitro and in patients with heart failure. The effect on myocardial energy metabolism however remains unclear, but is meaningful in light of a clinical application. We investigated the influence of pyruvate on contractility and oxygen consumption in isolated isometric contracting rabbit myocardium compared to beta-adrenergic stimulation with isoproterenol. Pyruvate (30 mM) increased developed force from 18.7+/-4.1 to 50.8+/-12.1 mN/mm2 (n=10, p<0.01). Force-time integral (FTI) increased by 329%, oxygen consumption assessed by diffusion-microelectrode technique increased from 2.86+/-0.30 mlO2/min*100 g to 6.28+/-1.28 mlO2/min*100 g (n=7, p<0.05). Economy of myocardial contraction calculated as the ratio of total FTI to oxygen consumption remained unchanged. In contrast, while isoproterenol (10 microM) produced a comparable increase in developed force from 21.4+/-8.3 to 67.3+/-15 mN/mm2 (n=7, p<0.01), FTI increased only by 260% and MVO2 increased from 2.96+/-0.43 to 6.12+/-1.01 mlO2/min*100 g (n=7, p<0.01); thus, economy decreased by 23% (n=7, p<0.05). Pyruvate does not impair economy of myocardial contraction while isoproterenol decreases economy. Regarding energy expenditure, pyruvate appears superior to isoproterenol for the purpose of positive inotropic stimulation.

Home inotropic therapy in advanced heart failure: cost analysis and clinical outcomes.

PubMed

Harjai, K J; Mehra, M R; Ventura, H O; Lapeyre, Y M; Murgo, J P; Stapleton, D D; Smart, F W

1997-11-05

This study was conducted to assess cost savings and clinical outcomes associated with the use of home i.v. inotropic therapy in patients with advanced (New York Heart Association [NYHA] class IV) heart failure. Retrospective analysis. Tertiary care referral center. Twenty-four patients (13 men, 11 women; age, 61+/-12 years) with left ventricular ejection fraction <30% and heart failure refractory to oral agents required home i.v. inotropic therapy for at least 4 consecutive weeks between May 1994 and April 1996. Inotropic agents used included dobutamine (n=20; dose, 5.0+/-2.2 microg/kg/min) or milrinone (n=7; dose, 0.53+/-0.05 microg/kg/min). Cost of care and clinical outcomes (hospital admissions, length of hospital stay, NYHA functional class) were compared during the period of inotropic therapy (study period) and the immediate preceding period of equal duration (control period). In comparison to the control period, the study period (3.9+/-2.7 months) was associated with a 16% reduction in cost, amounting to a calculated savings of $5,700 per patient or $1,465 per patient per month. Concomitantly, a decrease in the number of hospital admissions from 2.7+/-2.6 to 1.3+/-1.3 (p=0.056) and length of hospital stay from 20.9+/-12.7 to 5.5+/-5.4 days (p=0.0004) was observed with improvement in NYHA functional class from 4.0+/-0.0 to 2.7+/-0.9 (p<0.0001). Eight patients (38%) died after 2.8+/-1.7 months of home i.v. inotropic therapy. Home i.v. inotropic therapy reduces hospital admissions, length of stay, and cost of care and improves functional class in patients with advanced (NYHA class IV) heart failure.

Influence of the low thyroid state in diabetes mellitus on cardiac function and inotropic responsiveness to alpha 1-adrenoceptor stimulation: comparison with the role of hypothyroidism alone.

PubMed

Beenen, O H; Pfaffendorf, M; van Zwieten, P A

1996-10-01

The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state. Furthermore, we investigated the influence of diabetes and hypothyrodism on cardiac function and the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline in isolated perfused hearts. Fasted or nonfasted Wistar rats were made diabetic with STZ 20, 40 or 60 mg/kg intravenously (i.v.). Another group was made hypothyroid by addition of 6-n-propyl-2-thiouracil (PTU) to their drinking water. Rats receiving PTU became hypothyroid, whereas rats receiving STZ became simultaneously diabetic and hypothyroid. Basal functional parameters obtained in isolated perfused hearts were not influenced by diabetes, whereas maximal contractility was reduced in hearts obtained from hypothyroid animals. Cardiac inotropic responses to cirazoline were increased in diabetic rats, whereas responses in hypothyroid rats were not different from those in hearts obtained from control animals. Although diabetes mellitus and hypothyroidism are associated with various similar metabolic and haemodynamic parameters, the increased inotropic response to alpha 1-adrenoceptor stimulation as observed in isolated perfused hearts of diabetic rats cannot be explained by the decrease in serum thyroxine levels.

Dispersant use as a response to oil spills: toxicological effects on fish cardiac performance.

PubMed

Milinkovitch, Thomas; Thomas-Guyon, Hélène; Lefrançois, Christel; Imbert, Nathalie

2013-04-01

Dispersant use is a controversial technique used to respond to oil spills in nearshore areas. In order to assess the toxicity of this technique, this study evaluated the cardiac toxicological effects on juvenile golden grey mullets Liza aurata exposed for 48 h to either dispersant alone, chemically dispersed oil, mechanically dispersed oil, the water-soluble fraction of oil or a control condition. Following exposure, the positive inotropic effects of adrenaline were assessed in order to evaluate a potential impairment on the cardiac performance. The results revealed an impairment of the positive inotropic effects of adrenaline for all the contaminants (single dispersant, dispersed and undispersed oil, water-soluble fraction of oil). This suggests that: (1) cardiac performance is a valuable parameter to study the physiopathological effects of dispersed oil; (2) dispersant application is likely to impair cardiac performance.

[Effect of ciguatoxins on the cardiocirculatory system].

PubMed

Marquais, M; Sauviat, M P

1999-01-01

The aim of the present review was to collect the main observations reported until now concerning the cardio-circulatory effects of polyether toxins, called ciguatoxins, which are involved in an endemic intoxication named ciguatera found in tropical and subtropical countries. Ciguatera is caused by the ingestion of fishes contaminated with the dinoflagellate Gamberdiscus toxicus. Due to both tropical fish exportation destined for food and tourism, the disease has now spread out to temperate areas. Several toxins have been isolated and purified from different fish species living in different geographical areas. They are classified into three main groups by the nature of certain cycles of their carbon skeleton. Clinical reports show evidence that ciguatera intoxication affect both electrocardiograms and blood pressure. In most cases, ciguateric intoxication mainly evoked bradycardia, hypotension, and the alteration of S-T segment in the electrocardiogram. Isolated and purified ciguatoxins strongly altered the morphology of cardiac tissue inducing swelling of the cells and alterations of cellular organelles. These toxins impair the conduction of cardiac nerves and increase the opening probability of Na+ channels in intracardiac ganglions. Depending on the concentration applied, the substances exerted either a fast positive inotropic effect or a negative inotropic effect on the contraction of mammalian atrial and ventricular cardiac muscle. These effects were attributed to a release of noradrenaline and acetylcholine from neural terminals of the autonomic nervous system present in cardiac tissue. They also exert a slow delayed inotropic effect on the contraction which has been attributed to a direct effect of the toxins on tetrodotoxin-sensitive voltage-dependent Na+ channels of cardiac membranes. Ciguatoxins depolarized the membrane of mammalian atrial and ventricular preparations and shifted the threshold of sodium current activation to more negative membrane potentials. In conclusion, the inotropic effects of ciguatoxins on cardiac tissues mainly depend on the toxin concentration sensitivity of autonomic nerve terminals, which released noradrenaline and/or acetylcholine, while the ciguatoxin-induced increase of the sodium influx could be involved in the cardiac cell swelling which coincides with reports in which ciguatoxins induced a mannitol-inhibited swelling of the Node of Ranvier.

Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs.

PubMed

Bossu, Alexandre; Kostense, Amée; Beekman, Henriette D M; Houtman, Marien J C; van der Heyden, Marcel A G; Vos, Marc A

2018-05-16

Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na + /K + -transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated hemodynamic, electrophysiological and potential proarrhythmic and antiarrhythmic effects of istaroxime in control and chronic atrioventricular block (CAVB) dogs sensitive to drug-induced Torsades de Pointes arrhythmias (TdP). In isolated normal canine ventricular cardiomyocytes, istaroxime (0.3-10 μM) evoked no afterdepolarizations and significantly shortened action potential duration (APD) at 3 and 10 μM. Istaroxime at 3 μg/kg/min significantly increased left ventricular (LV) contractility (dP/dt+) and relaxation (dP/dt-) respectively by 81 and 94% in anesthetized control dogs (n = 6) and by 61 and 49% in anesthetized CAVB dogs (n = 7) sensitive to dofetilide-induced TdP. While istaroxime induced no ventricular arrhythmias in control conditions, only single ectopic beats occurred in 2/7 CAVB dogs, which were preceded by increase of short-term variability of repolarization (STV) and T wave alternans in LV unipolar electrograms. Istaroxime pre-treatment (3 μg/kg/min for 60 min) did not alleviate dofetilide-induced increase in repolarization and STV, and mildly reduced incidence of TdP from 6/6 to 4/6 CAVB dogs. In six CAVB dogs with dofetilide-induced TdP, administration of istaroxime (90 μg/kg/5 min) suppressed arrhythmic episodes in two animals. Taken together, inotropic and lusitropic properties of istaroxime in CAVB dogs were devoid of significant proarrhythmic effects in sensitive CAVB dogs, and istaroxime provides a moderate antiarrhythmic efficacy in prevention and suppression of dofetilide-induced TdP. Copyright © 2018. Published by Elsevier Ltd.

Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials

PubMed Central

You, Zhigang; Huang, Lin; Cheng, Xiaoshu; Wu, Qinghua; Jiang, Xinghua; Wu, Yanqing

2016-01-01

Background and aim Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. Method Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. Results Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: −6.52 to −1.68; P=0.0009) and mechanical ventilation (h) support (95% CI −5.00 to −0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). Conclusion Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients. PMID:26766900

Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials.

PubMed

You, Zhigang; Huang, Lin; Cheng, Xiaoshu; Wu, Qinghua; Jiang, Xinghua; Wu, Yanqing

2016-01-01

Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: -6.52 to -1.68; P=0.0009) and mechanical ventilation (h) support (95% CI -5.00 to -0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients.

Effect of milrinone on short term outcome of patients with myocardial dysfunction undergoing off-pump coronary artery bypass graft: a randomized clinical trial.

PubMed

Hadadzadeh, Mehdi; Hosseini, Seyed Habib; Mostafavi Pour Manshadi, Seyed Mohammad Yousof; Naderi, Nafiseh; Emami Meybodi, Mahmood

2013-01-01

Myocardial dysfunction is a major complication in cardiac surgery that needs inotropic support. This study evaluates the effect of milrinone on patients with low ventricular ejection fraction undergoing off- pump coronary artery bypass graft (OPCAB). The present study is designed to evaluate the effect of milrinone on myocardial dysfunction. Eighty patients with low ventricular ejection fraction (<35%), candidate for elective OPCAB, were enrolled in this study. They were randomly assigned to two groups. One group received milrinone (50 μg/kg) intravenously and another group received a saline as placebo followed by 24 hours infusion of each agent (0.5 μg/kg/min). Short outcome of patients such as hemodynamic parameters and left ventricular ejection fraction were variables evaluated. Serum levels of creatine phosphokinase, the MB isoenzyme of creatine kinase, occurrence of arrhythmias and mean duration of mechanical ventilation were significantly lower in milrinone group (P<0.05). The mean post operative left ventricular ejection fraction was significantly higher in milrinone group (P=0.031). There were no statistical significant differences between the two groups in terms of intra-aortic balloon pump, inotropic support requirement, myocardial ischemia, myocardial infarction, duration of inotropic support, duration of intensive care unit stay, mortality and morbidity rate. Administration of milrinone in patients undergoing OPCAB with low ventricular ejection fraction is useful and effective.

Effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy: pressure-volume analysis with a nonimaging scintillation probe.

PubMed

Bonow, R O; Ostrow, H G; Rosing, D R; Cannon, R O; Lipson, L C; Maron, B J; Kent, K M; Bacharach, S L; Green, M V

1983-11-01

To investigate the effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy, we studied 14 patients at catheterization with a nonimaging scintillation probe before and after serial intravenous infusions of low-, medium-, and high-dose verapamil (total dose 0.17 to 0.72 mg/kg). Percent change in radionuclide stroke counts after verapamil correlated well with percent change in thermodilution stroke volume (r = .87), and changes in diastolic and systolic counts were used to assess relative changes in left ventricular volumes after verapamil. Verapamil produced dose-related increases in end-diastolic counts (19 +/- 9% increase; p less than .001), end-systolic counts (91 +/- 54% increase; p less than .001), and stroke counts (7 +/- 10% increase; p less than .02). This was associated with a decrease in ejection fraction (83 +/- 8% control, 73 +/- 10% verapamil; p less than .001) and, in the 10 patients with left ventricular outflow tract gradients, a reduction in gradient (62 +/- 27 mm Hg control, 32 +/- 35 mm Hg verapamil; p less than .01). The end-systolic pressure-volume relation was shifted downward and rightward in all patients, suggesting a negative inotropic effect. In 10 patients, left ventricular pressure-volume loops were constructed with simultaneous micromanometer pressure recordings and the radionuclide time-activity curve. In five patients, verapamil shifted the diastolic pressure-volume curve downward and rightward, demonstrating improved pressure-volume relations despite the negative inotropic effect, and also increased the peak rate of rapid diastolic filling. In the other five patients, the diastolic pressure-volume relation was unaltered by verapamil, and increased end-diastolic volumes occurred at higher end-diastolic pressures; in these patients, the peak rate of left ventricular diastolic filling was not changed by verapamil. The negative inotropic effects of intravenous verapamil are potentially beneficial in patients with hypertrophic cardiomyopathy by decreasing left ventricular contractile function and increasing left ventricular volume. Verapamil also enhances left ventricular diastolic filling and improves diastolic pressure-volume relations in some patients despite its negative inotropic effect.

Characterization of the effects of neurokinins on canine antral muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koelbel, C.B.; Mayer, E.A.; Van Deventer, G.

1988-12-01

The excitation of longitudinal antral muscle by substance P (SP) involves both a myogenic and a cholinergic effect. To examine if these responses are mediated by different neurokinin receptors, the authors studied the mechanical response and the release of ({sup 3}H)acetylcholine from antral muscle strips in response to SP, substance P methylester (SPME), neurokinin A (NKA), neurokinin B (NKB), and several nonmammalian tachykinins. All peptides studied showed a dose-dependent inotropic and chronotropic effect on spontaneous phasic contractions. This ionotropic effect in longitudinal muscle was partially atropine sensitive for SPME, SP, and NKB but not for NKA, whereas neither atropine normore » tetrodotoxin had an effect in circular muscle. In longitudinal muscle, all three neurokinins were equipotent. In longitudinal muscle treated with atropine and in circular muscle, the rank order of potency for the inotropic response was NKA > NKB > SP > SPME. For the chronotropic response the rank order was SPME, SP > NKA > NKB. NKA, NKB, and SP caused a dose-dependent, tetrodotoxin-sensitive increase in ({sup 3}H)acetylcholine release from strips preincubated with ({sup 3}H)choline. NKA was significantly more potent to release ({sup 3}H)acetylcholine than either NKB or SP. The stimulated release was inhibited by (D-Ala{sup 2},D-Met{sup 5})methionine enkephalinamide and the SP antagonist, spantide. These results are consistent with the hypothesis that NKA is the natural ligand mediating the myogenic inotropic response in both muscle layers and the cholinergic response in longitudinal muscle.« less

Involvement of cyclooxygenase-2 in carbachol-induced positive inotropic response in mouse isolated left atrium.

PubMed

Hara, Yukio; Ike, Asako; Tanida, Riyo; Okada, Muneyoshi; Yamawaki, Hideyuki

2009-12-01

The mouse heart is expected to have characteristic contractile properties. However, basic information on the function of the mouse heart has not been accumulated sufficiently. In this study, the involvement of cyclooxygenase (COX)-2 in carbachol (CCh)-induced inotropic response was investigated in mouse isolated left atrium. Influences of CCh and their mechanisms of action on developed tension elicited by electrical stimulation were examined pharmacologically. The presence of COX-2 in atrium was examined by Western blotting and immunohistochemical analysis. CCh (3 microM for 15 min) produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. Atropine suppressed the biphasic inotropic response to CCh. A muscarinic M(3) receptor antagonist, 4-diphenyl-acetoxy-N-methlpiperidine, inhibited the late positive inotropic action. Blockade of prostaglandin (PG) E(2) or F(2alpha) receptor by 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) or 9alpha, 15R-dihydroxy-11beta-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta 5Z, 13E-dien-1-oic acid (AL8810), respectively, significantly suppressed the positive inotropic response to CCh. A nonselective COX inhibitor, indomethacin, and a selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) inhibited the positive response. A COX-1 inhibitor, valeroyl salicylate, did not affect the positive response. The positive response was almost completely abolished in the endocardial endothelium-deprived atria. Existence of COX-2 in endocardial endothelium was confirmed by Western blotting and immunohistochemical analysis. The present study indicated that the CCh-induced positive inotropic response was mediated by PGs, possibly PGE(2) and PGF(2alpha), released in part from endocardial endothelium. Furthermore, for the first time, we demonstrated that the production of PGs depended in part on COX-2 in endocardial endothelium through the muscarinic M(3) receptor stimulation.

An Appropriate Population for Acute Inpatient Rehabilitation? A Case Series of Three Patients With Advanced Heart Failure on Continuous Inotropic Support.

PubMed

McCormick, Zachary L; Chu, Samuel K; Goodman, Daniel; Oswald, Matthew; Reger, Christopher; Sliwa, James

2015-06-01

The number of individuals with heart failure and the treatment modalities available to manage heart failure are increasing. Continuous inotropic support is a treatment modality used in cases of severe heart failure. Although most patients initiated on continuous inotropic support are discharged home, those with greater functional compromise, comorbid conditions that cause disability, or other significant medical complexity may be referred to acute inpatient rehabilitation. The feasibility and benefits of acute inpatient rehabilitation in this population, however, has yet to be investigated. We report the functional progress and medical complications of 3 patients on continuous inotropic support who participated in acute inpatient rehabilitation. The patients demonstrated varying levels of success, highlighting a need for evidence-based, preadmission screening criteria for this population. Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Positive inotropes in heart failure: a review article

PubMed Central

Amin, Ahmad; Maleki, Majid

2012-01-01

Increasing myocardial contractility has long been considered a big help for patients with systolic heart failure, conferring an augmented haemodynamic profile in terms of higher cardiac output, lower cardiac filling pressure and better organ perfusion. Though concerns have been raised over the safety issues regarding the clinical trials of different inotropes in hearts with systolic dysfunction, they still stand as a main therapeutic strategy in many centres dealing with such patients. They must be used as short in duration, low in dose and stopped as early as possible. Evidence-based guidelines have provided clinicians with valuable data for better applying inotropes in heart failure patients. In this paper, the authors address clinical trials with different agents used for increasing cardiac contractility in heart failure patients. Furthermore, the authors focus on recent guidelines on making the most out of inotropes in heart failure patients. PMID:27326019

[Relationship between previous severity of illness and outcome of in-hospital cardiac arrest].

PubMed

Serrano, M; Rodríguez, J; Espejo, A; del Olmo, R; Llanos, S; Del Castillo, J; López-Herce, J

2014-07-01

To analyze the relationship between previous severity of illness, lactic acid, creatinine and inotropic index with mortality of in-hospital cardiac arrest (CA) in children, and the value of a prognostic index designed for adults. The study included total of 44 children aged from 1 month to 18 years old who suffered a cardiac arrest while in hospital. The relationship between previous severity of illness scores (PRIMS and PELOD), lactic acid, creatinine, treatment with vasoactive drugs, inotropic index with return of spontaneous circulation and survival at hospital discharge was analyzed. The large majority (90.3%) of patients had a return of spontaneous circulation, and 59% survived at hospital discharge. More than two-thirds (68.2%) were treated with inotropic drugs at the time of the CA. The patients who died had a higher lactic acid before the CA (3.4 mmol/L) than survivors (1.4 mmol/L), P=.04. There were no significant differences in PRIMS, PELOD, creatinine, inotropic drugs, and inotropic index before CA between patients who died and survivors. A high lactic acid previous to cardiac arrest could be a prognostic factor of in-hospital cardiac arrest in children. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Interaction of metabolic and respiratory acidosis with α and β-adrenoceptor stimulation in rat myocardium.

PubMed

Biais, Matthieu; Jouffroy, Romain; Carillion, Aude; Feldman, Sarah; Jobart-Malfait, Aude; Riou, Bruno; Amour, Julien

2012-12-01

The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.

Characterization of adenosine receptors in guinea-pig isolated left atria.

PubMed Central

Jahnel, U.; Nawrath, H.

1989-01-01

1. The effects of purinergic stimulation on action potential, force of contraction, 86Rb efflux and 45Ca uptake were investigated in guinea-pig left atria. 2. Adenosine exerted a negative inotropic effect which was antagonized by adenosine deaminase but enhanced by dipyridamole. 3. The negative inotropic effect of adenosine was mimicked by 5'-(N-ethyl)-carboxamido-adenosine (NECA) and the isomers of N6-(phenyl-isopropyl)-adenosine, R-PIA and S-PIA. NECA and R-PIA were about 100 times more potent than adenosine, whereas R-PIA was about 100 times more potent than S-PIA. 4. The inotropic effects of adenosine (in the presence of dipyridamole), NECA, R-PIA and S-PIA were competitively antagonized either by theophylline (pA2 about 4.5) or 8-phenyltheophylline (pA2 about 6.3). 5. NECA and R-PIA shortened the action potential duration and increased the rate constant of the efflux of 86Rb in a concentration-dependent manner with no differences in potency; the effects were competitively antagonized by 8-phenyltheophylline. 6. Barium ions reduced the efflux of 86Rb under control conditions and antagonized the increase induced by NECA and R-PIA. 7. NECA and R-PIA significantly reduced 45Ca uptake in beating preparations. 8. It is concluded that adenosine, NECA and R-PIA activate a common receptor population (P1 or A3) on the outside of the cell membrane of atrial heart muscle to increase the potassium conductance and to reduce the action potential and, thereby, calcium influx and force of contraction. PMID:2790380

Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation

PubMed Central

Koch, Sheryl E.; Gao, Xiaoqian; Haar, Lauren; Jiang, Min; Lasko, Valerie M.; Robbins, Nathan; Cai, Wenfeng; Brokamp, Cole; Varma, Priyanka; Tranter, Michael; Liu, Yong; Ren, Xiaoping; Lorenz, John N.; Wang, Hong-Sheng; Jones, W. Keith; Rubinstein, Jack

2012-01-01

Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of Transient Receptor Potential Vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2−/− mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca2+ handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca2+. PMID:22561103

A forskolin derivative, colforsin daropate hydrochloride, inhibits rat mesangial cell mitogenesis via the cyclic AMP pathway.

PubMed

Ogata, Junichi; Minami, Kouichiro; Segawa, Kayoko; Yamamoto, Chieko; Kim, Sung-Teh; Shigematsu, Akio

2003-11-01

A forskolin derivative, colforsin daropate hydrochloride (CDH), has been introduced as an inotropic agent that acts directly on adenylate cyclase to increase intracellular cyclic AMP (cAMP) levels and ventricular contractility, resulting in positive inotropic activity. We investigated the effects of CDH on rat mesangial cell (MC) proliferation. CDH (10(-7)-10(-5) mol/l) inhibited [(3)H]thymidine incorporation into cultured rat MCs in a concentration-dependent manner. CDH (10(-7)-10(-5) mol/l) also decreased cell numbers in a similar manner, and stimulated cAMP accumulation in MCs in a concentration-dependent manner. A protein kinase A inhibitor, H-89, abolished the inhibitory effects of CDH on MC mitogenesis. These findings suggest that CDH would inhibit the proliferation of rat MCs via the cAMP pathway. Copyright 2003 S. Karger AG, Basel

Reactive oxygen species potentiate the negative inotropic effect of cardiac M2-muscarinic receptor stimulation.

PubMed

Peters, S L; Sand, C; Batinik, H D; Pfaffendorf, M; van Zwieten, P A

2001-08-01

The aim of the present study was to investigate the influence of reactive oxygen species (ROS) on the contractile responses of rat isolated left atria to muscarinic receptor stimulation. ROS were generated by means of electrolysis (30 mA, 75 s) of the organ bath fluid. Twenty minutes after the electrolysis period, the electrically paced atria (3 Hz) were stimulated with the adenylyl cyclase activator forskolin (1 microM). Subsequently, cumulative acetylcholine concentration-response curves were constructed (0.01 nM-10 microM). In addition, phosphoinositide turnover and adenylyl cyclase activity under basal and stimulated conditions were measured. For these biochemical experiments we used the stable acetylcholine analogue carbachol. The atria exposed to reactive oxygen species were influenced more potently (pD2 control: 6.2 vs. 7.1 for electrolysis-treated atria, P<0.05) and more effectively (Emax control: 40% vs. 90% reduction of the initial amplitude, P<0.05) by acetylcholine. In contrast, ROS exposure did not alter the responses to adenosine, whose receptor is also coupled via a Gi-protein to adenylyl cyclase. The basal (40% vs. control, P<0.05) as well as the carbachol-stimulated (-85% vs. control, P<0.05) inositol-phosphate formation was reduced in atria exposed to ROS. The forskolin-stimulated adenylyl cyclase activity was identical in both groups but carbachol stimulation induced a more pronounced reduction in adenylyl cyclase activity in the electrolysis-treated atria. Accordingly we may conclude that ROS enhance the negative inotropic response of isolated rat atria to acetylcholine by both a reduction of the positive (inositide turnover) and increase of the negative (adenylyl cyclase inhibition) inotropic components of cardiac muscarinic receptor stimulation. This phenomenon is most likely M2-receptor specific, since the negative inotropic response to adenosine is unaltered by ROS exposure.

Effects of nesfatin-1 on atrial contractility and thoracic aorta reactivity in male rats.

PubMed

Barutcigil, Ayşe; Tasatargil, Arda

2017-10-13

This study aimed to examine the effects of nesfatin-1 on thoracic aorta vasoreactivity and to investigate the inotropic and chronotropic effects of nesfatin-1 on the spontaneous contractions of the isolated rat atria. Isolated right atria and thoracic aorta were used in organ baths. The reactivity of the thoracic aorta was evaluated by potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). The effects of nesfatin-1 on the spontaneous contractions of the rat atria were also examined. Nesfatin-1 (0.1-100 ng/ml) produced a concentration-dependent relaxation response in rat thoracic aorta. The relaxant responses to nesfatin-1 were inhibited by the removal of endothelium, NO synthase blocker N-nitro-L-arginine methyl ester (L-NAME, 10 -4  M), and soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 -5  M). Nesfatin-1 (10 ng/ml, 30 min) increased the relaxation responses to either ACh or SNP, and the contractile response to both Phe and KCl did not significantly change in the arteries that were incubated with nesfatin-1 compared with the controls. The thoracic aorta contractions induced by the stepwise addition of Ca 2+ to a high KCl solution with no Ca 2+ were not significantly changed by nesfatin-1. Under calcium-free conditions, the contractions of the thoracic aorta rings incubated with nesfatin-1 in response to Phe were not significantly lower than those of the rings from the control rats. Nesfatin-1 showed positive inotropic and chronotropic effects on rat atria. Nesfatin-1 significantly changed the vascular responsiveness in rat thoracic aorta and produced positive inotropic and chronotropic effects on rat atria.

The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents.

PubMed

Blot, Stijn I; Pea, Federico; Lipman, Jeffrey

2014-11-20

Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward. Copyright © 2014. Published by Elsevier B.V.

Nitric Oxide Synthase 1 Modulates Basal and β-Adrenergic-Stimulated Contractility by Rapid and Reversible Redox-Dependent S-Nitrosylation of the Heart

PubMed Central

Vielma, Alejandra Z.; León, Luisa; Fernández, Ignacio C.; González, Daniel R.

2016-01-01

S-nitrosylation of several Ca2+ regulating proteins in response to β-adrenergic stimulation was recently described in the heart; however the specific nitric oxide synthase (NOS) isoform and signaling pathways responsible for this modification have not been elucidated. NOS-1 activity increases inotropism, therefore, we tested whether β-adrenergic stimulation induces NOS-1-dependent S-nitrosylation of total proteins, the ryanodine receptor (RyR2), SERCA2 and the L-Type Ca2+ channel (LTCC). In the isolated rat heart, isoproterenol (10 nM, 3-min) increased S-nitrosylation of total cardiac proteins (+46±14%) and RyR2 (+146±77%), without affecting S-nitrosylation of SERCA2 and LTCC. Selective NOS-1 blockade with S-methyl-L-thiocitrulline (SMTC) and Nω-propyl-l-arginine decreased basal contractility and relaxation (−25–30%) and basal S-nitrosylation of total proteins (−25–60%), RyR2, SERCA2 and LTCC (−60–75%). NOS-1 inhibition reduced (−25–40%) the inotropic response and protein S-nitrosylation induced by isoproterenol, particularly that of RyR2 (−85±7%). Tempol, a superoxide scavenger, mimicked the effects of NOS-1 inhibition on inotropism and protein S-nitrosylation; whereas selective NOS-3 inhibitor L-N5-(1-Iminoethyl)ornithine had no effect. Inhibition of NOS-1 did not affect phospholamban phosphorylation, but reduced its oligomerization. Attenuation of contractility was abolished by PKA blockade and unaffected by guanylate cyclase inhibition. Additionally, in isolated mouse cardiomyocytes, NOS-1 inhibition or removal reduced the Ca2+-transient amplitude and sarcomere shortening induced by isoproterenol or by direct PKA activation. We conclude that 1) normal cardiac performance requires basal NOS-1 activity and S-nitrosylation of the calcium-cycling machinery; 2) β-adrenergic stimulation induces rapid and reversible NOS-1 dependent, PKA and ROS-dependent, S-nitrosylation of RyR2 and other proteins, accounting for about one third of its inotropic effect. PMID:27529477

Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope-Dependent Advanced Heart Failure Patients: Insights From the ROADMAP Study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients).

PubMed

Lanfear, David E; Levy, Wayne C; Stehlik, Josef; Estep, Jerry D; Rogers, Joseph G; Shah, Keyur B; Boyle, Andrew J; Chuang, Joyce; Farrar, David J; Starling, Randall C

2017-05-01

Timing of left ventricular assist device (LVAD) implantation in advanced heart failure patients not on inotropes is unclear. Relevant prediction models exist (SHFM [Seattle Heart Failure Model] and HMRS [HeartMate II Risk Score]), but use in this group is not established. ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) is a prospective, multicenter, nonrandomized study of 200 advanced heart failure patients not on inotropes who met indications for LVAD implantation, comparing the effectiveness of HeartMate II support versus optimal medical management. We compared SHFM-predicted versus observed survival (overall survival and LVAD-free survival) in the optimal medical management arm (n=103) and HMRS-predicted versus observed survival in all LVAD patients (n=111) using Cox modeling, receiver-operator characteristic (ROC) curves, and calibration plots. In the optimal medical management cohort, the SHFM was a significant predictor of survival (hazard ratio=2.98; P <0.001; ROC area under the curve=0.71; P <0.001) but not LVAD-free survival (hazard ratio=1.41; P =0.097; ROC area under the curve=0.56; P =0.314). SHFM showed adequate calibration for survival but overestimated LVAD-free survival. In the LVAD cohort, the HMRS had marginal discrimination at 3 (Cox P =0.23; ROC area under the curve=0.71; P =0.026) and 12 months (Cox P =0.036; ROC area under the curve=0.62; P =0.122), but calibration was poor, underestimating survival across time and risk subgroups. In non-inotrope-dependent advanced heart failure patients receiving optimal medical management, the SHFM was predictive of overall survival but underestimated the risk of clinical worsening and LVAD implantation. Among LVAD patients, the HMRS had marginal discrimination and underestimated survival post-LVAD implantation. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01452802. © 2017 American Heart Association, Inc.

The metabolic and renal effects of adrenaline and milrinone in patients with myocardial dysfunction after coronary artery bypass grafting

PubMed Central

Heringlake, Matthias; Wernerus, Marit; Grünefeld, Julia; Klaus, Stephan; Heinze, Hermann; Bechtel, Matthias; Bahlmann, Ludger; Poeling, Jochen; Schön, Julika

2007-01-01

Introduction Myocardial dysfunction necessitating inotropic support is a typical complication after on-pump cardiac surgery. This prospective, randomized pilot study analyzes the metabolic and renal effects of the inotropes adrenaline and milrinone in patients needing inotropic support after coronary artery bypass grafting (CABG). Methods During an 18-month period, 251 patients were screened for low cardiac output upon intensive care unit (ICU) admission after elective, isolated CABG surgery. Patients presenting with a cardiac index (CI) of less than 2.2 liters/minute per square meter upon ICU admission – despite adequate mean arterial (titrated with noradrenaline or sodium nitroprusside) and filling pressures – were randomly assigned to 14-hour treatment with adrenaline (n = 7) or milrinone (n = 11) to achieve a CI of greater than 3.0 liters/minute per square meter. Twenty patients not needing inotropes served as controls. Hemodynamics, plasma lactate, pyruvate, glucose, acid-base status, insulin requirements, the urinary excretion of alpha-1-microglobuline, and creatinine clearance were determined during the treatment period, and cystatin-C levels were determined up to 48 hours after surgery (follow-up period). Results After two to four hours after ICU admission, the target CI was achieved in both intervention groups and maintained during the observation period. Plasma lactate, pyruvate, the lactate/pyruvate ratio, plasma glucose, and insulin doses were higher (p < 0.05) in the adrenaline-treated patients than during milrinone or control conditions. The urinary excretion of alpha-1-microglobuline was higher in the adrenaline than in the control group 6 to 14 hours after admission (p < 0.05). No between-group differences were observed in creatinine clearance, whereas plasma cystatin-C levels were significantly higher in the adrenaline than in the milrinone or the control group after 48 hours (p < 0.05). Conclusion This suggests that the use of adrenaline for the treatment of postoperative myocardial dysfunction – in contrast to treatment with the PDE-III inhibitor milrinone – is associated with unwarranted metabolic and renal effects. Clinical trials registration: ClinicalTrials.gov NCT00446017. PMID:17470271

Effects of Combined Milrinone and Levosimendan Treatment on Systolic and Diastolic Function During Postischemic Myocardial Dysfunction in a Porcine Model.

PubMed

Axelsson, Birger; Häggmark, Sören; Svenmarker, Staffan; Johansson, Göran; Gupta, Anil; Tydén, Hans; Wouters, Patrick; Haney, Michael

2016-09-01

It is not known whether there are positive or negative interactions on ventricular function when a calcium-sensitizing inotrope is added to a phosphodiesterase inhibitor in the clinical setting of acute left ventricular (LV) dysfunction. We hypothesized that when levosimendan is added to milrinone treatment, there will be synergetic inotropic and lusitropic effects. This was tested in an anesthetized porcine postischemic global LV injury model, where ventricular pressures and volumes (conductance volumetry) were measured. A global ischemic injury was induced by repetitive left main stem coronary artery occlusions. Load-independent indices of LV function were assessed before and after ventricular injury, after milrinone treatment, and finally after addition of levosimendan to the milrinone treatment. Nonparametric, within-group comparisons were made. The protocol was completed in 12 pigs, 7 of which received the inotrope treatment and 5 of which served as controls. Milrinone led to positive lusitropic effects seen by improvement in tau after myocardial stunning. The addition of levosimendan to milrinone further increased lusitropic state. The latter effect could however not be attributed solely to levosimendan, since lusitropic state also improved spontaneously in time-matched controls at the same rate during the corresponding period. When levosimendan was added to milrinone infusion, there was no increase in systolic function (preload recruitable stroke work) compared to milrinone treatment alone. We conclude that in this model of postischemic LV dysfunction, there appears to be no clear improvement in systolic or diastolic function after addition of levosimendan to established milrinone treatment but also no negative effects of levosimendan in this context. © The Author(s) 2016.

Further evidence from functional studies for somatostatin receptor heterogeneity in guinea-pig isolated ileum, vas deferens and right atrium.

PubMed Central

Feniuk, W.; Dimech, J.; Jarvie, E. M.; Humphrey, P. P.

1995-01-01

1. Somatostatin (SRIF) causes a concentration-dependent inhibition of neurotransmission in guinea-pig ileum and vas deferens as well as negative inotropy in guinea-pig isolated right atrium. The SRIF receptors mediating these effects have now been further characterized by use of the peptides BIM-23027, BIM-23056 and L-362855, reported as selective for the recombinant SRIF receptor types, sst2, sst3 and sst5, respectively. 2. BIM-23027 was a highly potent agonist at causing an inhibition of neurotransmission in the guinea-pig ileum (EC50 value 1.9 nM), being about 3 times more potent than SRIF (EC50 value 6.8 nM). In contrast, in both guinea-pig vas deferens and right atrial preparations, BIM-23027 was a relatively weak agonist being at least 30-100 times weaker than SRIF. In guinea-pig atria, BIM-23027 (3 microM) antagonized the negative inotropic action of SRIF28 (apparent pKB = 5.9 +/- 0.1) but had no effect on the negative inotropic action of cyclohexyladenosine. 3. The inhibitory effect of BIM-23027 in the guinea-pig ileum was readily desensitized. Prior exposure to BIM-23027 (0.3 microM) markedly attenuated the inhibitory effect of SRIF but had no effect on the inhibitory action of clonidine suggesting that BIM-23027 and SRIF act via a common receptor mechanism. 4. L-362855 caused a concentration-dependent inhibition of neurotransmission in both the guinea-pig ileum and vas deferens as well as causing negative inotropy in the guinea-pig atrium but was at least 30-100 times weaker than SRIF. In guinea-pig isolated atria, L-362855 (3 microM) did not antagonize the negative inotropic action of SRIF28.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582529

Simultaneous pressure-volume measurements using optical sensors and MRI for left ventricle function assessment during animal experiment.

PubMed

Abi-Abdallah Rodriguez, Dima; Durand, Emmanuel; de Rochefort, Ludovic; Boudjemline, Younes; Mousseaux, Elie

2015-01-01

Simultaneous pressure and volume measurements enable the extraction of valuable parameters for left ventricle function assessment. Cardiac MR has proven to be the most accurate method for volume estimation. Nonetheless, measuring pressure simultaneously during MRI acquisitions remains a challenge given the magnetic nature of the widely used pressure transducers. In this study we show the feasibility of simultaneous in vivo pressure-volume acquisitions with MRI using optical pressure sensors. Pressure-volume loops were calculated while inducing three inotropic states in a sheep and functional indices were extracted, using single beat loops, to characterize systolic and diastolic performance. Functional indices evolved as expected in response to positive inotropic stimuli. The end-systolic elastance, representing the contractility index, the diastolic myocardium compliance, and the cardiac work efficiency all increased when inducing inotropic state enhancement. The association of MRI and optical pressure sensors within the left ventricle successfully enabled pressure-volume loop analysis after having respective data simultaneously recorded during the experimentation without the need to move the animal between each inotropic state. Copyright © 2014 IPEM. Published by Elsevier Ltd. All rights reserved.

Apelin Increases Cardiac Contractility via Protein Kinase Cε- and Extracellular Signal-Regulated Kinase-Dependent Mechanisms

PubMed Central

Perjés, Ábel; Skoumal, Réka; Tenhunen, Olli; Kónyi, Attila; Simon, Mihály; Horváth, Iván G.; Kerkelä, Risto; Ruskoaho, Heikki; Szokodi, István

2014-01-01

Background Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. Methods and Results In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. Conclusions Apelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure. PMID:24695532

Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently.

PubMed

Schwinger, R H; Pietsch, M; Frank, K; Brixius, K

2000-05-01

The mode of action of Crataegus extracts in the treatment of heart failure is still under examination. WS 1442, a standardized special extract from Crataegus leaves with flowers, exerts direct positive inotropic effects. This study was designed to investigate the mode of inotropic action of WS 1442 in human myocardium from patients with congestive heart failure (left ventricular myocardium from explanted hearts; NYHA IV, n = 8) as well as in nonfailing controls (right auricular trabeculae from patients with coronary heart disease, n = 8). WS 1442 effectively displaced specifically bound 3H-ouabain but did not influence the activity of adenylate cyclase [control, + Gpp(NH)p (10(-4) microM) 3,500 pmol cyclic adenosine monophosphate (cAMP)/20 min). In isolated left ventricular papillary muscle strips, WS 1442 significantly increased the force of contraction [basal, 1.8+/-0.2 mN; WS 1442 (50 microg/ml), 2.4+/-0.1 mN (130%)] and improved the frequency-dependent force generation (0.5 vs. 2.5 Hz: control, +0.1+/-0.01 mN; WS 1442, +0.9+/-0.3 mN) even in failing human myocardium. In fura-2-loaded muscle strips (right atrial trabeculae), WS 1442 increased both the Ca2+-transient and force generation. These effects also were observed in the lipophilic ethyl acetate-soluble fraction A, enriched in flavone derivatives. In conclusion, these findings suggest a pharmacologic mechanism of WS 1442 similar to the cAMP-independent positive inotropic action of cardiac glycosides. In addition, WS 1442 improves the force-frequency relation in failing human myocardium.

Successful treatment of inverted Takotsubo cardiomyopathy after severe traumatic brain injury with milrinone after dobutamine failure.

PubMed

Mrozek, Ségolène; Srairi, Mohamed; Marhar, Fouad; Delmas, Clément; Gaussiat, François; Abaziou, Timothée; Larcher, Claire; Atthar, Vincent; Menut, Rémi; Fourcade, Olivier; Geeraerts, Thomas

2016-01-01

Takotsubo cardiomyopathy can occur at the early phase of severe acute brain injuries. In the case of cardiac output decrease or shock, the optimal treatment is still a matter of debate. Due to massive stress hormone release, the infusion of catecholamines may have limited effects and may even aggravate cardiac failure. Other inotropic agents may be an option. Levosimendan has been shown to have potential beneficial effects in this setting, although milrinone has not been studied. We report a case of a young female presenting with inverted Takotsubo cardiomyopathy syndrome after severe traumatic brain injury. Due to hemodynamic instability and increasing levels of infused norepinephrine, dobutamine infusion was begun but rapidly stopped due to tachyarrhythmia. Milrinone infusion stabilized the patient's hemodynamic status and improved cardiac output without deleterious effects. Milrinone could be a good alternative when inotropes are required in Takotsubo cardiomyopathy and when dobutamine infusion is associated with tachyarrhythmia. Copyright © 2016 Elsevier Inc. All rights reserved.

Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation.

PubMed

Koch, Sheryl E; Gao, Xiaoqian; Haar, Lauren; Jiang, Min; Lasko, Valerie M; Robbins, Nathan; Cai, Wenfeng; Brokamp, Cole; Varma, Priyanka; Tranter, Michael; Liu, Yong; Ren, Xiaoping; Lorenz, John N; Wang, Hong-Sheng; Jones, W Keith; Rubinstein, Jack

2012-07-01

Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of transient receptor potential vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2(-/-) mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca(2+) handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca(2+). Copyright © 2012 Elsevier Ltd. All rights reserved.

ST-segment elevation during levosimendan infusion.

PubMed

Barillà, Francesco; Giordano, Federica; Jacomelli, Ilaria; Pellicano, Mariano; Dominici, Tania

2012-07-01

Levosimendan increases the sensitivity of the heart to calcium and consequently exerts positive inotropic effects. Levosimendan is indicated in acutely decompensated severe congestive heart failure. We report that levosimendan infusion may induce myocardial ischemia in patients with acute heart failure.

Mechanism of action of Ca2+ sensitizers--update 2001.

PubMed

Endoh, M

2001-09-01

Ca2+ sensitizers act on the central mechanism (Ca2+ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E-C coupling. Ca2+ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca2+ mobilization). Ca2+ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca2+ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca2+ sensitizing effect. No clinically available agents act primarily via Ca2+ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca2+ sensitivity. These agents are the hybrid of Ca2+ sensitizer and PDE III inhibitor. The extent of contribution of Ca2+ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca2+ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.

AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barrett, R.J.; Appell, K.C.; Kilpatrick, B.F.

1991-01-01

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) (3H)ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADPmore » (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) (3H)nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.« less

The cardiovascular system in the ageing patient

PubMed Central

Moore, A; Mangoni, A A; Lyons, D; Jackson, S H D

2003-01-01

The ageing process is associated with important changes in the responses of the cardiovascular system to pharmacological stimuli. They are not limited to the arterial system, involved in the modulation of cardiac afterload and vascular resistance, but they also involve the low-resistance capacitance venous system and the heart. The main changes include loss of large artery compliance, dysfunction of some of the systems modulating resistance vessel tone, increased activity of the sympathetic nervous system, and reduced haemodynamic responses to inotropic agents. This review focuses on the effects of ageing on arterial and venous reactivity to drugs and hormones, the autonomic nervous system, and the cardiovascular responses to inotropic agents. Some of the age-related changes might be at least partially reversible. This may have important therapeutic implications. PMID:12919173

Incidence, management and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants

PubMed Central

Fernandez, Erika; Watterberg, Kristi L.; Faix, Roger G.; Yoder, Bradley A.; Walsh, Michele C.; Lacy, Conra Backstrom; Osborne, Karen A.; Das, Abhik; Kendrick, Douglas E.; Stoll, Barbara J.; Poindexter, Brenda B.; Laptook, Abbot R.; Kennedy, Kathleen A.; Schibler, Kurt; Bell, Edward F.; Van Meurs, Krisa P.; Frantz, Ivan D.; Goldberg, Ronald N.; Shankaran, Seetha; Carlo, Waldemar A.; Ehrenkranz, Richard A.; Sánchez, Pablo J.; Higgins, Rosemary D.

2014-01-01

Objective To characterize the incidence, management and short term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating 4 separate pre-specified definitions. Study Design Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)

Effects of commonly used inotropes on myocardial function and oxygen consumption under constant ventricular loading conditions

PubMed Central

DeWitt, Elizabeth S.; Black, Katherine J.; Thiagarajan, Ravi R.; DiNardo, James A.; Colan, Steven D.; McGowan, Francis X.

2016-01-01

Inotropic medications are routinely used to increase cardiac output and arterial blood pressure during critical illness. However, few comparative data exist between these medications, particularly independent of their effects on venous capacitance and systemic vascular resistance. We hypothesized that an isolated working heart model that maintained constant left atrial pressure and aortic blood pressure could identify load-independent differences between inotropic medications. In an isolated heart preparation, the aorta and left atrium of Sprague Dawley rats were cannulated and placed in working mode with fixed left atrial and aortic pressure. Hearts were then exposed to common doses of a catecholamine (dopamine, epinephrine, norepinephrine, or dobutamine), milrinone, or triiodothyronine (n = 10 per dose per combination). Cardiac output, contractility (dP/dtmax), diastolic performance (dP/dtmin and tau), stroke work, heart rate, and myocardial oxygen consumption were compared during each 10-min infusion to an immediately preceding baseline. Of the catecholamines, dobutamine increased cardiac output, contractility, and diastolic performance more than clinically equivalent doses of norepinephrine (second most potent), dopamine, or epinephrine (P < 0.001). The use of triiodothyronine and milrinone was not associated with significant changes in cardiac output, contractility or diastolic function, either alone or added to a baseline catecholamine infusion. Myocardial oxygen consumption was closely related to dP/dtmax (r2 = 0.72), dP/dtmin (r2 = 0.70), and stroke work (r2 = 0.53). In uninjured, isolated working rodent hearts under constant ventricular loading conditions, dobutamine increased contractility and cardiac output more than clinically equivalent doses of norepinephrine, dopamine, and epinephrine; milrinone and triiodothyronine did not have significant effects on contractility. PMID:27150829

The effects of the NMR shift-reagents Dy(PPP)2, Dy(TTHA) and Tm(DOTP) on developed pressure in isolated perfused rat hearts. The role of shift-reagent calcium complexes.

PubMed

Gaszner, B; Simor, T; Hild, G; Elgavish, G A

2001-11-01

The 23Na NMR shift-reagent complexes (Dy(PPP)2, Dy(TTHA), and Tm(DOTP)) bind stoichiometric amounts of Ca2+. Thus, in perfused rat heart systems, a supplementation of Ca2+ is required to maintain the requisite extracellular free calcium concentration ([Ca(o)]f) and to approximate a physiological level of contractile function. The amount of reagent-bound Ca2+ in a heart perfusate that contains a shift-reagent depends on: (1) Ca2+ binding by excess ligand used during the preparation of the shift-reagent; and (2) the Ca2+ binding affinity of the shift-reagent. To address point 1), we introduced a 1H and 31P NMR spectroscopic titration method to quantify directly the concentration of the excess ligand. We also used this method to minimize the amount of excess ligand (L) and thus the amount of Ca*L complex. To address point (2), we determined the stepwise Kd (microm) values of the Ca complexes of the three shift-reagents.: Dy(PPP)2, Kd=0.09, Kd2=7.9; Dy(TTHA), Kd1=10.66, Kd2=10.12; and Tm(DOTP), K(d1)=0.502, Kd2=4.98. The Kd values of the Ca complexes of the phosphonate and triphosphate based shift-reagents, Tm(DOTP) and Dy(PPP)2, respectively, are lower than those of the polyaminocarboxylate-based Dy(TTHA), indicating stronger Ca binding affinities for the former two types of complexes. We have also shown a positive correlation between [Ca(o)]f and left ventricular developed pressure (LVDP) in perfused rat hearts. Dy(TTHA) has shown no effect on LVDP v[Ca(o)]f. The LVDP values in the presence of the phosphonate and triphosphate based shift-reagents, however, were significantly higher than expected from the [Ca(o)]f levels alone. Thus a positive inotropic effect, independent of [Ca(o)]f, is evident in the presence of Tm(DOTP) or Dy(PPP)2. Copyright 2001 Academic Press.

Risk modeling for ventricular assist device support in post-cardiotomy shock.

PubMed

Alsoufi, Bahaaldin; Rao, Vivek; Tang, Augustine; Maganti, Manjula; Cusimano, Robert

2012-04-01

Post-cardiotomy shock (PCS) has a complex etiology. Although treatment with inotrops and intra-aortic balloon pump (IABP) support improves cardiac performance, end-organ injuries are common and lead to prolonged ICU stay, extended hospitalization and increased mortality. Early consideration of mechanical circulatory support may prevent such complications and improve outcome. Between January 1997 and January 2002, 321 patients required IABP and inotropic support for PCS following coronary artery bypass grafting (CABG) at our institution. Perioperative variables including age, mixed venous saturation (MVO2), inotropic requirements and LV function were analyzed using multivariate statistical methods. All explanatory variables with a univariate p value <0.10 were entered into a stepwise logistic regression model to predict hospital mortality. Odds ratios from significant variables (p < 0.05) in the regression model were used to compose a risk score. Overall hospital mortality was 16%. The independent risk factors for mortality in this population were: MVO2 < 60% (OR = 3.2), milrinone > 0.5 μg/kg/min (OR = 3.2), age > 75 (OR = 2.7), adrenaline > 0.1 μg/kg/min (OR = 1.5). A 15-point risk score was developed based on the regression model. Hospital mortality in patients with a score >6 was 46% (n = 13/28), 3-6 was 31% (n = 9/29) and <3 was 11% (n = 29/264). A significant proportion of patients with PCS continue to face high mortality despite IABP and inotropic support. Advanced age, heavy inotropic dependency and poor oxygen delivery all predicted increased risk for death. Further investigation is needed to assess whether early institution of VAD support could improve outcome in this high-risk group of patients.

Effects of denopamine (TA-064), a new positive inotropic agent, on myocardial oxygen consumption and left ventricular dimension in anesthetized dogs.

PubMed

Ikeo, T; Nagao, T

1985-10-01

We compared the effects of denopamine (TA-064) and isoproterenol on hemodynamics, myocardial oxygen consumption and the left ventricular (LV) dimension in halothane-N2O anesthetized dogs. Denopamine (0.25-1 micrograms/kg/min, i.v., infusion X 15 min) produced a maximum increase in LV dp/dtmax by 64% of the control, without affecting aortic pressure significantly. Doses of isoproterenol (0.01-0.04 micrograms/kg/min, i.v., infusion X 15 min) were selected to produce a positive inotropic action similar to that of denopamine. Denopamine produced significantly less increasing effects in heart rate, cardiac output and myocardial oxygen consumption and had more reducing effects in LV internal diameter than isoproterenol, while isoproterenol tended to produce a more potent increase in coronary blood flow, but a smaller decrease in LV end-diastolic pressure than denopamine. PQ interval was similarly reduced. Denopamine caused no substantial increase in myocardial oxygen consumption at a lower dose, at which LV dp/dtmax was significantly increased. A weak effect of denopamine on myocardial oxygen consumption may result partly from a weak positive chronotropic effect and partly from a reduction of preload and cardiac size.

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Watanabe, Hitoshi; Honda, Yayoi; Deguchi, Jiro; Yamada, Toru; Bando, Kiyoko

2017-01-01

Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a β-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery.

Enoximon-echocardiography. A new diagnostic approach for the detection of viable myocardium comparison to dobutamin-echocardiography.

PubMed

Baumgart, D; Buck, T; Leischik, R; Oelert, H; Farahati, J; Reiners, C; Erbel, R

1994-08-01

Hypo- or akinetic myocardial regions can be identified as viable myocardium through recruitment of inotropic reserve. Both, dobutamine (D) as well as enoximone (E) mediate their inotropic action via an increase in intracellular c-AMP concentration based on a different action. In 10 patients with documented myocardial infarction either D (5 to 40 micrograms/kg/min, increments of 5 micrograms/kg/min every 3 min) or E (1 to 9 micrograms/kg/min, increments of 1 microgram/kg/min every 2 min) was administered intravenously on two consecutive days. Heart rate (HR), systolic and diastolic blood pressure (BP), as well as a wall motion score in 16 segment (WMS) and ejection fraction (EF) with 2D-echocardiography were determined at rest and during each increment. Viability of myocardial regions was assessed with 201thallium-SPECT (Table 1). *p < 0.05 vs. rest, data: mean +/- SD. While E did not cause any side effects, patients complained about rash (n = 10), headache (n = 8), angina pectoris (n = 5), and anxiety (n = 2) during the administration of D. D and E are both able to recruit a potential inotropic reserve in infarcted myocardium, and thus, identify viable myocardium. In contrast to E, D caused an increase in HR and systolic BP. Enoximone-echocardiography seems to be a new, promising tool for the identification of viable myocardium.

Rapid negative inotropic effect induced by TNF-α in rat heart perfused related to PKC activation.

PubMed

Jude, B; Vetel, S; Giroux-Metges, M A; Pennec, J P

2018-07-01

Myocardial depression, frequently observed in septic shock, is mediated by circulating molecules such as cytokines. TNF-α appears to be the most important pro-inflammatory cytokine released during the early phase of a septic shock. It was previously shown that TNF-α had a negative inotropic effect on myocardium. Now, the aim of this study was to investigate the effects of the activation of PKC by TNF-α on heart function, and to determine if this cytokine could induce a decrease of membrane excitability. Isolated rat hearts (n = 6) were perfused with Tyrode solution containing TNF-α at 20 ng/ml during 30 min by using a Langendorff technique. Expressions of PKC-α and PKC-ε were analysed by western blot on membrane and cytosol proteins extracted from ventricular myocardium. Patch clamp was performed on freshly isolated cardiomyocytes (n = 8). Compared to control situation, 30 min of TNF-α perfusion led to cardiac dysfunction with a decrease of the heart rate (-83%), the force (-20%) and speed of relaxation (-18%) and the coronary flow (-25%). This is associated with an activation and a membrane targeting of both PKC-α and PKC-ε isoforms in ventricle with respectively +123% and +54% compared to control hearts. Nevertheless, TNF-α had no significant effect on voltage-gated sodium current (109.0%+/- 12.5) after addition of the cytokine when compared to control. These results showed that TNF-α had a negative inotropic effect on the isolated rat heart and can induce PKC activation leading to an impaired contractility of the heart. However the early heart dysfunction induced by the cytokine was not associated to a decrease of cardiomyocytes membrane excitability as it has been evidenced in skeletal muscle fibres. Copyright © 2017 Elsevier Ltd. All rights reserved.

The inodilator levosimendan in repetitive doses in the treatment of advanced heart failure

PubMed Central

Delgado, Juan F.; Oliva, Fabrizio; Reinecke, Alexander

2017-01-01

Abstract Inotropes may be an appropriate response for some patients with advanced heart failure who remain highly symptomatic despite optimization of evidence-based therapy. These patients need to be supported waiting for a heart transplant or ventricular assist device, or may be candidates for inotropy as an intervention in its own right to maintain a patient in the best achievable circumstances. Objectives in such a situation include relieving symptoms, improving quality of life and reducing unplanned hospitalizations and the costs associated with such admissions. Levosimendan, a calcium sensitizer and potassium channel opener with inotrope and vasodilator actions, has emerged as a potentially valuable addition to the armamentarium in this context, used in repeated or intermittent cycles of therapy. Detailed proposals and guidance are offered for the identification of candidate patients with good prospects of a beneficial response to levosimendan, and for the safe and effective implementation of a course of therapy. PMID:29249905

The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

PubMed

Arioglu, E; Guner, S; Ozakca, I; Altan, V M; Ozcelikay, A T

2010-02-01

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Inotropic effects of extracts of Psidium guajava L. (guava) leaves on the guinea pig atrium.

PubMed

Conde Garcia, E A; Nascimento, V T; Santiago Santos, A B

2003-05-01

Many pharmacological effects have been ascribed to extracts of Psidium guajava L. (guava) leaves. However, in spite of its widespread use in Brazilian folk medicine and a reasonable number of scientific reports about it, we could not find any study dealing with its action on the mammalian myocardium. In the present study, by measuring isometric force, we observed that the crude extract of P. guajava (water-alcohol extract obtained by macerating dry leaves) depresses the guinea pig atrial contractility in a concentration-dependent fashion (N = 8 hearts, 15 trials). The compound with cardiac activity was concentrated by extraction in a Soxhlet apparatus using 17 M glacial acetic acid after removing the less polar fractions (hexane, chloroform, acetone, ethanol and methanol), suggesting that this compound is a highly polar substance. In the isolated guinea pig left atrium the acetic acid fraction (10-800 mg/l) of P. guajava 1) reversibly decreased myocardial force in a concentration-dependent fashion (EC50 = 0.07g/l, N = 5 hearts, 9 trials, P<0.05), 2) increased the atrial relaxation time measured at 20% of the force amplitude up to 35% (91 +/- 15 to 123 +/- 30 ms, N = 3 hearts, 6 trials, P<0.05), 3) abolished the positive staircase effect (Bowditch phenomenon) in a concentration-dependent fashion suggesting a decrease of the cellular inward calcium current (N = 4 hearts, 8 trials, P<0.05), and 4) its inotropic effect was abolished by cholinergic receptor blockade with 1.5 mM atropine sulfate, indicating a cholinergic involvement in the mechanism of action of the extract (N = 7 hearts, 15 trials, P<0.05). The acetic acid extract was 20 times more potent than crude extract (EC50 = 1.4 g/l). The results showed that extracts from P. guajava leaves depress myocardial inotropism.

Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qu, Yusheng, E-mail: yqu@amgen.com; Fang, Mei; Gao, BaoXi

Itraconazole (ITZ) is an approved antifungal agent that carries a “black box warning” in its label regarding a risk of negative cardiac inotropy based on clinical findings. Since the mechanism of the negative inotropic effect is unknown, we performed a variety of preclinical and mechanistic studies to explore the pharmacological profile of ITZ and understand the negative inotropic mechanism. ITZ was evaluated in: (1) an isolated rabbit heart (IRH) preparation using Langendorff retrograde perfusion; (2) ion channel studies; (3) a rat heart mitochondrial function profiling screen; (4) a mitochondrial membrane potential (MMP) assay; (5) in vitro pharmacology profiling assays (148more » receptors, ion channels, transporters, and enzymes); and (6) a kinase selectivity panel (451 kinases). In the IRH, ITZ decreased cardiac contractility (> 30%) at 0.3 μM, with increasing effect at higher concentrations, which indicated a direct negative inotropic effect upon the heart. It also decreased heart rate and coronary flow (≥ 1 μM) and prolonged PR/QRS intervals (3 μM). In mechanistic studies, ITZ inhibited the cardiac NaV channel (IC{sub 50}: 4.2 μM) and was devoid of any functional inhibitory effect at the remaining pharmacological targets. Lastly, ITZ did not affect MMP, nor interfere with mitochondrial enzymes or processes involved with fuel substrate utilization or energy formation. Overall, the cardiovascular and mechanistic data suggest that ITZ-induced negative inotropy is a direct effect on the heart, in addition, the potential involvement of mitochondria function and L-type Ca{sup 2+} channels are eliminated. The exact mechanism underlying the negative inotropy is uncertain, and requires further study. - Highlights: ► Effect of itraconazole (ITZ) was assessed in the isolated rabbit heart (IRH) assay. ► ITZ decreased ventricular contractility in IRH, indicating a direct effect. ► IC{sub 50} of ITZ on L-type I{sub Ca} was greater than 30 μM, on I{sub Na} was 4.2 μM. ► ITZ had minimal effects on mitochondrial functions. ► ITZ had minimal hits in pharmacology profiling and kinase selectivity panel.« less

Current real-life use of vasopressors and inotropes in cardiogenic shock - adrenaline use is associated with excess organ injury and mortality.

PubMed

Tarvasmäki, Tuukka; Lassus, Johan; Varpula, Marjut; Sionis, Alessandro; Sund, Reijo; Køber, Lars; Spinar, Jindrich; Parissis, John; Banaszewski, Marek; Silva Cardoso, Jose; Carubelli, Valentina; Di Somma, Salvatore; Mebazaa, Alexandre; Harjola, Veli-Pekka

2016-07-04

Vasopressors and inotropes remain a cornerstone in stabilization of the severely impaired hemodynamics and cardiac output in cardiogenic shock (CS). The aim of this study was to analyze current real-life use of these medications, and their impact on outcome and on changes in cardiac and renal biomarkers over time in CS. The multinational CardShock study prospectively enrolled 219 patients with CS. The use of vasopressors and inotropes was analyzed in relation to the primary outcome, i.e., 90-day mortality, with propensity score methods in 216 patients with follow-up data available. Changes in cardiac and renal biomarkers over time until 96 hours from baseline were analyzed with linear mixed modeling. Patients were 67 (SD 12) years old, 26 % were women, and 28 % had been resuscitated from cardiac arrest prior to inclusion. On average, systolic blood pressure was 78 (14) and mean arterial pressure 57 (11) mmHg at detection of shock. 90-day mortality was 41 %. Vasopressors and/or inotropes were administered to 94 % of patients and initiated principally within the first 24 hours. Noradrenaline and adrenaline were given to 75 % and 21 % of patients, and 30 % received several vasopressors. In multivariable logistic regression, only adrenaline (21 %) was independently associated with increased 90-day mortality (OR 5.2, 95 % CI 1.88, 14.7, p = 0.002). The result was independent of prior cardiac arrest (39 % of patients treated with adrenaline), and the association remained in propensity-score-adjusted analysis among vasopressor-treated patients (OR 3.0, 95 % CI 1.3, 7.2, p = 0.013); this was further confirmed by propensity-score-matched analysis. Adrenaline was also associated, independent of prior cardiac arrest, with marked worsening of cardiac and renal biomarkers during the first days. Dobutamine and levosimendan were the most commonly used inotropes (49 % and 24 %). There were no differences in mortality, whether noradrenaline was combined with dobutamine or levosimendan. Among vasopressors and inotropes, adrenaline was independently associated with 90-day mortality in CS. Moreover, adrenaline use was associated with marked worsening in cardiac and renal biomarkers. The combined use of noradrenaline with either dobutamine or levosimendan appeared prognostically similar.

Impact of hypotension after return of spontaneous circulation on survival in patients of out-of-hospital cardiac arrest.

PubMed

Chiu, Yu Koon; Lui, Chun Tat; Tsui, Kwok Leung

2018-01-01

To investigate the relationship between hypotension in the first 3h after return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest. This retrospective cohort study occurred at two regional hospitals and included adult OHCA patients who experienced ROSC from July 1, 2014 to December 31, 2015. Hemodynamic and inotrope administration data were retrieved for 3h after ROSC. We calculated the hypotensive exposure index (HEI) as the surrogate marker of the exposure of hypotension. The area under the ROC curve and multivariate logistic regression models were performed to analyze the effect of HEI on survival. Mean arterial pressure (MAP) was explored in the surviving and non-surviving patient groups using repeated measures MANCOVA, adjusted for the use of inotropes and down time. A total of 289 patients were included in the study, and 29 survived. The median 1-hour HEI and 3-hour HEI were significantly lower in the survival group (p<0.001). The area under the ROC curve for 3-hour HEI was 0.861. The repeated measures MANCOVA indicated that an interaction existed between post-ROSC time and downtime [F(5,197)=2.31, p=0.046]. No significant change in the MAP was observed in the 3h after ROSC, except in the group with a prolonged down time. According to the tests examining the effects of the use of inotropes on the survival outcomes of the different subjects, the MAP was significantly higher in the surviving group [F(1,201)=4.11; p=0.044; ηp2=0.020]. Among the patients who experienced ROSC after OHCA, post-ROSC hypotension was an independent predictor of survival. Copyright © 2017 Elsevier Inc. All rights reserved.

Temperature-dependent inotropic and lusitropic indices based on half-logistic time constants for four segmental phases in isovolumic left ventricular pressure-time curve in excised, cross-circulated canine heart.

PubMed

Mizuno, Ju; Mohri, Satoshi; Yokoyama, Takeshi; Otsuji, Mikiya; Arita, Hideko; Hanaoka, Kazuo

2017-02-01

Varying temperature affects cardiac systolic and diastolic function and the left ventricular (LV) pressure-time curve (PTC) waveform that includes information about LV inotropism and lusitropism. Our proposed half-logistic (h-L) time constants obtained by fitting using h-L functions for four segmental phases (Phases I-IV) in the isovolumic LV PTC are more useful indices for estimating LV inotropism and lusitropism during contraction and relaxation periods than the mono-exponential (m-E) time constants at normal temperature. In this study, we investigated whether the superiority of the goodness of h-L fits remained even at hypothermia and hyperthermia. Phases I-IV in the isovolumic LV PTCs in eight excised, cross-circulated canine hearts at 33, 36, and 38 °C were analyzed using h-L and m-E functions and the least-squares method. The h-L and m-E time constants for Phases I-IV significantly shortened with increasing temperature. Curve fitting using h-L functions was significantly better than that using m-E functions for Phases I-IV at all temperatures. Therefore, the superiority of the goodness of h-L fit vs. m-E fit remained at all temperatures. As LV inotropic and lusitropic indices, temperature-dependent h-L time constants could be more useful than m-E time constants for Phases I-IV.

Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function.

PubMed

Chiellini, Grazia; Frascarelli, Sabina; Ghelardoni, Sandra; Carnicelli, Vittoria; Tobias, Sandra C; DeBarber, Andrea; Brogioni, Simona; Ronca-Testoni, Simonetta; Cerbai, Elisabetta; Grandy, David K; Scanlan, Thomas S; Zucchi, Riccardo

2007-05-01

3-Iodothyronamine T1AM is a novel endogenous thyroid hormone derivative that activates the G protein-coupled receptor known as trace anime-associated receptor 1 (TAAR1). In the isolated working rat heart and in rat cardiomyocytes, T1AM produced a reversible, dose-dependent negative inotropic effect (e.g., 27+/-5, 51+/-3, and 65+/-2% decrease in cardiac output at 19, 25, and 38 microM concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T1AM were remarkably increased in the presence of the tyrosine kinase inhibitor genistein, whereas they were attenuated in the presence of the tyrosine phosphatase inhibitor vanadate. No effect was produced by inhibitors of protein kinase A, protein kinase C, calcium-calmodulin kinase II, phosphatidylinositol-3-kinase, or MAP kinases. Tissue cAMP levels were unchanged. In rat ventricular tissue, Western blot experiments with antiphosphotyrosine antibodies showed reduced phosphorylation of microsomal and cytosolic proteins after perfusion with synthetic T1AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [125I]T1AM was observed, with a dissociation constant in the low micromolar range (5 microM); and endogenous T1AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function.

Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn.

PubMed

Soyka, L F

1975-03-01

Digoxin rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Virtually nothing is known about the effects of transplacentally administered digoxin on the fetus. Toxicity has been reported in the fetus of a woman ingesting a huge overdose of digitoxin; the same result would be anticipated with digoxin poisoning. Serum levels in pregnant women receiving the standard dose of 0.25 mg tend to be subnormal and certain patients may require a small increase in dose during the last trimester. While the full-term neonate appears to tolerate relatively high doses and the resultant high serum levels, there is no compelling evidence that such doses are necessary or even useful. Since toxicity can and does occur in neonates, especially during administration of loading (digitalizing) doses, it is recommended that maintenance doses of 0.01 mg per kg per day be used routinely. If the full inotropic effect is needed immediately, a loading dose of 0.03 mg per kg may be employed. Maintenance therapy is then begun on the following day. Without a loading dose cumulation occurs for about 3 days; after 5 or so days, serum levels will equal those found after use of a loading dose followed by maintenance therapy. Results of a single study suggest that the daily dose should be divided and given every 12 hours. After about 1 week of therapy, the serum level should be determined and the dose modified to maintain a serum level of 1 to 2 ng per ml. If the therapeutic effect is less than desired, a cautions increase in dose to as high as 0.02 mg per kg per day or to that dose which produces serum levels up to 3 ng per ml can be tried. Certain infants appear to tolerate serum levels of 3.5 to 4 ng per ml but such infants must be closely monitored. There are no data which indicate that a greater inotropic response will occur at these high serum levels, though this point has not been definitively investigated, and is the highest priority question for research. The intramuscular route should be researved for the unusual situation. Vomiting should be considered an early sign of toxicity and may act as a "safety valve." When adminstered in solution (as in the elixir or solution for intravenous use), oral digoxin is rapidly absorbed an an inotropic response is found within minutes, reaching a peak within hours, so that little is gained by parenteral administration. If an inotropic effect is urgently needed, intravenous administration of ouabain will give an immediate response.

Reduction of perifusate magnesium alters inotropic response of papillary muscle to ion channel modulators.

PubMed

Manju, L; Nair, R Renuka

2005-09-01

Magnesium has a significant role in the regulation of ion transport. Marginal deficiency of Mg can therefore affect myocardial excitability and contractility. This study was taken up with the objective of examining the inotropic response of the myocardium to variation in extracellular [Mg]o and identifying the ion channels and pumps mediating the inotropic changes. Electrically stimulated rat papillary muscle was used as the experimental model and mechanical changes were recorded using a physiograph. Channel specific antagonists were used to identify the channels mediating the functional changes. Diastolic Ca2+ levels were determined in isolated myocytes by the ratiometric method using the fluorescent indicator Fura2-AM. A negative association was observed between the level of [Mg]o and force of contraction, with a peak at 0.48 mM Mg. The force of contraction in Mg deficient medium (0.48 mM) was 158% of control (1.2 mM Mg) (p < 0.001). Inotropic response to the L-type channel antagonist (verapamil-1 microm) and NaK ATPase inhibitor (Ouabain-0.3 mM) was augmented in Mg deficiency (p < 0.005), indicating activation of the channel and the pump. The response to T-type channel inhibitor (NiCl2-40 microM) was attenuated in Mg deficiency (p < 0.05). The response to the sarcoplasmic reticular Ca pump inhibitor (caffeine-10 mM) and the SR Ca2+ release channel inhibitor (ryanodine-1 microM) were not significantly affected by Mg deficiency. Diastolic level of Ca2+ increased with a decrease in Mg (p < 0.05). The observations of the study lead to the conclusion that the positive inotropic response in Mg deficiency is mediated by an increase in basal Ca2+ combined with Ca-induced-Ca release consequent to Ca2+ influx through L-type Ca channel. Variation in sensitivity to Ca channel blockers and NaK ATPase inhibitor in Mg deficiency can have pharmacological implications.

Cardiovascular and adenylate cyclase stimulating effects of colforsin daropate, a water-soluble forskolin derivative, compared with those of isoproterenol, dopamine and dobutamine.

PubMed

Yoneyama, Masahiko; Sugiyama, Atsushi; Satoh, Yoshioki; Takahara, Akira; Nakamura, Yuji; Hashimoto, Keitaro

2002-12-01

Colforsin daropate is a recently developed water-soluble derivative of forskolin that directly stimulates adenylate cyclase, unlike the catecholamines. The chronotropic, inotropic and coronary vasodilator actions of colforsin daropate were compared with those of isoproterenol, dopamine and dobutamine, using canine isolated, blood-perfused heart preparations. The stimulating effect of each drug on adenylate cyclase activity was also assessed. Colforsin daropate, as well as each of the catecholamines, exerted positive chronotropic, inotropic and coronary vasodilator actions. The order of selectivity for the cardiovascular variables of colforsin daropate was coronary vasodilation > positive inotropy > positive chronotropy; whereas that of isoproterenol, dopamine and dobutamine was positive inotropy > coronary vasodilation > positive chronotropy. Thus, a marked characteristic of colforsin daropate is its potent coronary vasodilator action. On the other hand, each drug significantly increased the adenylate cyclase activity in a dose-related manner: colforsin daropate > isoproterenol > dopamine = dobutamine. These results suggest that colforsin daropate may be preferable in the treatment of severe heart failure where the coronary blood flow is reduced and beta-adrenoceptor-dependent signal transduction pathway is down-regulated.

Inositol-1,4,5-trisphosphate increase by diadenosine tetraphosphate in preparations from failing human myocardium.

PubMed

Knapp, J; Bokník, P; Linck, B; Läer, S; Müller, F U; Neumann, J; Vahlensieck, U; Schlüter, H; Zidek, W; Schmitz, W

1999-09-01

In human ventricular trabeculae carneae 100 microM AP4A (diadenosine tetraphosphate) increased force of contraction to 162.8+/-15.7% of predrug value (n=9). This positive inotropic effect was accompanied by a prolongation of time parameters: time to peak tension and time of relaxation were prolonged by 7.8+/-1.3% and 14.9+/-3.8%, respectively (P<0.05). In the same trabeculae, AP4A increased IP3 (inositol-1,4,5-trisphosphate) content from 9.0+/-1.3 pmol/mg to 22.9+/-5.4 pmol/mg protein (n=5-9). In conclusion, the positive inotropic effect of AP4A in the human myocardium is likely due to an increase of IP3 mediated probably via Gq-coupled P2Y-purinoceptors. Because of the prominent role of Gq in the development of cardiac disease, these findings may lay the ground to further investigate the possible role of AP4A and/or related ligands (e.g. AP2A and AP3A) in heart failure.

Frequency-dependence of the slow force response.

PubMed

von Lewinski, Dirk; Zhu, Danan; Khafaga, Mounir; Kockskamper, Jens; Maier, Lars S; Hasenfuss, Gerd; Pieske, Burkert

2008-05-01

Stretch induces biphasic inotropic effects in mammalian myocardium. A delayed component (slow force response, SFR) has been demonstrated in various species, however, experimental conditions varied and the underlying mechanisms are controversial. The physiological relevance of the SFR is poorly understood. Experiments were performed in ventricular muscle strips from failing human hearts and non-failing rabbit hearts. Upon stretch, twitch force was assessed at basal conditions (1 Hz, 37 degrees C) and after changing stimulation frequency with and without blockade of the Na+/H+-exchanger-1 (NHE1) or reverse-mode Na+/Ca2+-exchange (NCX). Action potential duration (APD) was assessed using floating electrodes. Low stimulation rates (0.2 Hz) potentiated and higher stimulation rates (2 and 3 Hz) reduced the SFR. The extent of SFR inhibition by NHE1 or NCX inhibition was not affected by stimulation rate. APD decreased at 0.2 Hz but was not altered at higher stimulation rates. The data demonstrate frequency-dependence of the SFR with greater positive inotropic effects at lower stimulation rates. Subcellular mechanisms underlying the SFR are not fundamentally affected by stimulation rate. The SFR may have more pronounced physiological effects at lower heart rates.

Vascular dilation, tachycardia, and increased inotropy occur sequentially with increasing epinephrine dose rate, plasma and myocardial concentrations, and cAMP

PubMed Central

Maslov, Mikhail Y.; Wei, Abraham E.; Pezone, Matthew J.; Edelman, Elazer R.; Lovich, Mark A.

2015-01-01

Background While epinephrine infusion is widely used in critical care for inotropic support, there is no direct method to detect the onset and measure the magnitude of this response. We hypothesized that surrogate measurements, such as heart rate and vascular tone, may indicate if the plasma and tissue concentrations of epinephrine and cAMP are in a range sufficient to increase myocardial contractility. Methods Cardiovascular responses to epinephrine infusion (0.05–0.5 mcg·kg−1·min−1) were measured in rats using arterial and left ventricular catheters. Epinephrine and cAMP levels were measured using ELISA techniques. Results The lowest dose of epinephrine infusion (0.05 mcg·kg−1·min−1) did not raise plasma epinephrine level and did not lead to cardiovascular response. Incremental increase in epinephrine infusion (0.1 mcg·kg−1·min−1) elevated plasma but not myocardial epinephrine levels, providing vascular, but not cardiac effects. Further increase in the infusion rate (0.2 mcg·kg−1·min−1) raised myocardial tissue epinephrine levels sufficient to increase heart rate but not contractility. Inotropic and lusitropic effects were significant at the infusion rate of 0.3 mcg·kg−1·min−1. Correlation of plasma epinephrine to hemodynamic parameters suggest that as plasma concentration increases, systemic vascular resistance falls (EC50=47 pg/ml), then HR increases (ED50=168 pg/ml), followed by a rise in contractility and lusitropy (ED50=346 pg/ml and ED50=324 pg/ml accordingly). Conclusions The dose response of epinephrine is distinct for vascular tone, HR and contractility. The need for higher doses to see cardiac effects is likely due to the threshold for drug accumulation in tissue. Successful inotropic support with epinephrine cannot be achieved unless the infusion is sufficient to raise the heart rate. PMID:25790776

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart.

PubMed

Levitan, Bryana M; Manning, Janet R; Withers, Catherine N; Smith, Jeffrey D; Shaw, Robin M; Andres, Douglas A; Sorrell, Vincent L; Satin, Jonathan

2016-12-01

Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad -/- ) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad -/- confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad -/- . Rad -/- basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

PubMed Central

Levitan, Bryana M.; Manning, Janet R.; Withers, Catherine N.; Smith, Jeffrey D.; Shaw, Robin M.; Andres, Douglas A.; Sorrell, Vincent L.

2016-01-01

Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad−/−) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad−/− confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad−/−. Rad−/− basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support. PMID:27798760

The total artificial heart for biventricular heart failure and beyond.

PubMed

Kasirajan, Vigneshwar; Tang, Daniel G; Katlaps, Gundars J; Shah, Keyur B

2012-05-01

Treatment options for late-stage biventricular heart failure are limited but include medical therapy with intravenous inotropes, biventricular assist devices (Bi-VADs) and the total artificial heart (TAH). In this manuscript, we review the indications, surgical techniques and outcomes for the TAH. The TAH offers biventricular replacement, rather than 'assistance', as the device is placed orthotopically after excision of the entire ventricular myocardium and all four native valves. In contrast to patients with Bi-VADs, patients with the TAH have no postoperative inotrope requirements, arrhythmias or inflow/outflow cannulae-related complications. Additionally, patients participate in rehabilitation early after device placement and the development of a portable drive may facilitate hospital discharge in the USA. Furthermore, total heart replacement may be ideal for heart failure associated with unique anatomical and mechanical complications. The TAH is an effective therapeutic option for the treatment of patients dying of heart failure who may not be suitable candidates for left ventricular assist devices.

The role of elastic restoring forces in right-ventricular filling

PubMed Central

Pérez Del Villar, Candelas; Bermejo, Javier; Rodríguez-Pérez, Daniel; Martínez-Legazpi, Pablo; Benito, Yolanda; Antoranz, J. Carlos; Desco, M. Mar; Ortuño, Juan E.; Barrio, Alicia; Mombiela, Teresa; Yotti, Raquel; Ledesma-Carbayo, Maria J.; Del Álamo, Juan C.; Fernández-Avilés, Francisco

2015-01-01

Aims The physiological determinants of RV diastolic function remain poorly understood. We aimed to quantify the contribution of elastic recoil to RV filling and determine its sensitivity to interventricular interaction. Methods and results High-fidelity pressure–volume loops and simultaneous 3-dimensional ultrasound sequences were obtained in 13 pigs undergoing inotropic modulation, volume overload, and acute pressure overload induced by endotoxin infusion. Using a validated method, we isolated elastic restoring forces from ongoing relaxation using conventional pressure–volume data. The RV contracted below the equilibrium volume in >75% of the data sets. Consequently, elastic recoil generated strong sub-atmospheric passive pressure at the onset of diastole [−3 (−4 to −2) mmHg at baseline]. Stronger restoring suction pressure was related to a shorter isovolumic relaxation period, a higher rapid filling fraction, and lower atrial pressures (all P < 0.05). Restoring forces were mostly determined by the position of operating volumes around the equilibrium volume. By this mechanism, the negative inotropic effect of beta-blockade reduced and sometimes abolished restoring forces. During acute pressure overload, restoring forces initially decreased, but recovered at advanced stages. This biphasic response was related to alterations of septal curvature induced by changes in the diastolic LV–RV pressure balance. The constant of elastic recoil was closely related to the constant of passive stiffness (R = 0.69). Conclusion The RV works as a suction pump, exploiting contraction energy to facilitate filling by means of strong elastic recoil. Restoring forces are influenced by the inotropic state and RV conformational changes mediated by direct ventricular interdependence. PMID:25691537

Safety and feasibility of inpatient exercise training in pediatric heart failure: a preliminary report.

PubMed

McBride, Michael G; Binder, Tracy Jo; Paridon, Stephen M

2007-01-01

To determine the safety and feasibility of an inpatient exercise training program for a group of pediatric heart transplantation candidates on multiple inotropic support. Children with end-stage heart disease often require heart transplantation. Currently, no data exist on the safety and feasibility of an inpatient exercise training program in pediatric patients awaiting heart transplantation while on inotropic support. Twenty ambulatory patients (11 male; age, 13.6 +/- 3.2 years) were admitted, listed, and subsequently enrolled into an exercise training program while awaiting heart transplantation. Patient diagnoses consisted of dilated cardiomyopathy (n = 15), restrictive cardiomyopathy (n = 1), and failing single-ventricle physiology (n = 4). Inotropic support consisted of a combination of dobutamine, dopamine, or milrinone. Exercise sessions were scheduled three times a week lasting from 30 to 60 minutes and consisted of aerobic and musculoskeletal conditioning. Over 6.2 +/- 4.2 months, 1,251 of a possible 1,508 exercise training sessions were conducted, with a total of 615 hours (26.3 +/- 2.7 min/session) dedicated to low-intensity aerobic exercise. Reasons for noncompliance included a change in medical status, staffing, or patient cooperation. Two adverse episodes (seizures) occurred, neither of which resulted in termination from the program. No adverse episodes of hypotension or significant complex arrhythmias occurred. No complication of medication administration or loss of intravenous access occurred. Data from this study indicate that pediatric patients on inotropic support as a result of systemic ventricular or biventricular heart failure can safely participate in exercise training programs with relatively moderate to high compliance.

Cardiac dysfunction and ferritin as early markers of severity in pediatric sepsis.

PubMed

Tonial, Cristian T; Garcia, Pedro Celiny R; Schweitzer, Louise Cardoso; Costa, Caroline A D; Bruno, Francisco; Fiori, Humberto H; Einloft, Paulo R; Garcia, Ricardo Branco; Piva, Jefferson Pedro

The aim of this study was to verify the association of echocardiogram, ferritin, C-reactive protein, and leukocyte count with unfavorable outcomes in pediatric sepsis. A prospective cohort study was carried out from March to December 2014, with pediatric critical care patients aged between 28 days and 18 years. Inclusion criteria were diagnosis of sepsis, need for mechanical ventilation for more than 48h, and vasoactive drugs. Serum levels of C-reactive protein, ferritin, and leukocyte count were collected on the first day (D0), 24h (D1), and 72h (D3) after recruitment. Patients underwent transthoracic echocardiography to determine the ejection fraction of the left ventricle on D1 and D3. The outcomes measured were length of hospital stay and in the pediatric intensive care unit, mechanical ventilation duration, free hours of VM, duration of use of inotropic agents, maximum inotropic score, and mortality. Twenty patients completed the study. Patients with elevated ferritin levels on D0 had also fewer ventilator-free hours (p=0.046) and higher maximum inotropic score (p=0.009). Patients with cardiac dysfunction by echocardiogram on D1 had longer hospital stay (p=0.047), pediatric intensive care unit stay (p=0.020), duration of mechanical ventilation (p=0.011), maximum inotropic score (p=0.001), and fewer ventilator-free hours (p=0.020). Cardiac dysfunction by echocardiography and serum ferritin value was significantly associated with unfavorable outcomes in pediatric patients with sepsis. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

[Influence exogenous nicotinamide adenine dinucleotide (NAD+) on contractile and bioelectric activity of the rat heart].

PubMed

Pustovit, K B; Kuz'min, V S; Sukhova, G S

2014-04-01

This study is aimed to the investigation of the nicotinamide adenine dinucleotide (NAD+) effects and mechanisms of action in a heart. NAD+ (mcM) induces multiphase alternation of contractile activity of isolated rat heart: short positive inotropic action is followed by a negative inotropic phase. NAD+ (1-100 mcM) induces decreasing of action potential duration (APD) in rat atrial myocardium (from 45 +/- 0.82 ms in control experiments to 39 +/- 1.05 (n = 8) and 32 +/- 2 (n = 8) during application of 10 and 100 mcM of NAD+, respectively). Significant APD increase (from 45 +/- 0.82 ms to 74 +/- 1.89 (n = 8) ms) was observed during washing out of NAD+ (100 mcM). ATP or adenosine was unable to increase APD both during application or washing out. NAD+ induced APD decrease was not suppressed by P1-antagonist theophylline. P1-purinoreceptor and metabolite independent direct action of NAD+ in rat heart is suggested. Activation of P2X or P2Y receptors, cyclic ADP-ribose accumulation in cardiomyocytes is proposed as a main mechanism of NAD(+)-induced effects in the heart.

Cardiovascular effects of Urtica dioica L. (Urticaceae) roots extracts: in vitro and in vivo pharmacological studies.

PubMed

Testai, Lara; Chericoni, Silvio; Calderone, Vincenzo; Nencioni, Giulia; Nieri, Paola; Morelli, Ivano; Martinotti, Enrica

2002-06-01

Urtica dioica (Urticaceae) is a plant principally used in the traditional medicine of oriental Marocco as antihypertensive remedy (J. Ethnopharmacol., 58 (1997), 45). The aim of this work was to evaluate a possible direct cardiovascular action of the plant and to investigate its mechanism of action. In aortic preparations with intact and functional endothelial layer, pre-contracted with KCl 20 mM or norepinephrine 3 microM, the crude aqueous and methanolic extracts of the plant roots, as well as purified fractions elicited a vasodilator action. Nevertheless, the vasodilator activity was not present in aortic rings without endothelial layer. In aortic rings with intact endothelial layer, the vasorelaxing effect was abolished by L-NAME, a NO-biosynthesis inhibitor, and ODQ, a guanylate cyclase inhibitor. Furthermore, potassium channel blockers (TEA, 4-aminopyridine, quinine, but not glybenclamide) antagonized the vasodilator action of the purified fraction F1W of U. dioica. The same fraction produced a marked decrease of inotropic activity, in spontaneously beating atria of guinea-pig, and a marked, but transient, hypotensive activity on the blood pressure of anaesthetized rats. It is concluded that U. dioica can produce hypotensive responses, through a vasorelaxing effect mediated by the release of endothelial nitric oxide and the opening of potassium channels, and through a negative inotropic action.

THE EFFECT OF PRE-OPERATIVE NUTRITIONAL STATUS ON POST-OPERATIVE OUTCOMES IN CHILDREN UNDERGOING SURGERY FOR CONGENITAL HEART DEFECTS IN SAN FRANCISCO (UCSF) AND GUATEMALA CITY (UNICAR)

PubMed Central

Radman, Monique; Mack, Ricardo; Barnoya, Joaquin; Castañeda, Aldo; Rosales, Monica; Azakie, Anthony; Mehta, Nilesh; Keller, Roberta; Datar, Sanjeev; Oishi, Peter; Fineman, Jeffrey

2013-01-01

Objective To determine the association between preoperative nutritional status and postoperative outcomes in children undergoing surgery for congenital heart defects (CHD). Methods Seventy-one patients with CHD were enrolled in a prospective, two-center cohort study. We adjusted for baseline risk differences using a standardized risk adjustment score for surgery for CHD. We assigned a World Health Organization Z-score for each subjects’ preoperative triceps skinfold measurement, an assessment of total body fat mass. We obtained preoperative plasma concentrations of markers of nutritional status (prealbumin, albumin) and myocardial stress (B-type natriuretic peptide, BNP). Associations between indices of preoperative nutritional status and clinical outcomes were sought. Results Subjects had a median (IQR) age of 10.2 (33) months. In the UCSF cohort, duration of mechanical ventilation (median 19 hours, IQR 29), length of ICU stay (median 5 days, IQR 5), duration of any continuous inotropic infusion (median 66 hours, IQR 72) and preoperative BNP levels (median 30 pg/mL, IQR 75) were associated with a lower preoperative triceps skinfold Z-score (p<0.05). Longer duration of any continuous inotropic infusion and higher preoperative BNP levels were also associated with lower preoperative prealbumin (12.1 ± 0.5 mg/dL) and albumin (3.2 ± 0.1) (p<0.05). Conclusions Lower total body fat mass and acute and chronic malnourishment are associated with worse clinical outcomes in children undergoing surgery for CHD at UCSF, a resource-abundant institution. There is an inverse correlation between total body fat mass and BNP levels. Duration of inotropic support and BNP increase concomitantly as measures of nutritional status decrease, supporting the hypothesis that malnourishment is associated with decreased myocardial function. PMID:23583172

Ischemia/reperfusion-induced alterations of enzymatic and signaling functions of the rat cardiac Na+/K+-ATPase: protection by ouabain preconditioning.

PubMed

Belliard, Aude; Gulati, Gaurav K; Duan, Qiming; Alves, Rosana; Brewer, Shannon; Madan, Namrata; Sottejeau, Yoann; Wang, Xiaoliang; Kalisz, Jennifer; Pierre, Sandrine V

2016-10-01

Cardiac glycosides (CG) are traditionally known as positive cardiac inotropes that inhibit Na + /K + -ATPase-dependent ion transport. CG also trigger-specific signaling pathways through the cardiac Na + /K + -ATPase, with beneficial effects in ischemia/reperfusion (I/R) injury (e.g., ouabain preconditioning, known as OPC) and hypertrophy. Our current understanding of hypersensitivity to CG and subsequent toxicity in the ischemic heart is mostly based on specific I/R-induced alterations of the Na + /K + -ATPase enzymatic function and has remained incomplete. The primary goal of this study was to investigate and compare the impact of I/R on Na + /K + -ATPase enzymatic and signaling functions. Second, we assessed the impact of OPC on both functions. Langendorff-perfused rat hearts were exposed to 30 min of ischemia and 30 min of reperfusion. At the inotropic concentration of 50 μmol/L, ouabain increased ERK and Akt phosphorylation in control hearts. In I/R hearts, this concentration did not induced positive inotropy and failed to induce Akt or ERK phosphorylation. The inotropic response to dobutamine as well as insulin signaling persisted, suggesting specific alterations of Na + /K + -ATPase. Indeed, Na + /K + -ATPase protein expression was intact, but the enzyme activity was decreased by 60% and the enzymatic function of the isoform with high affinity for ouabain was abolished following I/R. Strikingly, OPC prevented all I/R-induced alterations of the receptor. Further studies are needed to reveal the respective roles of I/R-induced modulations of Na + /K + -ATPase enzymatic and signaling functions in cardiomyocyte death. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Diastolic scattered light fluctuation, resting force and twitch force in mammalian cardiac muscle

PubMed Central

Lakatta, E. G.; Lappé, D. L.

1981-01-01

1. When coherent light was passed through isolated isometric cardiac muscles during the diastolic or resting period, intensity fluctuations were observed in the scattered field. The frequency of these intensity fluctuations (f½) varied with many experimental interventions known to enhance Ca2+ flux into the cell. 2. In rat muscles stimulated at low frequencies (0.1 ± 2.0 min-1) stepwise increases (0.4-10 mm) of [Ca2+] in the bathing fluid ([Ca2+]e), or addition of ouabain (10-6-6 × 10-4 m) to the perfusate caused stepwise increases in f½. These were paralleled by increments in resting force (RF) such that the changes in f½ and RF were highly correlated. Substitution of K+ for Na+ in the perfusate resulted in parallel transients in RF and f½. 3. In contrast to the rat, most cat muscles stimulated at low frequencies in the steady state exhibited neither diastolic intensity fluctuations nor Ca2+-dependent changes in RF in [Ca2+]e of 10 mm or less; when [Ca2+]e was increased to 12-32 mm, however, steady-state Ca2+-dependent f½ and RF were observed. In a given [Ca2+]e reduction of [Na+]e increased f½. In the transient state following cessation of regular stimulation at more rapid rates (12-96 min-1) intensity fluctuations were present in all [Ca2+]e and decayed with time (seconds to minutes); the f½ and time course of the decay of the fluctuations were determined by the rate of prior stimulation and [Ca2+]e. 4. Maximum potentiation of twitch force in response to the above inotropic interventions was associated with an optimal level of f½ which was similar in both species; when higher levels of f½ were produced by more intense inotropic intervention, twitch force declined. Over the range of inotropic intervention up to and including that at which maximum twitch potentiation occurred, the increase in diastolic f½ predicted the extent of twitch potentiation with a high degree of accuracy (r > 0.97) both in the transient and steady states. 5. In contrast to the other inotropic interventions studied, catecholamines were unique in that neither f½ nor RF increased over a full range of concentrations that resulted in maximum potentiation of the twitch. 6. It is concluded from these observations that f½ reflects diastolic Ca2+-dependent myofilament interaction; the increase in the extent of this interaction by inotropic interventions that do not alter the affinity of the myofilaments for Ca2+ probably reflects an increase in diastolic myoplasmic [Ca2+], an optimal level of which is associated with maximal potentiation of twitch force; the difference in f½ in rat and cat muscles under a given set of in vitro conditions may be related to the marked species difference in the effectiveness of excitation—contraction coupling. PMID:7310715

Randomized Comparative Study of Intravenous Infusion of Three Different Fixed Doses of Milrinone in Pediatric Patients with Pulmonary Hypertension Undergoing Open Heart Surgery

PubMed Central

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Background: Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Methodology: Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. Results: MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Conclusion: Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay. PMID:28701597

Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery.

PubMed

Barnwal, Neeraj Kumar; Umbarkar, Sanjeeta Rajendra; Sarkar, Manjula Sudeep; Dias, Raylene J

2017-01-01

Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay.

Surgical Closure of Patent Ductus Arteriosus in Premature Neonates Weighing Less Than 1,000 grams: Contemporary Outcomes.

PubMed

Lehenbauer, David G; Fraser, Charles D; Crawford, Todd C; Hibino, Naru; Aucott, Susan; Grimm, Joshua C; Patel, Nishant; Magruder, J Trent; Cameron, Duke E; Vricella, Luca

2018-07-01

The safety of surgical closure of patent ductus arteriosus (PDA) in very low birth weight premature neonates has been questioned because of associated morbidities. However, these studies are vulnerable to significant bias as surgical ligation has historically been utilized as "rescue" therapy. The objective of this study was to review our institutions' outcomes of surgical PDA ligation. All neonates with operative weight of ≤1.00 kg undergoing surgical PDA ligation from 2003 to 2015 were analyzed. Records were queried to identify surgical complications, perioperative morbidity, and mortality. Outcomes included pre- and postoperative ventilator requirements, pre- and postoperative inotropic support, acute kidney injury, surgical complications, and 30-day mortality. One hundred sixty-six preterm neonates underwent surgical ligation. One hundred twenty-one (70.3%) had failed indomethacin closure. One hundred sixty-four (98.8%) patients required mechanical ventilation prior to surgery. At 17 postoperative days, freedom from the ventilator reached 50%. Of 109 (66.4%) patients requiring prolonged preoperative inotropic support, 59 (54.1%) were liberated from inotropes by postoperative day 1. Surgical morbidity was encountered in four neonates (2.4%): two (1.2%) patients had a postoperative pneumothorax requiring tube thoracostomy, one (0.6%) patient had a recurrent laryngeal nerve injury, and one (0.6%) patient had significant intraoperative bleeding. The 30-day all-cause mortality was 1.8% (n = 3); no deaths occurred intraoperatively. In this retrospective investigation, surgical PDA closure was associated with low 30-day mortality and minimal morbidity and resulted in rapid discontinuation of inotropic support and weaning from mechanical ventilation. Given the safety of this intervention, surgical PDA ligation merits consideration in the management strategy of the preterm neonate with a PDA.

Cardio-Pulmonary Response to Shock.

DTIC Science & Technology

1981-02-01

Maryland 21701 ( Contract No. DANID17-78-C-8026 Harvard Medical School 25 Shattuck St. D Boston, Massachusetts 02115 E L - C T E APR 16 1W84 Approved for...Controlling Offce) IS. SECURITY CLASS. (of this repot) ISa. DECL ASSIFICATION/DOWNGRADING SCHEDULE IS. DISTRIBUTION STATEMENT (of AdU Repoft) Approved...Circulating Negative Inotropes 1. Depressed left ventricular function following pulmonary embolism 2. Thromboxane mediation of cardio-pulmonary effects

Milrinone in advanced heart failure: dose and therapeutic monitor outside intensive care unit.

PubMed

Charisopoulou, Dafni; Leaver, Neil; Banner, Nicholas R

2014-04-01

Advanced chronic heart failure (ACHF) patients often require inotropes before transplantation or ventricular assist device implantation. Milrinone, an inotrope and vasodilator, may accumulate in cardiorenal syndrome with serious adverse effects. We investigated the potential for therapeutic drug monitoring of milrinone levels using High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS). 22 ACHF patients (15 males, 49±9 years) received milrinone 50 µg/kg intravenously (i.v.) during heart catheterization. Milrinone levels were 216±71 ng/ml (within the reported therapeutic range: 100-300 ng/ml), followed by improvements in cardiac index, pulmonary artery and wedge pressures (p < 0.005). 18 ACHF patients (17 males, 50±12 years, 13 had renal dysfunction) received continuous i.v. milrinone (5-26 days) at 0.1-0.2 µg/kg/min, titrated according to plasma milrinone levels. No adverse events occurred. Therapeutic levels were achieved with doses of 0.2±0.06 µg/Kg/min, below those recommended in Summary of Product Characteristics. Milrinone therapy can be noninvasively monitored by HPLC-MS, while avoiding toxicity in ACHF.

Beta-blocker use in decompensated heart failure.

PubMed

Alharethi, Rami; Hershberger, Ray E

2006-06-01

Despite the current advances in treatment, acute decompensated heart failure accounts for more than 1 million hospital admissions annually. Many of the patients hospitalized are already receiving long-term treatment with beta-blockers. For patients who receive full dose beta-blocker therapy and suffer acute decompensated heart failure, clinicians face two key questions: what to do, if anything, with the dosage of beta-blocker and what is the best way to integrate inotropic and beta-blocker therapies for patients who require inotropes. This article discusses these issues and reviews the available literature. Because these topics have received little systematic evaluation, we also present our clinical approaches to these problems.

Systolic blood pressure is superior to other haemodynamic predictors of outcome in community acquired pneumonia.

PubMed

Chalmers, J D; Singanayagam, A; Hill, A T

2008-08-01

Admission blood pressure (BP) assessment is a central component of severity assessment for community acquired pneumonia. The aim of this study was to establish which readily available haemodynamic measure on admission is most useful for predicting severity in patients admitted with community acquired pneumonia. A prospective observational study of patients admitted with community acquired pneumonia was conducted in Edinburgh, UK. The measurements compared were systolic and diastolic BP, mean arterial pressure and pulse pressure. The outcomes of interest were 30 day mortality and the requirement for mechanical ventilation and/or inotropic support. Admission systolic BP < 90 mm Hg, diastolic BP < or = 60 mm Hg, mean arterial pressure < 70 mm Hg and pulse pressure < or = 40 mm Hg were all associated with increased 30 day mortality and the need for mechanical ventilation and/or inotropic support on multivariate logistic regression. The AUC values for each predictor of 30 day mortality were as follows: systolic BP < 90 mm Hg 0.70; diastolic BP < or = 60 mm Hg 0.59; mean arterial pressure < 70 mm Hg 0.64; and pulse pressure < or = 40 mm Hg 0.60. The AUC values for each predictor of need for mechanical ventilation and/or inotropic support were as follows: systolic BP < 90 mm Hg 0.70; diastolic BP < or = 60 mm Hg 0.68; mean arterial pressure < 70 mm Hg 0.69; and pulse pressure < or = 40 mm Hg 0.59. A simplified CRB65 score containing systolic blood pressure < 90 mm Hg alone performed equally well to standard CRB65 score (AUC 0.76 vs 0.74) and to the standard CURB65 score (0.76 vs 0.76) for the prediction of 30 day mortality. The simplified CRB65 score was equivalent for prediction of mechanical ventilation and/or inotropic support to standard CRB65 (0.77 vs 0.77) and to CURB65 (0.77 vs 0.78). Systolic BP is superior to other haemodynamic predictors of 30 day mortality and need for mechanical ventilation and/or inotropic support in community acquired pneumonia. The CURB65 score can be simplified to a modified CRB65 score by omission of the diastolic BP criterion without compromising its accuracy.

Milrinone and thyroid hormone stimulate myocardial membrane Ca2+-ATPase activity and share structural homologies.

PubMed Central

Mylotte, K M; Cody, V; Davis, P J; Davis, F B; Blas, S D; Schoenl, M

1985-01-01

We have recently shown that thyroid hormone in physiological concentrations stimulates sarcolemma-enriched rabbit-myocardial-membrane Ca2+-ATPase in vitro. In this study, milrinone [2-methyl-5-cyano-(3,4'-bipyridin)-6(1H)-one], a cardiac inotropic agent, was thyromimetic in the same system. At clinically achievable concentrations (50-500 nM), milrinone significantly stimulated membrane Ca2+-ATPase in vitro. This action was antagonized by W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], an agent that also blocks thyroid hormone action on the Ca2+-ATPase, at concentrations as low as 5 microM. Progressive additions of milrinone to membranes incubated with a fixed concentration of thyroxine (0.10 nM) or triiodothyronine resulted in a progressive obliteration of the thyroid hormone effect on Ca2+-ATPase. Amrinone [5-amino-(3,4'-bipyridin)-6(1H)-one], the parent bipyridine of milrinone, had no effect on myocardial Ca2+-ATPase activity. X-ray crystallographic analysis of milrinone and amrinone revealed structural homologies between the phenolic ring of thyroxine and the substituted ring of milrinone, whereas amrinone did not share these homologies. The mechanism(s) of the inotropic actions of thyroxine and of milrinone is not clearly understood, but these observations implicate Ca2+-ATPase, a calcium pump-associated enzyme, as one mediator of the effects on the heart of these two compounds. PMID:2933747

Playing with Cardiac “Redox Switches”: The “HNO Way” to Modulate Cardiac Function

PubMed Central

Tocchetti, Carlo G.; Stanley, Brian A.; Murray, Christopher I.; Sivakumaran, Vidhya; Donzelli, Sonia; Mancardi, Daniele; Pagliaro, Pasquale; Gao, Wei Dong; van Eyk, Jennifer; Kass, David A.; Wink, David A.

2011-01-01

Abstract The nitric oxide (NO•) sibling, nitroxyl or nitrosyl hydride (HNO), is emerging as a molecule whose pharmacological properties include providing functional support to failing hearts. HNO also preconditions myocardial tissue, protecting it against ischemia-reperfusion injury while exerting vascular antiproliferative actions. In this review, HNO's peculiar cardiovascular assets are discussed in light of its unique chemistry that distinguish HNO from NO• as well as from reactive oxygen and nitrogen species such as the hydroxyl radical and peroxynitrite. Included here is a discussion of the possible routes of HNO formation in the myocardium and its chemical targets in the heart. HNO has been shown to have positive inotropic/lusitropic effects under normal and congestive heart failure conditions in animal models. The mechanistic intricacies of the beneficial cardiac effects of HNO are examined in cellular models. In contrast to β-receptor/cyclic adenosine monophosphate/protein kinase A-dependent enhancers of myocardial performance, HNO uses its “thiophylic” nature as a vehicle to interact with redox switches such as cysteines, which are located in key components of the cardiac electromechanical machinery ruling myocardial function. Here, we will briefly review new features of HNO's cardiovascular effects that when combined with its positive inotropic/lusitropic action may render HNO donors an attractive addition to the current therapeutic armamentarium for treating patients with acutely decompensated congestive heart failure. Antioxid. Redox Signal. 14, 1687–1698. PMID:21235349

E-1020, a water soluble imidazopyridine, has direct effects on Ca(2+)-dependent force and ATP hydrolysis of canine and bovine cardiac myofilaments.

PubMed

Powers, F M; Palmiter, K A; Solaro, R J

1996-01-01

E-1020 is a cardiotonic agent that acts as a cyclic-AMP phosphodiesterase inhibitor but also may have actions which alter myofilament response to Ca2+. To identify direct actions of E-1020 on cardiac contractile proteins, effects of E-1020 on myofibrillar Ca2+ dependent MgATPase and force generation in chemically skinned fiber bundles were measured. In bovine cardiac myofibrils, E-1020 (100 microM) significantly increased myofilament Ca2+ sensitivity and Ca(2+)-dependent ATPase activity at submaximal pCa values. At pCa 6.75, E-1020 significantly increased ATPase activity in bovine (10-100 microM) and canine (1-100 microM) cardiac myofibrils but had no effect on rat cardiac myofibrils. Moreover, in one population of canine ventricular fiber bundles, E-1020 (0.01-10 microM) significantly increased isometric tension at pCa 6.5 and 6.0, whereas in another population of bundles E-1020 had no effect on tension. In no case was resting (pCa 8.0) or maximal tension (pCa 4.5) increased by E-1020. Measurements of Ca2+ binding to canine ventricular skinned fiber preparations demonstrated that E-1020 does not alter the affinity of myofilament troponin C for Ca2+. We conclude that part of the mechanism by which E-1020 acts as an inotropic agent may involve alterations in the responsiveness of contractile proteins to Ca2+. The lack of effect of E-1020 on some preparations may be dependent on isoform populations of myofilament proteins.

Acute effect of Vagus nerve stimulation parameters on cardiac chronotropic, inotropic, and dromotropic responses

NASA Astrophysics Data System (ADS)

Ojeda, David; Le Rolle, Virginie; Romero-Ugalde, Hector M.; Gallet, Clément; Bonnet, Jean-Luc; Henry, Christine; Bel, Alain; Mabo, Philippe; Carrault, Guy; Hernández, Alfredo I.

2017-11-01

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy and depression, and is considered as a potential therapy for other pathologies, including Heart Failure (HF) or inflammatory diseases. In the case of HF, several experimental studies on animals have shown an improvement in the cardiac function and a reverse remodeling of the cardiac cavity when VNS is applied. However, recent clinical trials have not been able to reproduce the same response in humans. One of the hypothesis to explain this lack of response is related to the way in which stimulation parameters are defined. The combined effect of VNS parameters is still poorly-known, especially in the case of VNS synchronously delivered with cardiac activity. In this paper, we propose a methodology to analyze the acute cardiovascular effects of VNS parameters individually, as well as their interactive effects. A Latin hypercube sampling method was applied to design a uniform experimental plan. Data gathered from this experimental plan was used to produce a Gaussian process regression (GPR) model in order to estimate unobserved VNS sequences. Finally, a Morris screening sensitivity analysis method was applied to each obtained GPR model. Results highlight dominant effects of pulse current, pulse width and number of pulses over frequency and delay and, more importantly, the degree of interactions between these parameters on the most important acute cardiovascular responses. In particular, high interacting effects between current and pulse width were found. Similar sensitivity profiles were observed for chronotropic, dromotropic and inotropic effects. These findings are of primary importance for the future development of closed-loop, personalized neuromodulator technologies.

Protective effects of hydroalcoholic extract from rhizomes of Cynodon dactylon (L.) Pers. on compensated right heart failure in rats.

PubMed

Garjani, Alireza; Afrooziyan, Arash; Nazemiyeh, Hossein; Najafi, Moslem; Kharazmkia, Ali; Maleki-Dizaji, Nasrin

2009-08-05

The rhizomes of Cynodon dactylon are used for the treatment of heart failure in folk medicine. In the present study, we investigated the effects of hydroalcoholic extract of C. dactylon rhizomes on cardiac contractility in normal hearts and on cardiac functions in right-heart failure in rats. Right-heart failure was induced by intraperitoneal injection of monocrotaline (50 mg/kg). Two weeks later, the animals were treated orally with different doses of the extract for fifteen days. At the end of the experiments cardiac functions and markers of myocardial hypertrophy were measured. The treated rats showed very less signs of fatigue, peripheral cyanosis and dyspnea. The survival rate was high in the extract treated groups (90%). Administration of C. dactylon in monocrotaline-injected rats led to profound improvement in cardiac functions as demonstrated by decreased right ventricular end diastolic pressure (RVEDP) and elevated mean arterial pressure. RVdP/dtmax, and RVdP/dt/P as indices of myocardial contractility were also markedly (p < 0.001; using one way ANOVA) increased by the extract. The extract reduced heart and lung congestion by decreasing tissue wet/dry and wet/body weight ratios (p < 0.01). In the isolated rat hearts, the extract produced a remarkable (P < 0.001) positive inotropic effect concomitant with a parallel decrease in LVEDP. The results of this study indicated that C. dactylon exerted a strong protective effect on right heart failure, in part by positive inotropic action and improving cardiac functions.

Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial.

PubMed

Lester, S J; Baggott, M; Welm, S; Schiller, N B; Jones, R T; Foster, E; Mendelson, J

2000-12-19

The psychoactive stimulant 3, 4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," is widely used in nonmedical settings. Little is known about its cardiovascular effects. To evaluate the acute cardiovascular effects of MDMA by using transthoracic two-dimensional and Doppler echocardiography. Four-session, ascending-dose, double-blind, placebo-controlled trial. Urban hospital. Eight healthy adults who self-reported MDMA use. Echocardiographic effects of dobutamine (5, 20, and 40 microg/kg of body weight per minute) were measured in a preliminary session. Oral MDMA (0.5 and 1.5 mg/kg of body weight) or placebo was administered 1 hour before echocardiographic measurements in three weekly sessions. Heart rate and blood pressure were measured at regular intervals before and after MDMA administration. Echocardiographic measures of stroke volume, ejection fraction, cardiac output, and meridional wall stress were obtained 1 hour after MDMA administration and during dobutamine infusions. At a dose of 1.5 mg/kg, MDMA increased mean heart rate (by 28 beats/min), systolic blood pressure (by 25 mm Hg), diastolic blood pressure (by 7 mm Hg), and cardiac output (by 2 L/min). The effects of MDMA were similar to those of dobutamine, 20 and 40 microg/kg per minute. Inotropism, measured by using meridional wall stress corrected for ejection fraction, decreased after administration of dobutamine, 40 microg/kg per minute, but did not change after either dose of MDMA. Modest oral doses of MDMA increase heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to dobutamine, 20 to 40 microg/kg per minute. In contrast to dobutamine, MDMA has no measurable inotropic effects.

Proteomic analysis of the protective effects of aqueous bark extract of Terminalia arjuna (Roxb.) on isoproterenol-induced cardiac hypertrophy in rats.

PubMed

Kumar, Santosh; Jahangir Alam, Md; Prabhakar, Pankaj; Ahmad, Sayeed; Maulik, Subir K; Sharma, Manish; Goswami, Shyamal K

2017-02-23

Aqueous bark extract of Terminalia arjuna (TA) has been in use as an ethnomedicine for cardiovascular ailments in the Indian subcontinent for centuries. Studies using hemodynamic, ROS scavenging and anti-inflammatory parameters in animal models have shown its anti-atherogenic, hypotensive, inotropic, anti-inflammatory effects. However, details analysis on its effects on established molecular and cell biological markers are a prerequisite for its wider acceptance to the medical community. To test the efficacy of TA extract in ameliorating cardiac hypertrophy induced by ISO in rats. Cardiac hypertrophy was induced by ISO (5mg/kg/day s.c. for 14 days) in rats and a standardized aqueous extract of TA stem bark was orally administered by gavage. Total RNA and protein were isolated from control, ISO, ISO plus TA and TA treated rat hearts and analyzed for the transcripts for the markers of hypertrophy, signaling kinases, transcription factors and total protein profile. TA extract reversed the induction of fetal genes like β-myosin heavy chain, skeletal α-actin and brain natriuretic peptide in hypertrophic rat hearts. While ISO slightly increased the level of phospho-ERK, TA repressed it to about one third of the base line level. Survival kinase Akt, ER stress marker Grp78 and epigenetic regulator HDAC5 were augmented by ISO and TA restored them by various extents. ISO administration moderately increased the transcription factor NFκB binding activity, while coadministration of TA further increased it. AP-1 binding activity was largely unchanged by ISO treatment but it was upregulated when administered along with TA. MEF2D binding activity was increased by ISO and TA restored it to the baseline level. Global proteomic analysis revealed that TA treatment restored a subset of proteins up- and down-regulated in the hypertrophied hearts. Amongst those restored by TA were purinergic receptor X, myosin light chain 3, tropomyosin, and kininogen; suggesting a nodal role of TA in modulating cardiac function. This study for the first time reveals that TA partially or completely restores the marker mRNAs, signaling kinases, transcription factors and total protein profile in rat heart, thereby demonstrating its efficacy in preventing ISO-induced cardiac hypertrophy. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Neuromuscular electrical stimulation improves exercise tolerance in patients with advanced heart failure on continuous intravenous inotropic support use-randomized controlled trial.

PubMed

Forestieri, Patrícia; Bolzan, Douglas W; Santos, Vinícius B; Moreira, Rita Simone Lopes; de Almeida, Dirceu Rodrigues; Trimer, Renata; de Souza Brito, Flávio; Borghi-Silva, Audrey; de Camargo Carvalho, Antonio Carlos; Arena, Ross; Gomes, Walter J; Guizilini, Solange

2018-01-01

To evaluate the impact of a short-term neuromuscular electrical stimulation program on exercise tolerance in hospitalized patients with advanced heart failure who have suffered an acute decompensation and are under continuous intravenous inotropic support. A randomized controlled study. Initially, 195 patients hospitalized for decompensated heart failure were recruited, but 70 were randomized. Patients were randomized into two groups: control group subject to the usual care ( n = 35); neuromuscular electrical stimulation group ( n = 35) received daily training sessions to both lower extremities for around two weeks. The baseline 6-minute walk test to determine functional capacity was performed 24 hours after hospital admission, and intravenous inotropic support dose was daily checked in all patients. The outcomes were measured in two weeks or at the discharge if the patients were sent back home earlier than two weeks. After losses of follow-up, a total of 49 patients were included and considered for final analysis (control group, n = 25 and neuromuscular electrical stimulation group, n = 24). The neuromuscular electrical stimulation group presented with a higher 6-minute walk test distance compared to the control group after the study protocol (293 ± 34.78 m vs. 265.8 ± 48.53 m, P < 0.001, respectively). Neuromuscular electrical stimulation group also demonstrated a significantly higher dose reduction of dobutamine compared to control group after the study protocol (2.72 ± 1.72 µg/kg/min vs. 3.86 ± 1.61 µg/kg/min, P = 0.001, respectively). A short-term inpatient neuromuscular electrical stimulation rehabilitation protocol improved exercise tolerance and reduced intravenous inotropic support necessity in patients with advanced heart failure suffering a decompensation episode.

Analysis of the negative inotropic effect of acetylcholine on frog atrial fibres.

PubMed

Nargeot, J; Garnier, D; Rougier, O

1981-03-01

Voltage-clamp experiments have been performed on frog atrial preparations in order to study the mechanism of the inotropic effect of acetylcholine (ACh) at various concentrations. The amplitude of the slow inward current (Is) is reduced even at low ACh concentrations; such low concentrations have little or no effect on potassium permeability. Dose-effect relationships for Is inhibition (Is/Is max) by ACh show a half amplitude dose (K0.5 around 8 X 10(-8) M ACh. The reduction of Is is attributed largely to a decrease of the maximal conductance of the slow channel (gs). Steady-state activation and inactivation parameters are not affected by ACh. Experiments in a Na-free solution (Na replaced by Li ions) or in a Ca-free solution (with EGTA) indicate that the "slow sodium current" is more sensitive to ACh than the "slow Ca current", although these two currents both seem to flow through the slow channel. The decrease of the phasic component of contraction observed in the presence of ACh is very well correlated with the decrease of Is (K0.5 = 8 X 10(-8) M ACh), while the increase of the tonic tension may be related to the outward potassium current induced by high concentrations of ACh. The significant difference between the half amplitude dose (K0.5) observed in the dose effect curves with ACh for Is inhibition (K0.5 = 8 X 10(-8) M) and for ACh-induced extra-current (K0.5 - 10(-6) M) may indicate the presence of two muscarinic receptors.

Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum.

PubMed

Lupia, Enrico; Spatola, Tiziana; Cuccurullo, Alessandra; Bosco, Ornella; Mariano, Filippo; Pucci, Angela; Ramella, Roberta; Alloatti, Giuseppe; Montrucchio, Giuseppe

2010-09-01

Thrombopoietin (TPO) is a humoral growth factor that has been shown to increase platelet activation in response to several agonists. Patients with sepsis have increased circulating TPO levels, which may enhance platelet activation, potentially participating to the pathogenesis of multi-organ failure. Aim of this study was to investigate whether TPO affects myocardial contractility and participates to depress cardiac function during sepsis. We showed the expression of the TPO receptor c-Mpl on myocardial cells and tissue by RT-PCR, immunofluorescence and western blotting. We then evaluated the effect of TPO on the contractile function of rat papillary muscle and isolated heart. TPO did not change myocardial contractility in basal conditions, but, when followed by epinephrine (EPI) stimulation, it blunted the enhancement of contractile force induced by EPI both in papillary muscle and isolated heart. An inhibitor of TPO prevented TPO effect on cardiac inotropy. Treatment of papillary muscle with pharmacological inhibitors of phosphatidylinositol 3-kinase, NO synthase, and guanilyl cyclase abolished TPO effect, indicating NO as the final mediator. We finally studied the role of TPO in the negative inotropic effect exerted by human septic shock (HSS) serum and TPO cooperation with TNF-alpha and IL-1beta. Pre-treatment with the TPO inhibitor prevented the decrease in contractile force induced by HSS serum. Moreover, TPO significantly amplified the negative inotropic effect induced by TNF-alpha and IL-1beta in papillary muscle. In conclusion, TPO negatively modulates cardiac inotropy in vitro and contributes to the myocardial depressing activity of septic shock serum.

Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site

NASA Astrophysics Data System (ADS)

Fossa, Paola; Boggia, Raffaella; Mosti, Luisa

1998-07-01

Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes; five major PDE families or classes with distinctive properties have been identified. Among these a great deal of interest has recently been focused on the so called cGMP-inhibited low Km cAMP phosphodiesterase (cGI PDE) or PDE III. A number of positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective inhibitors. This paper presents the results of this theoretical approach.

Gastric exocrine “failure” in critically ill patients: incidence and associated features

PubMed Central

Stannard, V A; Hutchinson, A; Morris, D L; Byrne, A

1988-01-01

Following the observation that many critically ill patients cannot maintain their gastric juice pH below 4 without treatment a study was performed to measure the gastric juice pH in such patients and relate it to other clinical data. The case notes of 64 patients who had been admitted to the intensive care unit and taken part in two trials of ranitidine treatment were reviewed. During those trials gastric juice was aspirated hourly and the pH and volume measured. In this study the values recorded during a six hour untreated control phase were used. Data on age, diagnosis, treatment, outcome, episodes of hypoxia, episodes of hypotension, and use of inotropic drugs were also reviewed. Full data were available for 61 patients: 27 had a mean baseline pH of >5 during the control phase and 34 a mean baseline pH of <5. Significantly more of those with a high pH suffered hypotension (21/27 v 13/34) and received inotropic drugs (16/27 v 8/34). These findings suggest that hypotension in critically ill patients adversely affects gastric exocrine function; prophylaxis with drugs that can improve gastric mucosal blood flow may be more effective than with antacids. PMID:3122979

The effect of preoperative nutritional status on postoperative outcomes in children undergoing surgery for congenital heart defects in San Francisco (UCSF) and Guatemala City (UNICAR).

PubMed

Radman, Monique; Mack, Ricardo; Barnoya, Joaquin; Castañeda, Aldo; Rosales, Monica; Azakie, Anthony; Mehta, Nilesh; Keller, Roberta; Datar, Sanjeev; Oishi, Peter; Fineman, Jeffrey

2014-01-01

The objective of this study was to determine the association between preoperative nutritional status and postoperative outcomes in children undergoing surgery for congenital heart defects (CHD). Seventy-one patients with CHD were enrolled in a prospective, 2-center cohort study. We adjusted for baseline risk differences using a standardized risk adjustment score for surgery for CHD. We assigned a World Health Organization z score for each subject's preoperative triceps skin-fold measurement, an assessment of total body fat mass. We obtained preoperative plasma concentrations of markers of nutritional status (prealbumin, albumin) and myocardial stress (B-type natriuretic peptide [BNP]). Associations between indices of preoperative nutritional status and clinical outcomes were sought. Subjects had a median (interquartile range [IQR]) age of 10.2 (33) months. In the University of California at San Francisco (UCSF) cohort, duration of mechanical ventilation (median, 19 hours; IQR, 29 hours), length of intensive care unit stay (median, 5 days; IQR 5 days), duration of any continuous inotropic infusion (median, 66 hours; IQR 72 hours), and preoperative BNP levels (median, 30 pg/mL; IQR, 75 pg/mL) were associated with a lower preoperative triceps skin-fold z score (P < .05). Longer duration of any continuous inotropic infusion and higher preoperative BNP levels were also associated with lower preoperative prealbumin (12.1 ± 0.5 mg/dL) and albumin (3.2 ± 0.1; P < .05) levels. Lower total body fat mass and acute and chronic malnourishment are associated with worse clinical outcomes in children undergoing surgery for CHD at UCSF, a resource-abundant institution. There is an inverse correlation between total body fat mass and BNP levels. Duration of inotropic support and BNP increase concomitantly as measures of nutritional status decrease, supporting the hypothesis that malnourishment is associated with decreased myocardial function. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Computational analysis of the regulation of Ca2+ dynamics in rat ventricular myocytes

NASA Astrophysics Data System (ADS)

Bugenhagen, Scott M.; Beard, Daniel A.

2015-10-01

Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca2+ signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca2+ dynamics under physiologically relevant conditions. Ca2+ signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca2+ dynamics via β-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca2+ signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca2+ dynamics are not currently well understood. In order to better understand Ca2+ dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include β-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) β-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass

PubMed Central

Levin, Ricardo; Degrange, Marcela; Del Mazo, Carlos; Tanus, Eduardo; Porcile, Rafael

2012-01-01

BACKGROUND: The calcium sensitizer levosimendan has been used in cardiac surgery for the treatment of postoperative low cardiac output syndrome (LCOS) and difficult weaning from cardiopulmonary bypass (CPB). OBJECTIVES: To evaluate the effects of preoperative treatment with levosimendan on 30-day mortality, the risk of developing LCOS and the requirement for inotropes, vasopressors and intra-aortic balloon pumps in patients with severe left ventricular dysfunction. METHODS: Patient with severe left ventricular dysfunction and an ejection fraction <25% undergoing coronary artery bypass grafting with CPB were admitted 24 h before surgery and were randomly assigned to receive levosimendan (loading dose 10 μg/kg followed by a 23 h continuous infusion of 0.1μg/kg/min) or a placebo. RESULTS: From December 1, 2002 to June 1, 2008, a total of 252 patients were enrolled (127 in the levosimendan group and 125 in the control group). Individuals treated with levosimendan exhibited a lower incidence of complicated weaning from CPB (2.4% versus 9.6%; P<0.05), decreased mortality (3.9% versus 12.8%; P<0.05) and a lower incidence of LCOS (7.1% versus 20.8%; P<0.05) compared with the control group. The levosimendan group also had a lower requirement for inotropes (7.9% versus 58.4%; P<0.05), vasopressors (14.2% versus 45.6%; P<0.05) and intra-aortic balloon pumps (6.3% versus 30.4%; P<0.05). CONCLUSION: Patients with severe left ventricle dysfunction (ejection fraction <25%) undergoing coronary artery bypass grafting with CPB who were pretreated with levosimendan exhibited lower mortality, a decreased risk for developing LCOS and a reduced requirement for inotropes, vasopressors and intra-aortic balloon pumps. Studies with a larger number of patients are required to confirm whether these findings represent a new strategy to reduce the operative risk in this high-risk patient population. PMID:23620700

Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes.

PubMed

Müller, A; Linke, W; Klaus, W

1999-05-01

Crataegus extract is used in cardiology for the treatment of mild to moderate heart failure (NYHA II) in Germany. However, little is known about the electrophysiological actions of Crataegus extract in the heart. Recently, it was shown that Crataegus extract prolongs the refractory period in isolated perfused hearts and increases action potential duration in guinea pig papillary muscle. It was the aim of this study to find out the mechanism of the increase in action potential duration caused by Crataegus extract. Using the patch-clamp technique, we measured the effects of Crataegus extract (10 mg/l; flavonoid content: 2.25%, total procyanidin content: 11.3 +/- 0.4%) on the inward rectifier and the delayed rectifier potassium current in isolated guinea pig ventricular myocytes. To get some insight into the mechanism underlying the positive inotropic effect of Crataegus extract, we also looked for effects on the L-type calcium current. Crataegus extract slightly blocked both the delayed and the inward rectifier potassium current. The inhibition amounted to 25% and about 15%, respectively. This amount of inhibition of these repolarising currents is sufficient to explain the prolongation of action potential duration caused by Crataegus extract. To our surprise we could not detect any influence of Crataegus extract on the L-type calcium current. In summary, our results show that Crataegus extract blocks repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrhythmic effects described for Crataegus extract. Our measurements of the L-type calcium current indicate that Crataegus extract's positive inotropic effect is not caused by phosphodiesterase inhibition or a beta-sympathomimetic effect.

Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

PubMed

Šíma, M; Pokorná, P; Hronová, K; Slanař, O

2015-01-01

Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

Protective effects of hydroalcoholic extract from rhizomes of Cynodon dactylon (L.) Pers. on compensated right heart failure in rats

PubMed Central

Garjani, Alireza; Afrooziyan, Arash; Nazemiyeh, Hossein; Najafi, Moslem; Kharazmkia, Ali; Maleki-Dizaji, Nasrin

2009-01-01

Background The rhizomes of Cynodon dactylon are used for the treatment of heart failure in folk medicine. In the present study, we investigated the effects of hydroalcoholic extract of C. dactylon rhizomes on cardiac contractility in normal hearts and on cardiac functions in right-heart failure in rats. Methods Right-heart failure was induced by intraperitoneal injection of monocrotaline (50 mg/kg). Two weeks later, the animals were treated orally with different doses of the extract for fifteen days. At the end of the experiments cardiac functions and markers of myocardial hypertrophy were measured. Results The treated rats showed very less signs of fatigue, peripheral cyanosis and dyspnea. The survival rate was high in the extract treated groups (90%). Administration of C. dactylon in monocrotaline-injected rats led to profound improvement in cardiac functions as demonstrated by decreased right ventricular end diastolic pressure (RVEDP) and elevated mean arterial pressure. RVdP/dtmax, and RVdP/dt/P as indices of myocardial contractility were also markedly (p < 0.001; using one way ANOVA) increased by the extract. The extract reduced heart and lung congestion by decreasing tissue wet/dry and wet/body weight ratios (p < 0.01). In the isolated rat hearts, the extract produced a remarkable (P < 0.001) positive inotropic effect concomitant with a parallel decrease in LVEDP. Conclusion The results of this study indicated that C. dactylon exerted a strong protective effect on right heart failure, in part by positive inotropic action and improving cardiac functions. PMID:19653918

β-Adrenergic Inhibition Prevents Action Potential and Calcium Handling Changes during Regional Myocardial Ischemia

PubMed Central

Murphy, Shannon R.; Wang, Lianguo; Wang, Zhen; Domondon, Philip; Lang, Di; Habecker, Beth A.; Myles, Rachel C.; Ripplinger, Crystal M.

2017-01-01

β-adrenergic receptor (β-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of β-AR blockers on ventricular electrophysiology and intracellular Ca2+ handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca2+ (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts (n = 19). The impact of β-AR inhibition on isolated hearts was assessed by pre-treatment with 100 nM propranolol (Prop) prior to ischemia (n = 7). To control for chronotropy and inotropy, hearts were continuously paced at 3.3 Hz and contraction was inhibited with 20 μM blebbistatin. Untreated ischemic hearts displayed prototypical shortening of action potential duration (APD80) in the ischemic zone (IZ) compared to the non-ischemic zone (NI) at 10 and 15 min ischemia, whereas APD shortening was prevented with Prop. Untreated ischemic hearts also displayed significant changes in SR Ca2+ handling in the IZ, including prolongation of SR Ca2+ reuptake and SR Ca2+ alternans, which were prevented with Prop pre-treatment. At 5 min ischemia, Prop pre-treated hearts also showed larger SR Ca2+ release amplitude in the IZ compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, β-AR inhibition has a favorable effect during acute regional ischemia via direct effects on APD and Ca2+ handling. PMID:28894423

Hydroalcoholic extract from Nerium oleander L. (Apocynaceae) elicits arrhythmogenic activity.

PubMed

Botelho, Ana Flávia Machado; Santos-Miranda, Artur; Joca, Humberto Cavalcante; Mattoso, Cláudio Roberto Scabelo; de Oliveira, Maira Souza; Pierezan, Felipe; Cruz, Jader Santos; Soto-Blanco, Benito; Melo, Marília Martins

2017-07-12

Nerium oleander L. (OLE) has been used medicinally and is reported to possess a wide range of pharmacological activities. OLE effects are caused by different cardiac glycosides (CG), primarily oleandrin, found within the plant. CG can potentially impair sodium-potassium ATPase (NKA) pump activity and cause positive inotropic effects on the heart. The aim of this study was to investigate the potential arrhythmogenic effects of hydroalcoholic extracts from N. oleander (OLE). OLE hydroalcoholic extracts were obtained from N. oleander leaves and analyzed by HPLC. In vivo experiments with guinea pigs consisted if oral administration of water, 150mg/kg and 300mg/kg OLE extract. Clinical signs and ECG analysis were evaluated. Sample tissues from the heart were processed for histopathological and ultra-structural analysis. Autonomic effects were assessed through pharmacological blockade and ECG monitoring. In vitro experiments were conducted with isolated ventricular myocytes from adult mice. The effects of OLE extract on cardiac excitability, Na + /K + pump current and global Ca 2+ transients were evaluated. Our results demonstrated that OLE hydroalcoholic extract elicited severe cardiac arrhythmias that can lead to death with minimal tissue damage. In vitro experiments suggest that OLE causes electromechanical disturbances in the heart due to inhibition of Na + /K + pump, mitochondrial swelling, and modulation of the sarco(endo)plasmic Ca 2+ ATPase without interfering with the autonomic nervous system. Thus, arrhythmias and electrical conduction disturbances promoted by OLE are mainly associated with impaired cardiomyocyte dysfunction, rather than anatomical tissue remodeling and/or autonomic modulation. Our data revealed the potential cardiotoxicity and positive inotropic effect of OLE and its important role in modulation of electrophysiology in cardiomyocytes. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Secondary Increase of Lactate Levels in Asphyxiated Newborns during Hypothermia Treatment: Reflect of Suboptimal Hemodynamics (A Case Series and Review of the Literature)

PubMed Central

Al Balushi, Asim; Guilbault, Marie-Pier; Wintermark, Pia

2015-01-01

Objective To evaluate whether a secondary increase of serum lactate levels in asphyxiated newborns during hypothermia treatment may reflect suboptimal dynamics. Methods–Retrospective case series and review of the literature. We present the clinical course of four asphyxiated newborns treated with hypothermia who presented with hypotension requiring inotropic support, and who displayed a secondary increase of serum lactate levels during hypothermia treatment. Serial serum lactate levels are correlated with blood pressure and inotropic support within the first 96 hours of life. Results Lactate levels initially decreased in the four patients. However, each of them started to present lower blood pressure, and lactate levels started to increase again. Inotropic support was started to raise blood pressure. The introduction of an epinephrine drip consistently worsened the increase of lactate levels in these newborns, whereas dopamine and dobutamine enabled the clearance of lactate in addition to raising the blood pressure. Rewarming was associated with hemodynamics perturbations (a decrease of blood pressure and/or an increase of lactate levels) in the three newborns who survived. Conclusions Lactate levels during the first 4 days of life should be followed as a potential marker for suboptimal hemodynamic status in term asphyxiated newborns treated with hypothermia, for whom the maintenance of homeostasis during hypothermia treatment is of utmost importance to alleviate brain injury. PMID:26929870

Right ventricular contractile reserve in mitral stenosis: implications on hemodynamic burden and clinical outcome.

PubMed

Sade, Leyla Elif; Ozin, Bülent; Ulus, Taner; Açikel, Sadik; Pirat, Bahar; Bilgi, Muhammed; Uluçam, Melek; Müderrisoğlu, Haldun

2009-06-26

We investigated whether isovolumic acceleration (IVA) under inotropic stimulation as a means of right ventricular (RV) contractile reserve, is a surrogate for hemodynamic burden and has prognostic value in patients with mitral stenosis (MS). Thirty-one pure MS patients and 20 controls underwent cardiac catheterization, exercise test, and dobutamine stress echocardiography. RV fractional area change (FAC), +dP/dt/P(max), RV tissue Doppler indices (isovolumic contraction [IVC] and systolic [S] velocity, and IVA) were measured. Patients were followed-up for the occurrence of cardiac adverse events. Inotropic modulation unmasked statistically significant differences regarding magnitude of changes in IVA, IVC, S, and +dP/dt/P(max), but not RV FAC. Inability to increase IVA more than 6.5 m/s(2) was the only independent determinant of pulmonary capillary wedge pressure >or=18 mm Hg (P=.004). Although MS severity did not predict the RV contractile reserve and pulmonary artery pressure (PAP) behavior during inotropic stimulation, the RV contractile reserve was related to the degree of systolic PAP. IVA increases of <3.4 m/s(2) had 86% sensitivity and 75% specificity to predict unfavorable outcomes during long-term follow-up (20+/-8 months). RV contractile reserve provides complementary data to the hemodynamic significance of MS severity, may contribute to clinical decision making, and be of prognostic value in these patients.

Prenatal Exposure to Angiotensin II Receptor Blockers and Hemodynamic Effects on the Newborn.

PubMed

Rodríguez-Castaño, MaJosé; Corredera, Araceli; Aleo, Esther; Arruza, Luis

2015-04-01

Angiotensin II receptor blockers (ARBs) are potent antihypertensive agents that block the renin angiotensin aldosterone system (RAS). Their use in pregnancy may cause malformations, oligoanuria, hypotension, and death. Hypotension is observed up to 15% of cases and is described as refractory to volume and inotropic support, although its pathophysiology is unknown. We present a case of prenatal exposure to ARBs in order to characterize the hemodynamic compromise in the newborn, help in decision-making, and guide the therapeutic approach to these patients.

Bioenergetics in the pathogenesis, progression and treatment of cardiovascular disorders.

PubMed

Tanner, H A

1995-05-01

The aim of this manuscript is to review perturbations in bioenergetics that are redundant denominators in the diversity of factors mediating the pathogenesis and progression of coronary heart disease (CHD), congestive heart failure (CHF), hypertension and arrhythmias. This paper likewise assesses the pharmacodynamics of widely prescribed drugs that enhance cellular respiration, maintain positive inotropic, chronotropic, dromotropic cardiac effects, sustain myocardial biosynthesis, reverse the morbidity of heart disease, and assure low levels of toxicity commensurate with the agent's biocompatability. Conversely, it is essential to delineate the modality of xenobiotic drugs that inhibit energy transformations, enhance the pathogenesis of CHD, worsen survival in CHF, provoke arrhythmogenic effects, and induce serious side-effects. Documented evidence, derived from biochemical, physiological and pharmacological data sources, consistently links inhibited mitochondrial decarboxylation to aberrations in cholesterol metabolism, biosynthesis, and calcium balance. Underutilized citrates evolved from inhibited decarboxylation are degraded to acetyl CoA. The acetate is the source of steroid synthesis; its carbon atoms form the molecular basis for all endogenous cholesterol. Myocardial anoxia, a consequence of the atheromatous plaque, inhibits ATP production, impairs biosynthesis, induces negative cardiac inotropic and chronotropic effects, and enhances the pathogenesis of CHF. Inhibited decarboxylation is likewise a factor in the mobilization of in situ cardiac Ca2+, resulting in arrhythmias provoked by the cation's deficiency. The restoration of calcium homeostasis decreases peripheral vasotension, reducing hypertension. Parameters drawn from endocrinopathies and the new physiological dimension of microgravity are developed to illustrate the detrimental effect of inhibited bioenergetics on cardiac pathomorphism and cardiovascular dysfunction. In conclusion, anabolic agents, adjunctive to a productive life-style, can provide the rational basis for the prevention and treatment of cardiac diseases. Failure to understand mechanisms generating cardiovascular morbidity eventuates in ineffective and empirical treatment.

Electrophysiological effects of FK664, a new cardiotonic agent, on preparations from guinea pig ventricle and from rabbit sino-atrial node.

PubMed

Kodama, I; Anno, T; Sudo, Y; Satake, N; Shibata, S

1989-05-01

Effects of the cardiotonic agent FK664, 6-(3, 4-dimethoxy-phenyl)-1-ethyl-4-mesitylimino-3-methyl-3,4-dihydro-2 (1H)-pyrimidone, on isolated guinea pig ventricular muscles and rabbit sinus node pacemaker cells were studied using micro-electrode techniques. In ventricular muscles driven at 0.5-1.0 Hz, FK664 above 3 mumol.litre-1 caused an increase in contractile force and a shortening of time to peak tension. This positive inotropic effect of FK664 was accompanied by a slight elevation of the early plateau phase of the action potential, while other action potential variables were unaffected. The change in contractile force induced by FK664 was abolished in a low Ca2+ medium (0.12 mmol.litre-1) or by treatment with ryanodine (2 mumol.litre-1), whereas it was relatively well preserved in the preparations pretreated with nefedipine (1 mumol.litre-1). The slow action potentials induced by isoprenaline (0.3 mumol.litre-1) in high K+ medium (30 mmol.litre-1) and the slow inward current measured by single sucrose gap voltage clamp at a holding potential of -40 mV were unaffected by FK664. In sinus node pacemaker cells, FK664 (1-10 mumol.litre-1) caused a dose dependent acceleration of phase 4 depolarisation and a shortening of spontaneous firing cycle length. This positive chronotropic effect of FK664 was markedly inhibited in a low Ca2+ medium (0.3 mmol.litre-1). These findings suggest that FK664 has positive inotropic and chronotropic effects on the heart, due to an enhancement of transsarcolemmal calcium influx through the low threshold, dihydropyridine insensitive Ca2+ channel population.

Experience using high-dose glucose-insulin-potassium (GIK) in critically ill patients.

PubMed

Slob, Elise M A; Shulman, Rob; Singer, Mervyn

2017-10-01

To audit the use of GIK in terms of safety, haemodynamic effects, and impact on catecholamine dosage. A retrospective, descriptive, evaluative audit of GIK use within the adult ICU of a London teaching hospital was conducted. Rescue therapy of GIK (up to 1.0Unitsinsulin/kg/h) was administered to improve cardiac function. Outcomes were ICU survival, change in cardiac index (CI) and blood lactate levels, events of hypoglycaemia, hyperglycaemia, hypokalaemia and hyperkalaemia, and discontinuation time of catecholamine inotropes. Of 85 patients treated with GIK, 13 (15.3%) survived their ICU stay and 9 (10.5%) were discharged home. In patients surviving until 72h, a trend of improved CI and lactate levels was seen, often with reductions in catecholamine dosing. Inotropes were discontinued in 35 (54%) patients. Severe hypoglycaemia (<2mmol/l), hyperglycaemia (>20mmol/l), hypokalaemia (<2.5mmol/l) and hyperkalaemia (>7mmol/l) during GIK affected 1, 6, 8 and 1 patients, respectively. These abnormalities were quickly identified. No measurable harm was noted. High-dose GIK can be safely used in critically ill patients, though blood glucose and potassium levels must be monitored frequently. GIK was associated with improved CI and blood lactate levels. Impact on survival requires prospective evaluation. Copyright © 2017. Published by Elsevier Inc.

Levosimendan neither improves nor worsens mortality in patients with cardiogenic shock due to ST-elevation myocardial infarction

PubMed Central

Omerovic, Elmir; Råmunddal, Truls; Albertsson, Per; Holmberg, Mikael; Hallgren, Per; Boren, Jan; Grip, Lars; Matejka, Göran

2010-01-01

Background: The aim of this study was to evaluate the effect of levosimendan on mortality in cardiogenic shock (CS) after ST elevation myocardial infarction (STEMI). Methods and results: Data were obtained prospectively from the SCAAR (Swedish Coronary Angiography and Angioplasty Register) and the RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) about 94 consecutive patients with CS due to STEMI. Patients were classified into levosimendan-mandatory and levosimendan-contraindicated cohorts. Inotropic support with levosimendan was mandatory in all patients between January 2004 and December 2005 (n = 46). After the SURVIVE and REVIVE II studies were presented, levosimendan was considered contraindicated and was not used in consecutive patients between December 2005 and December 2006 (n = 48). The cohorts were similar with respect to pre-treatment characteristics and concomitant medications. There was no difference in the incidence of new-onset atrial fibrillation, in-hospital cardiac arrest and length of stay at the coronary care unit. There was no difference in adjusted mortality at 30 days and at one year. Conclusion: The use of levosimendan neither improves nor worsens mortality in patients with CS due to STEMI. Well-designed randomized clinical trials are needed to define the role of inotropic therapy in the treatment of CS. PMID:20859537

Mammalian tissue extracts used to treat cardiovascular disease as exemplified by Recosen.

PubMed

Fitzgerald, Desmond

2016-01-01

This paper reviews the cardiovascular effects of an aqueous extract of animal heart, which was in clinical development in the early 1950s. The aqueous extract reversed the negative inotropic effects of hypoxia in the frog heart preparation. In extensive observational clinical trials between 1950 and 1975, beneficial effects were reported on reducing cardiac arrhythmias, improving effort in angina pectoris, as well as improving heart failure. The majority of clinical publications came from Germany, Switzerland and Austria. Jackson and Temple identified tyramine as the main constituent in the aqueous extract. While the hemodynamic effects of tyramine in humans are well characterized, the relationship to its clinical efficacy remains speculative.

A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design.

PubMed

Zangrillo, Alberto; Alvaro, Gabriele; Pisano, Antonio; Guarracino, Fabio; Lobreglio, Rosetta; Bradic, Nikola; Lembo, Rosalba; Gianni, Stefano; Calabrò, Maria Grazia; Likhvantsev, Valery; Grigoryev, Evgeny; Buscaglia, Giuseppe; Pala, Giovanni; Auci, Elisabetta; Amantea, Bruno; Monaco, Fabrizio; De Vuono, Giovanni; Corcione, Antonio; Galdieri, Nicola; Cariello, Claudia; Bove, Tiziana; Fominskiy, Evgeny; Auriemma, Stefano; Baiocchi, Massimo; Bianchi, Alessandro; Frontini, Mario; Paternoster, Gianluca; Sangalli, Fabio; Wang, Chew-Yin; Zucchetti, Maria Chiara; Biondi-Zoccai, Giuseppe; Gemma, Marco; Lipinski, Michael J; Lomivorotov, Vladimir V; Landoni, Giovanni

2016-07-01

Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. Double-blind, placebo-controlled, multicenter randomized trial. Tertiary care hospitals. Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours. The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Hypotensive, vasorelaxant and cardiodepressant activities of the ethanol extract of Sideritis raeseri spp. raeseri Boiss & Heldr.

PubMed

Kitic, D; Brankovic, S; Radenkovic, M; Savikin, K; Zdunic, G; Kocic, B; Velickovic-Radovanovic, R

2012-10-01

Sideritis raeseri spp. raeseri Boiss & Heldr is a native plant from the Mediterranean region that is used due to its medicinal and culinary properties. The aim of this study was to evaluate the effects of ethanol extract of S. raeseri on the blood pressure, vascular and cardiac contractions. Arterial blood pressure was registered directly from the carotid artery in the anaesthetized rabbits. Aortic rings and the spontaneously beating atria were mounted in tissue bath. An intravenous injection of extract of S. raeseri (0.025-7.5 mg/kg) caused a dose dependent decrease of the arterial pressure and heart rate, with EC(50) value of 24.31±3.87 mg/kg and 88.14±7.51 mg/kg, respectively. In aortic preparations precontracted with KCl (80 mM), the extract of S. raeseri (0.005-1.5 mg/ml) elicited a vasodilatator action (EC(50) 0.11±0.008 mg/ml). In spontaneously beating rat atria, the extract of S. raeseri (0.005-1.5 mg/ml) produced decrease of chronotropic and inotropic activity (with EC(50) value of 0.63±0.03 mg/ml and 0.40±0.08 mg/ml). Administration of verapamil induced inhibition of force and rate of the atrial contraction. These results demonstrate that the ethanol extract of Sideritis raeseri spp. raeseri Boiss & Heldr can produce hypotension, vasodilatation, negative chronotropic and inotropic effects.

Asymmetry in the control of cardiac performance by dorsomedial hypothalamus.

PubMed

Xavier, Carlos Henrique; Beig, Mirza Irfan; Ianzer, Danielle; Fontes, Marco Antônio Peliky; Nalivaiko, Eugene

2013-04-15

Dorsomedial hypothalamus (DMH) plays a key role in integrating cardiovascular responses to stress. We have recently reported greater heart rate responses following disinhibition of the right side of the DMH (R-DMH) in anesthetized rats and greater suppression of stress-induced tachycardia following inhibition of the R-DMH in conscious rats [both compared with similar intervention in the left DMH (L-DMH)], suggesting existence of right/left side asymmetry in controlling cardiac chronotropic responses by the DMH. The aim of the present study was to determine whether similar asymmetry is present for controlling cardiac contractility. In anesthetized rats, microinjections of the GABAA antagonist bicuculline methiodide (BMI; 40 pmol/100 nl) into the DMH-evoked increases in heart rate (HR), left ventricular pressure (LVP), myocardial contractility (LVdP/dt), arterial pressure, and respiratory rate. DMH disinhibition also precipitated multiple ventricular and supraventricular ectopic beats. DMH-induced increases in HR, LVP, LVdP/dt, and in the number of ectopic beats dependent on the side of stimulation, with R-DMH provoking larger responses. In contrast, pressor and respiratory responses did not depend on the side of stimulation. Newly described DMH-induced inotropic responses were rate-, preload- and (largely) afterload-independent; they were mediated by sympathetic cardiac pathway, as revealed by their sensitivity to β-adrenergic blockade. We conclude that recruitment of DMH neurons causes sympathetically mediated positive chronotropic and inotropic effects, and that there is an asymmetry, at the level of the DMH, in the potency to elicit these effects, with R-DMH > L-DMH.

Na(+)/Ca(2+) exchanger inhibition exerts a positive inotropic effect in the rat heart, but fails to influence the contractility of the rabbit heart.

PubMed

Farkas, A S; Acsai, K; Nagy, N; Tóth, A; Fülöp, F; Seprényi, G; Birinyi, P; Nánási, P P; Forster, T; Csanády, M; Papp, J G; Varró, A; Farkas, A

2008-05-01

The Na(+)/Ca(2+) exchanger (NCX) may play a key role in myocardial contractility. The operation of the NCX is affected by the action potential (AP) configuration and the intracellular Na(+) concentration. This study examined the effect of selective NCX inhibition by 0.1, 0.3 and 1.0 microM SEA0400 on the myocardial contractility in the setting of different AP configurations and different intracellular Na(+) concentrations in rabbit and rat hearts. The concentration-dependent effects of SEA0400 on I(Na/Ca) were studied in rat and rabbit ventricular cardiomyocytes using a patch clamp technique. Starling curves were constructed for isolated, Langendorff-perfused rat and rabbit hearts. The cardiac sarcolemmal NCX protein densities of both species were compared by immunohistochemistry. SEA0400 inhibited I(Na/Ca) with similar efficacy in the two species; there was no difference between the inhibitions of the forward or reverse mode of the NCX in either species. SEA0400 increased the systolic and the developed pressure in the rat heart in a concentration-dependent manner, for example, 1.0 microM SEA0400 increased the maximum systolic pressures by 12% relative to the control, whereas it failed to alter the contractility in the rabbit heart. No interspecies difference was found in the cardiac sarcolemmal NCX protein densities. NCX inhibition exerted a positive inotropic effect in the rat heart, but it did not influence the contractility of the rabbit heart. This implies that the AP configuration and the intracellular Na(+) concentration may play an important role in the contractility response to NCX inhibition.

Milrinone and levosimendan during porcine myocardial ischemia -- no effects on calcium overload and metabolism.

PubMed

Axelsson, B; Johansson, G; Abrahamsson, P; Gupta, A; Tydén, H; Wouters, P; Haney, M

2013-07-01

Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia. Anaesthetised juvenile pigs, average weight 36 kg, were randomised to one of three intravenous treatment groups: milrinone 50 μg/kg bolus plus infusion 0.5 μg/kg/min (n = 7), levosimendan 24 μg/kg plus infusion 0.2 μg/kg/min (n = 7), or placebo (n = 6) for 60 min prior to and during a 45 min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. (45) Ca(2+) was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for (45) Ca(2+) recovery. During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable. These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium. © 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

The central action of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on cardiac inotropy and vascular resistance in the anaesthetized cat

PubMed Central

Ramage, Andrew G; de Burgh Daly, M

1998-01-01

Experiments were carried out to determine the effects of the application of the selective 5-HT2 receptor agonist DOI intravenously (in the presence of the peripherally acting 5-HT2 receptor antagonist, BW501C67, 1 mg kg−1, i.v.) or to the `glycine sensitive area' of the ventral surface (30 μg each side) on the left ventricular inotropic (left ventricular dP/dt max) and vascularly isolated hindlimb responses in anaesthetized cats. For the ventral surface experiments, NMDA (10 μg each side) was applied to act as a positive control. In all experiments heart rate and mean arterial blood pressure were held constant to exclude any secondary effects caused by changes in these variables.DOI (n=6) i.v or on the ventral surface had no effect on left ventricular dP/dt max but caused a significant increase in hindlimb perfusion pressure of 40±9 and 50±14 mmHg, respectively. Respiration was unaffected. NMDA (n=6), applied to the ventral surface, caused significant increases in both left ventricular dP/dt max and hindlimb perfusion pressure of 1950±349 mmHg s−1 and 69±17 mmHg respectively, with no associated change in left ventricular end-diastolic pressure. The amplitude of respiratory movements increased.It is concluded that activation of 5-HT2 receptors at the level of the rostral ventrolateral medulla (RVLM) excites sympathetic premotor neurons and/or their antecedents controlling hindlimb vascular resistance but not those controlling the inotropic effects on the left ventricle. PMID:9863644

Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes.

PubMed

Pöpping, S; Rose, H; Ionescu, I; Fischer, Y; Kammermeier, H

1995-11-01

The hawthorn extract LI 132 (crataegus), prepared from leaves and flowers, and standardised to 2.2% flavonoids, was investigated with respect to its effect on (1) the contraction, (2) the energy-turnover and (3) the apparent refractory period (t(ref)) of isolated cardiac myocytes from adult rats. (1) The contractile behaviour of attached myocytes was analyzed by an image processing system. (2) The energy turnover was calculated from the decrease in oxygen content in the myocyte suspension, brought about by cellular respiration. It was differentiated between energy turnover related to cell shortening and that required for ionic transport processes by application of the contraction-inhibiting agent 2,3-butanedione monoxime. (3) The apparent refractory period (t(ref)) was evaluated by pacing the myocytes with increasing stimulation rates and determining the frequency at which failure of single contractions occurred. For these purposes, the myocytes were incubated in a stimulation chamber, which is part of a computer-assisted system allowing to simultaneously evaluate the mechanics and energetics of electrically induced contraction. Within a range of 30-180 microg/ml, the hawthorn extract exhibited a positive inotropic effect on the contraction amplitude accompanied by a moderate increase of energy turnover both for mechanical and ionic processes. In comparison with other positive inotropic interventions, such as application of the beta-adrenergic agonist isoprenaline, or of the cardiac glycoside ouabain (g-strophantin), or elevation of the extracellular Ca++-concentration, the effects of the hawthorn extract were significantly more economical with respect to the energetics of the myocytes. Furthermore the extract prolonged the apparent refractory period in the presence and the absence of isoprenaline, which be indicative for an antiarrhythmic potential.

Cortisol intermediates and hydrocortisone responsiveness in critical neonatal disease.

PubMed

Khashana, Abdelmoneim; Saarela, Timo; Ramet, Mika; Hallman, Mikko

2017-07-01

Therapy-resistant hypotension complicates diseases in neonates. Our objective was to investigate whether lack of therapeutic response to plasma expanders and inotropes associates with serum levels of cortisol and its precursors. We investigated 96 infants with hypotension and critical neonatal disease for cortisol metabolism and are divided into responders and non-responders to plasma expanders and inotropes. Serum concentrations of steroids were analysed soon after the onset of volume expansion and inotrope treatment for shock. The 48 non-responders were treated with intravenous hydrocortisone (HC) and serum cortisol concentrations were monitored a week later. The mean cortisol concentrations did not differ between the responders and non-responders: 13.6 ± 2.5 and 12.5 ± 4.5 μg/dL, respectively. Dehydroepiandrosterone (37.3 ± 19.5 versus 324.0 ± 106.3; p < 0.0001) and 17-hydroxy-pregnenolone concentrations were lower in responders than in non-responders. Dehydroepiandrosterone levels in non-responders were inversely associated with postnatal age (r = 0.50, p < 0.0001). There were no differences in 17-hydroxy-progesterone, 11-deoxy-cortisol and cortisone between the responders and non-responders. Hydrocortisone administration acutely increased blood pressure. Six non-responders who died despite HC administration had low levels of cortisol. The responders had normal serum cortisol after HC treatment. Precursors of cortisol, proximal to the 3β-hydroxysteroid dehydrogenase activity, accumulated in neonates with hypotension, responding to HC treatment.

Desensitization by noradrenaline of responses to stimulation of pre- and postsynaptic adrenoceptors

PubMed Central

Ball, N.; Danks, J.L.; Dorudi, S.; Nasmyth, P.A.

1982-01-01

1 The effect of exposing isolated preparations of rat aortic strip, rat atria and mouse vas deferens to perfusions of Krebs solution containing various concentrations of noradrenaline on their sensitivity to the drug has been determined. 2 The responses evoked by stimulation of postsynaptic adrenoceptors in all the tissues and presynaptic α-adrenoceptors in the mouse vas deferens were diminished by the perfusion of noradrenaline through the organ bath for 30 min. 3 The concentration of noradrenaline required to produce desensitization was higher in the mouse vas deferens than in the other tissues and more was required to desensitize the chronotropic responses than the inotropic responses in rat isolated atria. 4 The inclusion of cocaine (10-5 M) in the bathing solution to block uptake1 increased the sensitivity of most tissues to noradrenaline. With the possible exception of the response to stimulation of presynaptic receptors in the mouse vas deferens, desensitization was somewhat increased in its presence. 5 When uptake2 was blocked by oestradiol (10-5 M), it was not possible to desensitize the contractor responses of the aortic strip and vas deferens to exogenous noradrenaline, nor the inotropic response of the atria to the drug. However, oestradiol failed to block the desensitization of chronotropic responses and responses to stimulation of presynaptic receptors in the vas deferens. 6 Blockade of monoamine oxidase (MAO) with iproniazid (7.2 × 10-4 M) or with pargyline (5 × 10-4 M) did not affect the desensitization process in the aortic strip. 7 Blockade of catechol-O-methyltransferase (COMT) with U-0521 (5.3 × 10-5 M) greatly increased desensitization in the aortic strip and desensitization of inotropic responses in the atria. It had no effect on desensitization of chronotropic responses. Its effect on responses in the mouse vas deferens was not determined. 8 The perfusion of methoxamine at concentrations about 1000 times higher than those of noradrenaline also produced desensitization in the aortic strip. 9 The desensitization of presynaptic receptors in the mouse vas deferens was shown to be specific and that of the responses to postsynaptic receptor stimulation to be non-specific. 10 It is concluded that responses to adrenoceptor stimulation may be desensitized by accumulation of noradrenaline inside the cells bearing the receptors and that the desensitization is caused by noradrenaline itself not by a metabolite. Desensitization may also be caused without accumulation of noradrenaline in uptake2 and for some receptors these may not be alternative mechanisms. PMID:7082904

Negative inotropic and chronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambola L. leaves.

PubMed

Vasconcelos, C M L; Araújo, M S; Silva, B A; Conde-Garcia, E A

2005-07-01

It has been reported that star fruit can lead to a fatal outcome in uremic patients. The intoxication syndrome consists of hiccups, mental confusion, dizziness, and vomiting. On the other hand, folk medicine uses teas and infusions of carambola leaves to treat headache, vomiting, cough, insomnia, and diabetes. This motivated us to determine if Averrhoa carambola can act on the contractility and automaticity of the guinea pig heart. We measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria. The carambola leaf extracts (1.5 mg/ml) abolished the contractile force in a concentration-dependent manner. Among the crude, methanolic, ethanolic, aqueous, and acetic extracts, the aqueous one was the most potent (EC50 = 520 +/- 94 microg/ml; flavonoids and tannins are the main constituents; Na+ and K+ contents in 1.0 mg/ml of aqueous extract were 0.12 +/- 0.016 and 1.19 +/- 0.15 mM, respectively). The aqueous extract abolished the positive Bowditch staircase phenomenon and reduced the inotropic response to CaCl2 (0.17-8.22 mM), events that are dependent on the cellular Ca2+ inward current. The adrenergic, muscarinic or opioid membrane receptors do not seem to participate in the mechanism of action of the cardioactive substance(s). In spontaneously beating atria, the aqueous extract promoted a negative chronotropic effect that was antagonized by 0.1 microM isoproterenol bitartrate. With this agonist, the EC50 of the aqueous extract increased from 133 +/- 58 to 650 +/- 100 microg/ml. These data regarding the effect of A. carambola on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.

Exaggerated cardiovascular effects of cocaine in conscious dogs with pacing-induced dilated cardiomyopathy.

PubMed

Mathier, Michael A; Shen, You-Tang; Shannon, Richard P

2002-12-01

The aim of this study was to explore the characteristics and mechanisms of the cardiovascular effects of cocaine in dilated cardiomyopathy. We studied the cardiovascular responses to acute intravenous cocaine (1 mg/kg) in 8 conscious, chronically instrumented dogs before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. To help elucidate the role of altered baroreflex function in mediating the cardiovascular effects of cocaine, we also studied responses in 3 conscious, chronically instrumented dogs that had undergone surgical sinoaortic baroreceptor denervation. Cocaine produced greater increases in heart rate (+57 +/- 8% from 112 +/- 5 beats/min versus +28 +/- 3% from 100 +/- 4 beats/min; P <.01), first derivative of left ventricular pressure (+30 +/- 5% from 1,714 +/- 147 mm Hg/sec versus +15 +/- 3% from 3,032 +/- 199 mm Hg/sec; P <.01), coronary vascular resistance (+28 +/- 5% from 2.3 +/- 0.3 mm Hg/mL/min versus +11 +/- 5% from 2.2 +/- 0.3 mm Hg/mL/min; P <.05) and plasma norepinephrine concentration (+130 +/- 31% from 462 +/- 102 pg/mL versus +86 +/- 32% from 286 +/- 77 pg/mL; P <.05) in dogs with dilated cardiomyopathy as compared to controls. In addition, responses were much more rapid in onset following the development of dilated cardiomyopathy. Chronotropic and inotropic responses to cocaine were similarly rapid and exaggerated in dogs after baroreceptor denervation. Cocaine produces rapid and exaggerated chronotropic, inotropic, and coronary vasoconstrictor responses in conscious dogs with pacing-induced dilated cardiomyopathy. Alterations in arterial baroreflex function may play a role in these observations, which in turn may underlie the clinically observed association between cocaine and heart failure.

Geraniol blocks calcium and potassium channels in the mammalian myocardium: useful effects to treat arrhythmias.

PubMed

de Menezes-Filho, José Evaldo Rodrigues; Gondim, Antônio Nei Santana; Cruz, Jader Santos; de Souza, Américo Azevedo; Santos, José Nilson Andrade Dos; Conde-Garcia, Eduardo Antônio; de Sousa, Damião Pergentino; Santos, Michel Santana; de Oliveira, Evaleide Diniz; de Vasconcelos, Carla Maria Lins

2014-12-01

Geraniol is a monoterpene present in several essential oils, and it is known to have a plethora of pharmacological activities. In this study, we explored the contractile and electrophysiological properties of geraniol and its antiarrhythmic effects in the heart. The geraniol effects on atrial contractility, L-type Ca(2+) current, K(+) currents, action potential (AP) parameters, ECG profile and on the arrhythmia induced by ouabain were evaluated. In the atrium, geraniol reduced the contractile force (~98%, EC = 1,510 ± 160 μM) and diminished the positive inotropism of CaCl2 and BAY K8644. In cardiomyocytes, the IC a,L was reduced by 50.7% (n = 5) after perfusion with 300 μM geraniol. Moreover, geraniol prolonged the AP duration (APD) measured at 50% (n = 5) after repolarization, without changing the resting potential. The increased APD could be attributed to the blockade of the transient outward K(+) current (Ito ) (59.7%, n = 4), the non-inactivation K(+) current (Iss ) (39.2%, n = 4) and the inward rectifier K(+) current (IK 1 ) (33.7%, n = 4). In isolated hearts, geraniol increased PRi and QTi without affecting the QRS complex (n = 6), and it reduced both the left ventricular pressure (83%) and heart rate (16.5%). Geraniol delayed the time to onset of ouabain-induced arrhythmias by 128%, preventing 30% of the increase in resting tension (n = 6). Geraniol exerts its negative inotropic and chronotropic responses in the heart by decreasing both L-type Ca(2+) and voltage-gated K(+) currents, ultimately acting against ouabain-induced arrhythmias. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Alteration of Left Ventricular Function with Dobutamine Challenge in Patients with Myocardial Bridge

PubMed Central

Jhi, Joon-Hyung; Ha, Jong-kun; Jung, Chan-Woo; kim, Bong-Jae; Park, Seong-Oh; Jo, A-Ra; Kim, Seong-Man; Lee, Hyeon-Gook; Kim, Tae-Ik

2011-01-01

Background/Aims The aim of this study was to identify changes in left ventricular (LV) performance in patients with a myocardial bridge (MB) in the left anterior descending coronary artery during resting and in an inotropic state. Methods Myocardial strain measurement by speckle-tracking echocardiography and conventional LV wall-motion scoring was performed in 18 patients with MB (mean age, 48.1 ± 1.7 years, eight female) during resting and intravenous dobutamine challenge (10 and 20 µg/kg/min). Results Conventional LV wall-motion scoring was normal in all patients during resting and in an inotropic state. Peak regional circumferential strain increased dose dependently upon dobutamine challenge. Longitudinal strains of the anterior and anteroseptal segments were, however, reduced at 20 µg/kg/min and showed a dyssynchronous pattern at 20 µg/kg/min. Although there were no significant differences in radial strain and displacement of all segments at rest compared with under 10 µg/kg/min challenge, radial strain and displacement of anterior segments at 20 µg/kg/min were significantly reduced compared with posterior segments at the papillary muscle level (44.8 ± 14.9% vs. 78.4 ± 20.1% and 5.3 ± 2.3 mm vs. 8.5 ± 1.8 mm, respectively; all p < 0.001), and showed plateau (40%) or biphasic (62%) patterns. Conclusions Reduced LV strain of patients with MB after inotropic stimulation was identified. Speckle-tracking strain echocardiography identified a LV myocardial dyssynchrony that was not demonstrated by conventional echocardiography in patients with MB. PMID:22205841

Anesthetic management of the neonate with congenital complete heart block: a 16-year review.

PubMed

Kussman, Barry D; Madril, Danielle R; Thiagarajan, Ravi R; Walsh, Edward P; Laussen, Peter C

2005-12-01

Anesthesia for patients with complete heart block can be associated with significant hemodynamic instability. The aim of this study is to review our anesthetic experience of neonates with congenital complete heart block (CCHB) who underwent placement of either a temporary epicardial pacing system or a permanent epicardial pacemaker. The anesthetic management of neonates with CCHB who underwent pacemaker placement at a single institution over a 16-year period was reviewed. Twenty-four neonates were identified, 17 with a structurally normal heart (NL) and seven with associated congenital heart defects (CHD). Median (range) gestational age was 36.9 (26-41) weeks, birth weight 2.9 (1.0-4.1) kg, and baseline heart rate 47 (38-80) b.min(-1). A temporary epicardial pacing system was placed in six patients (four CHD, two NL; P = 0.003) following institution of mechanical ventilation and inotropic support for a low cardiac output state, and a permanent epicardial pacemaker was placed in 18 patients. Atropine 0.02 mg.kg(-1) IV prior to induction (n = 5) increased heart rate less than 20%. Intraoperative hypotension was documented in nine neonates, five of seven with CHD and four of 17 with NL (P = 0.02). In four patients (44%) hypotension occurred despite concurrent inotropic support. Intraoperative cardiac arrest occurred in one neonate, necessitating institution of extracorporeal membrane oxygenation. Two patients (8.3%) died in hospital from complex CHD and complications of prematurity. Early institution of mechanical ventilation, inotropic support and pacing are necessary in the neonate with CCHB and poor hemodynamic function, particularly with coexisting CHD or prematurity.

Operative contractility: a functional concept of the inotropic state.

PubMed

Curiel, Roberto; Perez-Gonzalez, Juan; Torres, Edwar; Landaeta, Ruben; Cerrolaza, Miguel

2005-10-01

1. Initial unsuccessful attempts to evaluate ventricular function in terms of the 'heart as a pump' led to focusing on the 'heart as a muscle' and to the concept of myocardial contractility. However, no clinically ideal index exists to assess the contractile state. The aim of the present study was to develop a mathematical model to assess cardiac contractility. 2. A tri-axial system was conceived for preload (PL), afterload (AL) and contractility, where stroke volume (SV) was represented as the volume of the tetrahedron. Based on this model, 'operative' contractility ('OperCon') was calculated from the readily measured values of PL, AL and SV. The model was tested retrospectively under a variety of different experimental and clinical conditions, in 71 studies in humans and 29 studies in dogs. A prospective echocardiographic study was performed in 143 consecutive subjects to evaluate the ability of the model to assess contractility when SV and PL were measured volumetrically (mL) or dimensionally (cm). 3. With inotropic interventions, OperCon changes were comparable to those of ejection fraction (EF), velocity of shortening (Vcf) and dP/dt-max. Only with positive inotropic interventions did elastance (Ees) show significantly larger changes. With load manipulations, OperCon showed significantly smaller changes than EF and Ees and comparable changes to Vcf and dP/dt-max. Values of OperCon were similar when AL was represented by systolic blood pressure or wall stress and when volumetric or dimensional values were used. 4. Operative contractility is a reliable, simple and versatile method to assess cardiac contractility.

Elucidation of the Strongest Predictors of Cardiovascular Events in Patients with Heart Failure.

PubMed

Fukuda, Hiroki; Shindo, Kazuhiro; Sakamoto, Mari; Ide, Tomomi; Kinugawa, Shintaro; Fukushima, Arata; Tsutsui, Hiroyuki; Ito, Shin; Ishii, Akira; Washio, Takashi; Kitakaze, Masafumi

2018-06-20

In previous retrospective studies, we identified the 50 most influential clinical predictors of cardiovascular outcomes in patients with heart failure (HF). The present study aimed to use the novel limitless-arity multiple-testing procedure to filter these 50 clinical factors and thus yield combinations of no more than four factors that could potentially predict the onset of cardiovascular events. A Kaplan-Meier analysis was used to investigate the importance of the combinations. In a multi-centre observational trial, we prospectively enrolled 213 patients with HF who were hospitalized because of exacerbation, discharged according to HF treatment guidelines and observed to monitor cardiovascular events. After the observation period, we stratified patients according to whether they experienced cardiovascular events (rehospitalisation or cardiovascular death). Among 77,562 combinations of fewer than five clinical parameters, we identified 151 combinations that could potentially explain the occurrence of cardiovascular events. Of these, 145 combinations included the use of inotropic agents, whereas the remaining 6 included the use of diuretics without bradycardia or tachycardia, suggesting that the high probability of cardiovascular events is exclusively determined by these two clinical factors. Importantly, Kaplan-Meier curves demonstrated that the use of inotropes or of diuretics without bradycardia or tachycardia were independent predictors of a markedly worse cardiovascular prognosis. Patients treated with either inotropic agents or diuretics without bradycardia or tachycardia were at a higher risk of cardiovascular events. The uses of these drugs, regardless of heart rate, are the strongest clinical predictors of cardiovascular events in patients with HF. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Outcomes in Patients with Persistent Ventricular Dysfunction After Stage I Palliation for Hypoplastic Left Heart Syndrome.

PubMed

Jean-St-Michel, Emilie; Chetan, Devin; Schwartz, Steven M; Van Arsdell, Glen S; Floh, Alejandro A; Honjo, Osami; Conway, Jennifer

2016-02-01

We sought to describe the clinical course for patients with hypoplastic left heart syndrome and persistent ventricular dysfunction and identify risk factors for death or transplantation before stage II palliation. 138 children undergoing stage I palliation from 2004 to 2011 were reviewed. Twenty-two (16 %) patients (seven Hybrid, 15 Norwood) with two consecutive echocardiograms reporting at least moderate dysfunction were included and compared to case-matched controls. Eleven of the 22 patients with dysfunction (50 %) underwent stage II, seven (32 %) were transplanted, and four (18 %) died prior to stage II. Of the patients who survived to hospital discharge (n = 17) following stage 1, 14 (82 %) required readmission for heart failure (HF) compared to only two (10 %) for controls (p < 0.001). Among patients with ventricular dysfunction, there was an increased use of ACE inhibitors or beta-blockers (82 vs. 25 %; p = 0.001), inotropes (71 vs. 15 %; p = 0.001), ventilation (58 vs. 10 %; p = 0.001), and ECMO (29 vs. 0 %; p = 0.014) for HF management post-discharge when compared to controls. There was a lower heart transplant-free survival at 7 months in patients with dysfunction compared to controls (50.6 vs. 90.9 %; p = 0.040). ECMO support (p = 0.001) and duration of inotropic support (p = 0.04) were significantly associated with death or transplantation before stage II palliation. Patients with ventricular dysfunction received more HF management and related admissions. Longer inotropic support should prompt discussion regarding alternative treatment strategies given its association with death or transplant.

Steroids and statins: an old and a new anti-inflammatory strategy compared.

PubMed

Vukovic, Petar M; Maravic-Stojkovic, Vera R; Peric, Miodrag S; Jovic, Miomir Dj; Cirkovic, Milan V; Gradinac, Sinisa Dj; Djukanovic, Bosko P; Milojevic, Predrag S

2011-01-01

This study compared the anti-inflammatory effects of methylprednisolone (MP) and atorvastatin and analysed their influences on clinical variables in patients undergoing coronary revascularization. Ninety patients with compromised left ventricular ejection fraction (≤30%) undergoing elective coronary surgery were equally randomized to one of three groups: statin group, treatment with atorvastatin (20 mg/day) 3 weeks before surgery; methylprednisolone group, a single shot of methylpredniosolone (10mg/kg); and control group. Postoperative IL-6 was higher in the control group when compared to the methylprednisolone and statin groups (p<0.01). IL-6 was higher in the statin-treated patients (p<0.05 versus methylprednisolone). Administration of methylprednisolone as well as statin treatment increased postoperative cardiac index, left ventricular stroke work index, decreased postoperative atrial fibrilation rate and reduced ICU stay (p<0.05 versus control). The number of patients requiring inotropic support was lower in the methylprednisolone group when compared with the other two groups (p<0.01). Tracheal intubation time was reduced in patients who received methylprednisolone (p<0.01 versus control). Preoperative administration of either methylprednisolone or atorvastatin reduced pro-inflammatory cytokine release, improved haemodynamics, decreased postoperative atrial fibrilation rate and reduced ICU stay in patients with significantly impaired cardiac function undergoing coronary revascularization. Treatment with methylprednisolone was associated with less inotropic support requirements and reduced mechanical ventilation time.

Antitussive, antispasmodic, bronchodilating and cardiac inotropic effects of the essential oil from Blepharocalyx salicifolius leaves.

PubMed

Hernández, Jehison Jiménez; Ragone, María Inés; Bonazzola, Patricia; Bandoni, Arnaldo L; Consolini, Alicia E

2018-01-10

Blepharocalyx salicifolius (Kunth) O. Berg (Myrtaceae) is a tree native to Argentina and Uruguay that grows and is cultivated along the riverside of the Rio de la Plata. The leaves of this plant species, locally known as "anacahuita" are used in South America to prepare infusions for the empiric treatment of cough and bronchospasm, as well as diarrhoea and other intestinal disorders. Although previous phytochemical studies have been performed with the essential oil extracted from Blepharocalyx salicifolius, pharmacological evidence supporting its traditional use is still lacking. To experimentally evaluate the pharmacological properties of Blepharocalyx salicifolius based on its traditional use. The studies were performed with tincture (T-Bs) and essential oil (EO-Bs) prepared from its leaves, in isolated rat trachea, intestine and heart preparations. The ex-vivo effects of T-Bs and EO-Bs were evaluated with the agonists carbachol (CCh) and calcium chloride (Ca 2+ ) in the contractile concentration-response curves (CRC) of the isolated intestine. The muscle relaxant effect of EO-Bs was evaluated in the isolated trachea and compared with the effect achieved with papaverine as a positive control. The T-Bs and EO-Bs cardiac effects were analysed by perfusion of an isolated rat heart before a period of ischemia/reperfusion (stunning model). The antitussive effect of both T-Bs and EO-Bs was evaluated in mice exposed to ammonia using codeine as a positive control. Both T-Bs and EO-Bs induced a non-competitive inhibition of the CCh-CRC in the rat intestine, with IC 50 values of 170.3 ± 48.5µg T-Bs/mL (n = 6) and 5.9 ± 1.6µg EO-Bs/mL (n = 6), respectively. EO-Bs also inhibited non-competitively the Ca 2+ -CRC, with IC 50 value of 1.8 ± 0.3µg EO-Bs/mL (n = 8). A similar effect was obtained with the main active component of the EO-Bs 1,8-cineole. In isolated trachea, EO-Bs induced the relaxation of the CCh-contracted tissue (1.7 ± 0.2µg EO-Bs/mL, n = 11) up to a maximal relaxation that was 1.9 times higher than that of papaverine. In the isolated heart, EO-Bs induced a poor negative inotropic response, and did not improve the contractile and energetic recovery after ischemia and reperfusion. In the mouse cough model, EO-Bs (90mg/Kg) was as effective as codeine (30mg/Kg) in reducing cough frequency. The results indicate that the preparations from Blepharocalyx salicifolius leaves were effective as central antitussive, bronchodilating and antispasmodic agents, suggestive of a mechanism associated with the inhibition of Ca 2+ influx into smooth muscle. The EO-Bs displayed only a poor ability to reduce cardiac inotropism, and was devoid of any cardioprotective properties. Thus, the present study validates the traditional use of this South American plant for asthma, cough and bronchospasm, shedding new light into its potency and putative mechanism of action. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Remote Ischemic Preconditioning Fails to Benefit Pediatric Patients Undergoing Congenital Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Tie, Hong-Tao; Luo, Ming-Zhu; Li, Zhen-Han; Wang, Qian; Wu, Qing-Chen; Li, Qiang; Zhang, Min

2015-10-01

Remote ischemic preconditioning (RIPC) has been proven to reduce the ischemia-reperfusion injury. However, its effect on children receiving congenital cardiac surgery (CCS) was inconsistent. We therefore performed the current meta-analysis of randomized controlled trials (RCTs) to comprehensively evaluate the effect of RIPC in pediatric patients undergoing CCS.PubMed, Embase, and Cochrane library were searched to identify RCTs assessing the effect of RIPC in pediatric patients undergoing CCS. The outcomes included the duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, postoperative cardiac troponin (cTnI) level, hospital length of stay (HLOS), postoperative inotropic score, and mortality. Subgroup and sensitivity analysis were also performed as predesigned. The meta-analysis was performed with random-effects model despite of heterogeneity. Sensitivity and subgroup analysis were predesigned to identify the robustness of the pooled estimate.Nine RCTs with 697 pediatric patients were included in the meta-analysis. Overall, RIPC failed to alter clinical outcomes of duration of MV (standard mean difference [SMD] -0.03, 95% confidence interval [CI] -0.23-0.17), ICU length of stay (SMD -0.22, 95% CI -0.47-0.04), or HLOS (SMD -0.14, 95% CI -0.55-0.26). Additionally, RIPC could not reduce postoperative cTnI (at 4-6 hours: SMD -0.25, 95% CI -0.73-0.23; P = 0.311; at 20-24 hours: SMD 0.09, 95% CI -0.51-0.68; P = 0.778) or postoperative inotropic score (at 4-6 hours: SMD -0.19, 95% CI -0.51-0.14; P = 0.264; at 24 hours: SMD -0.15, 95% CI -0.49-0.18; P = 0.365).RIPC may have no beneficial effects in children undergoing CCS. However, this finding should be interpreted with caution because of heterogeneity and large-scale RCTs are still needed.

Validation of an in vitro contractility assay using canine ventricular myocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harmer, A.R., E-mail: alex.harmer@astrazeneca.com; Abi-Gerges, N.; Morton, M.J.

Measurement of cardiac contractility is a logical part of pre-clinical safety assessment in a drug discovery project, particularly if a risk has been identified or is suspected based on the primary- or non-target pharmacology. However, there are limited validated assays available that can be used to screen several compounds in order to identify and eliminate inotropic liability from a chemical series. We have therefore sought to develop an in vitro model with sufficient throughput for this purpose. Dog ventricular myocytes were isolated using a collagenase perfusion technique and placed in a perfused recording chamber on the stage of a microscopemore » at ∼ 36 °C. Myocytes were stimulated to contract at a pacing frequency of 1 Hz and a digital, cell geometry measurement system (IonOptix™) was used to measure sarcomere shortening in single myocytes. After perfusion with vehicle (0.1% DMSO), concentration–effect curves were constructed for each compound in 4–30 myocytes taken from 1 or 2 dog hearts. The validation test-set was 22 negative and 8 positive inotropes, and 21 inactive compounds, as defined by their effect in dog, cynolomolgous monkey or humans. By comparing the outcome of the assay to the known in vivo contractility effects, the assay sensitivity was 81%, specificity was 75%, and accuracy was 78%. With a throughput of 6–8 compounds/week from 1 cell isolation, this assay may be of value to drug discovery projects to screen for direct contractility effects and, if a hazard is identified, help identify inactive compounds. -- Highlights: ► Cardiac contractility is an important physiological function of the heart. ► Assessment of contractility is a logical part of pre-clinical drug safety testing. ► There are limited validated assays that predict effects of compounds on contractility. ► Using dog myocytes, we have developed an in vitro cardiac contractility assay. ► The assay predicted the in vivo contractility with a good level of accuracy.« less

Cardiovascular effects of Helichrysum ceres S Moore [Asteraceae] ethanolic leaf extract in some experimental animal paradigms.

PubMed

Musabayane, Cephas T; Kamadyaapa, Dave R; Gondwe, Mavuto; Moodley, Kogi; Ojewole, John A O

2008-01-01

The aim of this study was to examine some in vivo and in vitro cardiovascular effects of Helichrysum ceres leaf ethanolic extract (HCE) in experimental animal paradigms. The acute effects of HCE on blood pressure were studied in anaesthetised normotensive male Wistar rats challenged with intravenous hypotonic saline infusion after a 3.5-hour equilibration for four hours of one-hour control, 1.5-hour treatment and 1.5-hour recovery periods. HCE was added to the infusate during the treatment period. Sub-chronic hypotensive effects of HCE were examined in weanling Dahl saltsensitive (DSS) genetically hypertensive rats, which progressively develop hypertension with age, treated with HCE (80 mg/kg) every third consecutive day for seven weeks. Isolated atrial muscle strips, portal veins and descending thoracic aortic rings of healthy normotensive Wistar rats were used to investigate the vascular effects of HCE. Acute HCE administration caused a significant (p < 0.05) fall in blood pressure in the normotensive anaesthetised Wistar rats. DSS hypertensive rats treated with HCE displayed low arterial blood pressure and heart rate values from weeks five to seven. HCE produced concentrationdependent negative inotropic and chronotropic effects on rat isolated electrically driven left, and spontaneously beating right atrial muscle preparations, respectively. HCE also evoked concentration-dependent relaxation responses of endothelium-intact aortic rings and portal veins isolated from healthy normotensive Wistar rats. The vasorelaxant effects of HCE in intact aortic rings were significantly reduced, but not completely abolished by adding endothelial- derived factor (EDRF) inhibitor, L-NAME, suggesting that the vasorelaxant effect of the extract is mediated via EDRF-dependent and independent mechanisms. The results of the study suggest that the hypotensive action of HCE is elicited, in part, directly by decreasing myocardial contractile performance and total peripheral vascular resistance due to its negative inotropic and chronotropic effects on rat isolated atrial muscle strips; and vasorelaxant effects on isolated vascular smooth muscles. The observed cardiovascular effects of HCE partly support the basis for its use in the management of high blood pressure in folkloric medicine.

Cardiovascular effects of Helichrysum ceres S Moore [Asteraceae] ethanolic leaf extract in some experimental animal paradigms

PubMed Central

Musabayane, Cephas T; Kamadyaapa, Dave R; Gondwe, Mavuto; Moodley, Kogi; Ojewole, John AO

2008-01-01

Summary Summary The aim of this study was to examine some in vivo and in vitro cardiovascular effects of Helichrysum ceres leaf ethanolic extract (HCE) in experimental animal paradigms. The acute effects of HCE on blood pressure were studied in anaesthetised normotensive male Wistar rats challenged with intravenous hypotonic saline infusion after a 3.5-hour equilibration for four hours of one-hour control, 1.5-hour treatment and 1.5-hour recovery periods. HCE was added to the infusate during the treatment period. Sub-chronic hypotensive effects of HCE were examined in weanling Dahl salt-sensitive (DSS) genetically hypertensive rats, which progressively develop hypertension with age, treated with HCE (80 mg/kg) every third consecutive day for seven weeks. Isolated atrial muscle strips, portal veins and descending thoracic aortic rings of healthy normotensive Wistar rats were used to investigate the vascular effects of HCE. Acute HCE administration caused a significant (p < 0.05) fall in blood pressure in the normotensive anaesthetised Wistar rats. DSS hypertensive rats treated with HCE displayed low arterial blood pressure and heart rate values from weeks five to seven. HCE produced concentration-dependent negative inotropic and chronotropic effects on rat isolated electrically driven left, and spontaneously beating right atrial muscle preparations, respectively. HCE also evoked concentration-dependent relaxation responses of endothelium-intact aortic rings and portal veins isolated from healthy normotensive Wistar rats. The vasorelaxant effects of HCE in intact aortic rings were significantly reduced, but not completely abolished by adding endothelial-derived factor (EDRF) inhibitor, L-NAME, suggesting that the vasorelaxant effect of the extract is mediated via EDRF-dependent and independent mechanisms. The results of the study suggest that the hypotensive action of HCE is elicited, in part, directly by decreasing myocardial contractile performance and total peripheral vascular resistance due to its negative inotropic and chronotropic effects on rat isolated atrial muscle strips; and vasorelaxant effects on isolated vascular smooth muscles. The observed cardiovascular effects of HCE partly support the basis for its use in the management of high blood pressure in folkloric medicine. PMID:18997985

Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts

PubMed Central

Rhodes, Samhita S; Camara, Amadou KS; Ropella, Kristina M; Audi, Said H; Riess, Matthias L; Pagel, Paul S; Stowe, David F

2006-01-01

Background The phase-space relationship between simultaneously measured myoplasmic [Ca2+] and isovolumetric left ventricular pressure (LVP) in guinea pig intact hearts is altered by ischemic and inotropic interventions. Our objective was to mathematically model this phase-space relationship between [Ca2+] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca2+ sensitivity responsible for alterations in Ca2+-contraction coupling due to inotropic drugs in the presence and absence of ischemia reperfusion (IR) injury. Methods We used a four state computational model to predict LVP using experimentally measured, averaged myoplasmic [Ca2+] transients from unpaced, isolated guinea pig hearts as the model input. Values of model parameters were estimated by minimizing the error between experimentally measured LVP and model-predicted LVP. Results We found that IR injury resulted in reduced myofilament Ca2+ sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 μM) reduced myofilament Ca2+ sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 μM) reduced myofilament Ca2+ sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 μM) increased myofilament Ca2+ sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 μM) enhanced myofilament Ca2+ affinity and cross-bridge kinetics only after ischemia. Conclusion Estimated model parameters reveal mechanistic changes in Ca2+-contraction coupling due to IR injury, specifically the inefficient utilization of Ca2+ for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca2+-contraction coupling before and after IR injury. PMID:16512898

Is Serum Bicarbonate Level Associated With Negative Outcomes in Pediatric Patients?: A Retrospective Cohort Study.

PubMed

Poonai, Naveen; Mainprize, David; Travers, Carolyn; Vivas, Lilian Lee Yan; Tryphonopoulos, Peter; Sangha, Gurinder; Arbeau, Ryan; Seabrook, Jamie; Miller, Michael; Sarpal, Amrita; Lim, Rodrick

2017-11-01

Early identification of children at risk for adverse outcomes is important. Serum bicarbonate is easily collected and widely available. We described the relationship between bicarbonate and adverse outcomes in children presenting to the emergency department (ED). We conducted a retrospective cohort study of children aged 0 to 17 years from January 1, 2007, to December 31, 2011, who had a serum bicarbonate measured in the ED. Primary outcome was the predictive ability of bicarbonate for the individual components of the composite outcome that included at least one of the following: intensive care unit admission, assisted ventilation, inotropic support, cardiopulmonary resuscitation, or death. Secondary outcome was the relationship between bicarbonate level of greater and less than 13 mEq/L and the composite outcome. We reviewed 16,989 charts, of which 432 had an adverse outcome. Receiver operating characteristic curve analysis showed that a bicarbonate level of less than 18.5 mEq/L predicted inotropic support with an area under the curve of 0.69 (95% confidence interval [CI], 0.60-0.77; P < 0.001) and death with an area under the curve of 0.75 (CI, 0.66-0.85; P < 0.001). Significantly more patients with bicarbonate level of less than 13 mEq/L had at least 1 adverse outcome compared with those with bicarbonate level of greater than 13 mEq/L (4.4% vs 2.5%, P = 0.001), odds ratio 1.96 (95% CI, 1.3-2.97). Among children presenting to the ED, bicarbonate level of 18.5 mEq/L had fair specificity in predicting inotropic support and death. Negative outcomes are significantly associated with bicarbonate level of less than 13 mEq/L. Bicarbonate should routinely be measured in children at risk of clinical deterioration.

Variable use of amiodarone is associated with a greater risk of recurrence of atrial fibrillation in the critically ill.

PubMed

Mitrić, Goran; Udy, Andrew; Bandeshe, Hiran; Clement, Pierre; Boots, Rob

2016-04-02

Atrial fibrillation is a common rhythm disturbance in the general medical-surgical intensive care unit. Amiodarone is a popular drug in this setting but evidence to inform clinical practice remains scarce. We aimed to identify whether variation in the clinical use of amiodarone was associated with recurrent atrial fibrillation. This was a retrospective audit of 177 critically ill patients who developed new-onset atrial fibrillation after admission to a tertiary level medical-surgical trauma intensive care unit. Patterns of amiodarone prescription (including dosage schedule and duration) were assessed in relation to recurrence of atrial fibrillation during the intensive care unit stay. Known recurrence risk factors, such as inotrope administration, cardiac disease indices, Charlson Comorbidity Index, magnesium concentrations, fluid balance, and potassium concentrations, were also included in adjusted analysis using forward stepwise logistic regression modelling. The cohort had a median (interquartile range) age of 69 years (60-75), Acute Physiology and Chronic Health Evalution II score of 22 (17-28) and Charlson Comorbidity Index of 2 (1-4). A bolus dose of amiodarone followed by infusion (P = 0.02), in addition to continuing amiodarone infusion through to discharge from the intensive care unit (P < 0.001), were associated with less recurrent dysrhythmia. Recurrence after successful treatment was associated with ceasing amiodarone while an inotrope infusion continued (P < 0.001), and was more common in patients with a prior history of congestive cardiac failure (P = 0.04), and a diagnosis of systemic inflammatory response syndrome (P = 0.02). Amiodarone should be administered as a bolus dose followed immediately with an infusion when treating atrial fibrillation in the medical-surgical intensive care unit. Consideration should be given to continuing amiodarone infusions in patients on inotropes until they are ceased.

[Clinical experience with 53 consecutive heart transplants].

PubMed

Villavicencio, Mauricio; Rossel, Víctor; Larrea, Ricardo; Peralta, Juan Pablo; Larraín, Ernesto; Sung Lim, Jong; Rojo, Pamela; Gajardo, Francesca; Donoso, Erika; Hurtado, Margarita

2013-12-01

Heart transplantation is the therapy of choice for advance heart failure. Our group developed two transplant programs at Instituto Nacional del Tórax and Clínica Dávila. We report our clinical experience based on distinctive clinical policies. Fifty-three consecutive patients were transplanted between November 2008 and April 2013, representing 51% of all Chilean cases. Distinctive clinical policies include intensive donor management, generic immunosuppression and VAD (ventricular assist devices) insertion. Ischemic or dilated cardiomyopathy were the main indications (23 (43%) each), age 48 ± 13 years and 48 (91%) were male. Transplant listing Status: IA 14 (26%) (VAD or 2 inotropes), IB 14 (26%) (1 inotrope) and II25 (47%) (no inotrope). Mean waiting time 70 ± 83 days. Twelve (24%) were transplanted during VAD support (median support: 36 days). orthotopic bicaval transplant with ischemia time: 175 ± 54 min. Operative mortality: 3 (6%), all due to right ventricular failure. Re-exploration for bleeding 2 (4%), stroke 3 (6%), mediastinitis 0 (0%), pneumonia 4 (8%), and transient dialysis 6 (11%). Mean follow-up was 21 ± 14 months. Three-year survival was 86 ± 6%. One patient died of Pneumocystis jirovecii pneumonia and the other died suddenly (non-compliance). Freedom from rejection requiring specific therapy was 80 ± 7% at 3 years of follow-up. Four hundred eighty four endomyocardial biopsies were done: 11 (2.3%) had 2R rejection. All survivors are in NYHA (New York Heart Association) functional class I and all but one have normal biventricular function. Mid-term results are similar to those reported by the registry of the International Society for Heart and Lung Transplantation. This experience has a higher proportion of VAD support than previous national series. Rejection rates are low in spite of generic immunosuppression.

Paramyxovirus Infection: Mortality and Morbidity in a Pediatric Intensive Care Unit.

PubMed

Tong, Alice S W; Hon, Kam Lun; Tsang, Yin Ching K; Chan, Renee Wan Yi; Chan, Ching Ching; Leung, Ting Fan; Chan, Paul K S

2016-10-01

We investigated mortality and morbidity of patients admitted to a pediatric intensive care unit (PICU) with paramyxovirus infection. A retrospective study between October 2002 and March 2015 of children with a laboratory-confirmed paramyxovirus infection was included. In all, 98 (5%) PICU admissions were tested positive to have paramyxovirus infection (respiratory syncytial virus =  66, parainfluenza  =  27 and metapneumovirus  =  5). The majority of admissions were young patients (median age 1.05 years). Bacteremia and bacterial isolation in any site were present in 10% and 28%, respectively; 41% were mechanically ventilated, and 20% received inotropes. The three respiratory viruses caused similar mortality and morbidity in the PICU. Fatality (seven patients) was associated with malignancy, positive bacterial culture in blood, the use of mechanical ventilation, inotrope use, lower blood white cell count and higher C reactive protein (p  =  0.02-0.0005). Backward binary logistic regression for these variables showed bacteremia (odds ratio [OR]: 31.7; 95% CI: 2.3-427.8; p  =  0.009), malignancy (OR: 45.5; 95% CI: 1.4-1467.7; p  =  0.031) and use of inotropes (OR: 15.0; 95% CI: 1.1-196.1; p  =  0.039) were independently associated with non-survival. March and July appeared to be the two peak months for PICU hospitalizations with paramyxovirus infection. Infections with paramyxoviruses account for 5% of PICU admissions and significant morbidity. Patient with premorbid history of malignancy and co-morbidity of bacteremia are associated with non-survival. March and July appeared to be the two peak months for PICU admissions with paramyxoviruses. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Clinical significance of serum cortisol levels following surgery for congenital heart disease.

PubMed

Teagarden, Alicia M; Mastropietro, Christopher W

2017-03-01

Use of hydrocortisone to treat refractory haemodynamic instability in patients recovering from surgery for congenital heart disease is common practice at many centres. We aimed to determine whether there is a relationship between total serum cortisol concentrations and haemodynamic response to this therapy. Material and methods We retrospectively reviewed patients <21 years who underwent cardiac surgery from 2011 to 2013, received hydrocortisone within 72 hours postoperatively, and had total serum cortisol measurements contemporaneous with its administration. Favourable responders were defined as patients in whom, at 24 hours after hydrocortisone initiation, either (1) systolic blood pressure was increased or unchanged and vasoactive-inotrope score was decreased or (2) systolic blood pressure increased by ⩾10% of baseline and vasoactive-inotrope score was unchanged. Variables were compared using t-tests or Mann-Whitney U tests as appropriate. In total, 24 patients were reviewed, with a median age of 1.4 months and range of 0.1-232 months. Among them, 14 (58%) patients responded favourably to hydrocortisone. At 24 hours, the median change in vasoactive-inotrope score was -18% in favourable responders and +31% in those who did not respond favourably, p=0.001. The mean pre-hydrocortisone total serum cortisol in favourable responders was 17.4±10.9 µg/dl compared with 46.1±44.7 µg/dl in those who did not respond favourably, p=0.03. Total serum cortisol obtained before initiation of hydrocortisone was significantly lower in patients who responded favourably to this therapy. Total serum cortisol may therefore be helpful in identifying children recovering from cardiac surgery who may or may not haemodynamically improve with hydrocortisone.

Australasian trends in intra-aortic balloon counterpulsation weaning: results of a postal survey.

PubMed

Lewis, Peter A; Mullany, Daniel V; Courtney, Mary; Coyer, Fiona

2006-12-01

To generate baseline data describing Australasian intra-aortic balloon counterpulsation (IABP) weaning practice. A five-part questionnaire was mailed in April 2005 to all 192 intensive care units in Australia and New Zealand. 116 ICUs responded (response rate, 60%), and 54 reported using IABP. Most of the 54 were in hospitals which were public government-funded (65%), had between 100 and 500 beds (69%), and treated a minimum of 11 patients annually with IABP (60%). The most common method of withdrawing IABP support was ratio reduction alone (61%). ICUs most likely to undertake ratio weaning were higherend users of IABP (> 20 cases per annum) (P = 0.04). Other weaning practices involved a combination of ratio followed by volume reduction (17%), volume then ratio (11%), and volume only (4%). Approaching statistical significance, ratio reduction weaning less frequently required IABP reinsertion or inotropic increase after balloon removal (P = 0.07). ICUs with documented weaning policies were less likely to require IABP reinsertion or inotropic increase after balloon removal (P = 0.06). Criteria considered important before IABP weaning or removal were: blood pressure (92%); heart rate (76%); pulmonary artery wedge pressure (59%); noradrenaline dose (78%); adrenaline dose (57%); and dobutamine dose (57%). Ninety per cent of ICUs reported increasing inotropes after balloon removal only rarely (1:50 patients) or occasionally (1:10 patients), while 87% of ICUs reported never needing to reinsert the balloon or only rarely. The Australasian approach to IABP weaning is eclectic. While ratio reduction weaning appears the most successful manner of support withdrawal, it may be a consequence of a volume-outcome relationship, with high- end users achieving better results through IABP familiarity.

[The effect of uridine and uridine nucleotides on isolated rat heart performance in regional myocardial ischemia].

PubMed

Eliseev, V V; Rodionova, O M; Sapronov, N S; Selizarova, N O

2002-01-01

We studied the effects of uridine, uridine-5'-monophosphate (UMP), uridine-5'-diphosphate (UDP) and uridine-5'-triphosphate on contractility, coronary flow and heart rate in isolated perfused rat hearts under 60-minute regional ischemia of the left ventricle. All the compounds (50 mumol/l) induced a positive inotropic effect but had no effect on the heart rate. Uridine and UMP prevented the development of the contracture. UDP and especially UTP increased coronary flow. Probably, a protective effect of uridine and UMP is due to activation of myocardial glycogen synthesis while favourable effects of UDP and UTP on contractility and coronary flow are explained by their influence on P2U-receptors of cardiomyocytes. In addition, coronary dilatation induced by UDP and UTP promoted the reduction of the damaged zone.

Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium.

PubMed

Wallner, Markus; Kolesnik, Ewald; Ablasser, Klemens; Khafaga, Mounir; Wakula, Paulina; Ljubojevic, Senka; Thon-Gutschi, Eva Maria; Sourij, Harald; Kapl, Martin; Edmunds, Nicholas J; Kuzmiski, J Brent; Griffith, David A; Knez, Igor; Pieske, Burkert; von Lewinski, Dirk

2015-12-01

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP-1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of β-arrestin signaling was examined using a β-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP-1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pharmacokinetics and a simulation model of colforsin daropate, new forskolin derivative inotropic vasodilator, in patients undergoing coronary artery bypass grafting.

PubMed

Kikura, Mutsuhito; Morita, Koji; Sato, Shigehito

2004-03-01

Colforsin daropate, a water-soluble forskolin derivative, is an adenyl cyclase activator with positive inotropic and vasodilatory effects that are useful in the treatment of ventricular dysfunction. We investigated the pharmacokinetics of colforsin daropate in cardiac surgery patients and performed simulations to determine the dosage necessary to maintain an effective plasma concentration following cardiopulmonary bypass. In six patients undergoing coronary artery bypass graft, colforsin daropate (0.01mgkg(-1)) was administered immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16h and plasma concentrations of colforsin daropate and its initial active metabolite were determined by gas-chromatography. Extended nonlinear least-squares regression was used to fit a three-compartment model to each patient's data. Distribution half-life (t(1/2alpha)) was 3.9+/-1.1min, metabolic half-life (t(1/2beta)) was 1.9+/-0.7h, and elimination half-life (t(1/2gamma)) was 95.3+/-15.2h. Central-compartment volume was 591.0+/-42.8mlkg(-1), volume distribution was 2689.2+/-450.6mlkg(-1), and elimination clearance was 27.7+/-14.7mlkg(-1)min(-1). In the pharmacokinetic simulation model, 0.5, 0.75, and 1.0microgkg(-1)min(-1) continuous infusion of colforsin daropate produce effective concentration (5-10ngml(-1)) within 30, 20, and 10min, respectively following administration. An initial active metabolite of decreased rapidly to less than 1.0ngml(-1) within the first 10min.A colforsin daropate infusion of 0.7-1.0microgkg(-1)min(-1) for 10-20min followed by 0.5microgkg(-1)min(-1) continuous infusion is recommended to produce an effective concentration (5-10ngml(-1)) within 10-20min and to maintain a therapeutic concentration throughout the administration period after cardiopulmonary bypass.

GPER mediates cardiotropic effects in spontaneously hypertensive rat hearts.

PubMed

De Francesco, Ernestina Marianna; Angelone, Tommaso; Pasqua, Teresa; Pupo, Marco; Cerra, Maria Carmela; Maggiolini, Marcello

2013-01-01

Estrogens promote beneficial effects in the cardiovascular system mainly through the estrogen receptor (ER)α and ERβ, which act as ligand-gated transcription factors. Recently, the G protein-coupled estrogen receptor (GPER) has been implicated in the estrogenic signaling in diverse tissues, including the cardiovascular system. In this study, we demonstrate that left ventricles of male Spontaneously Hypertensive Rats (SHR) express higher levels of GPER compared to normotensive Wistar Kyoto (WKY) rats. In addition, we show that the selective GPER agonist G-1 induces negative inotropic and lusitropic effects to a higher extent in isolated and Langendorff perfused hearts of male SHR compared to WKY rats. These cardiotropic effects elicited by G-1 involved the GPER/eNOS transduction signaling, as determined by using the GPER antagonist G15 and the eNOS inhibitor L-NIO. Similarly, the G-1 induced activation of ERK1/2, AKT, GSK3β, c-Jun and eNOS was abrogated by G15, while L-NIO prevented only the eNOS phosphorylation. In hypoxic Langendorff perfused WKY rat heart preparations, we also found an increased expression of GPER along with that of the hypoxic mediator HIF-1α and the fibrotic marker CTGF. Interestingly, G15 and L-NIO prevented the ability of G-1 to down-regulate the expression of both HIF-1α and CTGF, which were found expressed to a higher extent in SHR compared to WKY rat hearts. Collectively, the present study provides novel data into the potential role played by GPER in hypertensive disease on the basis of its involvement in myocardial inotropism and lusitropism as well as the expression of the apoptotic HIF-1α and fibrotic CTGF factors. Hence, GPER may be considered as a useful target in the treatment of some cardiac dysfunctions associated with stressful conditions like the essential hypertension.

Single dosing comparison of the relative cardiac beta 1/beta 2 activity of inhaled fenoterol and salbutamol in normal subjects.

PubMed Central

Newnham, D M; Wheeldon, N M; Lipworth, B J; McDevitt, D G

1993-01-01

BACKGROUND--The aim of the present study was to compare the dose related effects of fenoterol and salbutamol on cardiac beta 1 and beta 2 receptors using the beta 1 selective antagonist atenolol, in order to dissect out relative beta 1/beta 2 mediated responses. METHODS--Fourteen normal volunteers were randomised to receive pretreatment with either atenolol 25 mg or placebo, followed by inhaled fenoterol or salbutamol in equal doses by weight (cumulative doses of 1 mg and 4 mg). Measurements were made 30 minutes after inhaling each dose of beta 2 agonist. Values (mean and 95% CI) were expressed as a change from baseline. RESULTS--At 4 mg fenoterol produced equivalent falls in serum potassium and increases in tremor to salbutamol. The mean (95% CI) increase in heart rate (beats/min) with fenoterol at 4 mg after placebo was 47 (41-53) and after atenolol was 34 (28-40), with values for salbutamol being 46 (40-52) after placebo and 30 (24-36) after atenolol. The inotropic response (stroke distance) after atenolol at the 4 mg dose was 5.0 (3.9-6.1) cm for fenoterol and 4.7 (3.5-5.9) cm for salbutamol. There were no significant differences in heart rate or stroke distance response between the two drugs after either placebo or atenolol. Furthermore, ECG effects (Q-Tc and T wave) of fenoterol and salbutamol were comparable at both doses. CONCLUSIONS--These results show that there is no difference in the respective chronotropic or inotropic activities of fenoterol and salbutamol on cardiac beta 1 or beta 2 receptors when given at higher than conventional doses. PMID:8102213

Milrinone and mortality in adult cardiac surgery: a meta-analysis.

PubMed

Zangrillo, Alberto; Biondi-Zoccai, Giuseppe; Ponschab, Martin; Greco, Massimiliano; Corno, Laura; Covello, Remo Daniel; Cabrini, Luca; Bignami, Elena; Melisurgo, Giulio; Landoni, Giovanni

2012-02-01

The authors conducted a review of randomized studies to show whether there are any increases or decreases in survival when using milrinone in patients undergoing cardiac surgery. A meta-analysis. Hospitals. Five hundred eighteen patients from 13 randomized trials. None. BioMedCentral, PubMed EMBASE, the Cochrane central register of clinical trials, and conference proceedings were searched for randomized trials that compared milrinone versus placebo or any other control in the setting of cardiac surgery that reported data on mortality. Overall analysis showed that milrinone increased perioperative mortality (13/249 [5.2%] in the milrinone group v 6/269 [2.2%] in the control arm, odds ratio [OR] = 2.67 [1.05-6.79], p for effect = 0.04, p for heterogeneity = 0.23, I(2) = 25% with 518 patients and 13 studies included). Subanalyses confirmed increased mortality with milrinone (9/84 deaths [10.7%] v 3/105 deaths [2.9%] with other drugs as control, OR = 4.19 [1.27-13.84], p = 0.02) with 189 patients and 5 studies included) but did not confirm a difference in mortality (4/165 [2.4%] in the milrinone group v 3/164 [1.8%] with placebo or nothing as control, OR = 1.27 [0.28-5.84], p = 0.76 with 329 patients and 8 studies included). This analysis suggests that milrinone might increase mortality in adult patients undergoing cardiac surgery. The effect was seen only in patients having an active inotropic drug for comparison and not in the placebo subgroup. Therefore, the question remains whether milrinone increased mortality or if the control inotropic drugs were more protective. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage.

PubMed

Mutoh, Tomoko; Mutoh, Tatsushi; Nakamura, Kazuhiro; Yamamoto, Yukiko; Tsuru, Yoshiharu; Tsubone, Hirokazu; Ishikawa, Tatsuya; Taki, Yasuyuki

2017-04-01

Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator. © 2017 John Wiley & Sons Australia, Ltd.

A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig

PubMed Central

Snowdy, Stephen; Liang, Hui Xiu; Blackburn, Brent; Lum, Robert; Nelson, Marek; Wang, Lisa; Pfister, Jürg; Sharma, Bhavender P; Wolff, Andrew; Belardinelli, Luiz

1999-01-01

The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 adenosine receptor (A1 receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem.In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S–H interval), a measure of slowing AV nodal conduction (EC50=41 nM) than to increase coronary conductance (EC50=200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 μM) that caused equal prolongation of S–H interval (∼10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50=73 nM) but not the ventricular monophasic action potentials (MAP).In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P–R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure.Both CVT-510 and diltiazem prolonged S–H interval, i.e., slowed AV nodal conduction. However, the A1 receptor-selective agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium. PMID:10051130

Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: impact on swelling-induced negative inotropic effect

PubMed Central

Gonano, Luis Alberto; Morell, Malena; Burgos, Juan Ignacio; Dulce, Raul Ariel; De Giusti, Verónica Celeste; Aiello, Ernesto Alejandro; Hare, Joshua Michael; Vila Petroff, Martin

2014-01-01

Aims Cardiomyocyte swelling occurs in multiple pathological situations and has been associated with contractile dysfunction, cell death, and enhanced propensity to arrhythmias. We investigate whether hypotonic swelling promotes nitric oxide (NO) release in cardiomyocytes, and whether it impacts on swelling-induced contractile dysfunction. Methods and results Superfusing rat cardiomyocytes with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca2+ transient, and increased NO-sensitive 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) fluorescence. When cells were exposed to HS + 2.5 mM of the NO synthase inhibitor l-NAME, cell swelling occurred in the absence of NO release. Swelling-induced NO release was also prevented by the nitric oxide synthase 1 (NOS1) inhibitor, nitroguanidine, and significantly reduced in NOS1 knockout mice. Additionally, colchicine (inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS, indicating that microtubule integrity is necessary for swelling-induced NO release. The swelling-induced negative inotropic effect was exacerbated in the presence of either l-NAME, nitroguandine, the guanylate cyclase inhibitor, ODQ, or the PKG inhibitor, KT5823, suggesting that NOS1-derived NO provides contractile support via a cGMP/PKG-dependent mechanism. Indeed, ODQ reduced Ca2+ wave velocity and both ODQ and KT5823 reduced the HS-induced increment in ryanodine receptor (RyR2, Ser2808) phosphorylation, suggesting that in this context, cGMP/PKG may contribute to preserve contractile function by enhancing sarcoplasmic reticulum Ca2+ release. Conclusions Our findings suggest a novel mechanism for NO release in cardiomyocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hypotonic swelling. PMID:25344365

A Cycle Ergometer Exercise Program Improves Exercise Capacity and Inspiratory Muscle Function in Hospitalized Patients Awaiting Heart Transplantation: a Pilot Study

PubMed Central

Forestieri, Patrícia; Guizilini, Solange; Peres, Monique; Bublitz, Caroline; Bolzan, Douglas W.; Rocco, Isadora S.; Santos, Vinícius B.; Moreira, Rita Simone L.; Breda, João R.; de Almeida, Dirceu R.; Carvalho, Antonio Carlos de C.; Arena, Ross; Gomes, Walter J.

2016-01-01

Objective The purpose of this study was to evaluate the effect of a cycle ergometer exercise program on exercise capacity and inspiratory muscle function in hospitalized patients with heart failure awaiting heart transplantation with intravenous inotropic support. Methods Patients awaiting heart transplantation were randomized and allocated prospectively into two groups: 1) Control Group (n=11) - conventional protocol; and 2) Intervention Group (n=7) - stationary cycle ergometer exercise training. Functional capacity was measured by the six-minute walk test and inspiratory muscle strength assessed by manovacuometry before and after the exercise protocols. Results Both groups demonstrated an increase in six-minute walk test distance after the experimental procedure compared to baseline; however, only the intervention group had a significant increase (P=0.08 and P=0.001 for the control and intervention groups, respectively). Intergroup comparison revealed a greater increase in the intervention group compared to the control (P<0.001). Regarding the inspiratory muscle strength evaluation, the intragroup analysis demonstrated increased strength after the protocols compared to baseline for both groups; statistical significance was only demonstrated for the intervention group, though (P=0.22 and P<0.01, respectively). Intergroup comparison showed a significant increase in the intervention group compared to the control (P<0.01). Conclusion Stationary cycle ergometer exercise training shows positive results on exercise capacity and inspiratory muscle strength in patients with heart failure awaiting cardiac transplantation while on intravenous inotropic support. PMID:27982348

Plasma marinobufagenin-like and ouabain-like immunoreactivity during saline volume expansion in anesthetized dogs.

PubMed

Bagrov, A Y; Fedorova, O V; Dmitrieva, R I; French, A W; Anderson, D E

1996-02-01

This study investigated effects of acute plasma volume expansion on plasma levels and urinary output of two endogenous Na,K-ATPase inhibitors, marinobufagenin-like and ouabain-like immunoreactive substances. Plasma volume was expanded for 3 h via intravenous saline infusion in three groups of anesthetized dogs--nontreated (n = 5); pretreated with rabbit antidigoxin (n = 5); and pretreated with rabbit antimouse (control) antibody (n = 4). Plasma marinobufagenin-like immunoreactivity increased to 11.87 +/- 3.16 nmol.l-1 (vs. 0.30 +/- 0.16 nmol.l-1) within 10 min of volume expansion, in parallel with a 15% increase in LVdP/dt, then decreased to 2.21 +/- 0.59 nmol.l-1, and in 90 min increased to 11.8 +/- 2.8 nmol.l-1, in parallel with the maximal natriuretic response. Plasma concentrations of ouabain-like immunoreactive material were increased after 90 min of saline infusion (0.019 +/- 0.004 nmol.l-1 vs. 0.139 +/- 0.056 nmol.l-1). Pretreatment of the animals with antidigoxin antibody blocked the positive inotropic and reduced natriuretic response to volume expansion, and decreased the urinary release of marinobufagenin-like, but not ouabain-like, material. These results show the presence of marinobufagenin-like immunoreactive substance in dog plasma and suggest that mammalian EDLF may have a bufodienolide nature. Endogenous marinobufagenin-like immunoreactive substance, which is likely to cross-react with antidigoxin antibody, is involved in the natriuretic and positive inotropic responses to plasma volume expansion.

Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns.

PubMed

Baker, C F W; Barks, J D E; Engmann, C; Vazquez, D M; Neal, C R; Schumacher, R E; Bhatt-Mehta, V

2008-06-01

The purpose of this observation was to evaluate the safety and efficacy of hydrocortisone (HC) for the treatment of refractory hypotension in term and preterm infants. A secondary purpose was to determine the utility of serum cortisol concentrations in predicting the response to treatment. This is a retrospective observational study of 117 infants treated with a standardized HC protocol for refractory hypotension. Refractory hypotension was defined as a mean arterial pressure (MAP) less than the gestational age (GA) despite a total inotrope dose of 20 microg per kg per min. Baseline serum cortisol concentrations were determined prior to treatment with stress dose HC. Treatment with HC increased the MAP at 2, 6, 12 and 24 h after initiation, decreased the total inotrope dose at 6, 12 and 24 h, and was associated with resolution of oliguria. There was no correlation between the pretreatment baseline cortisol concentration and GA, birth weight or the response to treatment. The incidence of grades III to IV intraventricular hemorrhage, periventricular leukomalacia, bacterial or fungal sepsis and spontaneous intestinal perforation (SIP) after HC treatment was similar to institutional historic controls prior to institution of this standardized HC protocol. HC treatment was associated with a rapid resolution of cardiovascular compromise. The incidence of significant side effects was similar to that in previously published reports, including a comparable incidence of SIP. On the basis of our results, measuring baseline serum cortisol concentration to guide the management of refractory hypotension is unwarranted.

NT-proBNP in cardiac surgery: a new tool for the management of our patients?

PubMed

Reyes, Guillermo; Forés, Gloria; Rodríguez-Abella, R Hugo; Cuerpo, Gregorio; Vallejo, José Luis; Romero, Carlos; Pinto, Angel

2005-06-01

Our aim was to determine NT-proBNP levels in patients undergoing cardiac surgery and if those levels are related to any of the baseline clinical characteristics of patients before surgery or any of the outcomes or events after surgery. Prospective, analytic study including 83 consecutive patients undergoing cardiac surgery. Preoperatory and postoperatory data were collected. NT-proBNP levels were measured before surgery, the day of surgery, twice the following day and every 24 h until a total of nine determinations. Venous blood was obtained by direct venipuncture and collected into serum separator tubes. Samples were centrifuged within 20 min from sampling and stored for a maximum of 12 h at 2-8 degrees C before the separation of serum. Serum was stored frozen at -40 degrees C and thawed only once at the time of analysis. Mean age was 65+/-11.8 years. An Euroscore 6 was found in 30% of patients. NYHA classification was as follows: I:27.7%; II:47%; III:25.3%. Preoperative atrial fibrilation occurred in 20.5% of patients. After surgery 18.1% of patients required inotropes. Only one death was recorded. A great variability was found in preoperative NT-proBNP levels; 759.9 (S.D.:1371.1); CI 95%: 464.9 to 1054.9 pg/ml, with a wide range (6.39-8854). Median was 366.5 pg/ml. Preoperative NT-proBNP levels were unrelated to the type of surgery (CABG vs. others), sex, age and any of the cardiovascular risk factors. NT-proBNP levels were higher in high risk patients (Euroscore 6); (P=0.021), worse NYHA class (P=0.020) and patients with preoperative atrial fibrilation (m 1767 (2205) vs m 621 (1017); P=0.001). After surgery NT-proBNP levels started increasing the following day until the fourth day (P=0.03), decreasing afterwards (P=0.019). These levels were significantly higher in patients requiring inotropes after surgery (P<0.001). We did not find any relationship between NT-proBNP levels and complications rate (P=0.59). Preoperative NT-proBNP levels depend on preoperative patient status (Euroscore, NYHA class and cardiac rhythm) and they increase significantly after cardiac surgery. This increase is higher when postoperative inotropes are needed. We found no relation between NT-proBNP levels and complications rate. An association have been shown between NT-proBNP levels and the use of inotropes after cardiac surgery.

Caveolin Contributes to the Modulation of Basal and β-Adrenoceptor Stimulated Function of the Adult Rat Ventricular Myocyte by Simvastatin: A Novel Pleiotropic Effect

PubMed Central

Agarwal, Shailesh R.; Harvey, Robert D.; Porter, Karen E.; Calaghan, Sarah

2014-01-01

The number of people taking statins is increasing across the globe, highlighting the importance of fully understanding statins' effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (‘pleiotropic effects’). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 µM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2+]i) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16 and troponin I at Ser23/24 was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered β-adrenoceptor signalling. In addition, as caveolin is ubiquitously expressed and has myriad tissue-specific functions, the impact of statin-dependent changes in caveolin is likely to have many other functional sequelae. PMID:25211146

[The role of delta-1 opiate receptors in regulation of contractility in isolated rat heart during normal oxygenation and ischemia-reperfusion].

PubMed

Lasukova, T V; Maslov, L N; Lishmanov, Iu B; Gross, G J

2004-01-01

The experiments on isolated rat heart demonstrated significant decrease in reperfusion-induced damage of cardiomyocytes by addition of selective delta 1 receptor agonist DPDPE (0.1 mg/l) to the perfusion solution. On the contrary, no cardioprotective effect was observed for 0.5 mg/l concentration of the peptide or after its intravenous injection. Stimulation of the cardiac delta 1 opioid receptors by intravenous injection of 0.5 mg/kg DPDPE or its addition to the perfusion solution decreased myocardial contractility both in conditions of normal oxygenation and during reperfusion. Thus, the cardioprotective and negative inotropic effect of DPDPE is mediated by activation of the cardiac delta 1 opioid receptors.

Earlier Right Ventricular Pacing in Cardiac Resynchronization Therapy for a Patient with Right Axis Deviation.

PubMed

Hattori, Yusuke; Ishibashi, Kohei; Noda, Takashi; Okamura, Hideo; Kanzaki, Hideaki; Anzai, Toshihisa; Yasuda, Satoshi; Kusano, Kengo

2017-09-01

We describe the case of a 37-year-old woman who presented with complete right bundle branch block and right axis deviation. She was admitted to our hospital due to severe heart failure and was dependent on inotropic agents. Cardiac resynchronization therapy was initiated but did not improve her condition. After the optimization of the pacing timing, we performed earlier right ventricular pacing, which led to an improvement of her heart failure. Earlier right ventricular pacing should be considered in patients with complete right bundle branch block and right axis deviation when cardiac resynchronization therapy is not effective.

The effect of short-term antiorthostatic hypokinesia on central and intracardiac hemodynamics and metabolism of a healthy person

NASA Technical Reports Server (NTRS)

Katkov, V. Y.; Chesturkhin, V. V.; Zybin, O. K.; Sukhotskiy, S. S.; Abrosimov, S. V.; Utkin, V. N.

1981-01-01

The right parts of the heart and the radial artery were catheterized in healthy male volunteers before and 5 days after strict bedrest in antiorthostatic position of the body (-4.5 deg). After immobilization, most values of central circulation showed no essential changes; the only exceptions were indicates characterizing the inotropic myocardial condition. A shift in the direction of acidosis of a mixed character was noted in mixed venous blood, the beta lipoprotein content increased. A decrease in the arteriovenous difference in oxygen was encountered in blood draining from the heart (from the coronary sinus).

Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children.

PubMed

Groselj-Grenc, Mojca; Ihan, Alojz; Pavcnik-Arnol, Maja; Kopitar, Andreja Natasa; Gmeiner-Stopar, Tanja; Derganc, Metka

2009-11-01

To compare the diagnostic accuracy of neutrophil and monocyte CD64 indexes (CD64in and CD64im) for sepsis in critically ill neonates and children with that of lipopolysaccharide-binding protein (LBP), procalcitonin (PCT) and C-reactive protein (CRP). Prospective, observational study in a level III multidisciplinary neonatal and pediatric intensive care unit (ICU). Forty-six neonates and 36 children with systemic inflammatory response syndrome (SIRS) and suspected infection, classified into two groups: those with bacterial sepsis (microbiologically proven or clinical sepsis) and those without bacterial sepsis (infection not supported by subsequent clinical course, laboratory data and microbiological tests). Flow cytometric CD64in and CD64im, serum LBP, PCT and CRP measurement on 2 consecutive days from admission to the ICU. There were 17 cases of bacterial sepsis in neonates and 24 cases of bacterial sepsis in children. All neonates and the majority of children were mechanically ventilated, and more than two-thirds of neonates with sepsis and one-third of children with sepsis needed inotropic/vasopressor drugs. The highest diagnostic accuracy for sepsis on the 1st day of suspected sepsis was achieved by LBP in neonates (0.86) and by CD64in in children (0.88) and 24 h later by CD64in in neonates (0.96) and children (0.98). Neutrophil CD64 index (CD64in) is the best individual marker for bacterial sepsis in children, while in neonates the highest diagnostic accuracy at the time of suspected sepsis was achieved by LBP and 24 h later by CD64in.

Sympathomimetic effects of Scoparia dulcis L. and catecholamines isolated from plant extracts.

PubMed

Freire, S M; Torres, L M; Souccar, C; Lapa, A J

1996-06-01

The herb Scoparia dulcis L. is used in Brazilian folk medicine to treat bronchitis, gastric disorders, haemorrhoids, insect bites and skin wounds, and in oriental medicine to treat hypertension. A previous study has shown that extracts of S. dulcis have analgesic and anti-inflammatory properties; in this work the sympathomimetic activity of an ethanolic extract of Scoparia dulcis L. has been investigated in rodent preparations in-vivo and in-vitro. Administration of the extract (0.5-2 mg kg-1, i.v.) to anaesthetized rats produced dose-related hypertension blocked by the alpha-adrenoceptor antagonist prazosin (1 mg kg-1). Partition of the extract in chloroform-water yielded an aqueous phase 20 times more potent than the extract; this produced hypertension in either reserpine-treated or pithed rats. In untreated and reserpine-treated rats the same fraction (1-3 x 10(3) micrograms mL-1) produced concentration-dependent contractions of the vas deferens musculature parallel to those obtained with noradrenaline (10(-8)-10(-4)M). Prazosin (10(-7)M) reduced the maximum contractile effect of the aqueous fraction, and shifted the concentration-response curves for noradrenaline to the right. The aqueous fraction (25 and 50 micrograms mL-1) increased the inotropism of electrically driven left atria of rats, the effect being blocked by propranolol (0.4 microgram mL-1). In preparations of guinea-pig tracheal rings the aqueous fraction (1-3 x 10(3) micrograms mL-1) relaxed the muscle contraction induced by histamine (10(-4) M) in proportion to the concentration. The effect was antagonized competitively by propranolol (1.5 microM). High-performance liquid-chromatographic analysis of the aqueous fraction revealed the presence of both noradrenaline and adrenaline in the plant extract. The results indicated that both catecholamines may account for the hypertensive and inotropic effects obtained after parenteral administration of S. dulcis extracts. This sympathomimetic activity is, however, unrelated to the previously reported analgesic and anti-inflammatory properties of the plant extract, but may explain its effectiveness upon topical application in the healing of mucosal and skin wounds.

β 1 Adrenoceptor antagonistic effects of the supposedly selective β 2 adrenoceptor antagonist ICI 118,551 on the positive inotropic effect of adrenaline in murine hearts.

PubMed

Pecha, Simon; Flenner, Frederik; Söhren, Klaus-Dieter; Lorenz, Kristina; Eschenhagen, Thomas; Christ, Torsten

2015-10-01

Studies on the relative contribution of β 1- and β 2-adrenoceptors (AR) generally employ selective β 1- and β 2-AR antagonists such as CGP 20712A and ICI 118,551, respectively, and assume that antagonism by one of these compounds indicates mediation by the respective AR subtype. Here, we evaluated the β 2-AR-selectivity of ICI 118,551 in ventricular muscle strips of transgenic mice lacking β 1-AR (β 1-KO), β 2-AR (β 2-KO), or both (β 1/β 2-KO). Strips were electrically driven and force development was measured. In wild type (WT), ICI 118,551 (100 nmol/L) shifted the concentration-response curve (CRC) for adrenaline by about 0.5 log units to the right, corresponding to the known affinity of ICI 118,551 to β 1-AR but not to β 2-AR. Conversely, the phosphodiesterase inhibitor rolipram (10 μmol/L) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive β 1-AR mediation even when PDE4 is inactive. In line with this, rolipram and ICI 118,551 had similar effects in β 2-KO than in WT. In contrast, β 1-KO did not show any inotropic reaction to adrenaline (+/- rolipram). In WT, the β 1-AR selective antagonist CGP 20712A (100 nmol/L) shifted the CRC for isoprenaline by 2.1 log units, corresponding to the affinity of CGP 20712A to β 1-AR. Rolipram increased the sensitivity to adrenaline independently of the presence of CGP 20712A. We conclude that effects sensitive to the β 2-AR antagonist ICI 118,551 are not necessarily β 2-AR-mediated and CGP 20712A-resistant effects cannot be simply interpreted as β 2-AR-mediated. Catecholamine effects in murine ventricles strictly depend on β 1-AR, even if PDE 4 is blocked.

β1 Adrenoceptor antagonistic effects of the supposedly selective β2 adrenoceptor antagonist ICI 118,551 on the positive inotropic effect of adrenaline in murine hearts

PubMed Central

Pecha, Simon; Flenner, Frederik; Söhren, Klaus-Dieter; Lorenz, Kristina; Eschenhagen, Thomas; Christ, Torsten

2015-01-01

Studies on the relative contribution of β1- and β2-adrenoceptors (AR) generally employ selective β1- and β2-AR antagonists such as CGP 20712A and ICI 118,551, respectively, and assume that antagonism by one of these compounds indicates mediation by the respective AR subtype. Here, we evaluated the β2-AR-selectivity of ICI 118,551 in ventricular muscle strips of transgenic mice lacking β1-AR (β1-KO), β2-AR (β2-KO), or both (β1/β2-KO). Strips were electrically driven and force development was measured. In wild type (WT), ICI 118,551 (100 nmol/L) shifted the concentration–response curve (CRC) for adrenaline by about 0.5 log units to the right, corresponding to the known affinity of ICI 118,551 to β1-AR but not to β2-AR. Conversely, the phosphodiesterase inhibitor rolipram (10 μmol/L) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive β1-AR mediation even when PDE4 is inactive. In line with this, rolipram and ICI 118,551 had similar effects in β2-KO than in WT. In contrast, β1-KO did not show any inotropic reaction to adrenaline (+/− rolipram). In WT, the β1-AR selective antagonist CGP 20712A (100 nmol/L) shifted the CRC for isoprenaline by 2.1 log units, corresponding to the affinity of CGP 20712A to β1-AR. Rolipram increased the sensitivity to adrenaline independently of the presence of CGP 20712A. We conclude that effects sensitive to the β2-AR antagonist ICI 118,551 are not necessarily β2-AR-mediated and CGP 20712A-resistant effects cannot be simply interpreted as β2-AR-mediated. Catecholamine effects in murine ventricles strictly depend on β1-AR, even if PDE 4 is blocked. PMID:26516580

A contraction-related component of slow inward current in dog ventricular muscle and its relation to Na(+)-Ca2+ exchange.

PubMed Central

Simurda, J; Simurdová, M; Bravený, P; Sumbera, J

1992-01-01

1. The slow inward current component related to contraction (Isic) was studied in voltage clamp experiments on canine ventricular trabeculae at 30 degrees C with the aims of (a) estimating its relation to electrogenic Na(+)-Ca2+ exchange and (b) comparing it with similar currents as reported in cardiac myocytes. 2. Isic may be recorded under conditions of augmented contractility in response to depolarizing pulses below the threshold of the classic slow inward current (presumably mediated by L-type Ca2+ channels). In responses to identical depolarizing clamp pulses the peak value of Isic is directly related to the amplitude of contraction (Fmax). Isic peaks about 60 ms after the onset of depolarization and declines with a half-time of about 110 ms. 3. The voltage threshold of Isic activation is the same as the threshold of contraction. The positive inotropic clamp preconditions shift both thresholds to more negative values of membrane voltage, i.e. below the threshold of the classic slow inward current. 4. Isic may also be recorded as a slowly decaying inwardly directed current 'tail' after depolarizing pulses. In this representation the peak value of Isic changes with duration of the depolarizing pulses, again in parallel with Fmax. In response to pulses shorter than 100 ms both variables increase with depolarization time. If initial conditions remain constant, further prolongation of the pulse does not significantly influence either one (tail currents follow a common envelope). 5. Isic differs from classic slow inward current by: (a) its direct relation to contraction, (b) the slower decay of the current tail on repolarization, (c) slower restitution corresponding to the mechanical restitution, (d) its relative insensitivity to Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic of Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic effect) and (e) its disappearance after Sr2+ substitution for Ca2+. 6. The manifestations of Isic in multicellular preparations do not differ significantly from those reported in isolated myocytes (in contrast to calcium current). 7. The analysis of the correlation between Isic and Fmax transients during trains of identical test depolarizing pulses at variable extra- and intracellular ionic concentrations (changes of [Ca2+]o, 50% Li+ substitution for Na+, strophanthidin) indicate that the observed effects conform to the predictions based on a quantitative model of Na(+)-Ca2+ exchange. 8. It is concluded that Isic is activated by a transient increase of [Ca2+]i, in consequence of the release from the reticular stores.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1293284

Sweet Chestnut (Castanea sativa Mill.) Bark Extract: Cardiovascular Activity and Myocyte Protection against Oxidative Damage

PubMed Central

Chiarini, Alberto; Micucci, Matteo; Ioan, Pierfranco; Fimognari, Carmela; Gallina Toschi, Tullia; Comandini, Patrizia; Hrelia, Silvana

2013-01-01

This work was aimed at evaluating the cardioprotective effects of Castanea sativa Mill. (CSM) bark extract characterized in its phenolic composition by HPLC-DAD-MS analysis. The study was performed using primary cultures of neonatal rat cardiomyocytes to investigate the antioxidant and cytoprotective effects of CSM bark extract and isolated guinea pig left and right atria, left papillary muscle, and aorta to evaluate its direct effect on cholinergic and adrenergic response. In cultured cardiomyocytes the CSM bark extract reduced intracellular reactive oxygen species formation and improved cell viability following oxidative stress in dose-dependent manner. Moreover, the extract decreased the contraction induced by noradrenaline (1 μM) in guinea pig aortic strips and induced transient negative chronotropic and positive inotropic effects without involvement of cholinergic or adrenergic receptors in the guinea pig atria. Our results indicate that CSM bark extract exhibits antioxidant activity and might induce cardioprotective effect. PMID:23533692

Comparative study of the venoms from three species of bees: effects on heart activity and blood.

PubMed

Hussein, A A; Nabil, Z I; Zalat, S M; Rakha, M K

2001-11-01

Crude venoms from three highly evolved aculeate species: Apis mellifera (highly social bees), Bombus morrisoni (eusocial bees), and Anthophora pauperata (solitary bees), were used for conducting this study to compare the effects of honey bee, bumble bee, and solitary bee venom on toad cardiac muscle activity. In addition, these venoms were tested on rat whole blood in order to determine their ability to induce red blood cell haemolysis. The main toxic effects on isolated toad heart were monitored by ECG after perfusion with different concentrations of each bee venom, and are represented as a decrease in the heart rate (HR) accompanied by an elongation in the P-R interval. A gradual and progressive increase in R-wave amplitude was also noted. Several electrocardiographic changes were noted 5-30 min after envenomation with any of the bee venoms. The mechanism of action of the three bee venoms was determined by direct application of atropine, nicotine, or verapamil to the isolated toad hearts. Comparison of the three venoms revealed that Anthophora pauperata venom is the most effective venom in inducing bradycardia, and it has the strongest negative dromotropic effect. Apis mellifera venom demonstrates the most positive inotropic effect of the three venoms. The effects of bee venom on the blood indices of erythrocyte osmotic fragility (EOF) and plasma albumin levels were studied after incubation of rat blood with each venom. It was noticed that RBCs decreased while Hb content, HCT, MCV, MCH, and MCHC increased, although this change did fluctuate and was not significant. A nonsignificant decrease in EOF was noted after 60 min with any of the venoms used. Incubation of rat whole blood with 1 microg/ml of any of the bee venom solutions revealed a highly significant decrease in plasma albumin levels. It can be concluded that venoms from the three species of bees we tested have negative chronotropic and dromotropic effects on isolated toad heart, with Anthophora pauperata being the most potent. In addition, the venoms have positive inotropic effects withApis mellifera being the most potent. The nonsignificant effects of venom on blood profiles and erythrocyte osmotic fragility, combined with the significant decrease in plasma albumin level suggest a protective effect of plasma albumin against bee venom induced toxicity to erythrocytes.

Effect of Crataegus Usage in Cardiovascular Disease Prevention: An Evidence-Based Approach

PubMed Central

Wang, Jie; Xiong, Xingjiang; Feng, Bo

2013-01-01

Hawthorn (Crataegus oxyacantha) is a widely used Chinese herb for treatment of gastrointestinal ailments and heart problems and consumed as food. In North America, the role of treatment for heart problems dates back to 1800. Currently, evidence is accumulating from various in vivo and in vitro studies that hawthorn extracts exert a wide range of cardiovascular pharmacological properties, including antioxidant activity, positive inotropic effect, anti-inflammatory effect, anticardiac remodeling effect, antiplatelet aggregation effect, vasodilating effect, endothelial protective effect, reduction of smooth muscle cell migration and proliferation, protective effect against ischemia/reperfusion injury, antiarrhythmic effect, lipid-lowering effect and decrease of arterial blood pressure effect. On the other hand, reviews of placebo-controlled trials have reported both subjective and objective improvement in patients with mild forms of heart failure (NYHA I–III), hypertension, and hyperlipidemia. This paper discussed the underlying pharmacology mechanisms in potential cardioprotective effects and elucidated the clinical applications of Crataegus and its various extracts. PMID:24459528

Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knapp, F.F. Jr.; McPherson, D.W.; Luo, H.

1995-06-01

Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development ofmore » the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.« less

[Myocardial mechanical injury in acute ischemia: a pathophysiologic and histopathologic review].

PubMed

Rossi, L; Matturri, L

1986-03-01

The recognition of histopathologic substrates of myocardial contractile damage in human acute ischemia is still very poor, notwithstanding the impressive advances in the inherent clinical diagnostic technology and concepts. The first and foremost inotropic abnormality ensuing ischemia, easily taken for atonic in origin, actually consists of a pathologic contracture of the injured myocardium, depending upon abrupt fall of ATP, and defective extrusion calcium pump with persistence of actomyosin rigor-complexes. In sustained ischemia, further membrane damage exposes the myocell to massive calcium intrusion, with eventual precipitation of it and cell death (reperfusion stone-heart). In case of transient, "hit and run" ischemia, the "stunned" myocardium undergoes prolonged contractile abnormalities. In keeping with fundamentals in pathophysiology of contraction, ischemic myofibrils in human hyperacute infarct, showed spare I bands, accounting for contracture and followed by loss of the regular cross-striation register; then, groups of adjacent sarcomeres were seen to join into true "contraction" bands, with Z lines impinging upon A bands and obliterating the I bands. Coagulative denaturation of contractile proteins follows, presenting as irregular, amorphous degeneration stripes astride irreversibly damaged myocells. As such, these cells can be passively overstretched by the nearby functioning muscle. In turn, the fixed waviness of viable, acutely ischemic myocardium was thought to configure, histologically, the loss of ATP-dependent "plasticity" of myofilaments, in a state of contracture. The "relaxant effect" of inotropic-chronotropic-positive catecholamines, favoring diastole, has been also pointed out. The present microscopic findings are cogent to clinicopathologic problems of coronary ischemia-reperfusion, and sudden death from cardiogenic shock.

Iloprost improves ventricular function in the hypertrophic and functionally impaired right heart by direct stimulation.

PubMed

Holmboe, Sarah; Andersen, Asger; Vildbrad, Mads D; Nielsen, Jan M; Ringgaard, Steffen; Nielsen-Kudsk, Jens E

2013-12-01

Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure-overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; [Formula: see text]), pulmonary trunk banding (PTB; [Formula: see text]), or a sham operation ([Formula: see text]). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a [Formula: see text] ([Formula: see text]) increase in stroke volume in the sham group and a [Formula: see text] ([Formula: see text]) increase in the PTB group. RV [Formula: see text] was elevated by [Formula: see text] ([Formula: see text]) in the sham group and by [Formula: see text] ([Formula: see text]) in the PTB group. An elevation in cardiac output of [Formula: see text] ([Formula: see text]) and an [Formula: see text] ([Formula: see text]) increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat.

Reconstituted fresh whole blood improves clinical outcomes compared with stored component blood therapy for neonates undergoing cardiopulmonary bypass for cardiac surgery: a randomized controlled trial.

PubMed

Gruenwald, Colleen E; McCrindle, Brian W; Crawford-Lean, Lynn; Holtby, Helen; Parshuram, Christopher; Massicotte, Patricia; Van Arsdell, Glen

2008-12-01

This study compared the effects of reconstituted fresh whole blood against standard blood component therapy in neonates undergoing cardiac surgery. Patients less than 1 month of age were randomized to receive either reconstituted fresh whole blood (n = 31) or standard blood component therapy (n = 33) to prime the bypass circuit and for transfusion during the 24 hours after cardiopulmonary bypass. Primary outcome was chest tube drainage; secondary outcomes included transfusion needs, inotrope score, ventilation time, and hospital length of stay. Patients who received reconstituted fresh whole blood had significantly less postoperative chest tube volume loss per kilogram of body weight (7.7 mL/kg vs 11.8 mL/kg; P = .03). Standard blood component therapy was associated with higher inotropic score (6.6 vs 3.3; P = .002), longer ventilation times (164 hours vs 119 hours; P = .04), as well as longer hospital stays (18 days vs 12 days; P = .006) than patients receiving reconstituted fresh whole blood. Of the different factors associated with the use of reconstituted fresh whole blood, lower platelet counts at 10 minutes and at the end of cardiopulmonary bypass, older age of cells used in the prime and throughout bypass, and exposures to higher number of allogeneic donors were found to be independent predictors of poor clinical outcomes. Reconstituted fresh whole blood used for the prime, throughout cardiopulmonary bypass, and for all transfusion requirements within the first 24 hours postoperatively results in reduced chest tube volume loss and improved clinical outcomes in neonatal patients undergoing cardiac surgery.

Superselective Embolization for Arterial Upper Gastrointestinal Bleeding Using N-Butyl Cyanoacrylate: A Single-Center Experience in 152 Patients.

PubMed

Hur, Saebeom; Jae, Hwan Jun; Lee, Hyukjoon; Lee, Myungsu; Kim, Hyo-Cheol; Chung, Jin Wook

2017-12-01

To evaluate 30-day safety and efficacy of superselective embolization for arterial upper gastrointestinal bleeding (UGIB) using N-butyl cyanoacrylate (NBCA). This single-center retrospective 10-year study included 152 consecutive patients with UGIB (gastric, n = 74; duodenal, n = 78) who underwent embolization with NBCA for angiographically positive arterial bleeding. The primary endpoint was clinical success rate defined as achievement of hemostasis without rebleeding or UGIB-related mortality within 30 days after embolization. Mean systolic blood pressure and heart rate were 121.2 mm Hg ± 27.4 and 97.9 beats/minute ± 22.5; 31.1% of patients needed intravenous inotropes, and 36.6% had coagulopathy. The etiology of bleeding was ulcer (80.3%) or iatrogenic injury (19.7%). Statistical analysis was performed to identify predictive factors for outcomes. Technical success rate was 100%. Clinical success, 1-month mortality, and major complication rates were 70.4%, 22.4%, and 0.7%. There were significant differences in the clinical success rates between gastric and duodenal bleeding (79.4% vs 62.2%; P = .025). The need for intravenous inotropes at the time of embolization was a significant negative predictive factor in both gastric (odds ratio [OR] = 0.091, P = .004) and duodenal (OR = 0.156, P = .002) bleeding. The use of a microcatheter with a smaller tip (2 F) was associated with better outcomes in duodenal bleeding (OR = 7.389, P = .005). Superselective embolization using NBCA is safe and effective for angiographically positive arterial UGIB. Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.

Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant.

PubMed

Aliakbarian, Mohsen; Nikeghbalian, Saman; Ghaffaripour, Sina; Bahreini, Amin; Shafiee, Mohammad; Rashidi, Mohammad; Rajabnejad, Yaser

2017-08-01

One of the main concerns in liver transplant is the prolonged ischemia time, which may lead to primary graft nonfunction or delayed function. N-acetylcysteine is known as a hepato-protective agent in different studies, which may improve human hepatocyte viability in steatotic donor livers. This study investigated whether N-acetylcysteine can decrease the rate of ischemia-reperfusion syndrome and improve short-term outcome in liver transplant recipients. This was a double-blind, randomized, control clinical trial of 115 patients. Between April 2012 and January 2013, patients with orthotopic liver transplant were randomly divided into 2 groups; in 49 cases N-acetylcysteine was added to University of Wisconsin solution as the preservative liquid (experimental group), and in 66 cases standard University of Wisconsin solution was used (control group). We compared postreperfusion hypotension, inotrope requirement before and after portal reperfusion, intermittent arterial blood gas analysis and potassium measurement, pathological review of transplanted liver, in-hospital complications, morbidity, and mortality. There was no significant difference between the groups regarding time to hepatic artery reperfusion, hospital stay, vascular complications, inotrope requirement before and after portal declamping, and blood gas analysis. Hypotension after portal reperfusion was significantly more common in experimental group compared with control group (P = .005). Retransplant and in-hospital mortality were comparable between the groups. Preservation of the liver inside Univer-sity of Wisconsin solution plus N-acetylcysteine did not change the rate of ischemia reperfusion injury and short-term outcome in liver transplant recipients.

Heartmate 3 fully magnetically levitated left ventricular assist device for the treatment of advanced heart failure -1 year results from the Ce mark trial.

PubMed

Krabatsch, Thomas; Netuka, Ivan; Schmitto, Jan D; Zimpfer, Daniel; Garbade, Jens; Rao, Vivek; Morshuis, Michiel; Beyersdorf, Friedhelm; Marasco, Silvana; Damme, Laura; Pya, Yuriy

2017-04-04

The HeartMate 3 Left Ventricular Assist System (LVAS) (St. Jude Medical Inc., St Paul, MN) with full magnetic levitation allows for wide and consistent blood flow paths and an artificial pulse designed for enhanced hemocompatibility. The HeartMate 3 received market approval in the European Union in 2015 following completion of a multicenter study. After reaching the 6-month study endpoint, patients continue to be followed for 2 years with the 1-year results presented herein. A prospective, non-randomized study included adults with advanced heart failure and ejection fraction (EF) ≤ 25%, cardiac index (CI) ≤ 2.2 L/min/m2 while not on inotropes, or inotrope dependent, or on optimal medical management for 45/60 days. Fifty patients-54% bridge to transplant (BTT) and 46% destination therapy (DT)-were enrolled and implanted with the HeartMate 3. At baseline, 92% of the patients were INTERMACS profiles 2-4, with cardiac index 1.8 + 0.5 L/min/m 2 and 58% were supported with inotropes. At 1 year, 74% of the patients remain on support, 18% expired, 6% transplanted, and 2% explanted. The adverse events include 12% gastrointestinal bleeding, 16% driveline infections, 18% strokes, and 2% outflow graft thrombosis. There was no hemolysis, pump thrombosis or pump malfunction through 1 year. The six-minute walk test distance increased from a mean of 273 m to 371 m (P <0.0001). EQ-5D quality-of-life score increased from a mean of 52.7 to 70.8 (P = 0.0006). The 1-year HeartMate 3 LVAS results show survival and adverse-event profile are similar to other approved devices, with no pump thrombosis or pump failure. Patient's functional status and quality of life significantly improved over time. Clinicaltrials.gov registration number: NCT02170363 . Registered June 19, 2014.

Early outcomes of on-pump versus off-pump coronary artery bypass grafting.

PubMed

Hussain, Ghulam; Azam, Hammad; Baig, Mirza Ahmad Raza; Ahmad, Naseem

2016-01-01

To see the early post-operative outcomes of off-pump versus on-pump coronary artery bypass graft surgery. This retrospective analytical study was conducted at Ch. Pervaiz Elahi Institute of Cardiology Multan, Pakistan. Our Primary outcome variables were; necessity of inotropic support, nonfatal myocardial infarction, ICU stay, nonfatal stroke, new renal failure requiring dialysis and death within 30 days after operation. There were two groups of patients; Group-I (On-pump group) and Group-II (Off-pump Group). SPSS V17 was used for data analysis. Independent sample t-test and Mann Whitney U test were used to compare quantitative Variables. Chi-square test and Fisher's exact test were used to analyze qualitative variables. P-value ≤ 0.05 was considered significant. Three hundred patients were included in this study. There were no significant difference regarding risk factors except hyper-cholestrolemia which was high in off pump group (p-value 0.05). Angiographic and Echocardiographic characteristics e.g. preoperative ejection fraction, LV function grade and severity of CAD was same between the groups. Mortality risk scores and Priority status for surgery were also same. Regarding post-operative outcomes; Post-op CKMB Levels, need and duration of inotropic support, mechanical ventilation time and ICU stay was significantly less in Off-Pump group (p-value 0.001, <0.0001, 0.006, 0.025 and 0.001 resp.). Peri-operative chest drainage was significantly high in On-pump CABG group (p-value 0.027). Incidence of post-op complications was not statistically different between the groups. At 30 days follow-up, Incidence of myocardial infarction, necessity and duration of inotropic support, ICU stay period and peri-operative bleeding were significantly less in off-pump group. The incidence of neurologic, pulmonary and renal complications was same between the off-pump and on-pump groups.

Early outcomes of on-pump versus off-pump coronary artery bypass grafting

PubMed Central

Hussain, Ghulam; Azam, Hammad; Baig, Mirza Ahmad Raza; Ahmad, Naseem

2016-01-01

Objectives: To see the early post-operative outcomes of off-pump versus on-pump coronary artery bypass graft surgery. Methods: This retrospective analytical study was conducted at Ch. Pervaiz Elahi Institute of Cardiology Multan, Pakistan. Our Primary outcome variables were; necessity of inotropic support, nonfatal myocardial infarction, ICU stay, nonfatal stroke, new renal failure requiring dialysis and death within 30 days after operation. There were two groups of patients; Group-I (On-pump group) and Group-II (Off-pump Group). SPSS V17 was used for data analysis. Independent sample t-test and Mann Whitney U test were used to compare quantitative Variables. Chi-square test and Fisher’s exact test were used to analyze qualitative variables. P-value ≤ 0.05 was considered significant. Results: Three hundred patients were included in this study. There were no significant difference regarding risk factors except hyper-cholestrolemia which was high in off pump group (p-value 0.05). Angiographic and Echocardiographic characteristics e.g. preoperative ejection fraction, LV function grade and severity of CAD was same between the groups. Mortality risk scores and Priority status for surgery were also same. Regarding post-operative outcomes; Post-op CKMB Levels, need and duration of inotropic support, mechanical ventilation time and ICU stay was significantly less in Off-Pump group (p-value 0.001, <0.0001, 0.006, 0.025 and 0.001 resp.). Peri-operative chest drainage was significantly high in On-pump CABG group (p-value 0.027). Incidence of post-op complications was not statistically different between the groups. Conclusions: At 30 days follow-up, Incidence of myocardial infarction, necessity and duration of inotropic support, ICU stay period and peri-operative bleeding were significantly less in off-pump group. The incidence of neurologic, pulmonary and renal complications was same between the off-pump and on-pump groups. PMID:27648039

Cardiovascular effects of Persea americana Mill (Lauraceae) (avocado) aqueous leaf extract in experimental animals.

PubMed

Ojewole, J A O; Kamadyaapa, D R; Gondwe, M M; Moodley, K; Musabayane, C T

2007-01-01

The cardiovascular effects of Persea americana Mill (Lauraceae) aqueous leaf extract (PAE) have been investigated in some experimental animal paradigms. The effects of PAE on myocardial contractile performance was evaluated on guinea pig isolated atrial muscle strips, while the vasodilatory effects of the plant extract were examined on isolated portal veins and thoracic aortic rings of healthy normal Wistar rats in vitro. The hypotensive (antihypertensive) effect of the plant extract was examined in healthy normotensive and hypertensive Dahl salt-sensitive rats in vivo. P americana aqueous leaf extract (25-800 mg/ml) produced concentration-dependent, significant (p < 0.05-0.001), negative inotropic and negative chronotropic effects on guinea pig isolated electrically driven left and spontaneously beating right atrial muscle preparations, respectively. Moreover, PAE reduced or abolished, in a concentration-dependent manner, the positive inotropic and chronotropic responses of guinea pig isolated atrial muscle strips induced by noradrenaline (NA, 10(-10)-10(-5) M), and calcium (Ca(2+), 5-40 mM). PAE (50-800 mg/ml) also significantly reduced (p < 0.05-0.001) or abolished, in a concentration-dependent manner, the rhythmic, spontaneous, myogenic contractions of portal veins isolated from healthy normal Wistar rats. Like acetylcholine (ACh, 10(-8)-10(-5) M), the plant extract (25- 800 mg/ml) produced concentration-related relaxations of isolated endothelium-containing thoracic aortic rings pre-contracted with noradrenaline. The vasorelaxant effects of PAE in the isolated, endothelium-intact aortic rings were markedly inhibited or annulled by N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) M), a nitric oxide synthase inhibitor. Furthermore, PAE (25-400 mg/kg iv) caused dose-related, transient but significant reductions (p < 0.05-0.001) in the systemic arterial blood pressure and heart rates of the anaesthetised normotensive and hypertensive rats used. The results of this laboratory animal study indicate that PAE caused bradycardia, vasorelaxation and hypotension in the mammalian experimental models used. The vasorelaxant action of PAE was endothelium dependent, and was, therefore, possibly dependent on the synthesis and release of nitric oxide (NO). The vasorelaxant effects of PAE appeared to contribute significantly to the hypotensive (antihypertensive) effects of the plant extract. However, the findings of this study tend to suggest that P americana leaf could be used as a natural supplementary remedy in essential hypertension and certain cases of cardiac dysfunctions in some rural Africa communities.

Increased red blood cell transfusions are associated with worsening outcomes in pediatric heart transplant patients.

PubMed

Howard-Quijano, Kimberly; Schwarzenberger, Johanna C; Scovotti, Jennifer C; Alejos, Alexandra; Ngo, Jason; Gornbein, Jeffrey; Mahajan, Aman

2013-06-01

Red blood cell (RBC) transfusions are associated with increased morbidity. Children receiving heart transplants constitute a unique group of patients due to their risk factors. Although previous studies in nontransplant patients have focused primarily on the effects of postoperative blood transfusions, a significant exposure to blood occurs during the intraoperative period, and a larger percentage of heart transplant patients require intraoperative blood transfusions when compared with general cardiac surgery patients. We investigated the relationship between clinical outcomes and the amount of blood transfused both during and after heart transplantation. We hypothesized that larger amounts of RBC transfusions are associated with worsening clinical outcomes in pediatric heart transplant patients. A database comprising 108 pediatric patients undergoing heart transplantation from 2004 to 2010 was queried. Preoperative and postoperative clinical risk factors, including the amount of blood transfused intraoperatively and 48 hours postoperatively, were analyzed. The outcome measures were length of hospital stay, duration of tracheal intubation, inotrope score, and major adverse events. Bivariate and multivariate analyses were performed to control for simultaneous risk factors and determine outcomes in which the amount of blood transfused was an independent risk factor. Ninety-four patients with complete datasets were included in the final analysis. Eighty-eight percent received RBC transfusions, with a median transfusion amount of 38.7 mL/kg. A multivariate analysis correcting for 8 covariate risk factors, including the Index for Mortality Prediction After Cardiac Transplantation, age, weight, United Network for Organ Sharing status, warm and cold ischemia time, repeat sternotomy, and pretransplant hematocrit, showed RBC transfusions were independently associated with increased length of intensive care unit stay (means ratio = 1.34; 95% confidence interval, 1.03-1.76; P = 0.03), and increased inotrope score in the first postoperative 24 hour (mean ratio = 1.26; 95% confidence interval, 1.04-1.52; P = 0.04). Patients suffering major adverse events received significantly larger median amounts of blood RBC transfusions (P = 0.002). Transfusions >60 mL/kg were also associated with increased risk of major adverse events (accuracy 76%) including postoperative sepsis, extracorporeal membrane oxygenation, open chest, dialysis, and graft failure. The majority of pediatric patients undergoing orthotropic heart transplantation receive RBC transfusions, with the largest amount transfused in the operating room. Escalating amounts of RBC transfusions are independently associated with increased length of intensive care unit stay, inotrope scores, and major adverse events. Since heart allografts are a limited resource, improvement in the blood transfusion and conservation practices can enhance clinical outcomes in pediatric heart transplant patients.

Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery.

PubMed

Senanayake, Eshan L; Howell, Neil J; Ranasinghe, Aaron M; Drury, Nigel E; Freemantle, Nick; Frenneaux, Michael; Oelofse, Tessa; Green, David; Wilson, Ian C; Rooney, Stephen J; Mascaro, Jorge; Graham, Timothy R; Bhudia, Sunil; Lewis, Michael; Pagano, Domenico

2015-09-01

Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR). In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR ± coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures. The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups. Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Hemodynamic changes during displacement of the beating heart using epicardial stabilization for off-pump coronary artery bypass graft surgery.

PubMed

Mishra, Manisha; Malhotra, Rajneesh; Mishra, Anil; Meharwal, Zile Singh; Trehan, Naresh

2002-12-01

To evaluate the hemodynamic alterations during off-pump coronary artery bypass graft surgery to determine the degree of impairment caused and the techniques to rectify them. Prospective, observational cohort study performed from January 2000 through September 2000. Patients (n = 500) with coronary artery disease undergoing multivessel off-pump coronary artery bypass graft surgery using the Octopus tissue stabilizer (Medtronic, Inc, Minneapolis, MN). Unstable patients with ongoing ischemia were excluded from the study. All patients were monitored with radial artery and pulmonary artery catheters and continuous transesophageal echocardiography monitoring with a multiplane transducer. The perioperative requirement of an intracoronary shunt, inotropes, or an intra-aortic balloon pump was noted. The effect of the Trendelenburg position and fluids on hemodynamics was observed. The need for defibrillation and institution of emergency cardiopulmonary bypass were major endpoints to determine the inability of the patient to tolerate displacement of the heart. Mean patient age was 59.3 +/- 11.6 years. There were 204 (40%) patients in the high-risk category; 54 (10.8%) patients had left ventricular ejection fraction <25%. The mean number of grafts was 2.7 +/- 0.8. Vertical displacement of the heart to access the lateral and inferior walls decreased the mean arterial pressure by 18 +/- 4% (p < 0.01), with a concomitant increase in central venous pressure of 66 +/- 18% (p < 0.001). The stroke volume and the cardiac index were reduced by 35.7 +/- 11% (p < 0.001) and 45 +/- 13% (p < 0.001). On transesophageal echocardiography, there was development of new regional wall motion abnormalities in 59.2% and a decrease in global left ventricular functions in 61.2%. The use of inotropes was highest during anastomosis on the posterior wall-78.4% compared with 21.9% for the anterior wall. An intra-aortic balloon pump was used in 55 (11.2%) patients, and 7 (0.71 %) patients had to be put on emergency CPB. The in-hospital mortality was 1.2%. Most patients had hemodynamic changes easily correctable by fluids and inotropes. Monitoring of left ventricular and right ventricular function by transesophageal echocardiography enhances safety of the procedure and is recommended. The use of the Octopus II tissue stabilizer proved to be a safe and versatile means to stabilize the heart during off-pump coronary artery bypass procedures, especially in high-risk patients. Copyright 2002, Elsevier Science (USA). All rights reserved.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

PubMed Central

Kiriazis, Helen; Tugiono, Niquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole L; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger J; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun

2013-01-01

BACKGROUND AND PURPOSE The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID:23750586

Oxygen-saving effect of a new cardiotonic agent, MCI-154, in diseased human hearts.

PubMed

Mori, M; Takeuchi, M; Takaoka, H; Hata, K; Hayashi, Y; Yamakawa, H; Yokoyama, M

1997-03-01

The aim of this study was to examine the left ventricular mechanoenergetic effects of a novel Ca2+ sensitizing agent, MCI-154, on diseased human hearts compared with dobutamine. Unlike conventional cardiotonic agents, a Ca2+ sensitizer that could produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ could generate force with smaller amounts of Ca2+; thus, it may potentially save energy expenditure. The left ventricular pressure-volume relation and myocardial oxygen consumption per beat (Vo2) were measured by a conductance (volume) catheter and a Webster catheter. Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2 were assessed before and after infusion of MCI-154 or dobut-amine. The PVA-independent Vo2 (Vo2 mainly for excitation-contraction coupling) was assessed as the Vo2 at zero PVA. Both agents increased Emax comparably (dobutamine: from 3.55 +/- 1.10 [mean +/- SD] to 5.04 +/- 1.16 mm Hg/ml per m2, p < 0.0001; MCI-154: from 3.36 +/- 1.26 to 5.37 +/- 2.14 mm Hg/ml per m2, p < 0.0001); dobutamine increased total Vo2 (from 0.22 +/- 0.08 to 0.27 +/- 0.09 ml O2, p < 0.05) and PVA-independent Vo2 (from 0.019 +/- 0.019 to 0.091 +/- 0.051 ml O2, p < 0.005); but MCI-154 did not change these variables significantly. Consequently, the oxygen cost of contractility (delta PVA-independent Vo2/delta Emax) was less with MCI-154 than with dobutamine (0.14 +/- 0.18 vs. 1.10 +/- 0.80 J/mm Hg per ml per m2, p < 0.05). These results suggest that the cardiotonic action mediated by MCI-154 could provide an energetic advantage over the conventional cardiotonic action with currently used inotropic agents.

Advances in the management of heart failure: the role of ivabradine

PubMed Central

Müller-Werdan, Ursula; Stöckl, Georg; Werdan, Karl

2016-01-01

A high resting heart rate (≥70–75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class “IIa” = weight of evidence/opinion is in favor of usefulness/efficacy: “should be considered”; level of evidence “B” = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5–7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication “HF with reduced EF” together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF. PMID:27895488

Rejection with hemodynamic compromise in the current era of pediatric heart transplantation: a multi-institutional study.

PubMed

Everitt, Melanie D; Pahl, Elfriede; Schechtman, Kenneth B; Zheng, Jie; Ringewald, Jeremy M; L'ecuyer, Thomas; Naftel, David C; Kirklin, James K; Blume, Elizabeth D; Bullock, Emily A; Canter, Charles E

2011-03-01

Survival after pediatric heart transplant has improved over time, as has the incidence of overall rejection. We studied the effect of era on the occurrence and outcome of rejection with hemodynamic compromise (HC). Data from 2227 patients who received allografts between 1993 and 2006 at 36 centers in the Pediatric Heart Transplant Study were analyzed to determine incidence, outcome, and risk factors for rejection with HC in early (1993-1999) and recent (2000-2006) eras. Rejection with HC was classified as severe (RSHC) when inotropes were used for circulatory support and mild (RMHC) when inotropes were not used. Of 1217 patients with any episode of rejection, 541 had rejection with HC. Freedom from RMHC improved at 1 year (81% vs 90%, p < 0.001) and at 5 years (74% vs 85%, p < 0.001) in the early vs recent eras, but freedom from RSHC was similar between eras (93% vs 95% at 1 year and 85% vs 87% at 5 years, p = 0.24). Survival after RSHC (63% at 1 year and 49% at 5 years) was worse than after RMHC (87% at 1 year and 72% at 5 years, p < 0.001) and did not change over time. Risk factors for RSHC were non-white race (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.29-2.32, p < 0.01), older age (HR, 2.85; 95% CI, 1.24-6.53; p = 0.01), and non-A blood type (HR, 1.51;, 95% CI, 1.11-2.04,; p = 0.01), but the only risk factor for RMHC was earlier era of transplant (HR, 1.94; 95% CI, 1.56-2.41; p < 0.001). The incidence of RMHC has declined over time but the same era effect has not occurred with RSHC. Close follow-up after RSHC is crucial because mortality is so high. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

[Myocardial depression in the burn patient].

PubMed

Carrillo-Esper, Raúl; Sánchez-Zúñiga, Martín de Jesús

2006-01-01

Myocardial depression and heart failure are frequent complications in critically ill burn patients. The physiopathology is complex and involves the activation of inflammatory pathways, ischemia-reperfusion, oxidative stress and endothelial lesion. Diagnosis should be made early by means of hemodynamic monitoring. Treatment is accomplished by inotropics that act on different pathways of the contractile function and immune response associated with antioxidants and allopurinol.

S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system.

PubMed

Carl, M; Alms, A; Braun, J; Dongas, A; Erb, J; Goetz, A; Goepfert, M; Gogarten, W; Grosse, J; Heller, A R; Heringlake, M; Kastrup, M; Kroener, A; Loer, S A; Marggraf, G; Markewitz, A; Reuter, D; Schmitt, D V; Schirmer, U; Wiesenack, C; Zwissler, B; Spies, C

2010-06-15

Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefässchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed. The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF).

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.

PubMed

Isbister, Geoffrey K; Ang, Karyn; Gorman, Kieron; Cooper, Joyce; Mostafa, Ahmed; Roberts, Michael S

2016-11-01

Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment. A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m 2 ). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX ® vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035-0.5 μg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [V m ], 9.57 mg h -1 , Michaelis constant [K m ], 1.97 mg L -1 . Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h. The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.

Wearable defibrillator use in heart failure (WIF): results of a prospective registry

PubMed Central

2012-01-01

Background Heart failure (HF) patients have a high risk of death, and implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death (SCD). However, a certain percentage of patients may not be immediate candidates for ICDs, particularly those having a short duration of risk or an uncertain amount of risk. This includes the newly diagnosed patients, as well as those on the cardiac transplant list or NYHA class IV heart failure patients who do not already have an ICD. In these patients, a wearable cardioverter defibrillator (WCD) may be used until long term risk of SCD is defined. The purpose of this study was to determine the incidence of SCD in this population, and the efficacy of early defibrillation by a WCD. Methods Ten enrolling centers identified 89 eligible HF patients who were either listed for cardiac transplantation, diagnosed with dilated cardiomyopathy, or receiving inotropic medications. Data collected included medical history, device records, and outcomes (including 90 day mortality). Results Out of 89 patients, final data on 82 patients has been collected. Patients wore the device for 75±58 days. Mean age was 56.8±13.2, and 72% were male. Most patients (98.8%) were diagnosed with dilated cardiomyopathy with a low ejection fraction (<40%) and twelve were listed for cardiac transplantation. Four patients were on inotropes. There were no sudden cardiac arrests or deaths during the study. Interestingly, 41.5% of patients were much improved after WCD use, while 34.1% went on to receive an ICD. Conclusions In conclusion, the WCD monitored HF patients until further assessment of risk. The leading reasons for end of WCD use were improvement in left ventricular ejection fraction (LVEF) or ICD implantation if there was no significant improvement in LVEF. PMID:23234574

Comparing the effect of preoperative administration of methylprednisolone and its administration before and during surgery on the clinical outcome in pediatric open heart surgeries.

PubMed

Soltani, Ghasem; Abbasi Tashnizi, Mohammad; Moeinipour, Ali Asghar; Ganjifard, Mahmoud; Esfahanizadeh, Jamil; Sepehri Shamloo, Alireza; Purafzali Firuzabadi, Seyed Javad; Zirak, Nahid

2013-06-01

Cardiac surgery under Cardiopulmonary bypass causes a systemic inflammatory response with a multifactorial etiology including direct tissue damage, ischemia and stimulation of immune system induced by cardiopulmonary bypass. This study was designed due to the high prevalence and complications of this stimulated immune system in mortality, morbidity, length of ICU stay, and mechanical ventilation. This study was aimed to compare preoperative and intraoperative methylprednisolone (MP) to intraoperative MP alone with respect to postbypass inflammation and clinical outcome. Sixty pediatric patients (age < 5years) undergoing cardiopulmonary bypass surgery between September 2011-2012 at Imam Reza hospital-Mashhad were randomly assigned to receive preoperative and intraoperative MP (group 1: 30 mg/kg, 4 hours before bypass and in bypass prime, n = 30) or intraoperative MP only (group 2: 30 mg/kg, n = 30). Postoperative temperature (peak temperature and average temperature during the first 24 hours), amount of inotropic, duration of mechanical ventilation, ICU stay, WBC, BUN, creatinine, and CRP were recorded and compared in both groups. Data were analyzed with SPSS version 13 by T-test, Mann-Whitney test if necessary, and Chi-squared distribution. Patient characteristics including age, weight, gender, and duration of bypass were almost similar in both groups (P > 0.05). No significant difference in amount of inotropic medications used for hemodynamic supports, duration of mechanical ventilation, peak and average temperature and length of ICU stay was observed. Among the laboratory tests (WBC, BUN, creatinine, CRP) only WBC counts raised more in group 2 when compared to group 1(P < 0.05). There was no difference in clinical outcome after cardiac surgery when we administered an additional dose of methylprednisolone compared to a single dose of methylprednisolone.

Comparing the Effect of Preoperative Administration of Methylprednisolone and its Administration Before and During Surgery on the Clinical Outcome in Pediatric Open Heart Surgeries

PubMed Central

Soltani, Ghasem; Abbasi Tashnizi, Mohammad; Moeinipour, Ali Asghar; Ganjifard, Mahmoud; Esfahanizadeh, Jamil; Sepehri Shamloo, Alireza; Purafzali Firuzabadi, Seyed Javad; Zirak, Nahid

2013-01-01

Background Cardiac surgery under Cardiopulmonary bypass causes a systemic inflammatory response with a multifactorial etiology including direct tissue damage, ischemia and stimulation of immune system induced by cardiopulmonary bypass. This study was designed due to the high prevalence and complications of this stimulated immune system in mortality, morbidity, length of ICU stay, and mechanical ventilation. Objectives This study was aimed to compare preoperative and intraoperative methylprednisolone (MP) to intraoperative MP alone with respect to postbypass inflammation and clinical outcome. Patients and Methods Sixty pediatric patients (age < 5years) undergoing cardiopulmonary bypass surgery between September 2011-2012 at Imam Reza hospital-Mashhad were randomly assigned to receive preoperative and intraoperative MP (group 1: 30 mg/kg, 4 hours before bypass and in bypass prime, n = 30) or intraoperative MP only (group 2: 30 mg/kg, n = 30). Postoperative temperature (peak temperature and average temperature during the first 24 hours), amount of inotropic, duration of mechanical ventilation, ICU stay, WBC, BUN, creatinine, and CRP were recorded and compared in both groups. Data were analyzed with SPSS version 13 by T-test, Mann-Whitney test if necessary, and Chi-squared distribution. Results Patient characteristics including age, weight, gender, and duration of bypass were almost similar in both groups (P > 0.05). No significant difference in amount of inotropic medications used for hemodynamic supports, duration of mechanical ventilation, peak and average temperature and length of ICU stay was observed. Among the laboratory tests (WBC, BUN, creatinine, CRP) only WBC counts raised more in group 2 when compared to group 1(P < 0.05). Conclusions There was no difference in clinical outcome after cardiac surgery when we administered an additional dose of methylprednisolone compared to a single dose of methylprednisolone. PMID:24349746

Comparison of local versus general anesthesia in patients undergoing transcatheter aortic valve replacement: A meta-analysis.

PubMed

Villablanca, Pedro A; Mohananey, Divyanshu; Nikolic, Katarina; Bangalore, Sripal; Slovut, David P; Mathew, Verghese; Thourani, Vinod H; Rode's-Cabau, Josep; Núñez-Gil, Iván J; Shah, Tina; Gupta, Tanush; Briceno, David F; Garcia, Mario J; Gutsche, Jacob T; Augoustides, John G; Ramakrishna, Harish

2018-02-01

Transcatheter aortic valve replacement (TAVR) is typically performed under general anesthesia (GA). However, there is increasing data supporting the safety of performing TAVR under local anesthesia/conscious sedation (LA). We performed a meta-analysis to gain better understanding of the safety and efficacy of LA versus GA in patients with severe aortic stenosis undergoing TAVR. We comprehensively searched EMBASE, PubMed, and Web of Science. Effect sizes were summarized using risk ratios (RRs) difference of the mean (DM), and 95% CIs (confidence intervals) for dichotomous and continuous variables respectively. Twenty-six studies and 10,572 patients were included in the meta-analysis. The use of LA for TAVR was associated with lower overall 30-day mortality (RR, 0.73; 95% CI, 0.57-0.93; P = 0.01), use of inotropic/vasopressor drugs (RR, 0.45; 95% CI, 0.28-0.72; P < 0.001), hospital length of stay (LOS) (DM, -2.09; 95% CI, -3.02 to -1.16; P < 0.001), intensive care unit LOS (DM, -0.18; 95% CI, -0.31 to -0.04; P = 0.01), procedure time (DM, -25.02; 95% CI, -32.70 to -17.35; P < 0.001); and fluoroscopy time (DM, -1.63; 95% CI, -3.02 to -0.24; P = 0.02). No differences were observed between LA and GA for stroke, cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, acute kidney injury, paravalvular leak, vascular complications, major bleeding, procedural success, conduction abnormalities, and annular rupture. Our meta-analysis suggests that use of LA for TAVR is associated with a lower 30-day mortality, shorter procedure time, fluoroscopy time, ICU LOS, hospital length of stay, and reduced need for inotropic support. © 2017 Wiley Periodicals, Inc.

Rationale and design of the multicenter randomized trial investigating the effects of levosimendan pretreatment in patients with low ejection fraction (≤40 %) undergoing CABG with cardiopulmonary bypass (LICORN study).

PubMed

Caruba, Thibaut; Hourton, Delphine; Sabatier, Brigitte; Rousseau, Dominique; Tibi, Annick; Hoffart-Jourdain, Cécile; Souag, Akim; Freitas, Nelly; Yjjou, Mounia; Almeida, Carla; Gomes, Nathalie; Aucouturier, Pascaline; Djadi-Prat, Juliette; Menasché, Philippe; Chatellier, Gilles; Cholley, Bernard

2016-08-05

Patients with a left ventricular ejection fraction (LVEF) of less than 40 % are at high risk of developing postoperative low cardiac output syndrome (LCOS). Despite actual treatments (inotropic agents and/or mechanical assist devices), the mortality rate of such patients remains very high (13 to 24 %). The LICORN trial aims at assessing the efficacy of a preoperative infusion of levosimendan in reducing postoperative LCOS in patients with poor LVEF undergoing coronary artery bypass grafting (CABG). LICORN study is a multicenter, randomized double-blind, placebo-controlled trial in parallel groups. 340 patients with LVEF ≤40 %, undergoing CABG will be recruited from 13 French hospitals. The study drug will be started after anaesthesia induction and infused over 24 h (0.1 μg/kg/min). The primary outcome (postoperative LCOS) is evaluated using a composite criterion composed of: 1) need for inotropic agents beyond 24 h following discontinuation of the study drug; 2) need for post-operative mechanical assist devices or failure to wean from these techniques when inserted pre-operatively; 3) need for renal replacement therapy. Secondary outcomes include: 1) mortality at Day 28 and Day 180; 2) each item of the composite criterion of the primary outcome; 3) the number of "ventilator-free" days and "out of intensive care unit" days at Day 28. The usefulness of levosimendan in the perioperative period has not yet been documented with a high level of evidence. The LICORN study is the first randomized controlled trial evaluating the clinical value of preoperative levosimendan in high risk cardiac surgical patients undergoing CABG. NCT02184819 (ClinicalTrials.gov).

Antihypertensive effect of the methanolic extract from Eruca sativa Mill., (Brassicaceae) in rats: muscarinic receptor-linked vasorelaxant and cardiotonic effects.

PubMed

Salma, Umme; Khan, Taous; Shah, Abdul Jabbar

2018-06-15

Eruca sativa Mill., (Brassicaceae) is a popular remedy for the treatment of hypertension in Pakistan. However, direct effect of the extract and its fractions on blood pressure and vascular tone are unknown. This investigation was aimed to explore the pharmacological base for the traditional use of E. sativa in hypertension. In-vivo blood pressure study was carried out using normotensive and high salt-induced hypertensive rats under anaesthesia. The cardiovascular mechanisms were explored using rat aorta and atria in-vitro. Preliminary phytochemical analysis, spectrophotometric detection of total phenols, flavonoids and HPLC analysis of crude extract were performed using quercetin and erucin as marker compounds. Intravenous injection of crude extract induced a fall in mean arterial pressure (MAP) in both normotensive (max fall: 41.79±1.55% mmHg) and hypertensive (max fall: 58.25±0.91% mmHg) rats. Atropine (1mg/kg) pretreatment attenuated this effect significantly (p < 0.001), suggesting the involvement of muscarinic receptor in its antihypertensive effect. Fractions also induced atropine-sensitive antihypertensive effect. Similarly, oral administration of crude and aqueous extracts resulted a fall in MAP in the hypertensive rats. In isolated rat aortic rings from normotensive rats, crude extract and fractions induced an endothelium-dependent relaxation. This relaxation was partially inhibited with L- NAME and atropine pretreatment and with denudation of aortic rings, indicating involvement of muscarinic receptor-linked nitric oxide (NO). In aorta from the hypertensive rats, crude extract and fractions induced endothelium-independent relaxation. This relaxation was not affected by pretreatment with L- NAME or atropine. Crude extract and fractions also suppressed phenylephrine contractions in Ca +2 free/EGTA medium. In isolated rat atrial preparations, crude extract and fractions induced negative inotropic and chronotropic effects with a positive inotropic effect by the n-hexane fraction, which were not affected with atropine pretreatment. Phytochemical screening and spectrophotometric analysis indicated the presence of phenols and flavonoids, whereas HPLC analysis of crude extract revealed the presence of quercetin (flavonoid) and erucin (isothiocyanate). The results suggest that E. sativa is an antihypertensive remedy which is mainly due to its vasodilatory and partly cardiac effects. Muscarinic receptors-linked NO release and dual inhibitory effect on Ca +2 influx and release underlie the vasodilation. This finding provides pharmacological base to the traditional use of E. sativa in hypertension. The presence of quercetin and erucin further support this finding. Copyright © 2018. Published by Elsevier B.V.

Cardio-Pulmonary Response to Shock.

DTIC Science & Technology

1983-09-30

attenuated by inhibition of Tx synthesis . These data indicate that the prostanoids exert direct and indirect acticns in moderating c function...identified as the circulating negative inotropic agent whose production is stimulated by PG synthesis during PEEP. - The large amount of prostacyclin...127 ml - in controls (p < 0.05). The importance of WBC Tx synthesis in the induction of permeability was tested by stimulating isolated WBC with the

Amiodarone. Haemodynamic profile during intravenous administration and effect on pacing-induced ischaemia in man.

PubMed

Remme, W J; van Hoogenhuyze, D C; Kruyssen, D A; Krauss, X H; Storm, C J

1985-03-01

The haemodynamic changes during intravenous amiodarone administration in laboratory animals and human studies are reviewed and compared with the results from our investigations. While the results of previous human studies have been rather variable, our investigations suggest that the cardiovascular changes following intravenous amiodarone include an early and usually short reduction of systemic and coronary vascular resistance, which may be partially due to the vasodilating properties of the solvent, polysorbate 80. As a result, a decrease in afterload and cardiac work and increases in cardiac output and coronary blood flow occur. Contrary to the observations in the animal experiments, heart rate increases in man, presumably as a result of the relatively greater fall in afterload which occurs. However, in spite of this increase in heart rate, contractility is reduced at the end of amiodarone administration and remains depressed after the infusion, resulting in a significant increase in left ventricular filling pressure. Neither myocardial oxygen demand nor consumption change during amiodarone administration. Although the intrinsic negative inotropic effects of amiodarone warrant a cautious approach in patients with left ventricular dysfunction, worsening of heart failure or the occurrence of myocardial ischaemia has been reported in only very few cases so far. In contrast, the drug was demonstrated to protect against pacing-induced myocardial ischaemia, in patients with both normal and depressed left ventricular function. These anti-ischaemic properties of amiodarone were investigated in a second study using a double pacing stress test protocol. Overall myocardial oxygen consumption did not change during pacing after amiodarone, but it clearly reduced (regional) myocardial ischaemia, as demonstrated by a reduction of ST-segment changes and anginal pain, and in particular by the absence of myocardial lactate production during pacing after amiodarone. These anti-ischaemic properties are mainly based on a reduction of myocardial oxygen demand, rather than on an improvement in coronary flow. It is concluded then, that amiodarone has significant haemodynamic effects as manifested by an early reduction in vascular resistance and a late negative inotropic effect. Although vasodilatation of short duration caused by its solvent, polysorbate 80, also occurs, the overall cardiovascular changes are caused by the direct, intrinsic haemodynamic effects of amiodarone alone. The important anti-ischaemic properties of amiodarone appear to result primarily from these cardiovascular actions and the inherent reduction in myocardial oxygen demand.

Caffeine: cognitive and physical performance enhancer or psychoactive drug?

PubMed

Cappelletti, Simone; Piacentino, Daria; Daria, Piacentino; Sani, Gabriele; Aromatario, Mariarosaria

2015-01-01

Caffeine use is increasing worldwide. The underlying motivations are mainly concentration and memory enhancement and physical performance improvement. Coffee and caffeine-containing products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects. Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main findings concerning caffeine's mechanisms of action (focusing on adenosine antagonism, intracellular calcium mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal role in intoxication or death. This could be due to caffeine's interaction with other substances or to the individuals' preexisting metabolism alterations or diseases.

Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?

PubMed Central

Cappelletti, Simone; Daria, Piacentino; Sani, Gabriele; Aromatario, Mariarosaria

2015-01-01

Caffeine use is increasing worldwide. The underlying motivations are mainly concentration and memory enhancement and physical performance improvement. Coffee and caffeine-containing products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects. Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main findings concerning caffeine’s mechanisms of action (focusing on adenosine antagonism, intracellular calcium mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal role in intoxication or death. This could be due to caffeine’s interaction with other substances or to the individuals' preexisting metabolism alterations or diseases. PMID:26074744

Purinoceptors exert negative inotropic effects on the heart in all major groups of reptiles.

PubMed

Joyce, William; Gesser, Hans; Wang, Tobias

2014-05-01

The few and fragmentary studies on purinergic regulation of the reptile heart have reached equivocal conclusions. Indeed, unlike fish, amphibians, and mammals, it has been suggested that the turtle heart lacks purinoceptors. Here, we study the effect of adenosine and ATP on isolated heart strips from three species of reptiles: the red-eared slider (Trachemys scripta), the ball python (Python regius) and the spectacled caiman (Caiman crocodilus). Both adenosine and ATP markedly decreased contractility in atria from all three species. This was attenuated by theophylline, suggesting that the response is mediated by P1 receptors. Ventricles were less sensitive, although high concentrations of the adenyl compounds evoked decreases in contractility. Our study suggests that cardiac purinoceptors are ubiquitous across reptiles, and may play an important and underappreciated role in reptile cardiovascular physiology. Copyright © 2014 Elsevier Inc. All rights reserved.

Aconite poisoning.

PubMed

Chan, Thomas Y K

2009-04-01

Aconitine and related alkaloids found in the Aconitum species are highly toxic cardiotoxins and neurotoxins. The wild plant (especially the roots and root tubers) is extremely toxic. Severe aconite poisoning can occur after accidental ingestion of the wild plant or consumption of an herbal decoction made from aconite roots. In traditional Chinese medicine, aconite roots are used only after processing to reduce the toxic alkaloid content. Soaking and boiling during processing or decoction preparation will hydrolyze aconite alkaloids into less toxic and non-toxic derivatives. However, the use of a larger than recommended dose and inadequate processing increases the risk of poisoning. A Medline search (1963-February 2009) was conducted. Key articles with information on the use of aconite roots in traditional medicine, active (toxic) ingredients, mechanisms of toxicity, toxicokinetics of Aconitum alkaloids, and clinical features and management of aconite poisoning were reviewed. The cardiotoxicity and neurotoxicity of aconitine and related alkaloids are due to their actions on the voltage-sensitive sodium channels of the cell membranes of excitable tissues, including the myocardium, nerves, and muscles. Aconitine and mesaconitine bind with high affinity to the open state of the voltage-sensitive sodium channels at site 2, thereby causing a persistent activation of the sodium channels, which become refractory to excitation. The electrophysiological mechanism of arrhythmia induction is triggered activity due to delayed after-depolarization and early after-depolarization. The arrhythmogenic properties of aconitine are in part due to its cholinolytic (anticholinergic) effects mediated by the vagus nerve. Aconitine has a positive inotropic effect by prolonging sodium influx during the action potential. It has hypotensive and bradycardic actions due to activation of the ventromedial nucleus of the hypothalamus. Through its action on voltage-sensitive sodium channels in the axons, aconitine blocks neuromuscular transmission by decreasing the evoked quantal release of acetylcholine. Aconitine, mesaconitine, and hypaconitine can induce strong contractions of the ileum through acetylcholine release from the postganglionic cholinergic nerves. Patients present predominantly with a combination of neurological, cardiovascular, and gastrointestinal features. The neurological features can be sensory (paresthesia and numbness of face, perioral area, and the four limbs), motor (muscle weakness in the four limbs), or both. The cardiovascular features include hypotension, chest pain, palpitations, bradycardia, sinus tachycardia, ventricular ectopics, ventricular tachycardia, and ventricular fibrillation. The gastrointestinal features include nausea, vomiting, abdominal pain, and diarrhea. The main causes of death are refractory ventricular arrhythmias and asystole and the overall in-hospital mortality is 5.5%. Management of aconite poisoning is supportive, including immediate attention to the vital functions and close monitoring of blood pressure and cardiac rhythm. Inotropic therapy is required if hypotension persists and atropine should be used to treat bradycardia. Aconite-induced ventricular arrhythmias are often refractory to direct current cardioversion and antiarrhythmic drugs. Available clinical evidence suggests that amiodarone and flecainide are reasonable first-line treatment. In refractory cases of ventricular arrhythmias and cardiogenic shock, it is most important to maintain systemic blood flow, blood pressure, and tissue oxygenation by the early use of cardiopulmonary bypass. The role of charcoal hemoperfusion to remove circulating aconitine alkaloids is not established. Aconite roots contain aconitine, mesaconitine, hypaconitine, and other Aconitum alkaloids, which are known cardiotoxins and neurotoxins. Patients present predominantly with neurological, cardiovascular, and gastrointestinal features. Management is supportive; the early use of cardiopulmonary bypass is recommended if ventricular arrhythmias and cardiogenic shock are refractory to first-line treatment.

Dipyridamole and paracetamol overdose resulting in multi-organ failure.

PubMed

Cullis, P S; Watson, D; Cameron, A; McKee, R F

2013-08-01

Dipyridamole intoxication is rare and few reports exist amongst the current literature. A case of dipyridamole and paracetamol overdose is described in a previously healthy 58-year-old woman, which resulted in multi-organ failure requiring dialysis, inotropic support, ventilation and extensive surgical intervention for small bowel ischaemia. This case highlights the dangers of an unusually large overdose of a commonly prescribed drug, and reviews current knowledge of dipyridamole intoxication.

Case report: paradoxical ventricular septal motion in the setting of primary right ventricular myocardial failure.

PubMed

Maslow, Andrew; Schwartz, Carl; Mahmood, Feroze; Singh, Arun; Heerdt, Paul M

2009-07-01

In this report, a case of right ventricular (RV) failure, hemodynamic instability, and systemic organ failure is described to highlight how paradoxical ventricular systolic septal motion (PVSM), or a rightward systolic displacement of the interventricular septum, may contribute to RV ejection. Multiple inotropic medications and vasopressors were administered to treat right heart failure and systemic hypotension in a patient following combined aortic and mitral valve replacement. In the early postoperative period, echocardiographic evaluation revealed adequate left ventricular systolic function, akinesis of the RV myocardial tissues, and PVSM. In the presence of PVSM, RV fractional area of contraction was > or =35% despite akinesis of the primary RV myocardial walls. The PVSM appeared to contribute toward RV ejection. As a result, the need for multiple inotropes was re-evaluated, in considering that end-organ dysfunction was the result of systemic hypotension and prolonged vasopressor administration. After discontinuation of phosphodiesterase inhibitors, native vascular tone returned and the need for vasopressors declined. This was followed by recovery of systemic organ function. Echocardiographic re-evaluation two years later, revealed persistent akinesis of the RV myocardial tissues and PVSM, the latter appearing to contribute toward RV ejection. This case highlights the importance of left to RV interactions, and how PVSM may mediate these hemodynamic interactions.

Levitronix bilateral ventricular assist device, a bridge to recovery in a patient with acute fulminant myocarditis and concomitant cerebellar infarction.

PubMed

Huang, Yi-Fan; Hsu, Po-Shun; Tsai, Chien-Sung; Tsai, Yi-Ting; Lin, Chih-Yuan; Ke, Hong-Yan; Lin, Yi-Chang; Yang, Hsiang-Yu

2018-02-07

We report on the case of a 27-year-old male who presented to our emergency room with chest tightness, dyspnoea and cold sweats. The 12-lead electrocardiogram showed diffuse ventricular tachycardia with wide QRS complexes. Troponin-I level was elevated to 100 ng/ml. The coronary angiogram showed good patency of all three coronary vessels, and acute fulminant myocarditis was suspected. The patient underwent cardiopulmonary resuscitation in the catheter room and high-dose inotropic support was initiated to stabilise his haemodynamic status. After resuscitation, the patient was in a coma and acute stroke was highly suspected. In addition, deteriorating cardiogenic shock with acute renal failure and pulmonary oedema were also detected. Due to haemodynamic compromise despite high-dose inotropic support, a Levitronix ® bilateral ventricular assist device (Bi-VAD) was implanted on an emergency basis for circulatory support. Postoperative brain computed tomography revealed acute left cerebellar infarction. Because the patient had left cerebellar infarction with right hemiplegia, heart transplantation was contraindicated. Eventually, cardiac systolic function recovered well and the patient underwent successful Bi-VAD removal after a total of 18 days on Levitronix ® haemodynamic support. He was weaned from the ventilator two weeks later and was discharged 10 days later.

In-vitro examination of the positive inotropic effect of caffeine and taurine, the two most frequent active ingredients of energy drinks.

PubMed

Chaban, R; Kornberger, A; Branski, N; Buschmann, K; Stumpf, N; Beiras-Fernandez, A; Vahl, C F

2017-08-10

Our study aimed to evaluate changes in the contractile behavior of human myocardium after exposure to caffeine and taurine, the main active ingredients of energy drinks (EDs), and to evaluate whether taurine exhibits any inotropic effect at all in the dosages commonly used in EDs. Myocardial tissue was removed from the right atrial appendages of patients undergoing cardiac surgery and prepared to obtain specimens measuring 4 mm in length. A total of 92 specimens were exposed to electrical impulses at a frequency of 75 bpm for at least 40 min to elicit their maximum contractile force before measuring the isometric contractile force (ICF) and duration of contraction (CD). Following this, each specimen was treated with either taurine (group 1, n = 29), or caffeine (group 2, n = 31) or both (group 3, n = 32). After exposure, ICF and CD measuring were repeated. Post-treatment values were compared with pre-treatments values and indicated as percentages. Exposure to taurine did not alter the contraction behavior of the specimens. Exposure to caffeine, in contrast, led to a significant increase in ICF (118 ± 03%, p < 0.01) und a marginal decrease in CD (95 ± 1.6%, p < 0.01). Exposure to a combination of caffeine and taurine also induced a statistically significant increase in ICF (124 ± 4%, p < 0.01) and a subtle reduction in CD (92 ± 1.4%, p < 0.01). The increase in ICF achieved by administration of caffeine was similar to that achieved by a combination of both caffeine and taurine (p = 0.2). The relative ICF levels achieved by administration of caffeine and a combination of taurine and caffeine, respectively, were both significantly higher (p < 0.01) than the ICF resulting from exposure to taurine only. While caffeine altered the contraction behavior of the specimen significantly in our in-vitro model, taurine did not exhibit a significant effect. Adding taurine to caffeine did not significantly enhance or reduce the effect of caffeine.

Septic Shock due to Vibrio alginolyticus in a Cirrhotic Patient: The First Case in Korea

PubMed Central

Lee, Dong-Young; Moon, Soo-Youn; Lee, Sang-Oh; Yang, Hee-Young; Lee, Hee-Joo

2008-01-01

We describe a case of septic shock due to Vibrio alginolyticus presenting with fever and bilateral leg pain. Despite intensive management with antibiotics and inotropic agents, the patient died from septic shock 1 day after hospitalization. V. alginolyticus was isolated from both leg wounds and a blood culture. To the best of our knowledge, this is the first reported case of V. alginolyticus bacteremia in Korea. PMID:18452273

Characterization of the Chemical Constitution and Profile of Pharmacological Activity of PGB(x).

DTIC Science & Technology

1982-02-26

ischemia. Fed. Proc. 40 , 692 (1980). 3. Burkman, A. M. and Phornchirasilp, S., Prostaglandin Bx enhances the inotropic efficacy (Emax) of...nitroketone 10 was then converted to the sodium salt of the corresponding nitronic acid on treatment with an equimolar amount of sodium metabolite in...bromide in chloroform-ethyl acetate to give unsaturated aldehyde 12 in 40 ’ yield. The reaction of compound 9 with dimethyl (2-oxoheptvl) phosphonate in

A randomized trial of protocol-based care for early septic shock.

PubMed

Yealy, Donald M; Kellum, John A; Huang, David T; Barnato, Amber E; Weissfeld, Lisa A; Pike, Francis; Terndrup, Thomas; Wang, Henry E; Hou, Peter C; LoVecchio, Frank; Filbin, Michael R; Shapiro, Nathan I; Angus, Derek C

2014-05-01

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

Transforming the "unacceptable" donor: outcomes from the adoption of a standardized donor management technique.

PubMed

Wheeldon, D R; Potter, C D; Oduro, A; Wallwork, J; Large, S R

1995-01-01

Donor management remains one of the most neglected areas of transplantation. A comprehensive donor management regimen has been developed. The results of the application of this strategy form the basis of this report. Full hemodynamic data were collected from 150 multiorgan donors between October 1990 and August 1993. The data were collected at the time of donor team arrival, after insertion of a pulmonary artery floatation catheter and immediately before cardiac excision. Fifty-two donors (35%) fell well outside our minimum acceptance criteria on arrival. Twenty-one of fifty-two had a mean arterial pressure less than 55 mm Hg (mean 47 mm Hg) despite inotropic support in most cases; 10 of 52 had a central venous pressure greater than 15 mm Hg (mean 18.0 mm Hg); 2 of 52 had a high inotrope requirement greater than 20 micrograms/kg/min (mean 25 micrograms/kg/min). After the insertion of a pulmonary artery floatation catheter, an additional 13 of 52 donors were found to have a pulmonary capillary wedge pressure greater than 15 mm Hg (mean 19.8 mm Hg), and the final 6 of 52 had a low left ventricular stroke work index, less than 15 gm (mean 12.8 gm). After optimal management, including hormone replacement 44 of 52 donors yielded transplantable organs (29 hearts, 15 heart and lung blocks). Thirty-seven of forty-four patients (84%) were alive and well from 13 to 48 months after transplantation. There were five early deaths (11%) caused by infection (heart), adult respiratory distress syndrome (heart), arrhythmia (heart), cerebrovascular event (heart and lung), and infection (heart, lung, and liver). Two late deaths (5%) occurred as a result of tamponade (3 months, heart) and infection (14 months, heart and lung). Eight of fifty-two organs were still unsuitable for transplantation after optimum management during the splanchnic dissection as a result of inotrope dependency (n = 4), left ventricular hypertrophy (n = 2), and coronary artery disease (n = 2). The data indicate that, of the organs which initially fall outside our transplant acceptance criteria, 92% are capable of functional resuscitation. Conversely, superficial assessment may not show compromised function. Optimizing cardiovascular performance also has important implications for the viability of all transplantable organs. This aggressive approach to donor management has resulted in the transplantation of 44 donor hearts that may otherwise have been turned down or inappropriately managed.

S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculary system

PubMed Central

Carl, M.; Alms, A.; Braun, J.; Dongas, A.; Erb, J.; Goetz, A.; Goepfert, M.; Gogarten, W.; Grosse, J.; Heller, A. R.; Heringlake, M.; Kastrup, M.; Kroener, A.; Loer, S. A.; Marggraf, G.; Markewitz, A.; Reuter, D.; Schmitt, D. V.; Schirmer, U.; Wiesenack, C.; Zwissler, B.; Spies, C.

2010-01-01

Hemodynamic monitoring and adequate volume-therapy, as well as the treatment with positive inotropic drugs and vasopressors are the basic principles of the postoperative intensive care treatment of patient after cardiothoracic surgery. The goal of these S3 guidelines is to evaluate the recommendations in regard to evidence based medicine and to define therapy goals for monitoring and therapy. In context with the clinical situation the evaluation of the different hemodynamic parameters allows the development of a therapeutic concept and the definition of goal criteria to evaluate the effect of treatment. Up to now there are only guidelines for subareas of postoperative treatment of cardiothoracic surgical patients, like the use of a pulmonary artery catheter or the transesophageal echocardiography. The German Society for Thoracic and Cardiovascular Surgery (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie, DGTHG) and the German Society for Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin, DGAI) made an approach to ensure and improve the quality of the postoperative intensive care medicine after cardiothoracic surgery by the development of S3 consensus-based treatment guidelines. Goal of this guideline is to assess the available monitoring methods with regard to indication, procedures, predication, limits, contraindications and risks for use. The differentiated therapy of volume-replacement, positive inotropic support and vasoactive drugs, the therapy with vasodilatators, inodilatators and calcium sensitizers and the use of intra-aortic balloon pumps will also be addressed. The guideline has been developed following the recommendations for the development of guidelines by the Association of the Scientific Medical Societies in Germany (AWMF). The presented key messages of the guidelines were approved after two consensus meetings under the moderation of the Association of the Scientific Medical Societies in Germany (AWMF). PMID:20577643

Glyburide, a K(+)(ATP)channel blocker, improves hypotension and survival in anaphylactic shock induced in Wistar rats sensitized to ovalbumin.

PubMed

Dhanasekaran, Subramanian; Nemmar, Abderrahim; Aburawi, Elhadi H; Kazzam, Elsadig E; Abdulle, Abdishakur; Bellou, Moufida; Bellou, Abdelouahab

2013-11-15

Allergens can induce anaphylactic shock and death due to serve hypotension. Potassium channel blockers (K(+)(ATP)) such as glyburide (GLY) induce vasoconstriction. The effect of (K(+)(ATP)) channel blockers on anaphylactic shock is poorly understood. Objective of the study was to test the hypothesis that GLY reduces hypotension induced in anaphylactic shock and increases survival. Rats were grouped into: G1-N=Naïve; G2-SC=Sensitized-Control; G3-SG=Sensitized-GLY (glyburide 40 mg/kg); G4-SE=Sensitized-EPI (epinephrine 10 mg/kg). G2 to G4 groups were sensitized with ovalbumin (OVA) and shock was induced by i.v. injection of OVA. Treatments were administered intravenously 5 min later. Mean arterial pressure (MAP), heart rate (HR), and mean survival time (MST) were measured for 60 min following OVA injection and treatments administration. At the end of the experiment, blood withdrawal was performed to measure plasma levels of histamine, leukotriene B(4) (LTB(4)), prostaglandin E(2) (PGE(2)) and prostaglandin F(2) (PGF(2)). Additionally blood gas (paO2, paCO2, SaO2) and electrolytes (Na(+), K(+) and Ca (++)) were measured. MAP was normal in G1-N; severe hypotension, negative inotropic and short MST were observed in G2-SC; normalization of MAP, with lesser negative inotropism and increased MST were observed in G3-SG; full recovery was observed in G4-SE. Histamine level was significantly higher in G2-SC; reduced in G3-SG and G4-SE. PGE(2) increased in G3-SG; PGF(2) increased in G2-SC and G3-SG. Na(+) and Ca (++) concentration decreased in sensitized rats but reversed in treated groups, without change in K(+) concentration. In conclusion, our data suggest that administration of GLY reduced hypotension and increases survival time in rat anaphylactic shock.

Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy.

PubMed

Saeedi Saravi, Seyed Soheil; Ghazi-Khansari, Mahmoud; Ejtemaei Mehr, Shahram; Nobakht, Maliheh; Mousavi, Seyyedeh Elaheh; Dehpour, Ahmad Reza

2016-05-21

To explore the role of mammalian target of rapamycin (mTOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition. Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon (CCl4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin (2 mg/kg per day). The QTc intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles were isolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-mTOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor (TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-mTOR protein. Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight (P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl4 (P < 0.001), while this prolongation was decreased with rapamycin treatment (P < 0.01). CCl4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-mTOR expression in left ventricles. Phosphorylated-mTOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-mTOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment. In this study, we demonstrated a potential role for cardiac mTOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-mTOR expression and myocardial localization in cirrhotic rats.

Levosimendan enhances memory through antioxidant effect in rat model: behavioral and molecular study.

PubMed

Rababa'h, Abeer M; Alzoubi, Karem H; Atmeh, Ala'a

2018-06-01

Impairment of learning and memory has been associated with accumulation of reactive oxygen species in the body. It has also been found that antioxidants enhance learning and memory. Levosimendan is a cardiac inotropic and vasodilator agent that has pleotropic effects including antioxidant, anti-inflammatory, and smooth muscle vasodilatory actions. In this study, we investigated the effect of levosimendan on learning and memory in rats. Levosimendan (12 µg/kg, intraperitoneally) or vehicle was administered once a week for 8 weeks. The radial arm water maze was used to assess spatial learning and memory. In addition, hippocampus levels of antioxidant biomarkers/enzyme - reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, glutathione peroxidase, superoxide dismutase, catalase, and thiobarbituric acid reactive substance - were assessed. Levosimendan significantly enhanced short-term (30 min) and long-term (5 h) memory. Levosimendan also significantly increased levels of glutathione peroxidase and GSH and decreased thiobarbituric acid reactive substance. There were no significant effects on the level of other oxidative stress biomarkers. In conclusion, levosimendan enhanced short-term and long-term memory by potentiating antioxidant defense mechanism in the hippocampus.

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper.

PubMed

Farmakis, Dimitrios; Alvarez, Julian; Gal, Tuvia Ben; Brito, Dulce; Fedele, Francesco; Fonseca, Candida; Gordon, Anthony C; Gotsman, Israel; Grossini, Elena; Guarracino, Fabio; Harjola, Veli-Pekka; Hellman, Yaron; Heunks, Leo; Ivancan, Visnja; Karavidas, Apostolos; Kivikko, Matti; Lomivorotov, Vladimir; Longrois, Dan; Masip, Josep; Metra, Marco; Morelli, Andrea; Nikolaou, Maria; Papp, Zoltán; Parkhomenko, Alexander; Poelzl, Gerhard; Pollesello, Piero; Ravn, Hanne Berg; Rex, Steffen; Riha, Hynek; Ricksten, Sven-Erik; Schwinger, Robert H G; Vrtovec, Bojan; Yilmaz, M Birhan; Zielinska, Marzenna; Parissis, John

2016-11-01

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial

PubMed Central

Drury, Nigel E.; Howell, Neil J.; Calvert, Melanie J.; Weber, Ralf J.M.; Senanayake, Eshan L.; Lewis, Michael E.; Hyde, Jonathan A.J.; Green, David H.; Mascaro, Jorge G.; Wilson, Ian C.; Graham, Timothy R.; Rooney, Stephen J.; Viant, Mark R.; Freemantle, Nick; Frenneaux, Michael P.; Pagano, Domenico

2015-01-01

OBJECTIVES Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56–1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07–0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34–0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. ClinicalTrials.Gov ID NCT00845364. PMID:24948413

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

PubMed

Drury, Nigel E; Howell, Neil J; Calvert, Melanie J; Weber, Ralf J M; Senanayake, Eshan L; Lewis, Michael E; Hyde, Jonathan A J; Green, David H; Mascaro, Jorge G; Wilson, Ian C; Graham, Timothy R; Rooney, Stephen J; Viant, Mark R; Freemantle, Nick; Frenneaux, Michael P; Pagano, Domenico

2015-03-01

Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. NCT00845364. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.

Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

PubMed

Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

2017-11-01

Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Automated In Vivo Platform for the Discovery of Functional Food Treatments of Hypercholesterolemia

PubMed Central

Littleton, Robert M.; Haworth, Kevin J.; Tang, Hong; Setchell, Kenneth D. R.; Nelson, Sandra; Hove, Jay R.

2013-01-01

The zebrafish is becoming an increasingly popular model system for both automated drug discovery and investigating hypercholesterolemia. Here we combine these aspects and for the first time develop an automated high-content confocal assay for treatments of hypercholesterolemia. We also create two algorithms for automated analysis of cardiodynamic data acquired by high-speed confocal microscopy. The first algorithm computes cardiac parameters solely from the frequency-domain representation of cardiodynamic data while the second uses both frequency- and time-domain data. The combined approach resulted in smaller differences relative to manual measurements. The methods are implemented to test the ability of a methanolic extract of the hawthorn plant (Crataegus laevigata) to treat hypercholesterolemia and its peripheral cardiovascular effects. Results demonstrate the utility of these methods and suggest the extract has both antihypercholesterolemic and postitively inotropic properties. PMID:23349685

Automated in vivo platform for the discovery of functional food treatments of hypercholesterolemia.

PubMed

Littleton, Robert M; Haworth, Kevin J; Tang, Hong; Setchell, Kenneth D R; Nelson, Sandra; Hove, Jay R

2013-01-01

The zebrafish is becoming an increasingly popular model system for both automated drug discovery and investigating hypercholesterolemia. Here we combine these aspects and for the first time develop an automated high-content confocal assay for treatments of hypercholesterolemia. We also create two algorithms for automated analysis of cardiodynamic data acquired by high-speed confocal microscopy. The first algorithm computes cardiac parameters solely from the frequency-domain representation of cardiodynamic data while the second uses both frequency- and time-domain data. The combined approach resulted in smaller differences relative to manual measurements. The methods are implemented to test the ability of a methanolic extract of the hawthorn plant (Crataegus laevigata) to treat hypercholesterolemia and its peripheral cardiovascular effects. Results demonstrate the utility of these methods and suggest the extract has both antihypercholesterolemic and postitively inotropic properties.

Pleural effusion leading to right atrial collapse.

PubMed

Khouzam, Rami N; Yusuf, Jawwad

2014-01-01

Rapid accumulation of pericardial fluid can lead to tamponade, resulting in cardiac chambers' collapse, which can lead to hemodynamic and clinical instability, potentially needing emergent pericardiocentesis. Pleural effusion should also be considered as a potential, if rare, cause of cardiac chambers' collapse and possibly cardiac tamponade. This phenomenon has clinical implications because hemodynamically unstable patients with moderate to large pleural effusion may actually need thoracentesis instead of massive volume resuscitation, inotropic agents, or pericardiocentesis. Copyright © 2013 Wiley Periodicals, Inc.

CARBONYLATION OF MYOSIN HEAVY CHAINS IN RAT HEARTS DURING DIABETES

PubMed Central

Shao, Chun-Hong; Rozanski, George J.; Nagai, Ryoji; Stockdale, Frank E.; Patel, Kaushik P.; Wang, Mu; Singh, Jaipaul; Mayhan, William G.; Bidasee, Keshore R.

2010-01-01

Cardiac inotropy progressively declines during diabetes mellitus. To date, the molecular mechanisms underlying this defect remain incompletely characterized. This study tests the hypothesis that ventricular myosin heavy chains (MHC) undergo carbonylation by reactive carbonyl species (RCS) during diabetes and these modifications contribute to the inotropic decline. Male Sprague-Dawley rats were injected with streptozotocin (STZ). Fourteen days later animals were divided into two groups: one group was treated with the RCS blocker aminoguanidine for six weeks, while the other group received no treatment. After eight weeks of diabetes, cardiac ejection fraction, fractional shortening, left ventricular pressure development (+dP/dt) and myocyte shortening were decreased by 9%, 16%, 34% and 18%, respectively. Ca2+- and Mg2+-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-α to MHC-β ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-α and MHC-β. Aminoguandine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca2+-sensitive ATPase activity, syneresis, myocyte shortening, cardiac ejection fraction, fractional shortening and +dP/dt induced by diabetes. From these new data it can be concluded that in addition to isozyme switching, modification of MHC by RCS also contributes to the inotropic decline seen during diabetes. PMID:20359464

Do preoperative oral carbohydrates improve postoperative outcomesin patients undergoing coronary artery bypass grafts?

PubMed

Şavluk, Ömer Faruk; Kuşçu, Mehmet Ali; Güzelmeriç, Füsun; Gürcü, Mustafa Emre; Erkılınç, Atakan; Çevirme, Deniz; Oğuş, Halide; Koçak, Tuncer

2017-12-19

Background/aim: The aim of this prospective study was to determine whether the preoperative oral intake of carbohydrate-rich drinks by patients undergoing a coronary artery bypass graft attenuates postoperative insulin requirements, improves postoperative patient discomfort, provides inotropic support, shortens the length of the ICU stay, and shortens the duration of postoperative mechanical ventilation. Materials and methods: This randomized prospective clinical study included 152 patients with coronary artery disease who were divided into 4 groups. Carbohydrates were administered to 3 groups at different hours and doses before operation. The fourth group had an 8-h preoperative fasting period. The inotropic and vasopressor requirements, ventilation time, and ICU stay time were recorded for all of the groups. Patient wellbeing, mouth dryness, hunger, anxiety, and nausea were assessed using VAS scores of 1-10. Results: Mouth dryness and hunger were significantly higher in the control group (P = 0.03, P = 0.02). The increase in blood glucose level was significantly higher in the control group (P = 0.04). The exogenous insulin requirement was significantly higher in the control group than in the other groups (P = 0.04). Conclusion: The administration of carbohydrates before elective cardiac surgery reduced insulin resistance. Based on the VAS scores, the intake of carbohydrates reduced mouth dryness and hunger. Overall, preoperative oral carbohydrate treatments can improve the postoperative outcomes of coronary artery bypass graft surgeries.

In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine.

PubMed

Howell, G; West, L; Jenkins, C; Lineberry, B; Yokum, D; Rockhold, R

2005-08-18

Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H1 receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models. In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M2 selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M3 selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25-35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals. The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors.

In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine

PubMed Central

Howell, G; West, L; Jenkins, C; Lineberry, B; Yokum, D; Rockhold, R

2005-01-01

Background Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H1 receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models. Results In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M2 selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M3 selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25–35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals. Conclusion The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors. PMID:16109168

Muscle RANK is a key regulator of Ca2+ storage, SERCA activity, and function of fast-twitch skeletal muscles.

PubMed

Dufresne, Sébastien S; Dumont, Nicolas A; Boulanger-Piette, Antoine; Fajardo, Val A; Gamu, Daniel; Kake-Guena, Sandrine-Aurélie; David, Rares Ovidiu; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M; Pape, Paul C; Tupling, A Russell; Frenette, Jérôme

2016-04-15

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca(2+)sensor, and altered activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) modulating Ca(2+)storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca(2+)storage and SERCA activity, ultimately affecting denervated skeletal muscle function. Copyright © 2016 the American Physiological Society.

Muscle RANK is a key regulator of Ca2+ storage, SERCA activity, and function of fast-twitch skeletal muscles

PubMed Central

Dufresne, Sébastien S.; Dumont, Nicolas A.; Boulanger-Piette, Antoine; Fajardo, Val A.; Gamu, Daniel; Kake-Guena, Sandrine-Aurélie; David, Rares Ovidiu; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M.; Pape, Paul C.; Tupling, A. Russell

2016-01-01

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca2+ sensor, and altered activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) modulating Ca2+ storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca2+ storage and SERCA activity, ultimately affecting denervated skeletal muscle function. PMID:26825123

Adding hydrocortisone as 1st line of inotropic treatment for hypotension in very low birth weight infants.

PubMed

Hochwald, Ori; Palegra, Gustavo; Osiovich, Horacio

2014-08-01

In this pilot study the authors demonstrate the feasibility, effectiveness and safety of the combined early treatment with hydrocortisone and dopamine for refractory hypotension in preterm newborns. Very low birth weight infants born at gestational age < 30 wk or birth weight < 1250 g in the first 48 h of life with hypotension after receiving 10-20 mL/kg bolus of normal saline, were randomized to receive concurrently with the initiation of dopamine, intravenous hydrocortisone (11 infants) or an equivalent volume of placebo (11 infants). Despite no significant clinical difference between the groups including gestational age, birth weight, prevalence of chorioamnionitis, prenatal steroid treatment, cord PH, baseline cortisol level, there was a trend towards lower incidence of bronchopulmonary dysplasia (BPD), and higher survival without BPD rate in the hydrocortisone group. In this very sick small group of infants, hydrocortisone was not associated with more adverse effects, but rather showed a trend toward association with better outcome, including survival without BPD.

Unusual presentation of phaeochromocytoma.

PubMed

Hope, D C D; Palan, J M

2016-05-10

A 44-year-old woman, with a background of heart, lung and renal transplantation secondary to cystic fibrosis and type 1 diabetes, presented with tachycardia, hyperglycaemia, nausea and vomiting. She was initially managed for diabetic ketoacidosis with severe dehydration. However, persistent episodic hypertension and tachycardia led the investigating team to identify significantly raised urinary metanephrines and a left-sided adrenal mass; Iodine-123-meta-iodobenzylguanidine single photon emission computer tomography scan (MIBG SPECT/CT) showed avid uptake of tracer, confirming a left-sided phaeochromocytoma. She was started on medical management and is awaiting an elective laparoscopic procedure. This case describes the presentation of a unilateral phaeochromocytoma as ketoacidosis in a patient with type 1 diabetes with no other apparent precipitant. This highlights the metabolic counter-regulatory effect of excess catecholamines in addition to the inotropic/chronotropic effects that are associated with this adrenal tumour. Recognition of atypical signs and symptoms may point towards an atypical precipitant of diabetic ketoacidosis-a medical emergency presenting to front-line clinicians. 2016 BMJ Publishing Group Ltd.

Unusual presentation of phaeochromocytoma

PubMed Central

Hope, D C D; Palan, J M

2016-01-01

A 44-year-old woman, with a background of heart, lung and renal transplantation secondary to cystic fibrosis and type 1 diabetes, presented with tachycardia, hyperglycaemia, nausea and vomiting. She was initially managed for diabetic ketoacidosis with severe dehydration. However, persistent episodic hypertension and tachycardia led the investigating team to identify significantly raised urinary metanephrines and a left-sided adrenal mass; Iodine-123-meta-iodobenzylguanidine single photon emission computer tomography scan (MIBG SPECT/CT) showed avid uptake of tracer, confirming a left-sided phaeochromocytoma. She was started on medical management and is awaiting an elective laparoscopic procedure. This case describes the presentation of a unilateral phaeochromocytoma as ketoacidosis in a patient with type 1 diabetes with no other apparent precipitant. This highlights the metabolic counter-regulatory effect of excess catecholamines in addition to the inotropic/chronotropic effects that are associated with this adrenal tumour. Recognition of atypical signs and symptoms may point towards an atypical precipitant of diabetic ketoacidosis—a medical emergency presenting to front-line clinicians. PMID:27166010

Ayurvedic preparation of Zingiber officinale Roscoe: effects on cardiac and on smooth muscle parameters.

PubMed

Leoni, Alberto; Budriesi, Roberta; Poli, Ferruccio; Lianza, Mariacaterina; Graziadio, Alessandra; Venturini, Alice; Broccoli, Massimiliano; Micucci, Matteo

2017-08-28

The rhizome of the Zingiber officinale Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high-performance liquid chromatography, we have seen that its main phytomarkers were 6-gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC 50  = 0.66 mg/mL versus EC 50  = 1.45 mg/mL.

Vasoactive drugs and the gut: is there anything new?

PubMed

Woolsey, Cheryl A; Coopersmith, Craig M

2006-04-01

Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function. Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models. Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

Hibiscus Sabdariffa L. Flowers and Olea Europea L. Leaves Extract-Based Formulation for Hypertension Care: In Vitro Efficacy and Toxicological Profile.

PubMed

Micucci, Matteo; Angeletti, Andrea; Cont, Massimiliano; Corazza, Ivan; Aldini, Rita; Donadio, Elisa; Chiarini, Alberto; Budriesi, Roberta

2016-05-01

Olea europaea L. leaves extract (Oe) and Hybiscus sabdariffa L. flowers extract (Hs) have calcium antagonistic properties. Aim of this work was to study the cardiovascular effects of Pres Phytum(®), a nutraceutical formulation containing a mixture of the two extracts and the excipients, and investigate its possible off-target effects, using in vitro biological assays on guinea pig isolated organs. Cardiovascular effects were assessed using guinea pig atria and aorta. The effects of Pres Phytum on spontaneous gastrointestinal, urinary, and respiratory tracts smooth muscle contractility were evaluated. Pres Phytum exerted a vasorelaxant effect (IC50 = 2.38 mg/mL) and a negative chronotropic effect (IC50 = 1.04 mg/mL) at concentrations lower than those producing smooth muscle spontaneous contractility alterations in the other organs. Compared to Pres Phytum, the mixture did not exert negative inotropic activity, while it maintained a negative chronotropic efficacy (IC50 = 1.04 mg/mL). These experimental data suggest a possible nutraceutical use of this food supplement for the management of preclinical hypertension.

Ergotamine-Induced Takotsubo Cardiomyopathy.

PubMed

Ozpelit, Ebru; Ozpelit, Mehmet E; Akdeniz, Bahri; Göldeli, Özhan

2016-01-01

Takotsubo cardiomyopathy (TC) is a recently increasing diagnosed disease showed by transient apical or mid-apical left ventricular dysfunction. It is known as a disease of postmenopausal women, which is usually triggered by emotional or physical stress. Although the trigger is mostly endogenous, some drugs have also been reported as the cause. Published case reports of TC associated with drug usage consist of sympathomimetic drugs, inotropic agents, thyroid hormone, cocaine, and 5-fluorouracil. We present an unusual case of TC in which the possible trigger is ergotamine toxicity.

Perioperative management of a child with glutaric aciduria type I undergoing cardiac surgery.

PubMed

Kölker, Stefan; Eichhorn, Joachim; Sebening, Christian; Klein, Berthold; Springer, Wolfgang; Bopp, Christian; Rauch, Helmut

2013-10-01

Patients with glutaric aciduria type I are at risk for acute striatal injury precipitated by catabolic stress. Here, we report the successful interdisciplinary anesthetic and perioperative management of a child with glutaric aciduria type I undergoing cardiac surgery with extracorporeal circulation. Given the central focus on prevention of acute striatal injury, our anesthetic strategy emphasized avoiding a high protein load, high-dose inotropics, especially epinephrine (associated with impaired glucose utilization), deliberate hyperventilation, and other interventions associated with systemic inflammatory response.

Asplenic fulminant sepsis secondary to a dog bite complicated by toxic epidermal necrolysis/Stevens-Johnson syndrome.

PubMed

Teo, Ken G; Anavekar, Namrata S; Yazdabadi, Anosha; Ricketts, Sophie

2012-07-29

We report a case of asplenic fulminant sepsis in Australia following a dog bite which was complicated by toxic epidermal necrolysis/Stevens-Johnson syndrome (TENS/SJS). Capnocytophaga canimorsus, the infective organism, is a rare cause of septicaemia: a high degree of suspicion of this unusual organism and its early aggressive management is paramount. The diagnostic and management difficulties of TENS/SJS in the context of a patient with fulminant sepsis, DIC and on inotropes are also highlighted.

Identification and Comparison of Candidate Olfactory Genes in the Olfactory and Non-Olfactory Organs of Elm Pest Ambrostoma quadriimpressum (Coleoptera: Chrysomelidae) Based on Transcriptome Analysis.

PubMed

Wang, Yinliang; Chen, Qi; Zhao, Hanbo; Ren, Bingzhong

2016-01-01

The leaf beetle Ambrostoma quadriimpressum (Coleoptera: Chrysomelidae) is a predominant forest pest that causes substantial damage to the lumber industry and city management. However, no effective and environmentally friendly chemical method has been discovered to control this pest. Until recently, the molecular basis of the olfactory system in A. quadriimpressum was completely unknown. In this study, antennae and leg transcriptomes were analyzed and compared using deep sequencing data to identify the olfactory genes in A. quadriimpressum. Moreover, the expression profiles of both male and female candidate olfactory genes were analyzed and validated by bioinformatics, motif analysis, homology analysis, semi-quantitative RT-PCR and RT-qPCR experiments in antennal and non-olfactory organs to explore the candidate olfactory genes that might play key roles in the life cycle of A. quadriimpressum. As a result, approximately 102.9 million and 97.3 million clean reads were obtained from the libraries created from the antennas and legs, respectively. Annotation led to 34344 Unigenes, which were matched to known proteins. Annotation data revealed that the number of genes in antenna with binding functions and receptor activity was greater than that of legs. Furthermore, many pathway genes were differentially expressed in the two organs. Sixteen candidate odorant binding proteins (OBPs), 10 chemosensory proteins (CSPs), 34 odorant receptors (ORs), 20 inotropic receptors [1] and 2 sensory neuron membrane proteins (SNMPs) and their isoforms were identified. Additionally, 15 OBPs, 9 CSPs, 18 ORs, 6 IRs and 2 SNMPs were predicted to be complete ORFs. Using RT-PCR, RT-qPCR and homology analysis, AquaOBP1/2/4/7/C1/C6, AquaCSP3/9, AquaOR8/9/10/14/15/18/20/26/29/33, AquaIR8a/13/25a showed olfactory-specific expression, indicating that these genes might play a key role in olfaction-related behaviors in A. quadriimpressum such as foraging and seeking. AquaOBP4/C5, AquaOBP4/C5, AquaCSP7/9/10, AquaOR17/24/32 and AquaIR4 were highly expressed in the antenna of males, suggesting that these genes were related to sex-specific behaviors, and expression trends that were male specific were observed for most candidate olfactory genes, which supported the existence of a female-produced sex pheromone in A. quadriimpressum. All of these results could provide valuable information and guidance for future functional studies on these genes and provide better molecular knowledge regarding the olfactory system in A. quadriimpressum.

Resveratrol and polydatin as modulators of Ca2+ mobilization in the cardiovascular system.

PubMed

Liu, Wenjuan; Chen, Peiya; Deng, Jianxin; Lv, Jingzhang; Liu, Jie

2017-09-01

In the cardiovascular system, Ca 2+ controls cardiac excitation-contraction coupling and vascular contraction and dilation. Disturbances in intracellular Ca 2+ homeostasis induce malfunctions of the cardiovascular system, including cardiac pump dysfunction, arrhythmia, remodeling, and apoptosis, as well as hypertension and impairment of vascular reactivity. Therefore, developing drugs and strategies manipulating Ca 2+ handling are highly valued in the treatment of cardiovascular disease. Resveratrol (Res) and polydatin (PD), a Res glucoside, have been well established to have beneficial effects on improving cardiovascular function. Studies from our laboratory and others have demonstrated that they exhibit inotropic effects on normal heart and therapeutic effects on hypertension, cardiac ischemia/reperfusion injury, hypertrophy, and heart failure by manipulating Ca 2+ mobilization. The actions of Res and PD on Ca 2+ signals delicately manipulated by multiple Ca 2+ -handling proteins are pleiotropic and somewhat controversial, depending on cellular species and intracellular oxidative status. Here, we focus on the effects of Res and PD on controlling Ca 2+ homeostasis in the heart and vasculature under normal and diseased conditions and highlight the key direct and indirect molecules mediating these effects. © 2017 New York Academy of Sciences.

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

PubMed

Shettigar, Vikram; Zhang, Bo; Little, Sean C; Salhi, Hussam E; Hansen, Brian J; Li, Ning; Zhang, Jianchao; Roof, Steve R; Ho, Hsiang-Ting; Brunello, Lucia; Lerch, Jessica K; Weisleder, Noah; Fedorov, Vadim V; Accornero, Federica; Rafael-Fortney, Jill A; Gyorke, Sandor; Janssen, Paul M L; Biesiadecki, Brandon J; Ziolo, Mark T; Davis, Jonathan P

2016-02-24

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease

PubMed Central

Shettigar, Vikram; Zhang, Bo; Little, Sean C.; Salhi, Hussam E.; Hansen, Brian J.; Li, Ning; Zhang, Jianchao; Roof, Steve R.; Ho, Hsiang-Ting; Brunello, Lucia; Lerch, Jessica K.; Weisleder, Noah; Fedorov, Vadim V.; Accornero, Federica; Rafael-Fortney, Jill A.; Gyorke, Sandor; Janssen, Paul M. L.; Biesiadecki, Brandon J.; Ziolo, Mark T.; Davis, Jonathan P.

2016-01-01

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca2+ signal. Promisingly, our smartly formulated Ca2+-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease. PMID:26908229

Infective endocarditis.

PubMed

Dunne, B; Marr, T; Kim, D; Andrews, D; Edwards, M; Merry, C; Larbalestier, R

2014-07-01

Infective endocarditis continues to pose a therapeutic challenge to treating clinicians. We believe that the successful management of endocarditis mandates a thorough understanding of the risk factors for adverse outcomes and a co-ordinated team approach. Between the years 2000 and 2009, 85 patients required surgery for infective endocarditis, with a total of 112 infected valves being treated surgically. Data was analysed to determine factors significantly associated with morbidity and mortality. The mean age was 50.5 years. Nine (10.5%) of these patients had Prosthetic Valve Endocarditis, the remaining 76 (89.5%) had Native Valve Endocarditis. Twenty-nine percent of patients were NYHA 4 pre-operatively, 15% of patients were haemodynamically unstable requiring inotropic support, 34% were persistently febrile despite antibiotic therapy, and 48% had suffered any embolic event, 20% suffered cerebral emboli. The commonest causative organism in our series was Staphylococcus Aureus (54.1%) with 2.3% of cases being due to MRSA. The second commonest organism isolated was Streptococcus spp. at 21.1%. Operative mortality was 12.9%, of which on-table mortality was 2.2%. Mean follow-up was 56 months (range 1-151). Early recurrence rates (<3 months) were 2.3%. Late recurrence was 7.0%. The pre-operative factors associated with increased mortality were age over 65, inotropic requirement, uncontrolled sepsis and cerebral emboli. We summarise our experience and recommendations for a team approach to the management of infective endocarditis. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Outcomes of Minimally Invasive Temporary Right Ventricular Assist Device Support for Acute Right Ventricular Failure During Minimally Invasive Left Ventricular Assist Device Implantation.

PubMed

Schaefer, Andreas; Reichart, Daniel; Bernhardt, Alexander M; Kubik, Mathias; Barten, Markus J; Wagner, Florian M; Reichenspurner, Hermann; Philipp, Sebastian A; Deuse, Tobias

Right ventricular failure (RVF) may still occur despite the benefits of minimally invasive left ventricular assist device (MI-LVAD) implantation. Our center strategy aims to avoid aggressive postoperative inotrope use by using mechanical support to facilitate right ventricle recovery and adaptation. We herein report first outcomes of patients with minimally invasive temporary right ventricular assist device (MI-t-RVAD) support for RVF during MI-LVAD implantation. Right ventricular failure was defined as requiring more than moderate inotopic support after weaning from cardiopulmonary bypass according to Interagency Registry for Mechanically Assisted Circulatory Support adverse event definitions. All patients requiring MI-t-RVAD support for RVF during MI-LVAD implantation between January, 2012 and April, 2016 were retrospectively reviewed. Clinical endpoints were death or unsuccessful RVAD weaning. Overall 10 patients (90% male, mean age 49.6 ± 14.8 years) underwent MI-t-RVAD implantation. Duration of MI-t-RVAD support was 16.2 ± 11.6 days. Right ventricular assist device weaning and subsequent uneventful awake device explantation was successful in all cases. The 30 day survival was 80%. Our results confirm safety and feasibility of MI-t-RVAD support for acute RVF in the setting of MI-LVAD implantation. The potential benefits of this strategy are more stable hemodynamics in the first postoperative days that usually are crucial for LVAD patients and reduced inotrope requirement.

Heart sounds analysis via esophageal stethoscope system in beagles.

PubMed

Park, Sang Hi; Shin, Young Duck; Bae, Jin Ho; Kwon, Eun Jung; Lee, Tae-Soo; Shin, Ji-Yun; Kim, Yeong-Cheol; Min, Gyeong-Deuk; Kim, Myoung hwan

2013-10-01

Esophageal stethoscope is less invasive and easy to handling. And it gives a lot of information. The purpose of this study is to investigate the correlation of blood pressure and heart sound as measured by esophageal stethoscope. Four male beagles weighing 10 to 12 kg were selected as experimental subjects. After general anesthesia, the esophageal stethoscope was inserted. After connecting the microphone, the heart sounds were visualized and recorded through a self-developed equipment and program. The amplitudes of S1 and S2 were monitored real-time to examine changes as the blood pressure increased and decreased. The relationship between the ratios of S1 to S2 (S1/S2) and changes in blood pressure due to ephedrine was evaluated. The same experiment was performed with different concentration of isoflurane. From S1 and S2 in the inotropics experiment, a high correlation appeared with change in blood pressure in S1. The relationship between S1/S2 and change in blood pressure showed a positive correlation in each experimental subject. In the volatile anesthetics experiment, the heart sounds decreased as MAC increased. Heart sounds were analyzed successfully with the esophageal stethoscope through the self-developed program and equipment. A proportional change in heart sounds was confirmed when blood pressure was changed using inotropics or volatile anesthetics. The esophageal stethoscope can achieve the closest proximity to the heart to hear sounds in a non-invasive manner.

Coupled Plasma Filtration and Adsorption (CPFA): A Single Center Experience.

PubMed

Abdul Cader, Rizna; Abdul Gafor, Halim; Mohd, Rozita; Yen Kong, Wei; Arshad, Norazimah; Kong, Norella

2013-09-01

Coupled plasma filtration adsorption (CPFA) is a novel extracorporeal blood purification therapy for sepsis which adsorbs both proinflammatory and anti-inflammatory mediators from filtered plasma, thereby achieving early haemodynamic stability and a reduction in inotropic support requirement. The main objective was to review our centers' experience with CPFA in septic patients. A retrospective chart review of all septic patients who received CPFA was performed. All patients were initially treated according to the 'surviving sepsis care bundle' with fluid resuscitation, antibiotics, and inotropes as required. CPFA was started as soon as possible after a nephrologists' assessment. Twenty five patients with sepsis received CPFA (15 M, 10 F, mean age 49.60 ± 18.97 years). Comorbidities included hypertension (n = 10, 40%), diabetes mellitus (n = 6, 24%), ischemic heart disease (n = 6, 24%), and an immunosuppressed state (n = 10, 40%). All patients received one cycle of CPFA with median duration of 5 (1-10) hours. CPFA was well tolerated but we encountered technical problems, especially filter clotting as CPFA was performed heparin free. 14 (56%) patients died within 28 days of treatment. CRP correlated with PCT (P = 0.040) and had an inverse trend with albumin (P = 0.066). Serum albumin was a strong predictor of mortality. The high prevalence of fungaemia and mortality could be attributed to many patients on chronic immunosuppressive therapy. Nonetheless, CPFA albeit expensive, does add to our armamentarium of extracorporeal treatment for severe sepsis. Regional citrate anticoagulation with CPFA may overcome problems with filter clotting.

Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine

PubMed Central

Brierley, Joe; Carcillo, Joseph A.; Choong, Karen; Cornell, Tim; DeCaen, Allan; Deymann, Andreas; Doctor, Allan; Davis, Alan; Duff, John; Dugas, Marc-Andre; Duncan, Alan; Evans, Barry; Feldman, Jonathan; Felmet, Kathryn; Fisher, Gene; Frankel, Lorry; Jeffries, Howard; Greenwald, Bruce; Gutierrez, Juan; Hall, Mark; Han, Yong Y.; Hanson, James; Hazelzet, Jan; Hernan, Lynn; Kiff, Jane; Kissoon, Niranjan; Kon, Alexander; Irazusta, Jose; Lin, John; Lorts, Angie; Mariscalco, Michelle; Mehta, Renuka; Nadel, Simon; Nguyen, Trung; Nicholson, Carol; Peters, Mark; Okhuysen-Cawley, Regina; Poulton, Tom; Relves, Monica; Rodriguez, Agustin; Rozenfeld, Ranna; Schnitzler, Eduardo; Shanley, Tom; Skache, Sara; Skippen, Peter; Torres, Adalberto; von Dessauer, Bettina; Weingarten, Jacki; Yeh, Timothy; Zaritsky, Arno; Stojadinovic, Bonnie; Zimmerman, Jerry; Zuckerberg, Aaron

2013-01-01

Background The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote “best practices” and to improve patient outcomes. Objective 2007 update of the 2002 American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock. Participants Society of Critical Care Medicine members with special interest in neonatal and pediatric septic shock were identified from general solicitation at the Society of Critical Care Medicine Educational and Scientific Symposia (2001–2006). Methods The Pubmed/MEDLINE literature database (1966–2006) was searched using the keywords and phrases: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation (ECMO), and American College of Critical Care Medicine guidelines. Best practice centers that reported best outcomes were identified and their practices examined as models of care. Using a modified Delphi method, 30 experts graded new literature. Over 30 additional experts then reviewed the updated recommendations. The document was subsequently modified until there was greater than 90% expert consensus. Results The 2002 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and AHA sanctioned recommendations. Centers that implemented the 2002 guidelines reported best practice outcomes (hospital mortality 1%–3% in previously healthy, and 7%– 10% in chronically ill children). Early use of 2002 guidelines was associated with improved outcome in the community hospital emergency department (number needed to treat = 3.3) and tertiary pediatric intensive care setting (number needed to treat = 3.6); every hour that went by without guideline adherence was associated with a 1.4-fold increased mortality risk. The updated 2007 guidelines continue to recognize an increased likelihood that children with septic shock, compared with adults, require 1) proportionally larger quantities of fluid, 2) inotrope and vasodilator therapies, 3) hydrocortisone for absolute adrenal insufficiency, and 4) ECMO for refractory shock. The major new recommendation in the 2007 update is earlier use of inotrope support through peripheral access until central access is attained. Conclusion The 2007 update continues to emphasize early use of age-specific therapies to attain time-sensitive goals, specifically recommending 1) first hour fluid resuscitation and inotrope therapy directed to goals of threshold heart rates, normal blood pressure, and capillary refill ≤2 secs, and 2) subsequent intensive care unit hemodynamic support directed to goals of central venous oxygen saturation >70% and cardiac index 3.3–6.0 L/min/m2. PMID:19325359

Alkaline phosphatase activity after cardiothoracic surgery in infants and correlation with post-operative support and inflammation: a prospective cohort study.

PubMed

Davidson, Jesse; Tong, Suhong; Hauck, Amanda; Lawson, D Scott; Jaggers, James; Kaufman, Jon; da Cruz, Eduardo

2012-08-20

Limited evidence suggests that serum alkaline phosphatase activity may decrease after cardiac surgery in adults and children. The importance of this finding is not known. Recent studies, however, have identified a potential role for alkaline phosphatase as modulator of inflammation in multiple settings, including during adult cardiopulmonary bypass. We sought to describe the change in alkaline phosphatase activity after cardiothoracic surgery in infants and to assess for a correlation with intensity and duration of post-operative support, markers of inflammation, and short-term clinical outcomes. Sub-analysis of a prospective observational study on the kinetics of procalcitonin in 70 infants (≤ 90 days old) undergoing cardiothoracic surgery. Subjects were grouped based on the use of cardiopulmonary bypass and delayed sternal closure. Alkaline phosphatase, procalcitonin, and C-reactive protein (CRP) levels were obtained pre-operation and on post-operative day 1. Mean change in alkaline phosphatase activity was determined in each surgical group. Generalized linear modeling and logistic regression were employed to assess for associations between post-operative alkaline phosphatase activity and post-operative support, inflammation, and short term outcomes. Primary endpoints were vasoactive-inotropic score at 24 hours and length of intubation. Secondary endpoints included procalcitonin/CRP levels on post-operative day 1, length of hospital stay, and cardiac arrest or death. Mean decrease in alkaline phosphatase was 30 U/L (p = 0.01) in the non-bypass group, 114 U/L (p < 0.0001) in the bypass group, and 94 U/L (p < 0.0001) in the delayed sternal closure group. On multivariate analysis, each 10 U/L decrease in alkaline phosphatase activity on post-operative day 1 was independently associated with an increase in vasoactive-inotropic score by 0.7 (p < 0.0001), intubation time by 6% (p < 0.05), hospital stay by 5% (p < 0.05), and procalcitonin by 14% (P < 0.01), with a trend towards increased odds of cardiac arrest or death (OR 1.3; p = 0.06). Post-operative alkaline phosphatase activity was not associated with CRP (p = 0.7). Alkaline phosphatase activity decreases after cardiothoracic surgery in infants. Low post-operative alkaline phosphatase activity is independently associated with increased procalcitonin, increased vasoactive/inotropic support, prolonged intubation time, and prolonged hospital stay. Alkaline phosphatase may serve as a biomarker and potential modulator of post-operative support and inflammation following cardiothoracic surgery in infants.

Alkaline phosphatase activity after cardiothoracic surgery in infants and correlation with post-operative support and inflammation: a prospective cohort study

PubMed Central

2012-01-01

Introduction Limited evidence suggests that serum alkaline phosphatase activity may decrease after cardiac surgery in adults and children. The importance of this finding is not known. Recent studies, however, have identified a potential role for alkaline phosphatase as modulator of inflammation in multiple settings, including during adult cardiopulmonary bypass. We sought to describe the change in alkaline phosphatase activity after cardiothoracic surgery in infants and to assess for a correlation with intensity and duration of post-operative support, markers of inflammation, and short-term clinical outcomes. Methods Sub-analysis of a prospective observational study on the kinetics of procalcitonin in 70 infants (≤90 days old) undergoing cardiothoracic surgery. Subjects were grouped based on the use of cardiopulmonary bypass and delayed sternal closure. Alkaline phosphatase, procalcitonin, and C-reactive protein (CRP) levels were obtained pre-operation and on post-operative day 1. Mean change in alkaline phosphatase activity was determined in each surgical group. Generalized linear modeling and logistic regression were employed to assess for associations between post-operative alkaline phosphatase activity and post-operative support, inflammation, and short term outcomes. Primary endpoints were vasoactive-inotropic score at 24 hours and length of intubation. Secondary endpoints included procalcitonin/CRP levels on post-operative day 1, length of hospital stay, and cardiac arrest or death. Results Mean decrease in alkaline phosphatase was 30 U/L (p = 0.01) in the non-bypass group, 114 U/L (p<0.0001) in the bypass group, and 94 U/L (p<0.0001) in the delayed sternal closure group. On multivariate analysis, each 10 U/L decrease in alkaline phosphatase activity on post-operative day 1 was independently associated with an increase in vasoactive-inotropic score by 0.7 (p<0.0001), intubation time by 6% (p<0.05), hospital stay by 5% (p<0.05), and procalcitonin by 14% (P<0.01), with a trend towards increased odds of cardiac arrest or death (OR 1.3; p = 0.06). Post-operative alkaline phosphatase activity was not associated with CRP (p = 0.7). Conclusions Alkaline phosphatase activity decreases after cardiothoracic surgery in infants. Low post-operative alkaline phosphatase activity is independently associated with increased procalcitonin, increased vasoactive/inotropic support, prolonged intubation time, and prolonged hospital stay. Alkaline phosphatase may serve as a biomarker and potential modulator of post-operative support and inflammation following cardiothoracic surgery in infants. PMID:22906145

Unloading therapy by intravenous diuretic in chronic heart failure: a double-edged weapon?

PubMed

De Vecchis, Renato; Ciccarelli, Antonio; Pucciarelli, Armando

2010-08-01

A well established part of therapeutic approaches applying to cases of chronic heart failure (CHF) with extreme fluid retention is represented by intensive intravenous (i.v.) therapy with loop diuretics. This kind of therapy, if appropriately modulated according to the individual clinical picture and biohumoral pattern, is able to decrease the abnormally high ventricular filling pressures, thereby relieving the breathlessness while being able to retrieve a suitable urine output, so as to propitiate regression or disappearance of edema without unfavorable influences on renal clearance of nitrogenous compounds. Nevertheless, the intensive i.v. diuretic therapy should be tailored on the basis of a close assessment of baseline hemodynamic data and hemodynamic response to the medications, in addition to the careful diuretic dose titration and cautious evaluation of risk/benefit ratio. Actually, by using this kind of therapy, there is a risk that a tubular or glomerular injury can be generated and that a frequently preexisting renal dysfunction can be aggravated, especially when excessive doses of loop diuretics are being erroneously administered, so as to cause hypotension, hypoperfusion and/or relative dehydration in patients with decompensated CHF who could have expressly benefitted from intensive unloading therapy. Recently, the genesis of CHF-related progressive renal deterioration has been highlighted by affirming that a major role may be played rather by neurovegetative disorders, that is, by increase in sympathetic tone and abnormalities in kidney's vasomotility than by cardiac inotropism deficiency. The measures, thought to be able to prevent renal arterial constriction and to impede deterioration of glomerular filtration rate (GFR) due to the ischemic-necrotic tubular injury, as occurring in the set of intensive unloading therapy with i.v. furosemide or other loop diuretic, are represented by application of inotropic and renal vasodilator support by dopamine i.v. infusion at low doses or by other inotropic agents provided with recognized renal vasodilator properties and/or by addition to i.v. furosemide of osmotic agents able to expand the hematic volume, so counteracting or minimizing the reflex renal vasoconstriction induced by furosemide-related reduction in intravascular circulating volume: i.v. infusion of small volumes of hypertonic saline solution, as well as administration of albumin, mannitol and/or plasma expanders. Because renal impairment, as developing in the setting of CHF, has proven to represent a very important indicator of adverse outcome, every effort should be addressed to prevent any significant (>25% of basal value) rise in serum creatinine consequent to diuretic unloading therapy or to other procedures (paracentesis of tense ascites, ultrafiltration) aimed at rapid fluid removal in edematous or ascitic CHF or cardiogenetic anasarca. Ultrafiltration, even though a promising technique highly valued for its acknowledged property to obtain a more rapid fluid and weight loss in CHF patients with marked fluid retention, has been demonstrated so far to produce neurohumoral activation, creatinine abnormalities and symptomatic hypotensions similar to those due to i.v. loop diuretics; thus, the hypothesized advantages of this technique remain to be further clarified and confirmed, with regard to its safety profile and cost-effectiveness.

Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial.

PubMed

Nalos, Marek; Leverve, Xavier; Huang, Stephen; Weisbrodt, Leonie; Parkin, Ray; Seppelt, Ian; Ting, Iris; Mclean, Anthony

2014-03-25

Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF. We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann's solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality. The infusion of half-molar sodium lactate increased (mean ± SD) CO from 4.05 ± 1.37 L/min to 5.49 ± 1.9 L/min (P < 0.01) and TAPSE from 14.7 ± 5.5 mm to 18.3 ± 7 mm (P = 0.02). Plasma sodium and pH increased (136 ± 4 to 146 ± 6 and 7.40 ± 0.06 to 7.53 ± 0.03, respectively; both P < 0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality. Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function. Clinicaltrials.gov NCT01981655. Registered 13 August 2013.

Cardiovascular consequences of sympathetic hyperactivity.

PubMed

Leenen, F H

1999-03-01

The sympathetic nervous system plays an integral role in many aspects of cardiovascular homeostasis. However, intermittent or chronic sympathetic hyperactivity can also initiate or accelerate cardiovascular pathology and provoke clinical events in the presence of cardiovascular disease. Both alpha- and beta-receptors mediate these responses. In the case of the heart, alpha- and beta- receptors contribute to ventricular arrhythmias and cardiac hypertrophy. Moreover, cardiac beta2-receptors mediate not only chronotropic and inotropic responses at the postsynaptic level, but also noradrenalin release at the presynaptic level. To block the adverse effects of sympathetic hyperactivity optimally, one would therefore need both alpha- and nonselective beta-receptor blockade. On the other hand, prevention or reversal of sympathetic hyperactivity at the central level appears to be an attractive alternative. Alpha2-agonists such as clonidine and alpha-methyldopa are clearly effective in this regard but are associated with side effects. More recent research indicates that in the central nervous systen (CNS) other classes such as dihydropyridines (eg, nifedipine) or angiotensin II type 1 receptor blockers (eg, losartan) also can decrease elevated sympathetic nerve activity. The therapeutic relevance of these CNS effects and differences between lipophilic and hydrophilic compounds provide intriguing new avenues for research in disorders such as hypertension and congestive heart failure.

Rupture of abdominal aortic aneurysm into sigmoid colon: A case report

PubMed Central

Aksoy, Murat; Yanar, Hakan; Taviloglu, Korhan; Ertekin, Cemalettin; Ayalp, Kemal; Yanar, Fatih; Guloglu, Recep; Kurtoglu, Mehmet

2006-01-01

Primary aorto-colic fistula is rarely reported in the literature. Although infrequently encountered, it is an important complication since it is usually fatal unless detected. Primary aorto-colic fistula is a spontaneous rupture of abdominal aortic aneurysm into the lumen of the adjacent colon loop. Here we report a case of primary aorto-colic fistula in a 54-year old male. The fistulated sigmoid colon was repaired by end-to-end anastomosis. Despite inotropic support, the patient died of sepsis and multiorgan failure on the first postoperative day. PMID:17167850

Femtosecond dynamics in ionic structures of a heart medicine

NASA Astrophysics Data System (ADS)

Gil, M.; Douhal, A.

2006-12-01

Femtosecond studies of ionic structures of milrinone - a medicine used to help the heart to recuperate its life - in acidic and alkaline water solutions show that the intramolecular charge transfer in the cation and in the anion happen in 550 fs and ˜1.2 ps, respectively. These times are longer than 100 fs, observed in the keto (inotropic) form. The transients also show a 2-3 ps component, assigned to cooling and twisting motion in the produced states. The result might be used for a better understanding of other functional molecules.

Effects of amitriptyline and clomipramine in the isolated, perfused rabbit heart.

PubMed

Nielsen-Kudsk, F; Quist, S

1980-04-01

The cardiac effects of supratherapeutic concentrations of two tricyclic antidepressants were studied in isolated rabbit hearts, which were perfused with a modified Krebs-Henseleit solution containing 0.25 or 0.50 micrograms ml-1 of amitriptyline or 0.28 micrograms mg-1 of clomipramine. The following parameters were continuously recorded:heart rate, amplitude and rate of contraction, coronary flow rate, myocardial oxygen consumption and ECG. The lowest concentration of amitriptyline caused a time correlated decrease (20%) in the frequency of spontaneous beating and a pronounced decrease in the amplitude (62%) and rate of cardiac contraction (58%). Maximum increases of the PQ-interval of about 46% and of the QRS-complex of about 100% were observed. At the higher amitriptyline concentration these effect further increased. Clomipramine 0.28 micrograms ml-1 also had a very pronounced and time correlated negative inotropic effect, but the effects upon the conduction velocities were substantially lesser than those produced by the equimilar concentration of amitriptyline. The compounds caused only insignificant changes in coronary flow. The oxygen consumption did not decrease in proportion to the decrease in contractility, as an expression of decreased myocardial efficiency. The effects of the drugs are discussed in relation to theri myocardial accumulation pharmacokinetics and influence upon the membraneous sodium and calcium flux and intracellular metabolism.

Safety and Efficacy of the Off-Label Use of Milrinone in Pediatric Patients with Heart Diseases

PubMed Central

Lee, Joowon; Kwon, Hye Won; Kwon, Bo Sang; Bae, Eun Jung; Noh, Chung Il; Lim, Hong Gook; Kim, Woong Han; Lee, Jeong Ryul; Kim, Yong Jin

2014-01-01

Background and Objectives Milrinone is often used in children to treat acute heart failure and prevent low cardiac output syndrome after cardiac surgery. Due to the lack of studies on the long-term milrinone use in children, the objective of this study was to assess the safety and efficacy of the current patterns of milrinone use for ≥3 days in infants and children with heart diseases. Subjects and Methods We retrospectively reviewed the medical records of patients aged <13 years who received milrinone for ≥3 days from January 2005 to December 2012. Patients' characteristics including age, sex, height, weight, and body surface area were recorded. The following parameters were analyzed to identify the clinical application of milrinone: initial infusion rate, maintenance continuous infusion rate, total duration of milrinone therapy, and concomitantly infused inotropes. The safety of milrinone was determined based on the occurrence of adverse events such as hypotension, arrhythmia, chest pain, headache, hypokalemia, and thrombocytopenia. Results We assessed 730 admissions (684 patients) during this period. Ventricular septal defects were the most common diagnosis (42.4%) in these patients. Milrinone was primarily used after cardiac surgery in 715 admissions (97.9%). The duration of milrinone treatment varied from 3 to 64.4 days (≥7 days in 149 admissions). Ejection fraction and fractional shortening of the left ventricle improved in patients receiving milrinone after cardiac surgery. Dose reduction of milrinone due to hypotension occurred in only 4 admissions (0.5%). Although diverse arrhythmias occurred in 75 admissions (10.3%), modification of milrinone infusion to manage arrhythmia occurred in only 3 admissions (0.4%). Multivariate analysis indicated that the development of arrhythmia was not influenced by the pattern of milrinone use. Conclusion Milrinone was generally administered for ≥3 days in children with heart diseases. The use of milrinone for ≥3 days was effective in preventing low cardiac output after cardiac surgery when combined with other inotropes, suggesting that milrinone could be safely employed in pediatric patients with heart diseases. PMID:25278985

Angiotensin II in Refractory Septic Shock.

PubMed

Antonucci, Elio; Gleeson, Patrick J; Annoni, Filippo; Agosta, Sara; Orlando, Sergio; Taccone, Fabio Silvio; Velissaris, Dimitrios; Scolletta, Sabino

2017-05-01

Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin-angiotensin-aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

Energy Drinks and Myocardial Ischemia: A Review of Case Reports.

PubMed

Lippi, Giuseppe; Cervellin, Gianfranco; Sanchis-Gomar, Fabian

2016-07-01

The use and abuse of energy drinks (EDs) is constantly increasing worldwide. We performed a systematic search in Medline, Scopus and Web of Science to identify evidence about the potential link between these beverages and myocardial ischemia. Overall, 8 case reports could be detected, all of which described a realistic association between large intake of EDs and episodes of myocardial ischemia. Interestingly, no additional triggers of myocardial ischemia other than energy drinks could be identified in the vast majority of cases. Some plausible explanations can be brought in support of this association. Most of the biological effects of EDs are seemingly mediated by a positive inotropic effect on cardiac function, which entails increase in heart rate, cardiac output and contractility, stroke volume and arterial blood pressure. Additional biological abnormalities reported after EDs intake include increased platelet aggregation, endothelial dysfunction, hyperglycemia as well as an increase in total cholesterol, triglycerides and low-density lipoprotein cholesterol. Although a causal relationship between large consumption of EDs and myocardial ischemia cannot be definitely established so far, concerns about the cardiovascular risk of excessive consumption of these beverages are seemingly justified.

Trial watch

PubMed Central

Menger, Laurie; Vacchelli, Erika; Kepp, Oliver; Eggermont, Alexander; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2013-01-01

Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na+/K+-ATPase, hence promoting—via an indirect mechanism—the intracellular accumulation of Ca2+ ions. In cardiomyocytes, increased intracellular Ca2+ concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications. PMID:23525565

Inotropic responses of the frog ventricle to adenosine triphosphate and related changes in endogenous cyclic nucleotides.

PubMed

Flitney, F W; Singh, J

1980-07-01

1. A study has been made of a well documented but poorly understood response of the isolated frog ventricle to treatment with exogenous adenosine 5' triphosphate (ATP). Measurements of membrane potential, isometric twitch tension and levels of endogenous 3',5'-cyclic nucleotides have been made at various times during the ATP-induced response. 2. ATP elicits a characteristic triphasic response, which comprises an initial, abrupt increase in contractility, rising to a maximum within a few beats (first phase); followed by a period when the twitch amplitude falls, sometimes to below the control level (second phase); and superceded by a more slowly developing and longer-lasting increase in contractile force (third phase). The response is unaffected by atropine, propranolol or phentolamine. However, the prostaglandin synthetase inhibitor indomethacin depresses the first phase and entirely suppresses the third phase. 3. The inotropic effects of ATP are accompanied by changes in the shape of the action potential. These effects are dose-related. The duration of the action potential (D-30mV) and its positive overshoot (O) are increased during all phases of the response, for [ATP]o's up to 10(-5) M. However, at higher [ATP]o's, D-30mV and O ar both reduced during the second phase (but not the first or third phase), when isometric twitch tension is also depressed. The relationship between action potential duration and twitch tension (P) for different [ATP]o's is linear for all three phases of the response, but the slopes of the curves (delta P/delta D) are markedly different, indicating that the sensitivity of the contractile system to membrane depolarization is not constant, but varies continuously throughout the response. 4. ATP has a potent stimulatory effect on the metabolism of endogenous 3',5'-cyclic nucleotides. The time courses of the changes in adenosine 3','5-cyclic monophosphate (3',5'-cyclic AMP) and guanosine 3',5'-cyclic monophosphate (3',5'-cyclic GMP) are complex, but the accompanying change in isometric twitch tension is paralleled closely by corresponding changes in the ratio 3',5'cyclic AMP:3',5'-cyclic GMP. 5. It is concluded that ATP exerts a dual effect on the ventricle and that the contractile response is regulated by changes in the metabolism of 3',5'-cyclic nucleotides. The effects of indomethacin indicate a possible involvement of prostaglandins in mediating the ATP response. It is suggested that the initial effect of ATP on the ventricle is to increase the permeability of the fibres to Ca2+. 6. The relationship between 3',5' cyclic nucleotide levels and ventricular contractility is discussed. It is postulated that the antagonistic effects of 3',5'-cyclic AMP and 3',5'-cyclic GMP are expressed at the level of certain phosphoproteins which regulate both the availability of Ca2+ and the sensitivity of the contractile proteins to Ca2+.

Can the Seattle heart failure model be used to risk-stratify heart failure patients for potential left ventricular assist device therapy?

PubMed

Levy, Wayne C; Mozaffarian, Dariush; Linker, David T; Farrar, David J; Miller, Leslie W

2009-03-01

According to results of the REMATCH trial, left ventricular assist device therapy in patients with severe heart failure has resulted in a 48% reduction in mortality. A decision tool will be necessary to aid in the selection of patients for destination left ventricular assist devices (LVADs) as the technology progresses for implantation in ambulatory Stage D heart failure patients. The purpose of this analysis was to determine whether the Seattle Heart Failure Model (SHFM) can be used to risk-stratify heart failure patients for potential LVAD therapy. The SHFM was applied to REMATCH patients with the prospective addition of inotropic agents and intra-aortic balloon pump (IABP) +/- ventilator. The SHFM was highly predictive of survival (p = 0.0004). One-year SHFM-predicted survival was similar to actual survival for both the REMATCH medical (30% vs 28%) and LVAD (49% vs 52%) groups. The estimated 1-year survival with medical therapy for patients in REMATCH was 30 +/- 21%, but with a range of 0% to 74%. The 1- and 2-year estimated survival was

Ductal stenting retrains the left ventricle in transposition of great arteries with intact ventricular septum.

PubMed

Sivakumar, Kothandam; Francis, Edwin; Krishnan, Prasad; Shahani, Jagdish

2006-11-01

In late presenters with transposition of the great arteries, intact ventricular septum, and regressing left ventricle, left ventricular retraining by pulmonary artery banding and aortopulmonary shunt is characterized by a stormy postoperative course and high costs. Ductal stenting in the cardiac catheterization laboratory is conceptualized to retrain the left ventricle with less morbidity. Recanalization and transcatheter stenting of patent ductus arteriosus was performed in patients with transposition to induce pressure and volume overload to the regressing left ventricle. Serial echocardiographic monitoring of left ventricular shape, mass, free wall thickness, and volumes was done, and once the left ventricle was adequately prepared, an arterial switch was performed. The ductal stent was removed and the remaining surgical steps were similar to a 1-stage arterial switch operation. Postoperative course, need for inotropic agents, and left ventricular function were monitored. Ductal stenting in 2 patients aged 3 months resulted in improvement of indexed left ventricular mass from 18.9 to 108.5 g/m2, left ventricular free wall thickness from 2.5 to 4.8 mm, and indexed left ventricular volumes from 7.6 to 29.5 mL/m2 within 3 weeks. Both patients underwent arterial switch (bypass times 125 and 158 minutes) uneventfully, needed inotropic agents and ventilatory support for 3 days, and were discharged in 8 and 10 days. Ductal stenting is a less morbid method of left ventricular retraining in transposition of the great arteries with regressed left ventricle. Its major advantages lie in avoiding pulmonary artery distortion and neoaortic valve regurgitation resulting from banding and also in avoiding thoracotomy.

Renal ultrasound provides low utility in evaluating cardiac surgery associated acute kidney injury.

PubMed

Young, Allen; Crawford, Todd; Pierre, Alejandro Suarez; Trent Magruder, J; Fraser, Charles; Conte, John; Whitman, Glenn; Sciortino, Christopher

2017-09-02

Renal ultrasonography is part of the algorithm in assessing acute kidney injury (AKI). The purpose of this study was to assess the clinical utility of renal US in postoperative cardiac patients who develop AKI. We conducted a retrospective study of 90 postoperative cardiac surgery patients at a single institution from 1/19/2010 to 3/19/2016 who underwent renal US for AKI. We reviewed provider documentation to determine whether renal US changed management. We defined change as: administration of crystalloid or colloid, addition of inotropic or vasopressor, or procedural interventions on the renal system. Mean age of study patients was 68 ± 13 years. 48/90 patients (53.3%) had pre-existing chronic kidney disease of varying severity. 48 patients (53.3%) had normal renal US with incidental findings and 31 patients (34.4%) had US evidence of medical kidney disease. 10 patients (11.1%) had limited US results due to poor visualization and 1 patient (1.1%) had mild right-sided hydronephrosis. No patients were found to have obstructive uropathy or renal artery stenosis. Clinical management was altered in only 4/90 patients (4.4%), which included 3 patients that received a fluid bolus and 1 patient that received a fluid bolus and inotropes. No vascular or urologic procedures resulted from US findings. Although renal ultrasound is often utilized in the work-up of AKI, our study shows that renal US provides little benefit in managing postoperative cardiac patients. This diagnostic modality should be scrutinized rather than viewed as a universal measure in the cardiac surgery population.

Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility

NASA Technical Reports Server (NTRS)

Greenberg, Neil L.; Firstenberg, Michael S.; Castro, Peter L.; Main, Michael; Travaglini, Agnese; Odabashian, Jill A.; Drinko, Jeanne K.; Rodriguez, L. Leonardo; Thomas, James D.; Garcia, Mario J.

2002-01-01

BACKGROUND: Myocardial fiber strain is directly related to left ventricular (LV) contractility. Strain rate can be estimated as the spatial derivative of velocities (dV/ds) obtained by tissue Doppler echocardiography (TDE). The purposes of the study were (1) to determine whether TDE-derived strain rate may be used as a noninvasive, quantitative index of contractility and (2) to compare the relative accuracy of systolic strain rate against TDE velocities alone. METHODS AND RESULTS: TDE color M-mode images of the interventricular septum were recorded from the apical 4-chamber view in 7 closed-chest anesthetized mongrel dogs during 5 different inotropic stages. Simultaneous LV volume and pressure were obtained with a combined conductance-high-fidelity pressure catheter. Peak elastance (Emax) was determined as the slope of end-systolic pressure-volume relationships during caval occlusion and was used as the gold standard of LV contractility. Peak systolic TDE myocardial velocities (Sm) and peak (epsilon'(p)) and mean (epsilon'(m)) strain rates obtained at the basal septum were compared against Emax by linear regression. Emax as well as TDE systolic indices increased during inotropic stimulation with dobutamine and decreased with the infusion of esmolol. A stronger association was found between Emax and epsilon'(p) (r=0.94, P<0.01, y=0.29x+0.46) and epsilon'(m) (r=0.88, P<0.01) than for Sm (r=0.75, P<0.01). CONCLUSIONS: TDE-derived epsilon'(p) and epsilon'(m) are strong noninvasive indices of LV contractility. These indices appear to be more reliable than S(m), perhaps by eliminating translational artifact.

End-of-life care in the general wards of a Singaporean hospital: an Asian perspective.

PubMed

Phua, Jason; Kee, Adrian Chin-Leong; Tan, Adeline; Mukhopadhyay, Amartya; See, Kay Choong; Aung, Ngu Wah; Seah, Angeline S T; Lim, Tow Keang

2011-12-01

Despite international differences in cultural perspectives on end-of-life issues, little is known of the care for the dying in the general wards of acute hospitals in Asia. We performed a retrospective medical chart review of all 683 adult patients who died without intensive care unit (ICU) admission in our Singaporean hospital in 2007. We first evaluated the prevalence of do-not-resuscitate (DNR) orders and orders for or against life-sustaining therapies; second, if such orders were discussed with the patients and/or family members; and third, the actual treatments provided before death. There were DNR orders for 66.2% of patients and neither commitment for DNR nor cardiopulmonary resuscitation (CPR) for 28.1%. Orders to limit life-sustaining therapies, including ICU admission, intubation, and vasopressors/inotropes were infrequent. Only 6.2% of the alert and conversant patients with DNR orders were involved in discussions on these orders. In contrast, such discussions with their family members occurred 82.9% of the time. Interventions in the last 24 hours of life included CPR (9.4%), intubation (6.4%), vasopressors/inotropes (14.8%), tube feeding (24.7%), and antibiotics (44.9%). Analgesia was provided in 29.1% of patients. There was a lack of commitment by doctors on orders for DNR/CPR and to limit life-sustaining therapies, infrequent discussions with patients on end-of-life decisions, and excessive burdensome interventions with inadequate palliative care for the dying. These findings may reflect certain Asian cultural biases. More work is required to improve our quality of end-of-life care.

Forward and Backward Pressure Waveform Morphology in Hypertension

PubMed Central

Li, Ye; Gu, Haotian; Fok, Henry; Alastruey, Jordi

2017-01-01

We tested the hypothesis that increased pulse wave reflection and altered backward waveform morphology contribute to increased pulse pressure in subjects with higher pulse pressure compared with lower pulse pressure and to actions of vasoactive drugs to increase pulse pressure. We examined the relationship of backward to forward wave morphology in 158 subjects who were evaluated for hypertension (including some normotensive subjects) divided into 3 groups by central pulse pressure: group 1, 33±6.5 mm Hg; group 2, 45±4.1 mm Hg; and group 3, 64±12.9 mm Hg (means±SD) and in healthy normotensive subjects during administration of inotropic and vasomotor drugs. Aortic pressure and flow in the aortic root were estimated by carotid tonometry and Doppler sonography, respectively. Morphology of the backward wave relative to the forward wave was similar in subjects in the lowest and highest tertiles of pulse pressure. Similar results were seen with the inotropic, vasopressor and vasodilator drugs, dobutamine, norepinephrine, and phentolamine, with the backward wave maintaining a constant ratio to the forward wave. However, nitroglycerin, a drug with a specific action to dilate muscular conduit arteries, reduced the amplitude of the backward wave relative to the forward wave from 0.26±0.018 at baseline to 0.19±0.019 during nitroglycerin 30 μg/min IV (P<0.01). These results are best explained by an approximately constant amount of reflection of the forward wave from the peripheral vasculature. The amount of reflection can be modified by dilation of peripheral muscular conduit arteries but contributes little to increased pulse pressure in hypertension. PMID:27920128

Carnitine derivatives: clinical usefulness.

PubMed

Malaguarnera, Mariano

2012-03-01

Carnitine and its derivatives are natural substances involved in both carbohydrate and lipid metabolism. This review summarizes the recent progress in the field in relation to the molecular mechanisms. The pool of different carnitine derivatives is formed by acetyl-L-carnitine (ALC), propionyl-L-carnitine (PLC), and isovaleryl-carnitine. ALC may have a preferential effect on the brain tissue. ALC represents a compound of great interest for its wide clinical application in various neurological disorders: it may be of benefit in treating Alzheimer's dementia, depression in the elderly, HIV infection, chronic fatigue syndrome, peripheral neuropathies, ischemia and reperfusion of the brain, and cognitive impairment associated with various conditions. PLC has been demonstrated to replenish the intermediates of the tricarboxylic acid cycle by the propionyl-CoA moiety, a greater affinity for the sarcolemmal carrier, peripheral vasodilator activity, a greater positive inotropism, and more rapid entry into myocytes. Most studies of the therapeutic use of PLC are focused on the prevention and treatment of ischemic heart disease, congestive heart failure, hypertrophic heart disease, and peripheral arterial disease. ALC and PLC are considered well tolerated without significant side-effects. A number of therapeutic effects possibly come from the interaction of carnitine and its derivatives with the elements of cellular membranes.

Milrinone and levosimendan administered after reperfusion improve myocardial stunning in swine.

PubMed

Shibata, Itsuko; Cho, Sungsam; Yoshitomi, Osamu; Ureshino, Hiroyuki; Maekawa, Takuji; Hara, Tetsuya; Sumikawa, Koji

2013-02-01

We assessed the effect of milrinone application timing after reperfusion against myocardial stunning as compared with levosimendan in swine. Furthermore, we examined the role of p38 mitogen-activated protein kinase (p38 MAPK) in the milrinone-induced cardioprotection. All swine were subjected to 12-minutes ischemia followed by 90-minutes reperfusion to generate stunned myocardium. Milrinone or levosimendan was administered intravenously either for 20 minutes starting just after reperfusion or for 70 minutes starting 20 minutes after reperfusion. In another group, SB203580, a selective p38 MAPK inhibitor, was administered with and without milrinone. Regional myocardial contractility was assessed by percent segment shortening (%SS). Milrinone starting just after reperfusion, but not starting 20 minutes after reperfusion, improved %SS at 30, 60, and 90 minutes after reperfusion compared with that in the control group. SB203580 abolished the beneficial effect of milrinone. On the other hand, levosimendan starting 20 minutes after reperfusion, but not for 20 minutes starting just after reperfusion, improved %SS at 60 and 90 minutes after reperfusion. Milrinone should be administered just after reperfusion to protect myocardial stunning through p38 MAPK, whereas levosimendan improvement of contractile function could be mainly dependent on its positive inotropic effect.

Functional requirements of a mathematical model of the heart.

PubMed

Palladino, Joseph L; Noordergraaf, Abraham

2009-01-01

Functional descriptions of the heart, especially the left ventricle, are often based on the measured variables pressure and ventricular outflow, embodied as a time-varying elastance. The fundamental difficulty of describing the mechanical properties of the heart with a time-varying elastance function that is set a priori is described. As an alternative, a new functional model of the heart is presented, which characterizes the ventricle's contractile state with parameters, rather than variables. Each chamber is treated as a pressure generator that is time and volume dependent. The heart's complex dynamics develop from a single equation based on the formation and relaxation of crossbridge bonds. This equation permits the calculation of ventricular elastance via E(v) = partial differentialp(v)/ partial differentialV(v). This heart model is defined independently from load properties, and ventricular elastance is dynamic and reflects changing numbers of crossbridge bonds. In this paper, the functionality of this new heart model is presented via computed work loops that demonstrate the Frank-Starling mechanism and the effects of preload, the effects of afterload, inotropic changes, and varied heart rate, as well as the interdependence of these effects. Results suggest the origin of the equivalent of Hill's force-velocity relation in the ventricle.

Milrinone attenuates arteriolar vasoconstriction and capillary perfusion deficits on endotoxemic hamsters.

PubMed

de Miranda, Marcos Lopes; Pereira, Sandra J; Santos, Ana O M T; Villela, Nivaldo R; Kraemer-Aguiar, Luiz Guilherme; Bouskela, Eliete

2015-01-01

Apart from its inotropic property, milrinone has vasodilator, anti-inflammatory and antithrombotic effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of milrinone on endotoxemia-related microcirculatory changes and compares them to those observed with the use of norepinephrine. After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were treated with two regimens of intravenous milrinone (0.25 or 0.5 μg.kg-1.min-1). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables. Macro-hemodynamic, biochemical, and hematological parameters and survival rate were also analyzed. Endotoxemic non-treated animals, endotoxemic animals treated with norepinephrine (0.2 μg.kg-1.min-1), and non-endotoxemic hamsters served as controls. Milrinone (0.5 μg.kg-1.min-1) was effective in reducing lipopolysaccharide-induced arteriolar vasoconstriction, capillary perfusion deficits, and inflammatory response, and in increasing survival. Norepinephrine treated animals showed the best mean arterial pressure levels but the worst functional capillary density values among all endotoxemic groups. Our data suggests that milrinone yielded protective effects on endotoxemic animals' microcirculation, showed anti-inflammatory properties, and improved survival. Norepinephrine did not recruit the microcirculation nor demonstrated anti-inflammatory effects.

Continuous Intravenous Milrinone Therapy in Pediatric Outpatients.

PubMed

Curley, Michelle; Liebers, Jill; Maynard, Roy

Milrinone is a phosphodiesterase 3 inhibitor with both positive inotropic and vasodilator properties. Administered as a continuous infusion, milrinone is indicated for the short-term treatment of patients with acute decompensated heart failure. Despite limited data supporting long-term milrinone therapy in adults with congestive heart failure, children managed as outpatients may benefit from continuous milrinone as a treatment for cardiac dysfunction, as a destination therapy for cardiac transplant, or as palliative therapy for cardiomyopathy. The aim of this article is to review the medical literature and describe a home infusion company's experience with pediatric outpatient milrinone therapy.

Continuous Intravenous Milrinone Therapy in Pediatric Outpatients

PubMed Central

Curley, Michelle; Liebers, Jill

2017-01-01

Milrinone is a phosphodiesterase 3 inhibitor with both positive inotropic and vasodilator properties. Administered as a continuous infusion, milrinone is indicated for the short-term treatment of patients with acute decompensated heart failure. Despite limited data supporting long-term milrinone therapy in adults with congestive heart failure, children managed as outpatients may benefit from continuous milrinone as a treatment for cardiac dysfunction, as a destination therapy for cardiac transplant, or as palliative therapy for cardiomyopathy. The aim of this article is to review the medical literature and describe a home infusion company's experience with pediatric outpatient milrinone therapy. PMID:28248808

Minimized extracorporeal circulation is improving outcome of coronary artery bypass surgery in the elderly.

PubMed

Freundt, Miriam; Ried, Michael; Philipp, Alois; Diez, Claudius; Kolat, Philipp; Hirt, Stephan W; Schmid, Christof; Haneya, Assad

2016-03-01

Advanced age is a known risk factor for morbidity and mortality after coronary artery bypass grafting (CABG). Minimized extracorporeal circulation (MECC) has been shown to reduce the negative effects associated with conventional extracorporeal circulation (CECC). This trial assesses the impact of MECC on the outcome of elderly patients undergoing CABG. Eight hundred and seventy-five patients (mean age 78.35 years) underwent isolated CABG using CECC (n=345) or MECC (n=530). The MECC group had a significantly shorter extracorporeal circulation time (ECCT), cross-clamp time and reperfusion time and lower transfusion needs. Postoperatively, these patients required significantly less inotropic support, fewer blood transfusions, less postoperative hemodialysis and developed less delirium compared to CECC patients. In the MECC group, intensive care unit (ICU) stay was significantly shorter and 30-day mortality was significantly reduced [2.6% versus 7.8%; p<0.001]. In conclusion, MECC improves outcome in elderly patients undergoing CABG surgery. © The Author(s) 2015.

Impact of intravenous nitroglycerin in the management of acute decompensated heart failure.

PubMed

den Uil, Corstiaan A; Brugts, Jasper J

2015-02-01

Intravenous nitroglycerin is a well-known, but underused, treatment for acute decompensated heart failure. Nitroglycerin has a rapid onset of action and short half-life and there is a clear dose-response curve on both global hemodynamics and peripheral circulation. IV nitroglycerin reduces LV and RV filling pressures and afterload. In the case of acute decompensated heart failure, there is a typical decreased bioavailability of nitric oxide (NO), which needs to be supplemented by exogenous nitrates. Additionally, there is benefit on clinical endpoints, such as fast optimization of arterial oxygenation, lower rates of mechanical ventilation, and improved survival. Drawbacks of therapy include not only side effects such as headache, resistance, and development of tolerability to nitrates but also free radical production. However, nitrates in combination with diuretics remain the cornerstone of acute decompensated heart failure treatment. We propose a more aggressive use of nitrates and a more limited use of inotropes (due to ischemic demand and pro-arrhythmogenic characteristics) in normo- or hypertensive patients with acute heart failure.

Neurohormonal Imbalance: A Neglected Problem-And Potential Therapeutic Target-In Acute Heart Failure.

PubMed

Goldsmith, Steven R; Bart, Bradley A; Pin A, Ileana L

2017-12-16

Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical trials update from the Heart Failure Society of America: EMOTE, HERB-CHF, BEST genetic sub-study and RHYTHM-ICD.

PubMed

Lalukota, Krishna; Cleland, John G F; Ingle, Lee; Clark, Andrew L; Coletta, Alison P

2004-12-01

This article summarises key presentations relevant to the pathophysiology, prevention or treatment of heart failure, from the Heart Failure Society of America annual meeting held in Toronto, Canada. Data from the EnoxiMone in intravenous inOTropE-dependent subjects (EMOTE) study suggest that the oral PDE-3 inhibitor enoximone may be effective for weaning severe heart failure patients from intravenous inotropic therapy. Hawthorn Extract Randomised Blinded Trial in CHF (HERB-CHF) failed to show a benefit of hawthorn extract added to conventional heart failure therapy. A genetic sub-group analysis of the Blocker Evaluation of Survival Trial (BEST) study showed that bucindolol reduced mortality and hospitalisations in patients who were homozygous for the Arg389 variant of the beta(1) adrenoceptor. In the Resynchronisation Hemodynamic Treatment for Heart Failure Management (RHYTHM-ICD) study, patients randomised to cardiac resynchronisation therapy (CRT) showed an improvement in symptoms and functional capacity compared to the control group.

Pharmacology of RG W-2938: a cardiotonic agent with vasodilator activity.

PubMed

Barrett, J A; Woltmann, R F; Swillo, R S; Kasiewski, C; Faith, W C; Campbell, H F; Perrone, M H

1990-10-01

The cardiovascular effects of RG W-2938, 6-[6-(3,4-dihydro-3-methyl-2(1H)-2-oxoquinazolinyl)]-4,5-dihydro-3 (2H-pyridazinone, a new nonglycoside, noncatecholamine cardiotonic/vasodilator agent were examined in vivo in anesthetized and conscious dogs and in vitro in isolated guinea pig hearts; in the latter, RG W-2938 5 nmol-5 mumol increased contractility in a dose-related fashion. RG W-2938 30-300 micrograms/kg administered intravenously (i.v.) to anesthetized dogs increased contractile force while decreasing arterial pressure and total peripheral resistance (TPR) in a dose-related manner. Heart rate (HR) was only slightly increased, and aortic flow was not appreciably altered. A single oral dose of RG W-2938 0.3 mg/kg administered to conscious chronically instrumented dogs produced a marked and sustained increase in contractility 15-240 min after treatment while only slightly increasing HR. The effects of RG W-2938 30-300 micrograms/kg, i.v. were studied in a mecamylamine-propranolol-induced model of heart failure. RG W-2938 effectively reversed the drug-induced heart failure by increasing myocardial contractility and decreasing arterial pressure while only slightly affecting HR. These studies show that RG W-2938 is an orally effective positive inotropic/vasodilator agent.

Extraction and phytochemical investigation of Calotropis procera: effect of plant extracts on the activity of diverse muscles.

PubMed

Moustafa, A M Y; Ahmed, S H; Nabil, Z I; Hussein, A A; Omran, M A

2010-10-01

Calotropis procera (Ait.) R.Br. (Asclepiadaceae) is a shrub or small tree that grows wild in Egypt. Calotropis acts as a purgative, anthelmintic, anticoagulant, palliative (in problems with respiration, blood pressure), antipyretic, and analgesic, and induces neuromuscular blocking activity. Little research has been done to study the electrophysiological effects of this plant's extracts on cardiac, smooth, and skeletal muscle activities. The present study was conducted to determine the phytochemical composition and the effect of the total alcohol extract of the shoot of the plant, which contains almost all of C. procera's cardiac glycosides, flavonoids, and saponins. Also, this study attempted to throw more light on the electrophysiological effects of the plant extracts on cardiac, smooth, and skeletal muscle activities and to clarify the mechanism(s) of their observed action(s). The aerial parts of the plant were air dried and their ethanol extracts partitioned with successive solvents. Cardiac, smooth, and skeletal muscles were used in this study to investigate the physiological and pharmacological effects of the plant extracts from different solvents. The data were analyzed by paired t-test. The phytochemical investigation of Calotropis procera revealed the presence of cardenolides, flavonoids, and saponins. The effects of ethanol, n-butanol, and ethyl acetate (EtOAc) extracts were each evaluated on isolated toad heart and their mechanisms of action determined. Perfusion with 2 μg/mL ethanol, 0.2 μg/mL butanol, and 0.2 μg/mL EtOAc extracts caused a significant decrease in heart rate (bradycardia), significant increase in the force of ventricular contraction, and increase in T-wave amplitude. In addition, the effects of different extracts of the studied plant on smooth muscle and skeletal muscle were investigated in this study. The different extracts and latex of C. procera induced a negative chronotropic effect and decreased the heart rate (HR) of isolated toad heart. The different extracts increased the power of contraction of the duodenum (trace a). Pretreatment with atropine sulfate as a muscarinic receptor blocker abolished the stimulatory effect of the different plant extracts and latex of C. procera (trace b). The present data suggest that ethanol, butanol, and EtOAc extracts of Calotropis procera have negative chronotropism and positive inotropism. Verapamil could abolish the inotropic effect of ethanol as well as that of butanol and EtOAc extracts. Meanwhile, atropine did not abolish the observed negative chronotropic effect. The ethanol extract increased the power of contraction of rabbit duodenum, but atropine abolished this effect. It also decreased the skeletal muscle contraction; this effect could be through blocking of the nicotinic receptors. Butanol and EtOAc extract data for smooth and skeletal muscles are very close to those for the corresponding ethanol extract of the studied plant. The present data for C. procera indicate its direct action on the myocardium, its increase of smooth muscle motility, and its relaxation of skeletal muscle contraction. The chemical constituents could directly affect the cell membrane probably through receptors coupling to G proteins. They regulate the ion channel physiology as in the myocardium. The present data on the extracts of C. procera indicate a direct action on the myocardium, stimulatory effect on smooth muscle motility, and relaxant action on skeletal muscle contraction. Chemical constituents could directly affect the cell membrane probably through receptors coupling to G proteins. They regulate the ion channel physiology as in the myocardium.

The cardio-respiratory effects of intra-abdominal hypertension: Considerations for critical care nursing practice.

PubMed

Christensen, Martin; Craft, Judy

2018-02-01

Intra-abdominal hypertension can be classified as either primary or secondary. Primary intra-abdominal hypertension is often associated through trauma or diseases of the abdominopelvic region such as pancreatitis or abdominal surgery, while secondary intra-abdominal hypertension is the result of extra-abdominal causes such as sepsis or burns. The critically ill patient offers some challenges in monitoring in particular secondary intra-abdominal hypertension because of the effects of fluid resuscitation, the use of inotropes and positive pressure ventilation. Recent work suggests that intensive care unit nurses are often unaware of the secondary effects of intra-abdominal pressure and therefore this is not monitored effectively. Therefore being aware of the cardio-respiratory effects may alert theintensive care nurse nurse to the development of intra-abdominal hypertension. The aim of this paper is to discuss the pathophysiology associated with the cardio-respiratory effects seen with intra-abdominal hypertension in the critically ill. In particular it will discuss how intra-abdominal hypertension can inadvertently be overlooked because of the low flow states that it produces which could be misconstrued as something else. It will also discuss how intra-abdominal hypertension impedes ventilation and respiratory mechanics which can often result in a non-cardiogenic pulmonary oedema. To close, the paper will offer some implications for critical care nursing practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

(-)-Terpinen-4-ol changes intracellular Ca2+ handling and induces pacing disturbance in rat hearts.

PubMed

Gondim, Antonio Nei Santana; Lara, Aline; Santos-Miranda, Artur; Roman-Campos, Danilo; Lauton-Santos, Sandra; Menezes-Filho, José Evaldo Rodrigues; de Vasconcelos, Carla Maria Lins; Conde-Garcia, Eduardo Antonio; Guatimosim, Silvia; Cruz, Jader S

2017-07-15

(-)-Terpinen-4-ol is a naturally occurring plant monoterpene and has been shown to have a plethora of biological activities. The objective of this study was to investigate the effects of (-)-terpinen-4-ol on the rat heart, a key player in the control and maintenance of arterial blood pressure. The effects of (-)-terpinen-4-ol on the rat heart were investigated using isolated left atrium isometric force measurements, in vivo electrocardiogram (ECG) recordings, patch clamp technique, and confocal microscopy. It was observed that (-)-terpinen-4-ol reduced contraction force in an isolated left atrium at millimolar concentrations. Conversely, it induced a positive inotropic effect and extrasystoles at micromolar concentrations, suggesting that (-)-terpinen-4-ol may have arrhythmogenic activity on cardiac tissue. In anaesthetized animals, (-)-terpinen-4-ol also elicited rhythm disturbance, such as supraventricular tachycardia and atrioventricular block. To investigate the cellular mechanism underlying the dual effect of (-)-terpinen-4-ol on heart muscle, experiments were performed on isolated ventricular cardiomyocytes to determine the effect of (-)-terpinen-4-ol on L-type Ca 2+ currents, Ca 2+ sparks, and Ca 2+ transients. The arrhythmogenic activity of (-)-terpinen-4-ol in vitro and in vivo may be explained by its effect on intracellular Ca 2+ handling. Taken together, our data suggest that (-)-terpinen-4-ol has cardiac arrhythmogenic activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Anesthetic complications in dogs undergoing hepatic surgery: cholecystectomy versus non-cholecystectomy.

PubMed

Burns, Brigid R; Hofmeister, Erik H; Brainard, Benjamin M

2014-03-01

To determine if dogs that undergo laparotomy for cholecystectomy suffer from a greater number or magnitude of perianesthetic complications, including hypotension, hypothermia, longer recovery time, and lower survival rate, than dogs that undergo laparotomy for hepatic surgery without cholecystectomy. Retrospective cohort study. One hundred and three dogs, anesthetised between January 2007 and October 2011. The variables collected from the medical record included age, weight, gender, surgical procedure, pre-operative bloodwork, American Society of Anesthesiologists (ASA) status, emergency status, total bilirubin concentration, anesthetic agents administered, body temperature nadir, final body temperature, hypotension, duration of hypotension, blood pressure nadir, intraoperative drugs, anesthesia duration, surgery duration, time to extubation, final diagnosis, days spent in the intensive care unit (ICU), total bill, survival to discharge, and survival to follow-up. No significant difference in body temperature nadir, final temperature, presence of hypotension, duration of hypotension, blood pressure nadir, the use of inotropes, or final outcome was found between dogs undergoing cholecystectomy and dogs undergoing exploratory laparotomy for other hepatic disease. Dogs that had cholecystectomy had longer anesthesia durations and longer surgery durations than dogs that did not have cholecystectomy. No significant differences existed for temperature nadir (34.8 versus 35.3°C; non-cholecystectomy versus cholecystectomy), final temperature (35.6 versus 35.9°C), time to extubation (30 versus 49 minutes), duration of hypotension (27 versus 21 minutes), or MAP nadir (56 versus 55 mmHg). Hypotension occurred in 66% and 74% and inotropes were used in 64% and 53%, for non-cholecystectomy and cholecystectomy patients, respectively. Dogs that underwent cholecystectomies did not suffer a greater number of anesthesia complications than did dogs undergoing hepatic surgery without cholecystectomies. © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Incidence, characteristics, and survival following cardiopulmonary resuscitation in the quaternary neonatal intensive care unit.

PubMed

Foglia, Elizabeth E; Langeveld, Robert; Heimall, Lauren; Deveney, Alyson; Ades, Anne; Jensen, Erik A; Nadkarni, Vinay M

2017-01-01

The contemporary characteristics and outcomes of cardiopulmonary resuscitation (CPR) in the neonatal intensive care unit (NICU) are poorly described. The objectives of this study were to determine the incidence, interventions, and outcomes of CPR in a quaternary referral NICU. Retrospective observational study of infants who received chest compressions for resuscitation in the Children's Hospital of Philadelphia NICU between April 1, 2011 and June 30, 2015. Patient, event, and survival characteristics were abstracted from the medical record and the hospital-wide resuscitation database. The primary outcome was survival to hospital discharge. Univariable and multivariable analyses were performed to identify patient and event factors associated with survival to discharge. There were 1.2 CPR events per 1000 patient days. CPR was performed in 113 of 5046 (2.2%) infants admitted to the NICU during the study period. The median duration of chest compressions was 2min (interquartile range 1, 6min). Adrenaline was administered in 34 (30%) CPR events. Of 113 infants with at least one CPR event, 69 (61%) survived to hospital discharge. Factors independently associated with decreased survival to hospital discharge were inotrope treatment prior to CPR (adjusted Odds Ratio [aOR] 0.14, 95% Confidence Interval [CI] 0.04, 0.54), and adrenaline administration during CPR (aOR 0.14, 95% CI 0.04, 0.50). Although it was not uncommon, the incidence of CPR was low (<3%) among infants hospitalized in a quaternary referral NICU. Infants receiving inotropic therapy prior to CPR and adrenaline administration during CPR were less likely to survive to hospital discharge. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mechanically ventilated children with 2009 pandemic influenza A/H1N1: results from the National Pediatric Intensive Care Registry in Japan.

PubMed

Tokuhira, Natsuko; Shime, Nobuaki; Inoue, Miho; Kawasaki, Tatsuya; Sakurai, Yoshio; Kurosaka, Norimasa; Ueta, Ikuya; Nakagawa, Satoshi

2012-09-01

To outline the characteristics, clinical course, and outcome of pediatric patients requiring mechanical ventilation with influenza A/H1N1 infection in Japan. Prospective case registry analysis. Eleven pediatric or general intensive care units in Japan. Consecutive patients infected with A/H1N1, aged from 1 month to 16 yrs old admitted to the intensive care unit for mechanical ventilation between July 2009 and March 2010. None. Eighty-one children, aged 6.3 [0.8-13.6] (median [interquartile range]) years, were enrolled. Seventy-four (91%) had mechanical ventilation with tracheal intubation. Median duration of mechanical ventilation was 4 days (range 0.04-87) and 18 patients (23%) required mechanical ventilation >7 days. Two patients (2%) required extracorporeal membrane oxygenation. The in-hospital mortality was 1%. Forty-one patients (50%) had at least one underlying chronic condition, including 31 with asthma. Associated clinical symptoms and diagnosis were as follows: acute respiratory distress syndrome (9%), asthma or bronchitis (37%), pneumonia (68%) with 8 (14%) having bacterial pneumonia, neurological symptoms (32%), myocarditis (2%), and rhabdomyolysis (1%). Therapeutic interventions include inotropic support (21%), methylprednisolone therapy (33%), and antimicrobial therapy (88%). Multivariate analysis revealed that inotropic support was the only statistically significant factor associated with mechanical ventilation for more than a week (odds ratio 5.5, 95% confidence interval 1.5-20.5, p = .005). The clinical presentations of pediatric patients requiring mechanical ventilation for A/H1N1 in Japan were diverse. In-hospital mortality of this population was remarkably low. Rapid access to medical facilities in combination with early administration of antiviral agents may have contributed to the low mortality in this population.

High mortality in patients with influenza A pH1N1 2009 admitted to a pediatric intensive care unit: a predictive model of mortality.

PubMed

Torres, Silvio Fabio; Iolster, Thomas; Schnitzler, Eduardo Julio; Farias, Julio Alberto; Bordogna, Adriana Claudia; Rufach, Daniel; Montes, María José; Siaba, Alejandro Javier; Rodríguez, María Gabriela; Jabornisky, Roberto; Colman, Carmen; Fernández, Analia; Caprotta, Gustavo; Diaz, Silvia; Poterala, Roxana; De Meyer, Marcela; Penazzi, Matías Enrique; González, Gustavo; Saenz, Silvia; Recupero, Oscar; Zapico, Luis; Alarcon, Blanca; Ariel, Esen; Minces, Pablo; Mari, Eduardo; Carnie, Antonio; Garea, Mónica; Jaen, Roxana

2012-03-01

To describe the clinical characteristics and outcome of patients admitted to pediatric intensive care with influenza A (pH1N1) 2009 in Argentina. Retrospective observational study. Thirteen pediatric intensive care units in Argentina. One hundred and forty-two patients with confirmed or suspected influenza A (H1N1). None. We included 142 critically ill patients. The median age was 19 months (range, 2-110 months) with 39% of the patients <24 months of age. Ninety-nine patients (70%) had an underlying disease. Influenza A (pH1N1) 2009 infection was confirmed in 90 patients and the remaining 52 had a positive direct immunofluorescence assay for influenza A. The median length of stay in the pediatric intensive care unit was 12 days (range, 2-52 days). One hundred eighteen patients (83%) received invasive mechanical ventilation and 19 patients were treated with noninvasive ventilation; however, seven of the patients receiving noninvasive ventilation later needed mechanical ventilation. Sixty-eight patients died (47%) with the most frequent cause refractory hypoxemia. Multivariate logistic regression analysis showed that age <24 months (odds ratio, 2.87; 2.35-3.93), asthma (odds ratio, 1.34; 1.20-2.91), and respiratory coinfection with respiratory syncytial virus (odds ratio, 2.92; 1.20-4.10) were associated with higher mortality. As expected, mechanical ventilation and treatment with inotropes were also associated with increased mortality. The mortality of children admitted to the pediatric intensive care unit with 2009 pH1N1 influenza was high (47%) in our population. Age <24 months, asthma, respiratory coinfection, need of mechanical ventilation, and treatment with inotropes were predictors of poorer outcome.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

PubMed

Clyman, Ronald I; Wickremasinghe, Andrea; Merritt, T Allen; Solomon, Tabitha; McNamara, Patrick; Jain, Amish; Singh, Jaideep; Chu, Alison; Noori, Shahab; Sekar, Krishnamurthy; Lavoie, Pascal M; Attridge, Joshua T; Swanson, Jonathan R; Gillam-Krakauer, Maria; Reese, Jeff; DeMauro, Sara; Poindexter, Brenda; Aucott, Sue; Satpute, Monique; Fernandez, Erika; Auchus, Richard J

2014-06-01

To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 μg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [μg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production. Copyright © 2014 Elsevier Inc. All rights reserved.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones

PubMed Central

Clyman, Ronald I.; Wickremasinghe, Andrea; Merritt, T. Allen; Solomon, Tabitha; McNamara, Patrick; Jain, Amish; Singh, Jaideep; Chu, Alison; Noori, Shahab; Sekar, Krishnamurthy; Lavoie, Pascal M.; Attridge, Joshua T.; Swanson, Jonathan R.; Gillam-Krakauer, Maria; Reese, Jeff; DeMauro, Sara; Poindexter, Brenda; Aucott, Sue; Satpute, Monique; Fernandez, Erika; Auchus, Richard J.

2014-01-01

Objective To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. Study design We performed a multicenter study of infants born at <32 weeks gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured three times: before and after a cosyntropin (1.0 microgram/kg) stimulation test (performed prior to the ligation), and at 10–12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified Inotrope Score (1 x dopamine (μg/kg/min) + 1 x dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their highest Inotrope Score was >15. Results Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low post-operative cortisol levels were not associated with the overall incidence of hypotension following ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the odds ratio for developing catecholamine-resistant hypotension was OR=36.6, CI=2.8–476, p=0.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not due to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. Conclusion Infants with low cortisol concentrations following PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production. PMID:24636853

Intra-Aortic Balloon Counterpulsation in Patients with Chronic Heart Failure and Cardiogenic Shock: Clinical Response and Predictors of Stabilization

PubMed Central

Sintek, Marc A.; Gdowski, Mark; Lindman, Brian R.; Nassif, Michael; Lavine, Kory J.; Novak, Eric; Bach, Richard G.; Silvestry, Scott C.; Mann, Douglas L.; Joseph, Susan M.

2015-01-01

Objective To characterize the clinical response and identify predictors of clinical stabilization after intra-aortic balloon counterpulsation (IABP) support in patients with chronic systolic heart failure in cardiogenic shock prior to implantation of a left ventricular assist device (LVAD). Background Limited data exist regarding the clinical response to IABP in patients with chronic heart failure in cardiogenic shock. Methods We identified 54 patients supported with IABP prior to LVAD implantation. Criteria for clinical decompensation after IABP insertion and before LVAD included the need for more advanced temporary support, initiation of mechanical ventilation or dialysis, increase in vasopressors/inotropes, refractory ventricular arrhythmias, or worsening acidosis. The absence of these indicated stabilization. Results Clinical decompensation after IABP occurred in 23 (43%) patients. Both patients who decompensated and those who stabilized had similar hemodynamic improvements after IABP support but patients who decompensated required more vasopressors/inotropes. Clinical decompensation after IABP was associated with worse outcomes after LVAD implantation, including a 3-fold longer intensive care unit stay and 5-fold longer time on mechanical ventilation (p<0.01 for both). While baseline characteristics were similar between groups, right and left ventricular cardiac power indices (Cardiac power Index= Cardiac Index × Mean arterial pressure / 451)identified patients who were likely to stabilize (AUC=0.82). Conclusions Among patients with chronic systolic heart failure who develop cardiogenic shock, more than half of patients stabilized with IABP support as a bridge to LVAD. Baseline measures of right and left ventricular cardiac power, both measures of work performed for a given flow and pressure, may allow clinicians to identify patients with sufficient contractile reserve who will be likely to stabilize with an IABP versus those who may need more aggressive ventricular support. PMID:26164215

Blood transfusion in pediatric cardiac surgery.

PubMed

Durandy, Yves

2010-11-01

The aim of the study is to measure the volume of homologous blood needed for one pediatric patient during his hospital stay. Over a 4-month period, all the patients operated upon with a blood prime or requiring blood transfusion during their hospital stay were included in this study.The cardiopulmonary bypass protocol associates a miniaturized bypass circuit, vacuum-assisted venous drainage, and microplegia. The volume of each blood product opened is known and the volume of blood product remaining, following the last transfusion, is measured. Data collected areas follows: patient weight; hemoglobin level before surgery,during bypass, and in intensive care after the last transfusion;time to extubation; and degree of inotropic support.Forty-six patients weighing 5.1 1.5 kg were included in this study. Cardiopulmonary bypass priming volume was 100 mL for patients up to 3.5 kg, 120 mL for patients between 3.6 and 7.5 kg, and 160 mL for patients between 7.6 and 8.6 kg. The volume of blood transfusion was 271 112 mL, hemoglobin level before surgery was 10.3 1.7 g/dL, hemoglobin level during surgery was 11.0 1.5 g/dL, and hemoglobin level after the last transfusion was 12.3 2.4 g/dL. Time to extubation was 12 3.3 h, and inotropic support was enoximone in 37 patients,whereas 6 patients needed enoximone and epinephrine.No patient needed reexploration for bleeding and one patient received a platelet transfusion.The mean blood transfusion volume was equivalent to 60% of the patient’s total blood volume (estimated to be 80 mL/kg).

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis.

PubMed

Bennett, Tellen D; Fluchel, Mark; Hersh, Aimee O; Hayward, Kristen N; Hersh, Adam L; Brogan, Thomas V; Srivastava, Rajendu; Stone, Bryan L; Korgenski, E Kent; Mundorff, Michael B; Casper, T Charles; Bratton, Susan L

2012-12-01

To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use. A total of 121 children at 28 children's hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin-1 antagonists. Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease. Copyright © 2012 by the American College of Rheumatology.

The Association between End-of-Life Care and the Time Interval between Provision of a Do-Not-Resuscitate Consent and Death in Cancer Patients in Korea.

PubMed

Baek, Sun Kyung; Chang, Hye Jung; Byun, Ja Min; Han, Jae Joon; Heo, Dae Seog

2017-04-01

We explored the relationship between the use of each medical intervention and the length of time between do-not-resuscitate (DNR) consent and death in Korea. A total of 295 terminal cancer patients participated in this retrospective study. Invasive interventions (e.g., cardiopulmonary resuscitation, intubation, and hemodialysis), less invasive interventions (e.g., transfusion, antibiotic use, inotropic use, and laboratory tests), and the time interval between the DNR order and death were evaluated. The subjects were divided into three groups based on the amount of time between DNR consent and death (G1, time interval ≤ 1 day; G2, time interval > 1 day to ≤ 3 days; and G3, time interval > 3 days). In general, there were fewer transfusions and laboratory tests near death. Invasive interventions tended to be implemented only in the G1 group. There was also less inotrope use and fewer laboratory tests in the G3 group than G1 and G2. Moreover, the G3 group received fewer less invasive interventions than those in G1 (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.03 to 0.84; 3 days before death, and OR, 0.16; 95% CI, 0.04 to 0.59; the day before death). The frequency of less invasive interventions both 1 and 3 days before death was significantly lower for the G3 group than the G1 (p ≤ 0.001) and G2 group compared to G1 (p=0.001). Earlier attainment of DNR permission was associated with reduced use of medical intervention. Thus, physicians should discuss death with terminal cancer patients at the earliest practical time to prevent unnecessary and uncomfortable procedures and reduce health care costs.

Altered LV inotropic reserve and mechanoenergetics early in the development of heart failure.

PubMed

Prabhu, S D; Freeman, G L

2000-03-01

To test the hypothesis that alterations in left ventricular (LV) mechanoenergetics and the LV inotropic response to afterload manifest early in the evolution of heart failure, we examined six anesthetized dogs instrumented with LV micromanometers, piezoelectric crystals, and coronary sinus catheters before and after 24 h of rapid ventricular pacing (RVP). After autonomic blockade, the end-systolic pressure-volume relation (ESPVR), myocardial O(2) consumption (MVO(2)), and LV pressure-volume area (PVA) were defined at several different afterloads produced by graded infusions of phenylephrine. Short-term RVP resulted in reduced preload with proportionate reductions in stroke work and the maximum first derivative of LV pressure but with no significant reduction in baseline LV contractile state. In response to increased afterload, the baseline ESPVR shifted to the left with maintained end-systolic elastance (E(es)). In contrast, after short-term RVP, in response to comparable increases in afterload, the ESPVR displayed reduced E(es) (P < 0.05) and significantly less leftward shift compared with control (P < 0.05). Compared with the control MVO(2)-PVA relation, short-term RVP significantly increased the MVO(2) intercept (P < 0.05) with no change in slope. These results indicate that short-term RVP produces attenuation of afterload-induced enhancement of LV performance and increases energy consumption for nonmechanical processes with maintenance of contractile efficiency, suggesting that early in the development of tachycardia heart failure, there is blunting of length-dependent activation and increased O(2) requirements for excitation-contraction coupling, basal metabolism, or both. Rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.

Brain injury and altered brain growth in preterm infants: predictors and prognosis.

PubMed

Kidokoro, Hiroyuki; Anderson, Peter J; Doyle, Lex W; Woodward, Lianne J; Neil, Jeffrey J; Inder, Terrie E

2014-08-01

To define the nature and frequency of brain injury and brain growth impairment in very preterm (VPT) infants by using MRI at term-equivalent age and to relate these findings to perinatal risk factors and 2-year neurodevelopmental outcomes. MRI scans at term-equivalent age from 3 VPT cohorts (n = 325) were reviewed. The severity of brain injury, including periventricular leukomalacia and intraventricular and cerebellar hemorrhage, was graded. Brain growth was assessed by using measures of biparietal width (BPW) and interhemispheric distance. Neurodevelopmental outcome at age 2 years was assessed across all cohorts (n = 297) by using the Bayley Scales of Infant Development, Second Edition (BSID-II) or Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and evaluation for cerebral palsy. Of 325 infants, 107 (33%) had some grade of brain injury and 33 (10%) had severe injury. Severe brain injury was more common in infants with lower Apgar scores, necrotizing enterocolitis, inotropic support, and patent ductus arteriosus. Severe brain injury was associated with delayed cognitive and motor development and cerebral palsy. Decreased BPW was related to lower gestational age, inotropic support, patent ductus arteriosus, necrotizing enterocolitis, prolonged parenteral nutrition, and oxygen at 36 weeks and was associated with delayed cognitive development. In contrast, increased interhemispheric distance was related to male gender, dexamethasone use, and severe brain injury. It was also associated with reduced cognitive development, independent of BPW. At term-equivalent age, VPT infants showed both brain injury and impaired brain growth on MRI. Severe brain injury and impaired brain growth patterns were independently associated with perinatal risk factors and delayed cognitive development. Copyright © 2014 by the American Academy of Pediatrics.

Bidirectional superior cavopulmonary anastomosis with or without cardiopulmonary bypass: A randomized study.

PubMed

Talwar, Sachin; Gupta, Anish; Nehra, Ashima; Makhija, Neeti; Kapoor, Poonam Malhotra; Sreenivas, Vishnubhatla; Choudhary, Shiv Kumar; Airan, Balram

2017-06-01

This study aims to compare the bidirectional superior cavopulmonary anastomosis (BDG) with or without cardiopulmonary bypass (CPB). 100 patients undergoing BDG were randomized into two groups: Off-CPB or on-CPB groups. All patients underwent near-infrared spectrophotometry (NIRS) and bispectral index (BIS) monitoring and pre- and postoperative serum 100 beta protein measurements (Sβ100) and neuro-cognitive evaluation. Postoperative intensive care unit (ICU) parameters were also studied. The median age of patients in the on-CPB and off-CPB group were 42 and 48 months, respectively (p = 0.11). Median weights in the on-CPB group and off-CPB group were 13.5 (5-50) kg and 15 (7-36) kg, respectively (p = 0.927). There was a significant rise in superior vena cava (SVC) pressure on SVC clamping in the off-CPB group (23.12 ± 6.84 vs 2.98 ± 2.22 mmHg) on-CPB group (p < 0.001). There was a significant fall in NIRS and BIS values from baseline in the off-CPB group during the anastomosis but there was no statistically significant change in serum Sβ100from pre-clamp to post-clamp in either group. Inotropic support, duration of ventilation, ICU stay, and hospital stay were significantly less in the off-CPB group (p < 0.001). Assessment of Social Adaptive Functioning revealed no adverse sequelae. There were significant cost savings if surgery was performed off-CPB (p < 0.001). Off CPB-BDG is an economical and safe procedure. Duration of inotropic and mechanical ventilatory support, ICU, and hospital stay is significantly less. We did not observe any early adverse neurologic sequelae in patients undergoing off-CPB BDG. © 2017 Wiley Periodicals, Inc.

Incidence, characteristics, and survival following cardiopulmonary resuscitation in the quaternary neonatal intensive care unit

PubMed Central

Foglia, Elizabeth E.; Langeveld, Robert; Heimall, Lauren; Deveney, Alyson; Ades, Anne; Jensen, Erik A.; Nadkarni, Vinay M.

2016-01-01

Background The contemporary characteristics and outcomes of cardiopulmonary resuscitation (CPR) in the neonatal intensive care unit (NICU) are poorly described. The objectives of this study were to determine the incidence, interventions, and outcomes of CPR in a quaternary referral NICU. Methods Retrospective observational study of infants who received chest compressions for resuscitation in the Children’s Hospital of Philadelphia NICU between April 1, 2011 and June 30, 2015. Patient, event, and survival characteristics were abstracted from the medical record and the hospital-wide resuscitation database. The primary outcome was survival to hospital discharge. Univariable and multivariable analyses were performed to identify patient and event factors associated with survival to discharge. Results There were 1.2 CPR events per 1,000 patient days. CPR was performed in 113 of 5,046 (2.2%) infants admitted to the NICU during the study period. The median duration of chest compressions was 2 minutes (interquartile range 1, 6 minutes). Adrenaline was administered in 34 (30%) CPR events. Of 113 infants with at least one CPR event, 69 (61%) survived to hospital discharge. Factors independently associated with decreased survival to hospital discharge were inotrope treatment prior to CPR (adjusted Odds Ratio [aOR] 0.14, 95% Confidence Interval [CI] 0.04, 0.54), and adrenaline administration during CPR (aOR 0.14, 95% CI 0.04, 0.50). Conclusions Although it was not uncommon, the incidence of CPR was low (<3%) among infants hospitalized in a quaternary referral NICU. Infants receiving inotropic therapy prior to CPR and adrenaline administration during CPR were less likely to survive to hospital discharge. PMID:27984153

Forward and Backward Pressure Waveform Morphology in Hypertension.

PubMed

Li, Ye; Gu, Haotian; Fok, Henry; Alastruey, Jordi; Chowienczyk, Philip

2017-02-01

We tested the hypothesis that increased pulse wave reflection and altered backward waveform morphology contribute to increased pulse pressure in subjects with higher pulse pressure compared with lower pulse pressure and to actions of vasoactive drugs to increase pulse pressure. We examined the relationship of backward to forward wave morphology in 158 subjects who were evaluated for hypertension (including some normotensive subjects) divided into 3 groups by central pulse pressure: group 1, 33±6.5 mm Hg; group 2, 45±4.1 mm Hg; and group 3, 64±12.9 mm Hg (means±SD) and in healthy normotensive subjects during administration of inotropic and vasomotor drugs. Aortic pressure and flow in the aortic root were estimated by carotid tonometry and Doppler sonography, respectively. Morphology of the backward wave relative to the forward wave was similar in subjects in the lowest and highest tertiles of pulse pressure. Similar results were seen with the inotropic, vasopressor and vasodilator drugs, dobutamine, norepinephrine, and phentolamine, with the backward wave maintaining a constant ratio to the forward wave. However, nitroglycerin, a drug with a specific action to dilate muscular conduit arteries, reduced the amplitude of the backward wave relative to the forward wave from 0.26±0.018 at baseline to 0.19±0.019 during nitroglycerin 30 μg/min IV (P<0.01). These results are best explained by an approximately constant amount of reflection of the forward wave from the peripheral vasculature. The amount of reflection can be modified by dilation of peripheral muscular conduit arteries but contributes little to increased pulse pressure in hypertension. © 2016 The Authors.

Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2.

PubMed

Burns, David P; Rowland, Jane; Canavan, Leonie; Murphy, Kevin H; Brannock, Molly; O'Malley, Dervla; O'Halloran, Ken D; Edge, Deirdre

2017-09-01

What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg -1 ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg -1 ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Calcium channel blockers: spectrum of side effects and drug interactions.

PubMed

Hedner, T

1986-01-01

Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of beta-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.

A comparative dose-effect study with cardiac glycosides assessing cardiac and extracardiac responses in normal subjects.

PubMed

Alken, R G; Belz, G G

1984-01-01

We tested the hypothesis that differences exist in the pharmacodynamic pattern of different cardiac glycosides. We conducted a randomized, placebo-controlled study in normal volunteers and evaluated the effects of weekly increased oral dosing of digoxin (n = 10; from 0.25 to 1.0 mg/day), meproscillarin (n = 10; from 0.5 to 2.0 mg/day), and placebo (n = 5). To determine the glycoside effects, corrected electromechanical systole (QS2c) was used to measure inotropy and the PQ interval to test dromotropy. Red-green discrimination and critical flicker fusion (CFF) assessed visual functions. Subjective complaints were collected using rating lists. Both glycosides dose dependently shortened QS2c and prolonged PQ interval. PQ prolongations over +20 ms occurred in seven of 10 digoxin subjects, in two of 10 meproscillarin, and in one of five placebo. Equi-inotropic response, identified at 12 ms mean QS2c shortening, revealed the relative potency of digoxin to be 2.4 times higher than meproscillarin; this ratio increased to sevenfold for equi-effective negative dromotropic effects at 12 ms mean PQ prolongation. Each drug was associated with a dominant subjective complaint: digoxin with anergy and meproscillarin with diarrhea. Red-green discrimination was better under meproscillarin and CFF was depressed by digoxin. The results indicate that pharmacodynamic differences exist between cardiac glycosides. A differential use of various glycosides should be considered and tested clinically.

Milrinone Attenuates Arteriolar Vasoconstriction and Capillary Perfusion Deficits on Endotoxemic Hamsters

PubMed Central

de Miranda, Marcos Lopes; Pereira, Sandra J.; Santos, Ana O. M. T.; Villela, Nivaldo R.; Kraemer-Aguiar, Luiz Guilherme; Bouskela, Eliete

2015-01-01

Background and Objective Apart from its inotropic property, milrinone has vasodilator, anti-inflammatory and antithrombotic effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of milrinone on endotoxemia-related microcirculatory changes and compares them to those observed with the use of norepinephrine. Materials and Methods After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were treated with two regimens of intravenous milrinone (0.25 or 0.5 μg.kg-1.min-1). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables. Macro-hemodynamic, biochemical, and hematological parameters and survival rate were also analyzed. Endotoxemic non-treated animals, endotoxemic animals treated with norepinephrine (0.2 μg.kg-1.min-1), and non-endotoxemic hamsters served as controls. Results Milrinone (0.5 μg.kg-1.min-1) was effective in reducing lipopolysaccharide-induced arteriolar vasoconstriction, capillary perfusion deficits, and inflammatory response, and in increasing survival. Norepinephrine treated animals showed the best mean arterial pressure levels but the worst functional capillary density values among all endotoxemic groups. Conclusion Our data suggests that milrinone yielded protective effects on endotoxemic animals’ microcirculation, showed anti-inflammatory properties, and improved survival. Norepinephrine did not recruit the microcirculation nor demonstrated anti-inflammatory effects. PMID:25646813

Oral theophylline in chronic heart failure

PubMed Central

Al-Damluji, S.; Johnston, A.; Spurrell, R. A. J.; Nathan, A. W.; Banim, S. O.; Camm, A. J.

1982-01-01

Theophylline choline 600 mg was given as a single oral dose to nine patients in chronic left ventricular failure due to myocardial dysfunction. Cardiac output, left ventricular filling pressure (LVFP) and right atrial pressure (RAP) were measured with a pulmonary artery thermodilution catheter for the following 3 hr. Continuous recordings of cardiac rhythm were made throughout the study. Mean cardiac index increased from 1·75 (±0·14 s.e. mean) to 2·04 (±0·11) 1/min/m2 (P<0·02), mean LVFP fell from 27 (±2·4) to 22 (±1·5) mmHg (P<0·01), mean RAP fell from 5 (±1·3) to 3 (±2·0) mmHg (P<0·05) and mean systemic arterial pressure rose from 80 (±3) to 86 (±3·5) mmHg (P<0·05). There were no significant changes in heart rate or systemic vascular resistance; thus the increase in cardiac output was probably due to a positive inotropic effect. Side effects were seen in two patients, both of whom proved to have toxic plasma theophylline concentrations. This study demonstrated a beneficial acute haemodynamic effect of oral theophylline in chronic cardiac failure. PMID:7111101

'Twisted plywood' structure and mineralization in the scales of a primitive living fish Amia calva.

PubMed

Meunier, F J

1981-01-01

The basal plate of the scales of Amia calva is composed of regular double twisted plywood, as in Latimeria and Dipnoan scales. However, the progressive rotation of the fibrils direction is left-handed in Amia and right-handed in the 'Sarcopterygians'. So, the similarity between these peculiar plywoods is probably the result of convergence. The basal plate of Amia scales is incompletely mineralized. There are numerous calcified ovoid corpuscles which look very like the Mandl's corpuscles of Teleost scales. The mineralization probably progresses essentially by the fusion of these corpuscles, as in Teleost scales, and would be inotropic rather than spheritic.

Complex Care Options for Patients With Advanced Heart Failure Approaching End of Life.

PubMed

Wordingham, Sara E; McIlvennan, Colleen K; Dionne-Odom, J Nicholas; Swetz, Keith M

2016-02-01

Care for patients with advanced cardiac disease continues to evolve in a complex milieu of therapeutic options, advanced technological interventions, and efforts at improving patient-centered care and shared decision-making. Despite improvements in quality of life and survival with these interventions, optimal supportive care across the advanced illness trajectory remains diverse and heterogeneous. Herein, we outline challenges in prognostication, communication, and caregiving in advanced heart failure and review the unique needs of patients who experience frequent hospitalizations, require chronic home inotropic support, and who have implantable cardioverter-defibrillators and mechanical circulatory support in situ, to name a few.

A painful pulsatile abdominal mass in a young man with elevated blood pressures: an unusual presentation of phaeochromocytoma.

PubMed

Lee, B M K; Ti, L K

2002-08-01

We report an unusual presentation of phaeochromocytoma in a young man with a painful, pulsatile abdominal mass and elevated blood pressures. This led to a delay in diagnosis and resulted in the administration of triggers of catecholamine release, possibly causing a catecholamine surge. This caused the development of catecholamine-induced cardiomyopathy and multiple organ failure, requiring inotropic and ventilatory support, intra-aortic balloon pump and dialysis. Fortunately, his condition reversed with supportive treatment and alpha-adrenergic blockade. This illustrates the importance of having a high index of suspicion of phaeochromocytoma, especially in young patients with elevated blood pressures.

Cardiovascular Drugs in Avian, Small Mammal, and Reptile Medicine.

PubMed

Fitzgerald, Brenna Colleen; Dias, Sara; Martorell, Jaume

2018-05-01

Cardiovascular disease, including congestive heart failure, pericardial disease, and atherosclerosis, is becoming increasingly better recognized in companion birds, small mammals, and reptiles. A wide range of medications is available to treat these conditions, including diuretics, vasodilators, positive and negative inotropes, antiarrhythmic agents, and pentoxifylline. This review systematically discusses each of these drug classes and their potential applications in exotic species. Although treatment approaches remain largely empirical and extrapolated from small animal and human medicine, the management strategies presented here have the potential to both maintain quality of life and extend survival time for the exotic cardiac patient. Copyright © 2018 Elsevier Inc. All rights reserved.

Enantioselective binding of L, D-phenylalanine to ct DNA

NASA Astrophysics Data System (ADS)

Zhang, Lijin; Xu, Jianhua; Huang, Yan; Min, Shungeng

2009-10-01

The enantioselective binding of L, D-phenylalanine to calf thymus DNA was studied by absorption, circular dichroism, fluorescence quenching, viscosity, salt effect and emission experiments. The results obtained from absorption, circular dichroism, fluorescence quenching and viscosity experiments excluded the intercalative binding and salt effect experiments did not support electrostatic binding. So the binding of L, D-phenylalanine to ct DNA should be groove binding. Furthermore, the emission spectra revealed that the binding is enantioselective.

Enantioselective binding of L,D-phenylalanine to ct DNA.

PubMed

Zhang, Lijin; Xu, Jianhua; Huang, Yan; Min, Shungeng

2009-10-15

The enantioselective binding of L,D-phenylalanine to calf thymus DNA was studied by absorption, circular dichroism, fluorescence quenching, viscosity, salt effect and emission experiments. The results obtained from absorption, circular dichroism, fluorescence quenching and viscosity experiments excluded the intercalative binding and salt effect experiments did not support electrostatic binding. So the binding of l,d-phenylalanine to ct DNA should be groove binding. Furthermore, the emission spectra revealed that the binding is enantioselective.

Two nucleotide binding sites modulate ( sup 3 H) glyburide binding to rat cortex membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, D.E.; Gopalakrishnan, M.; Triggle, D.J.

1991-03-11

The effects of nucleotides on the binding of the ATP-dependent K{sup +}-channel antagonist ({sup 3}H)glyburide (GLB) to rat cortex membranes were examined. Nucleotide triphosphates (NTPs) and nucleotide diphosphate (NDPs) inhibited the binding of GLB. This effect was dependent on the presence of dithiothreitol (DTT). Inhibition of binding by NTPs, with the exception of ATP{gamma}S, was dependent on the presence of Mg{sup 2+}. GLB binding showed a biphasic response to ADP: up to 3 mM, ADP inhibited binding, and above this concentration GLB binding increased rapidly, and was restored to normal levels by 10 mM ADP. In the presence of Mg{supmore » 2+}, ADP did not stimulate binding. Saturation analysis in the presence of Mg{sup 2+} and increasing concentrations of ADP showed that ADP results primarily in a change of the B{sub max} for GLB binding. The differential effects of NTPS and NDPs indicate that two nucleotide binding sites regulate GLB binding.« less

What Do We Learn from Binding Features? Evidence for Multilevel Feature Integration

ERIC Educational Resources Information Center

Colzato, Lorenza S.; Raffone, Antonino; Hommel, Bernhard

2006-01-01

Four experiments were conducted to investigate the relationship between the binding of visual features (as measured by their after-effects on subsequent binding) and the learning of feature-conjunction probabilities. Both binding and learning effects were obtained, but they did not interact. Interestingly, (shape-color) binding effects…

The electrophysiologic properties of esmolol, a short acting beta-blocker.

PubMed

Greenspan, A M; Spielman, S R; Horowitz, L N; Laddu, A; Senior, S

1988-04-01

Although beta-blockers have established efficacy in treating ventricular ectopy and PSVT, their applicability for acute antiarrhythmic interventions in patients with organic heart disease or COPD, is frequently limited by negative inotropic or bronchospastic side effects. The development of an ultrashort acting beta-blocker with rapid reversibility of its side effects would widen their applicability. Therefore, we tested the electrophysiologic properties of such a new short acting beta-blocker, esmolol, in 14 patients (10 with organic heart disease) with a mean EF of 47.6 +/- 17%, undergoing standard clinical electrophysiologic studies for various indications. Like most other beta-blockers, esmolol's major direct effects were on sinus node function and AV nodal conduction characteristics; significantly prolonging sinus cycle length, cycle length to Wenckebach and AH interval in sinus rhythm and at a paced cycle length of 600 ms. In contrast to most other beta-blockers, following termination of its infusion, esmolol shortened parameters of sinus node function and AV nodal refractoriness, with respect to the control values, suggesting a possible rebound phenomena. These effects occurred within 5 min of terminating the intravenous drug infusion. Esmolol had no significant effect on systolic blood pressure, electrocardiographic intervals and had rare adverse reactions. We conclude that esmolol is an ultra-short acting beta-blocker, with typical direct electrophysiologic effects on sinus node and AV nodal function, and a possible rebound phenomena following its discontinuation that may make it particularly suited to acute antiarrhythmic interventions in patients susceptible to adverse beta-blocker side effects.

Digoxin Induces Cardiac Hypertrophy Without Negative Effects on Cardiac Function and Physical Performance in Trained Normotensive Rats.

PubMed

Neves, Claodete Hasselstrom; Tibana, Ramires Alsamir; Prestes, Jonato; Voltarelli, Fabricio Azevedo; Aguiar, Andreo Fernando; Ferreira Mota, Gustavo Augusto; de Sousa, Sergio Luiz Borges; Leopoldo, Andre Soares; Leopoldo, Ana Paula Lima; Mueller, Andre; Aguiar, Danilo Henrique; Navalta, James Wilfred; Sugizaki, Mario Mateus

2017-04-01

Cardiotonic drugs and exercise training promote cardiac inotropic effects, which may affect training-induced cardiac adaptations. This study investigated the effects of long-term administration of digoxin on heart structure and function, and physical performance of rats submitted to high-intensity interval training (HIIT). Male Wistar rats, 60 days old, were divided into control (C), digoxin (DIGO), trained (T), and trained with digoxin (TDIGO). Digoxin was administered by gavage (30 µg/kg/day) for 75 days. The HIIT program consisted of treadmill running 60 min/day (8 min at 80% of the maximum speed (MS) and 2 min at 20% of the MS), 5 days per week during 60 days. The main cardiac parameters were evaluated by echocardiograph and cardiomyocyte area was determined by histology. There were no group x time effects of digoxin, HIIT or interactions (digoxin and HIIT) on functional echocardiographic parameters (heart rate; ejection fraction) or in the maximum exercise test. There was a group x time interaction, as evidenced by observed cardiac hypertrophy in the TDIGO group evaluated by ratio of left ventricle weight to body weight (p<0.002) and cardiomyocyte area (p<0.000002). Long-term administration of digoxin promoted cardiac hypertrophy without affecting cardiac function and physical performance in rats submitted to HIIT. © Georg Thieme Verlag KG Stuttgart · New York.

Cardiovascular effects of Nemopilema nomurai (Scyphozoa: Rhizostomeae) jellyfish venom in rats.

PubMed

Kim, Euikyung; Lee, Seunghwan; Kim, Jong-Shu; Yoon, Won Duk; Lim, Donghyun; Hart, Andrew J; Hodgson, Wayne C

2006-12-15

Over the past few years, populations of the giant jellyfish Nemopilema nomurai (Scyphozoa: Rhizostomeae) have increased dramatically in the waters of China, Korea, and Japan without any definitive reason. This has resulted in severe damage to fisheries in the areas. During a pilot study, we observed that the venom of N. nomurai produced a functional cardiac depression in mice. However, the mechanism of action was not examined. In the present study, we investigated the cardiovascular effects of nematocyst-derived venom from N. nomurai in anesthetized rats. Venom (0.1-2.4 mg protein/kg, i.v.) produced dose-dependent hypotension (65+/-12% of initial at a cumulative dose of 3 mg/kg) and bradycardia (80+/-5% of initial at a cumulative dose of 3 mg/kg). At the highest dose, this was characterized by a transient decrease in blood pressure (phase 1) followed by a return to basal level and then a slower decrease in blood pressure (phase 2). Venom also produced a decrease in rate and force of contraction in the rat isolated atria. Interestingly, venom induced a contraction of isolated aortic rings which was blocked by felodipine but not by prazosin, suggesting the contraction is mediated by calcium channel activation. These results suggest that the negative inotropic and chronotropic effects of the venom of N. nomurai may be due to a direct effect on the heart.

Correlation of Local Effects of DNA Sequence and Position of Beta-Alanine Inserts with Polyamide-DNA Complex Binding Affinities and Kinetics

PubMed Central

Wang, Shuo; Nanjunda, Rupesh; Aston, Karl; Bashkin, James K.; Wilson, W. David

2012-01-01

In order to better understand the effects of β-alanine (β) substitution and the number of heterocycles on DNA binding affinity and selectivity, the interactions of an eight-ring hairpin polyamide (PA) and two β derivatives as well as a six-heterocycle analog have been investigated with their cognate DNA sequence, 5′-TGGCTT-3′. Binding selectivity and the effects of β have been investigated with the cognate and five mutant DNAs. A set of powerful and complementary methods have been employed for both energetic and structural evaluations: UV-melting, biosensor-surface plasmon resonance, isothermal titration calorimetry, circular dichroism and a DNA ligation ladder global structure assay. The reduced number of heterocycles in the six-ring PA weakens the binding affinity; however, the smaller PA aggregates significantly less than the larger PAs, and allows us to obtain the binding thermodynamics. The PA-DNA binding enthalpy is large and negative with a large negative ΔCp, and is the primary driving component of the Gibbs free energy. The complete SPR binding results clearly show that β substitutions can substantially weaken the binding affinity of hairpin PAs in a position-dependent manner. More importantly, the changes in PA binding to the mutant DNAs further confirm the position-dependent effects on PA-DNA interaction affinity. Comparison of mutant DNA sequences also shows a different effect in recognition of T•A versus A•T base pairs. The effects of DNA mutations on binding of a single PA as well as the effects of the position of β substitution on binding tell a clear and very important story about sequence dependent binding of PAs to DNA. PMID:23167504

To bind or not to bind? Different temporal binding effects from voluntary pressing and releasing actions.

PubMed

Zhao, Ke; Chen, Yu-Hsin; Yan, Wen-Jing; Fu, Xiaolan

2013-01-01

Binding effect refers to the perceptual attraction between an action and an outcome leading to a subjective compression of time. Most studies investigating binding effects exclusively employ the "pressing" action without exploring other types of actions. The present study addresses this issue by introducing another action, releasing action or the voluntary lifting of the finger/wrist, to investigate the differences between voluntary pressing and releasing actions. Results reveal that releasing actions led to robust yet short-lived temporal binding effects, whereas pressing condition had steady temporal binding effects up to super-seconds. The two actions also differ in sensitivity to changes in temporal contiguity and contingency, which could be attributed to the difference in awareness of action. Extending upon current models of "willed action," our results provide insights from a temporal point of view and support the concept of a dual system consisting of predictive motor control and top-down mechanisms.

Chelate effects in sulfate binding by amide/urea-based ligands.

PubMed

Jia, Chuandong; Wang, Qi-Qiang; Begum, Rowshan Ara; Day, Victor W; Bowman-James, Kristin

2015-07-07

The influence of chelate and mini-chelate effects on sulfate binding was explored for six amide-, amide/amine-, urea-, and urea/amine-based ligands. Two of the urea-based hosts were selective for SO4(2-) in water-mixed DMSO-d6 systems. Results indicated that the mini-chelate effect provided by a single urea group with two NH binding sites appears to provide enhanced binding over two amide groups. Furthermore, additional urea binding sites incorporated into the host framework appeared to overcome to some extent competing hydration effects with increasing water content.

The effects of pargyline and 2-phenylethylamine on D1-like dopamine receptor binding.

PubMed

Berry, Mark D

2011-07-01

2-Phenylethylamine (PE) potentiates neuronal responses to dopamine by an unknown post-synaptic mechanism. Here, whether PE modifies D1-like receptor binding was examined. An unexpected effect of the monoamine oxidase inhibitor pargyline was observed, which did not involve competition for ligand binding. PE did not affect ligand binding in the presence or absence of pargyline. It is concluded that the effect of pargyline does not involve elevation of endogenous PE, and PE effects on dopaminergic neurotransmission are not due to altered D1-like receptor binding.

Hawthorn: pharmacology and therapeutic uses.

PubMed

Rigelsky, Janene M; Sweet, Burgunda V

2002-03-01

The uses, pharmacology, clinical efficacy, dosage and administration, adverse effects, and drug interactions of hawthorn are discussed. Hawthorn (Crataegus oxyacantha) is a fruit-bearing shrub with a long history as a medicinal substance. Uses have included the treatment of digestive ailments, dyspnea, kidney stones, and cardiovascular disorders. Today, hawthorn is used primarily for various cardiovascular conditions. The cardiovascular effects are believed to be the result of positive inotropic activity, ability to increase the integrity of the blood vessel wall and improve coronary blood flow, and positive effects on oxygen utilization. Flavonoids are postulated to account for these effects. Hawthorn has shown promise in the treatment of New York Heart Association (NYHA) functional class II congestive heart failure (CHF) in both uncontrolled and controlled clinical trials. There are also suggestions of a beneficial effect on blood lipids. Trials to establish an antiarrhythmic effect in humans have not been conducted. The recommended daily dose of hawthorn is 160-900 mg of a native water-ethanol extract of the leaves or flowers (equivalent to 30-169 mg of epicatechin or 3.5-19.8 mg of flavonoids) administered in two or three doses. At therapeutic dosages, hawthorn may cause a mild rash, headache, sweating, dizziness, palpitations, sleepiness, agitation, and gastrointestinal symptoms. Hawthorn may interact with vasodilating medications and may potentiate or inhibit the actions of drugs used for heart failure, hypertension, angina, and arrhythmias. The limited data about hawthorn suggest that it may be useful in the treatment of NYHA functional class II CHF.

Myocardial Dysfunction and Shock after Cardiac Arrest

PubMed Central

Jentzer, Jacob C.; Chonde, Meshe D.; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies. PMID:26421284

Myocardial Dysfunction and Shock after Cardiac Arrest.

PubMed

Jentzer, Jacob C; Chonde, Meshe D; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies.

Non-invasive ventilation in prone position for refractory hypoxemia after bilateral lung transplantation.

PubMed

Feltracco, Paolo; Serra, Eugenio; Barbieri, Stefania; Persona, Paolo; Rea, Federico; Loy, Monica; Ori, Carlo

2009-01-01

Temporary graft dysfunction with gas exchange abnormalities is a common finding during the postoperative course of a lung transplant and is often determined by the post-reimplantation syndrome. Supportive measures including oxygen by mask, inotropes, diuretics, and pulmonary vasodilators are usually effective in non-severe post-reimplantation syndromes. However, in less-responsive clinical pictures, tracheal intubation with positive pressure ventilation, or non-invasive positive pressure ventilation (NIV), is necessary. We report on the clinical course of two patients suffering from refractory hypoxemia due to post-reimplantation syndrome treated with NIV in the prone and Trendelenburg positions. NIV was well tolerated and led to resolution of atelectactic areas and dishomogeneous lung infiltrates. Repeated turning from supine to prone under non invasive ventilation determined a stable improvement of gas exchange and prevented a more invasive approach. Even though NIV in the prone position has not yet entered into clinical practice, it could be an interesting option to achieve a better match between ventilation and perfusion. This technique, which we successfully applied in lung transplantation, can be easily extended to other lung diseases with non-recruitable dorso-basal areas.

Prevention of acute kidney injury in Intensive Care Units.

PubMed

Mas-Font, S; Ros-Martinez, J; Pérez-Calvo, C; Villa-Díaz, P; Aldunate-Calvo, S; Moreno-Clari, E

2017-03-01

Acute kidney injury (AKI) is a growing concern in Intensive Care Units. The advanced age of our patients, with the increase in associated morbidity and the complexity of the treatments provided favor the development of AKI. Since no effective treatment for AKI is available, all efforts are aimed at prevention and early detection of the disorder in order to establish secondary preventive measures to impede AKI progression. In critical patients, the most frequent causes are sepsis and situations that result in renal hypoperfusion; preventive measures are therefore directed at securing hydration and correct hemodynamics through fluid perfusion and the use of inotropic or vasoactive drugs, according to the underlying disease condition. Apart from these circumstances, a number of situations could lead to AKI, related to the administration of nephrotoxic drugs, intra-tubular deposits, the administration of iodinated contrast media, liver failure and major surgery (mainly heart surgery). In these cases, in addition to hydration, there are other specific preventive measures adapted to each condition. Copyright © 2017 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Efficiency and Safety of Prolonged Levosimendan Infusion in Patients with Acute Heart Failure

PubMed Central

Aidonidis, Georgios; Kanonidis, Ioannis; Koutsimanis, Vasileios; Neumann, Till; Erbel, Raimund; Sakadamis, Georgios

2011-01-01

Background. Levosimendan is an inotropic drug with unique pharmacological advantages in patients with acute heart failure. Scope of this study is to determine whether longer infusion patterns without the hypotension-inducing loading dose could justify an effective and safe alternative approach. Methods. 70 patients admitted to the emergencies with decompensated chronic heart failure received intravenously levosimendan without a loading dose up to 72 hours. Clinical parameters, BNP (Brain Natriuretic Peptide) and signal-averaged-ECG data (SAECG) were recorded up to 72 hours. Results. The 48-hour group demonstrated a statistically significant BNP decrease (P < .001) after 48 hours, which also maintained after 72 hours. The 72-hour group demonstrated a bordeline decrease of BNP after 48 hours (P = .039), necessitating an additional 24-hour infusion to achieve significant reduction after 72 hours (P < .004). SAECG data demonstrated a statistically significant decrease after 72 hours (P < .04). Apart from two deaths due to advanced heart failure, no major complications were observed. Conclusion. Prolonged infusion of levosimendan without a loading dose is associated with an acceptable clinical and neurohumoral response. PMID:21559263

Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure.

PubMed

Stehlik, Josef; Movsesian, Matthew A

2006-07-01

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with beta-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.

Oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} channel Ca{sub v}1.2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ullrich, Nina D.; Koschak, Alexandra; MacLeod, Kenneth T.

2007-09-21

Oestrogen can modify the contractile function of vascular smooth muscle and cardiomyocytes. The negative inotropic actions of oestrogen on the heart and coronary vasculature appear to be mediated by L-type Ca{sup 2+} channel (Ca{sub v}1.2) inhibition, but the underlying mechanisms remain elusive. We tested the hypothesis that oestrogen directly inhibits the cardiovascular L-type Ca{sup 2+} current, I {sub CaL}. The effect of oestrogen on I {sub CaL} was measured in Ca{sub v}1.2-transfected HEK-293 cells using the whole-cell patch-clamp technique. The current revealed typical activation and inactivation profiles of nifedipine- and cadmium-sensitive I {sub CaL}. Oestrogen (50 {mu}M) rapidly reduced Imore » {sub CaL} by 50% and shifted voltage-dependent activation and availability to more negative potentials. Furthermore, oestrogen blocked the Ca{sup 2+} channel in a rate-dependent way, exhibiting higher efficiency of block at higher stimulation frequencies. Our data suggest that oestrogen inhibits I {sub CaL} through direct interaction of the steroid with the channel protein.« less

Interactions between acetylcholine, 5-hydroxytryptamine, nicotine and morphine on isolated rabbit atria

PubMed Central

Chittal, S. M.; Dadkar, N. K.; Gaitondé, B. B.

1968-01-01

1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied. 2. 5-Hydroxytryptamine (10 μg/ml.) and morphine (20 μg/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine. 3. Nicotine (20 μg/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline. 4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine. 5. 5-Hydroxytryptamine (20 μg/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline. 6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines. PMID:4386371

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

PubMed

de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

2016-01-01

Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

Batrachotoxin Changes the Properties of the Muscarinic Receptor in Rat Brain and Heart: Possible Interaction(s) between Muscarinic Receptors and Sodium Channels

NASA Astrophysics Data System (ADS)

Cohen-Armon, Malca; Kloog, Yoel; Henis, Yoav I.; Sokolovsky, Mordechai

1985-05-01

The effects of Na+-channel activator batrachotoxin (BTX) on the binding properties of muscarinic receptors in homogenates of rat brain and heart were studied. BTX enhanced the affinity for the binding of the agonists carbamoylcholine and acetylcholine to the muscarinic receptors in brainstem and ventricle, but not in the cerebral cortex. Analysis of the data according to a two-site model for agonist binding indicated that the effect of BTX was to increase the affinity of the agonists to the high-affinity site. Guanyl nucleotides, known to induce interconversion of high-affinity agonist binding sites to the low-affinity state, canceled the effect of BTX on carbamoylcholine and acetylcholine binding. BTX had no effect on the binding of the agonist oxotremorine or on the binding of the antagonist [3H]-N-methyl-4-piperidyl benzilate. The local anesthetics dibucaine and tetracaine antagonized the effect of BTX on the binding of muscarinic agonists at concentrations known to inhibit the activation of Na+ channels by BTX. On the basis of these findings, we propose that in specific tissues the muscarinic receptors may interact with the BTX binding site (Na+ channels).

Curcuma longa L. as a therapeutic agent in intestinal motility disorders. 2: Safety profile in mouse.

PubMed

Micucci, Matteo; Aldini, Rita; Cevenini, Monica; Colliva, Carolina; Spinozzi, Silvia; Roda, Giulia; Montagnani, Marco; Camborata, Cecilia; Camarda, Luca; Chiarini, Alberto; Mazzella, Giuseppe; Budriesi, Roberta

2013-01-01

Curcuma extract exerts a myorelaxant effect on the mouse intestine. In view of a possible use of curcuma extract in motor functional disorders of the gastrointestinal tract, a safety profile study has been carried out in the mouse. Thirty mice were used to study the in vitro effect of curcuma on gallbladder, bladder, aorta and trachea smooth muscular layers and hearth inotropic and chronotropic activity. The myorelaxant effect on the intestine was also thoroughly investigated. Moreover, curcuma extract (200 mg/Kg/day) was orally administered to twenty mice over 28 days and serum liver and lipids parameters were evaluated. Serum, bile and liver bile acids qualitative and quantitative composition was were also studied. In the intestine, curcuma extract appeared as a not competitive inhibitor through cholinergic, histaminergic and serotoninergic receptors and showed spasmolytic effect on K(+) induced contraction at the level of L type calcium channels. No side effect was observed on bladder, aorta, trachea and heart when we used a dose that is effective on the intestine. An increase in gallbladder tone and contraction was observed. Serum liver and lipids parameters were normal, while a slight increase in serum and liver bile acids concentration and a decrease in bile were observed. Although these data are consistent with the safety of curcuma extract as far as its effect on the smooth muscular layers of different organs and on the heart, the mild cholestatic effect observed in absence of alteration of liver function tests must be further evaluated and the effective dose with minimal side effects considered.

Curcuma longa L. as a Therapeutic Agent in Intestinal Motility Disorders. 2: Safety Profile in Mouse

PubMed Central

Micucci, Matteo; Aldini, Rita; Cevenini, Monica; Colliva, Carolina; Spinozzi, Silvia; Roda, Giulia; Montagnani, Marco; Camborata, Cecilia; Camarda, Luca; Chiarini, Alberto; Mazzella, Giuseppe; Budriesi, Roberta

2013-01-01

Background Curcuma extract exerts a myorelaxant effect on the mouse intestine. In view of a possible use of curcuma extract in motor functional disorders of the gastrointestinal tract, a safety profile study has been carried out in the mouse. Methods Thirty mice were used to study the in vitro effect of curcuma on gallbladder, bladder, aorta and trachea smooth muscular layers and hearth inotropic and chronotropic activity. The myorelaxant effect on the intestine was also thoroughly investigated. Moreover, curcuma extract (200 mg/Kg/day) was orally administered to twenty mice over 28 days and serum liver and lipids parameters were evaluated. Serum, bile and liver bile acids qualitative and quantitative composition was were also studied. Results In the intestine, curcuma extract appeared as a not competitive inhibitor through cholinergic, histaminergic and serotoninergic receptors and showed spasmolytic effect on K+ induced contraction at the level of L type calcium channels. No side effect was observed on bladder, aorta, trachea and heart when we used a dose that is effective on the intestine. An increase in gallbladder tone and contraction was observed. Serum liver and lipids parameters were normal, while a slight increase in serum and liver bile acids concentration and a decrease in bile were observed. Conclusions Although these data are consistent with the safety of curcuma extract as far as its effect on the smooth muscular layers of different organs and on the heart, the mild cholestatic effect observed in absence of alteration of liver function tests must be further evaluated and the effective dose with minimal side effects considered. PMID:24260512

Visual feature binding in younger and older adults: encoding and suffix interference effects.

PubMed

Brown, Louise A; Niven, Elaine H; Logie, Robert H; Rhodes, Stephen; Allen, Richard J

2017-02-01

Three experiments investigated younger (18-25 yrs) and older (70-88 yrs) adults' temporary memory for colour-shape combinations (binding). We focused upon estimating the magnitude of the binding cost for each age group across encoding time (Experiment 1; 900/1500 ms), presentation format (Experiment 2; simultaneous/sequential), and interference (Experiment 3; control/suffix) conditions. In Experiment 1, encoding time did not differentially influence binding in the two age groups. In Experiment 2, younger adults exhibited poorer binding performance with sequential relative to simultaneous presentation, and serial position analyses highlighted a particular age-related difficulty remembering the middle item of a series (for all memory conditions). Experiments 1-3 demonstrated small to medium binding effect sizes in older adults across all encoding conditions, with binding less accurate than shape memory. However, younger adults also displayed negative effects of binding (small to large) in two of the experiments. Even when older adults exhibited a greater suffix interference effect in Experiment 3, this was for all memory types, not just binding. We therefore conclude that there is no consistent evidence for a visual binding deficit in healthy older adults. This relative preservation contrasts with the specific and substantial deficits in visual feature binding found in several recent studies of Alzheimer's disease.

Effect of antemortem and postmortem factors on ( sup 3 H)MK-801 binding in the human brain: Transient elevation during early childhood

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kornhuber, J.; Mack-Burkhardt, F.; Konradi, C.

1989-01-01

The effect of a number of antemortem and postmortem factors on ({sup 3}H)MK-801 binding was investigated under equilibrium conditions in the frontal cortex of human brains of 38 controls. Binding values transiently increased during the early postnatal period reaching a maximum at the age of about 2 years. After age 10 years ({sup 3}H)MK-801 binding sites disappeared at 5.7% per decade. The storage time of brain tissue had a reducing effect on these binding sites. There was no effect of gender, brain weight or postmortem time interval and the binding sites were bilaterally symmetrically distributed in the frontal cortex.

Using extracorporeal membrane oxygenation support preoperatively and postoperatively as a successful bridge to recovery in a patient with a large infarct-induced ventricular septal defect.

PubMed

Jacob, Samuel; Patel, Mitesh J; Lima, Brian; Felius, Joost; Malyala, Rajasekhar S; Chamogeorgakis, Themistokles; MacHannaford, Juan C; Gonzalez-Stawinski, Gonzalo V; Rafael, Aldo E

2016-07-01

Rupture of the ventricular septum during acute myocardial infarction usually occurs within the first week. The event is usually followed by low cardiac output, heart failure, and multiorgan failure. Despite the many advances in the nonoperative treatment of heart failure and cardiogenic shock, including the intra-aortic balloon pump and a multitude of new inotropic agents and vasodilators, these do not supplant the need for operative intervention in these critically ill patients. This article describes the successful use of extracorporeal membrane oxygenation support as a bridge to recovery postoperatively in a patient with a large infarct-produced ventricular septal defect.

Using extracorporeal membrane oxygenation support preoperatively and postoperatively as a successful bridge to recovery in a patient with a large infarct-induced ventricular septal defect

PubMed Central

Jacob, Samuel; Patel, Mitesh J.; Lima, Brian; Felius, Joost; Malyala, Rajasekhar S.; Chamogeorgakis, Themistokles; MacHannaford, Juan C.; Gonzalez-Stawinski, Gonzalo V.

2016-01-01

Rupture of the ventricular septum during acute myocardial infarction usually occurs within the first week. The event is usually followed by low cardiac output, heart failure, and multiorgan failure. Despite the many advances in the nonoperative treatment of heart failure and cardiogenic shock, including the intra-aortic balloon pump and a multitude of new inotropic agents and vasodilators, these do not supplant the need for operative intervention in these critically ill patients. This article describes the successful use of extracorporeal membrane oxygenation support as a bridge to recovery postoperatively in a patient with a large infarct-produced ventricular septal defect. PMID:27365878

Multiorgan failure following mass wasp stings.

PubMed

Lin, Cheng-Jui; Wu, Chih-Jen; Chen, Han-Hsiang; Lin, Hsin-Chang

2011-05-01

Wasp bites usually bring temporary discomfort and pain, but on occasion, they can cause serious infections and fatal allergic reactions. We report on a patient who experienced massive wasp stings and developed multiple organ failure, including acute kidney, hepatic failure, and circulatory collapse 4 days later. He was treated with aggressive fluid resuscitation, inotropic agent, intravenous injection of steroids, broad-spectrum antibiotics, and hemodialysis. After intensive treatment, his liver function recovered one month later. Recovery of renal function was delayed, and the patient needed temporary regular hemodialysis. The pathology of kidney biopsy showed acute tubulointerstitial nephritis. This case shows that toxic reactions following massive wasp attacks may happen several days after the fact and result in severe, multiorgan system dysfunction.

Something fishy: an unusual Erysipelothrix rhusiopathiae infection in an immunocompromised individual.

PubMed

Sinclair, Marie; Hawkins, Angela; Testro, Adam

2013-04-03

A 39-year-old man with a history of Crohn's disease presented to the emergency department with a 12-h history of worsening febrile illness. He deteriorated rapidly with progression to sepsis and was admitted to the intensive care unit. Initial treatment comprised broad spectrum antibiotics and inotropic support resulting in rapid improvement. With the immunocompromised state of the patient, and multiple blood cultures revealing Erysipelothrix rhusiopathiae, a detailed history disclosed a recent injury sustained from a fishing wire as the probable source of an infection. Treatment was narrowed to target the identified pathogen, the patient made a full recovery, and was counselled to be more cautious in future fishing activities.

Something fishy: an unusual Erysipelothrix rhusiopathiae infection in an immunocompromised individual

PubMed Central

Sinclair, Marie; Hawkins, Angela; Testro, Adam

2013-01-01

A 39-year-old man with a history of Crohn's disease presented to the emergency department with a 12-h history of worsening febrile illness. He deteriorated rapidly with progression to sepsis and was admitted to the intensive care unit. Initial treatment comprised broad spectrum antibiotics and inotropic support resulting in rapid improvement. With the immunocompromised state of the patient, and multiple blood cultures revealing Erysipelothrix rhusiopathiae, a detailed history disclosed a recent injury sustained from a fishing wire as the probable source of an infection. Treatment was narrowed to target the identified pathogen, the patient made a full recovery, and was counselled to be more cautious in future fishing activities. PMID:23559657

Effects of N-acetylimidazole on oxytocin binding in bovine mammary tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, X.; Gorewit, R.C.; Currie, W.B.

1990-01-01

The effects of N-acetylimidazole on specific binding of oxytocin to microsomal fractions of bovine mammary gland were studied. N-acetylimidazole suppressed oxytocin binding, with time and concentration dependence. Decreased oxytocin binding activity appeared to be due to decreased affinity of the hormone for its receptor. Acetylation of oxytocin, rather than of oxytocin receptors, seemed to be responsible for the decreased binding.

Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.

PubMed

Pearse, Rupert M; Harrison, David A; MacDonald, Neil; Gillies, Michael A; Blunt, Mark; Ackland, Gareth; Grocott, Michael P W; Ahern, Aoife; Griggs, Kathryn; Scott, Rachael; Hinds, Charles; Rowan, Kathryn

2014-06-04

Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. To evaluate the clinical effectiveness of a perioperative, cardiac output-guided hemodynamic therapy algorithm. OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. Patients were randomly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). The primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care-free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. Baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, -0.3% to 13.9%]; P = .07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). In a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates. isrctn.org Identifier: ISRCTN04386758.

Autoradiographic analysis of tritiated imipramine binding in the human brain post mortem: effects of suicide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gross-Isseroff, R.; Israeli, M.; Biegon, A.

In vitro quantitative autoradiography of high-affinity tritiated imipramine binding sites was performed on brains of 12 suicide victims and 12 matched controls. Region-specific differences in imipramine binding were found between the two groups. Thus, the pyramidal and molecular layers of the cornu ammoni hippocampal fields and the hilus of the dentate gyrus exhibited 80%, 60%, and 90% increases in binding in the suicide group, respectively. The postcentral cortical gyrus, insular cortex, and claustrum had 45%, 28%, and 75% decreases in binding in the suicide group, respectively. No difference in imipramine binding was observed in prefrontal cortical regions, in the basalmore » ganglia, and in mesencephalic nuclei. No sex and postmortem delay effects on imipramine binding were found. Imipramine binding was positively correlated with age, the effect of age being most pronounced in portions of the basal ganglia and temporal cortex.« less

Role of levosimendan in the management of subarachnoid hemorrhage.

PubMed

Varvarousi, Giolanda; Xanthos, Theodoros; Sarafidou, Pavlina; Katsioula, Ellisavet; Georgiadou, Marianthi; Eforakopoulou, Maria; Pavlou, Hlias

2016-02-01

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the leading causes of neurologic disability accounting for dismal long term survival rates. aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemodynamic instability which may critically hamper brain perfusion and oxygenation. In the setting of acute aSAH, administration of vasoactive drugs aims at stabilizing impaired hemodynamics. However, studies have shown that conventional treatment with vasoactive drugs that lead to Ca(+2) overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow. Levosimendan is a non-adrenergic inotropic Ca(+2) sensitizer with not only beneficial hemodynamic properties but also pleiotropic effects, contributing to its cardioprotective and neuroprotective role. Although there have been limited data available regarding the use of levosimendan in patients with aSAH, current evidence suggests that levosimendan may have a role in the setting of post-aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments and in intensive care units. The purpose of this review is to provide an overview of studies of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH. Copyright © 2015 Elsevier Inc. All rights reserved.

Use of Levosimendan in Cardiac Surgery: An Update After the LEVO-CTS, CHEETAH, and LICORN Trials in the Light of Clinical Practice.

PubMed

Guarracino, Fabio; Heringlake, Matthias; Cholley, Bernard; Bettex, Dominique; Bouchez, Stefaan; Lomivorotov, Vladimir V; Rajek, Angela; Kivikko, Matti; Pollesello, Piero

2018-01-01

Levosimendan is a calcium sensitizer and adenosine triphosphate-dependent potassium channel opener, which exerts sustained hemodynamic, symptomatic, and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past 15 years, levosimendan has been widely used in clinical practice and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, 3 randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH, and LEVO-CTS) have been published reporting on the perioperative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in perioperative settings. By contrast, the latest 3 studies were neutral or inconclusive. To understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the 3 most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.

A randomized hemodynamic comparison of intravenous amiodarone with and without Tween 80.

PubMed

Munoz, A; Karila, P; Gallay, P; Zettelmeier, F; Messner, P; Mery, M; Grolleau, R

1988-02-01

In 20 patients undergoing coronary arteriography, the hemodynamic effects of an experimental preparation of i.v. amiodarone 5 mg kg-1 without Tween 80 (N) (10 patients) were compared with those of the commercial form with Tween 80 (A) (10 patients). Analysis of variance demonstrated differences during the 3 min of injection and for 3 min afterwards: left ventricular systolic pressure decreased from 110 + 11 to 86 +/- 11 mmHg (P = 0.001) after A and from 114 +/- 22 to 106 +/- 19 (P = 0.05) after N (comparison P = 0.01) while related tachycardia was also more pronounced after A (comparison P = 0.001). Left ventricular end diastolic pressure transiently decreased after A while continuously increasing after N (P = 0.05). During the following 30 min both A and N caused similar bradycardia, increase in ventricular filling pressure, vascular resistance and decrease in cardiac and contractility indexes. Amiodarone blood levels were similar after A or N. These data document a significant initial short duration vasoplegia, mainly related to Tween 80, after A, when amiodarone itself after producing a similar very slight effect causes bradycardia, and a moderate and progressive negative inotropic effect. It was concluded that while the experimental form would be of interest, the risk of severe hypotension after i.v. Cordarone can be largely avoided by using a slower rate of infusion, especially in patients with hypovolemic status.

Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes.

PubMed

Zimmermann, W H; Fink, C; Kralisch, D; Remmers, U; Weil, J; Eschenhagen, T

2000-04-05

A technique is presented that allows neonatal rat cardiac myocytes to form spontaneously and coherently beating 3-dimensional engineered heart tissue (EHT) in vitro, either as a plane biconcaval matrix anchored at both sides on Velcro-coated silicone tubes or as a ring. Contractile activity was monitored in standard organ baths or continuously in a CO(2) incubator for up to 18 days (=26 days after casting). Long-term measurements showed an increase in force between days 8 and 18 after casting and stable forces thereafter. At day 10, the twitch amplitude (TA) of electrically paced EHTs (average length x width x thickness, 11 x 6 x 0.4 mm) was 0.51 mN at length of maximal force development (L(max)) and a maximally effective calcium concentration. EHTs showed typical features of neonatal rat heart: a positive force-length and a negative force-frequency relation, high sensitivity to calcium (EC(50) 0.24 mM), modest positive inotropic (increase in TA by 46%) and pronounced positive lusitropic effect of isoprenaline (decrease in twitch duration by 21%). Both effects of isoprenaline were sensitive to the muscarinic receptor agonist carbachol in a pertussis toxin-sensitive manner. Adenovirus-mediated gene transfer of beta-galactosidase into EHTs reached 100% efficiency. In summary, EHTs retain many of the physiological characteristics of rat cardiac tissue and allow efficient gene transfer with subsequent force measurement. Copyright 2000 John Wiley & Sons, Inc.

Load dependence of left ventricular contraction and relaxation. Effects of caffeine.

PubMed

Leite-Moreira, A F; Correia-Pinto, J; Gillebert, T C

1999-08-01

Load dependence of left ventricular (LV) contraction and relaxation was investigated at baseline and after alteration of intracellular calcium handling by caffeine. Afterload was increased by aortic clamp occlusions (n = 281) in anesthetized open-chest dogs (n = 7). Control and first heartbeat after the intervention were considered for analysis. Caffeine (50 mg/kg, iv) had no inotropic effect. The systolic LV pressure (LVP), developed in response to aortic occlusion, decreased as ejection proceeded and this pressure generating capacity was not affected by caffeine. Late-systolic aortic occlusions induced premature onset and accelerated rate of initial LVP fall at baseline and similarly after caffeine. Graded diastolic aortic occlusions induced systolic LVP elevations of various magnitudes. Smaller LVP elevations prolonged ejection and accelerated LVP fall, while larger elevations had opposite effects. The transition from acceleration to deceleration was observed at 83.1 +/- 1.1% of peak isovolumetric LVP at baseline and at lower loads, at 77.6 +/- 1.2%, after caffeine (p < 0.01). Isovolumetric heartbeats prolonged the time constant tau by 238 +/- 70% at baseline and only by 155 +/- 44% after caffeine (p < 0.01). The relaxation-systolic pressure relation, which describes afterload dependence of relaxation, was also modified by caffeine. Caffeine affected LV relaxation without altering contractility. As a consequence contraction-relaxation coupling was modified by caffeine. These results might help to understand load dependence of relaxation in conditions where intracellular calcium handling is altered.

Phytochemical and pharmacological activity profile of Crataegus oxyacantha L. (hawthorn) - A cardiotonic herb.

PubMed

Orhan, Ilkay Erdogan

2016-09-18

Crataegus oxyacantha L. (syn. C. rhipidophylla Gand.) (Rosaceae) is one of two medicinally recognized hawthorn species in European Pharmacopeia. Standardization of the extract prepared from the berry and flowers of the plant is required according to its oligomeric procyanidins. C. oxyacantha is well-known for its use in the treatment of various heart problems particularly, including heart failure in cases of declining cardiac performance equivalent to stages I and II of the New York Heart Association classification, angina pectoris, hypertension with myocardial insufficiency, mild alterations of cardiac rhythm, and atherosclerosis. C. oxyacantha has been reported to exert several other pharmacological activities such as hypotensive, antihyperlipidemic, antihyperglycemic, anxiolytic, immunomodulatory, and antimutagenic. Oligomeric procyanidins and flavone/flavonol types of flavonoids, which are considered to be the chief groups of active substances, phenolic acids, triterpenes, fatty acids, and sterols are present in the plant. The present review aims mainly to outline cardiotonic effect of C. oxyacantha as well as its brief phytochemistry. Numerous experiments and clinical studies have underlined cardiovascular efficacy of the plant through various mechanisms including positive inotropic and negative chronotropic effects, escalation in coronary blood flow and exercise tolerance, inhibition of the enzymes such as angiotensin-converting enzyme (ACE) and phosphodiesterase, anti-inflammatory and antihyperlipidemic effects, improving status of antioxidant enzymes, etc., which support its cardioactive efficacy. The plant possesses several other bioactivities for human health usually concomitant to its rich polyphenolic content.

Super-high-affinity binding site for [3H]diazepam in the presence of Co2+, Ni2+, Cu2+, or Zn2+.

PubMed

Mizuno, S; Ogawa, N; Mori, A

1982-12-01

Chloride salts of Li+, Na+, K+, Mg2+, Ca2+, Cr3+, Mn2+, Fe2+, and Fe3+ had no effect on [3H]diazepam binding. Chloride salts of Co2+, Ni2+, Cu2+, and Zn2+ increased [3H]diazepam binding by 34 to 68% in a concentration-dependent fashion. Since these divalent cations potentiated the GABA-enhanced [3H]diazepam binding and the effect of each divalent cation was nearly additive with GABA, these cations probably act at a site different from the GABA recognition site in the benzodiazepine-receptor complex. Scatchard plots of [3H]diazepam binding without an effective divalent cation showed a single class of binding, with a Kd value of 5.3 nM. In the presence of 1 mM Co2+, Ni2+, Cu2+, or Zn2+, two distinct binding sites were evident with apparent Kd values of 1.0 nM and 5.7 nM. The higher-affinity binding was not detected in the absence of an effective divalent cation and is probably a novel, super-high-affinity binding site.

Clinical characteristics of zinc phosphide poisoning in Thailand.

PubMed

Trakulsrichai, Satariya; Kosanyawat, Natcha; Atiksawedparit, Pongsakorn; Sriapha, Charuwan; Tongpoo, Achara; Udomsubpayakul, Umaporn; Rittilert, Panee; Wananukul, Winai

2017-01-01

The objectives of this study were to describe the clinical characteristics and outcomes of poisoning by zinc phosphide, a common rodenticide in Thailand, and to evaluate whether these outcomes can be prognosticated by the clinical presentation. A 3-year retrospective cohort study was performed using data from the Ramathibodi Poison Center Toxic Exposure Surveillance System. In total, 455 poisonings were identified. Most were males (60.5%) and from the central region of Thailand (71.0%). The mean age was 39.91±19.15 years. The most common route of exposure was oral (99.3%). Most patients showed normal vital signs, oxygen saturation, and consciousness at the first presentation. The three most common clinical presentations were gastrointestinal (GI; 68.8%), cardiovascular (22.0%), and respiratory (13.8%) signs and symptoms. Most patients had normal blood chemistry laboratory results and chest X-ray findings at presentation. The median hospital stay was 2 days, and the mortality rate was 7%. Approximately 70% of patients underwent GI decontamination, including gastric lavage and a single dose of activated charcoal. In all, 31 patients were intubated and required ventilator support. Inotropic drugs were given to 4.2% of patients. Four moribund patients also received hyperinsulinemia-euglycemia therapy and intravenous hydrocortisone; however, all died. Patients who survived and died showed significant differences in age, duration from taking zinc phosphide to hospital presentation, abnormal vital signs at presentation (tachycardia, low blood pressure, and tachypnea), acidosis, hypernatremia, hyperkalemia, in-hospital acute kidney injury, in-hospital hypoglycemia, endotracheal tube intubation, and inotropic requirement during hospitalization ( P <0.05). Zinc phosphide poisoning causes fatalities. Most patients have mild symptoms, and GI symptoms are the most common. Patients who present with abnormal vital signs or electrolytes might have more severe poisoning and should be closely monitored and aggressively treated. All patients should be observed in the hospital for 2 days and followed up for cardiovascular and respiratory symptoms, electrolyte balances, kidney function, and blood glucose.

Biotransformation of the novel inotropic agent toborinone (OPC-18790) in rats and dogs. Evidence for the formation of novel glutathione and two cysteine conjugates.

PubMed

Kitani, M; Miyamoto, G; Nagasawa, M; Yamada, T; Matsubara, J; Uchida, M; Odomi, M

1997-06-01

The metabolism of toborinone, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin - olinone, a novel inotropic agent, was studied in rats and dogs after intravenous administration. Chemical structures of the 13 metabolites were characterized by direct-probe FAB/MS and field desorption/MS, LC/FAB/MS, and various NMR measurements. After intravenous dosing of 10 mg/kg [14C]toborinone, fecal and urinary recoveries of the 14C dose were approximately 70% and 26-30%, respectively, in both rats and dogs. The predominant component of radioactivity was the unchanged toborinone in every biological specimen in rats and dogs. Although unchanged toborinone was predominantly observed, toborinone underwent extensive conjugations with glucuronic acid, sulfate, and glutathione, either directly or following phase I reaction. Metabolites resulting from oxidative N-C cleavage were minor both in number and in quantity in every biological specimen in rats and dogs. In rats, toborinone underwent O-demethylation to form M-7 and successive phase it reaction to yield the glucuronide M-1 and the sulfoconjugate M-2, and deconjugation to yield M-7, which was a primary metabolite accounted for 35.67% of the radioactivity excreted in the feces by 48 hr. Conjugates M-1 and M-2 were the major metabolites in rat plasma. In dogs, toborinone was metabolized via mercapturic acid pathway to yield the primary metabolites, cysteine conjugates M-10 and M-11 that accounted for 19.10% and 6.70% of the radioactivity excreted in the feces by 48 hr and that were detected species specifically in dogs. The glutathione conjugate M-13, which was isolated from in vitro incubations using dog liver, led us to consider a possible mercapturic acid pathway from the parent compound to M-10. Metabolites in dog plasma and those in urine in both rats and dogs were minor in quantity. The metabolic pathways of toborinone in rats and dogs are proposed herein.

Positive inotropism in mammalian skeletal muscle in vitro during and after fatigue.

PubMed

Reading, S A; Murrant, C L; Barclay, J K

2004-04-01

We tested the hypothesis that positive inotropic factors decrease fatigue and improve recovery from fatigue in mammalian skeletal muscle in vitro. To induce fatigue, we stimulated mouse soleus and extensor digitorum longus (EDL) to perform isometric tetanic contractions (50 impulses x s(-1) for 0.5 s) at 6 contractions x min(-1) for 60 min in soleus and 3 contractions x min(-1) for 20 min in EDL. Muscles were submerged in Krebs-Henseleit bicarbonate solution (Krebs) at 27 degrees C gassed with 95% nitrogen - 5% carbon dioxide (anoxia). Before and for 67 min after the fatigue period, muscles contracted at 0.6 contractions x min(-1) in 95% oxygen - 5% carbon dioxide (hyperoxia). We added a permeable cAMP analog (N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophosphate at 10(-3) mol x L(-1) (dcAMP)), caffeine (2 x 10(-3) mol x L(-1), or Krebs as vehicle control at 25 min before, during, or at the end of the fatigue period. In soleus and EDL, both challenges added before fatigue significantly increased developed force but only caffeine increased developed force when added during the fatigue period. At the end of fatigue, the decrease in force in challenged muscles was equal to or greater than in controls so that the force remaining was the same or less than in controls. EDL challenged with dcAMP or caffeine at any time recovered more force than controls. In soleus, caffeine improved recovery except when added before fatigue. With dcAMP added to soleus, recovery was better after challenges at 10 min and the end of the fatigue period. Thus, increased intracellular concentrations of cAMP and (or) Ca2+ did not decrease fatigue in either muscle but improved recovery from fatigue in EDL and, in some conditions, in soleus.

Identifying Vasopressor and Inotrope Use for Health Services Research

PubMed Central

Fawzy, Ashraf; Bradford, Mark; Lindenauer, Peter K.

2016-01-01

Rationale: Identifying vasopressor and inotrope (vasopressor) use from administrative claims data may provide an important resource to study the epidemiology of shock. Objectives: Determine accuracy of identifying vasopressor use using International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) coding. Methods: Using administrative data enriched with pharmacy billing files (Premier, Inc., Charlotte, NC), we identified two cohorts: adult patients admitted with a diagnosis of sepsis from 2010 to 2013 or pulmonary embolism (PE) from 2008 to 2011. Vasopressor administration was obtained using pharmacy billing files (dopamine, dobutamine, epinephrine, milrinone, norepinephrine, phenylephrine, vasopressin) and compared with ICD-9-CM procedure code for vasopressor administration (00.17). We estimated performance characteristics of the ICD-9-CM code and compared patients’ characteristics and mortality rates according to vasopressor identification method. Measurements and Main Results: Using either pharmacy data or the ICD-9-CM procedure code, 29% of 541,144 patients in the sepsis cohort and 5% of 81,588 patients in the PE cohort were identified as receiving a vasopressor. In the sepsis cohort, the ICD-9-CM procedure code had low sensitivity (9.4%; 95% confidence interval, 9.2–9.5), which increased over time. Results were similar in the PE cohort (sensitivity, 5.8%; 95% confidence interval, 5.1–6.6). The ICD-9-CM code exhibited high specificity in the sepsis (99.8%) and PE (100%) cohorts. However, patients identified as receiving vasopressors by ICD-9-CM code had significantly higher unadjusted in-hospital mortality, had more acute organ failures, and were more likely hospitalized in the Northeast and West. Conclusions: The ICD-9-CM procedure code for vasopressor administration has low sensitivity and selects for higher severity of illness in studies of shock. Temporal changes in sensitivity would likely make longitudinal shock surveillance using ICD-9-CM inaccurate. PMID:26653145

In permanent atrial fibrillation, PDE3 reduces force responses to 5‐HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias

PubMed Central

Schwarz, Simon; Ravens, Ursula; Knaut, Michael

2016-01-01

Abstract Background and Purpose 5‐HT increases force and L‐type Ca2 + current (ICa,L) and causes arrhythmias through 5‐HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5‐HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 μM) respectively. Experimental Approach Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. Key Results Maximum force responses to 5‐HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5‐HT in peAF and the inotropic potency of 5‐HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5‐HT were not decreased in peAF. Responses of ICa,L to 5‐HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5‐HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. Conclusions and Implications PDE3, but not PDE4, reduced inotropic responses to 5‐HT in peAF, independently of lusitropy and ICa,L, but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5‐HT to induce arrhythmias by inhibition of PDE3 plus PDE4. PMID:27238373

Milrinone Use is Associated With Postoperative Atrial Fibrillation Following Cardiac Surgery

PubMed Central

Fleming, Gregory A.; Murray, Katherine T.; Yu, Chang; Byrne, John G.; Greelish, James P.; Petracek, Michael R.; Hoff, Steven J.; Ball, Stephen K.; Brown, Nancy J.; Pretorius, Mias

2009-01-01

Background Postoperative atrial fibrillation (AF), a frequent complication following cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. Methods and Results We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven (28.9%) patients developed AF a mean of 2.9±2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in non-users, P<0.001). Older age (63.4±10.7 versus 56.7±12.3 years, P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (PAP) (27.1±9.3 versus 21.8±7.5 mmHg, P=0.001) were also associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio 4.86, 95% CI 2.31-10.25, P<0.001) independently predicted postoperative AF. When data only from patients with pulmonary artery catheters were analyzed and PAP was included in the model, age, milrinone use (odds ratio 4.45, 95% CI 2.01-9.84, P<0.001), and higher PAP (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. Conclusion Milrinone use is an independent risk factor for postoperative AF following elective cardiac surgery. PMID:18824641

Sedation and Anesthesia in Pediatric and Congenital Cardiac Catheterization: A Prospective Multicenter Experience.

PubMed

Lin, C Huie; Desai, Sanyukta; Nicolas, Ramzi; Gauvreau, Kimberlee; Foerster, Susan; Sharma, Anshuman; Armsby, Laurie; Marshall, Audrey C; Odegard, Kirsten; DiNardo, James; Vincent, Julie; El-Said, Howaida; Spaeth, James; Goldstein, Bryan; Holzer, Ralf; Kreutzer, Jackie; Balzer, David; Bergersen, Lisa

2015-10-01

Sedation/anesthesia is critical to cardiac catheterization in the pediatric/congenital heart patient. We sought to identify current sedation/anesthesia practices, the serious adverse event rate related to airway, sedation, or anesthesia, and the rate of intra-procedural conversion from procedural sedation to the use of assisted ventilation or an artificial airway. Data from 13,611 patients who underwent catheterization at eight institutions were prospectively collected from 2007 to 2010. Ninety-four (0.69 %) serious sedation/airway-related adverse events occurred; events were more likely to occur in smaller patients (<4 kg, OR 4.4, 95 % CI 2.3-8.2, p < 0.001), patients with non-cardiac comorbidities (OR 1.7, 95 % CI 1.1-26, p < 0.01), and patients with low mixed venous oxygen saturation (OR 2.3, 95 % CI 1.4-3.6, p < 0.001). Nine thousand three hundred and seventy-nine (69 %) patients were initially managed with general endotracheal anesthesia, LMA, or tracheostomy, whereas 4232 (31 %) were managed with procedural sedation without an artificial airway, of which 75 (1.77 %) patients were converted to assisted ventilation/general anesthesia. Young age (<12 months, OR 5.2, 95 % CI 2.3-11.4, p < 0.001), higher-risk procedure (category 4, OR 10.1, 95 % CI 6.5-15.6, p < 0.001), and continuous pressor/inotrope requirement (OR 11.0, 95 % CI 8.6-14.0, p < 0.001) were independently associated with conversion. Cardiac catheterization in pediatric/congenital patients was associated with a low rate of serious sedation/airway-related adverse events. Smaller patients with non-cardiac comorbidities or low mixed venous oxygen saturation may be at higher risk. Patients under 1 year of age, undergoing high-risk procedures, or requiring continuous pressor/inotrope support may be at higher risk of requiring conversion from procedural sedation to assisted ventilation/general anesthesia.

Does Survival on the Heart Transplant Waiting List Depend on the Underlying Heart Disease?

PubMed Central

Hsich, Eileen M.; Rogers, Joseph G.; McNamara, Dennis M.; Taylor, David O.; Starling, Randall C.; Blackstone, Eugene H.; Schold, Jesse D.

2016-01-01

Objective The aim was to identify differences in survival based on type of heart disease while awaiting orthotopic heart transplantation (OHT). Background Restrictive cardiomyopathy (RCM), congenital heart disease (CHD), and hypertrophic cardiomyopathy (HCM) patients may be at a disadvantage while awaiting OHT since they often are poor candidates for mechanical circulatory support and/or inotropes. Methods We included all adults in the Scientific Registry of Transplant Recipients database awaiting OHT from 2004–2014 and evaluated outcomes based on type of heart disease. The primary endpoint was time to all-cause mortality censored at last patient follow-up and time of transplantation. Multivariable Cox proportional hazards models were performed to evaluate survival by type of cardiomyopathy. Results There were 14447 DCM, 823 RCM, 11799 ischemic cardiomyopathy (ICM), 602 HCM, 964 CHD, 584 valvular disease, and 1528 “other” (including 1216 for re-transplantation). During median follow-up of 3.7 months, 4943 died (1253 F, 3690 M). After adjusting for possible confounding variables including age, renal function, inotropes, mechanical ventilation and mechanical circulatory support, the adjusted hazard ratio (aHR) by diagnoses relative to DCM were RCM aHR 1.70 (1.43–2.02), ICM aHR 1.10 (1.03–1.18), HCM aHR 1.23 (0.98–1.54), valvular disease aHR 1.30 (1.07–1.57), CHD aHR 1.37 (1.17–1.61) and “Other” aHR 1.51 (1.34–1.69). Sex was a significant modifier of mortality for ICM, RCM and “other” (P<0.05 for interaction). Conclusion In the United States, patients with RCM, CHD and prior heart transplantation had a higher risk of death awaiting OHT than patients with a DCM, ICM, HCM and valvular heart disease. PMID:27179836

Commercial valerian interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes.

PubMed

Ortiz, José G; Rassi, Nicole; Maldonado, Patricia M; González-Cabrera, Silvia; Ramos, Igmeris

2006-09-01

Valeriana officinalis extracts are used in folkloric medicine for their sedative, hypnotic and tranquilizer effects. Using [3H]flunitrazepam binding as an indicator, the interactions of commercial Valerian extracts with GABA(A) receptors were examined. There was considerable fluctuation among the different extracts, some mildly enhanced [3H]flunitrazepam binding, others had no effect and others had inhibitory effects, independent of standardization by valerenic acid. Central depression can also be accomplished by a reduction of excitatory transmission. Valerian extracts had modest inhibitory effects on [3H]MK-801 binding, an indicator of NMDA-Valerian interactions. Spectral analyses (UV region) did not show marked differences among the different extracts. The inhibitory effects of one of the extracts on [3H]flunitrazepam binding was somewhat stable, while on [3H]MK-801 binding the inhibitory effects were lost within months. These results suggest that particular care should be taken in analysing and interpreting results from commercial Valerian preparations. Copyright (c) 2006 John Wiley & Sons, Ltd.

Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.

PubMed

El-Bizri, Nesrine; Bkaily, Ghassan; Wang, Shimin; Jacques, Danielle; Regoli, Domenico; D'Orléans-Juste, Pedro; Sukarieh, Rami

2003-03-01

Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.

[Effect of aceclofenac on thyroid hormone binding and thyroid function].

PubMed

Nadler, K; Buchinger, W; Semlitsch, G; Pongratz, R; Rainer, F

2000-01-01

Influences of non-steroidal anti-inflammatory drugs (NSAID) on concentrations of thyroid hormones are known for a long time. These effects could be explained with interference between NSAIDs and thyroid hormone binding. We investigated the effects of a single dose of aceclofenac on thyroid function and thyroid hormone binding in 18 healthy volunteers. Serum levels of free thyroid hormones (FT3, FT4) and thyrotropin (TSH) were measured with commercial available kids and thyroid hormone binding was estimated with a specially modified horizontal argarose-gel-electrophoresis prior to and 2 hours after receiving a single dose of aceclofenac. We found a significant decrease in T3 binding on TBG and a significant increase of albumin-bound T3. All other investigated thyroid hormone binding parameters, FT3 and FT4, showed no significant changes. We conclude that aceclofenac leads to a significant redistribution of T3 protein binding. These effects seem to be explained by T3 displacement from TBG induced by aceclofenac.

The influence of action-outcome delay and arousal on sense of agency and the intentional binding effect.

PubMed

Wen, Wen; Yamashita, Atsushi; Asama, Hajime

2015-11-01

The sense of agency refers to the feeling of being able to initiate and control events through one's actions. The "intentional binding" effect (Haggard, Clark, & Kalogeras, 2002), refers to a subjective compression of the temporal interval between actions and their effects. The present study examined the influence of action-outcome delays and arousal on both the subjective judgment of agency and the intentional binding effect. In the experiment, participants pressed a key to trigger a central square to jump after various delays. A red central square was used in the high-arousal condition. Results showed that a longer interval between actions and their effects was associated with a lower sense of agency but a stronger intentional binding effect. Furthermore, although arousal enhanced the intentional binding effect, it did not influence the judgment of agency. Copyright © 2015 Elsevier Inc. All rights reserved.

MutaBind estimates and interprets the effects of sequence variants on protein-protein interactions.

PubMed

Li, Minghui; Simonetti, Franco L; Goncearenco, Alexander; Panchenko, Anna R

2016-07-08

Proteins engage in highly selective interactions with their macromolecular partners. Sequence variants that alter protein binding affinity may cause significant perturbations or complete abolishment of function, potentially leading to diseases. There exists a persistent need to develop a mechanistic understanding of impacts of variants on proteins. To address this need we introduce a new computational method MutaBind to evaluate the effects of sequence variants and disease mutations on protein interactions and calculate the quantitative changes in binding affinity. The MutaBind method uses molecular mechanics force fields, statistical potentials and fast side-chain optimization algorithms. The MutaBind server maps mutations on a structural protein complex, calculates the associated changes in binding affinity, determines the deleterious effect of a mutation, estimates the confidence of this prediction and produces a mutant structural model for download. MutaBind can be applied to a large number of problems, including determination of potential driver mutations in cancer and other diseases, elucidation of the effects of sequence variants on protein fitness in evolution and protein design. MutaBind is available at http://www.ncbi.nlm.nih.gov/projects/mutabind/. Published by Oxford University Press on behalf of Nucleic Acids Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Effects of the Hydroxyl Group on Phenyl Based Ligand/ERRγ Protein Binding

PubMed Central

2015-01-01

Bisphenol-A (4,4′-dihydroxy-2,2-diphenylpropane, BPA, or BPA-A) and its derivatives, when exposed to humans, may affect functions of multiple organs by specific binding to the human estrogen-related receptor γ (ERRγ). We carried out atomistic molecular dynamics (MD) simulations of three ligand compounds including BPA-A, 4-α-cumylphenol (BPA-C), and 2,2-diphenylpropane (BPA-D) binding to the ligand binding domain (LBD) of a human ERRγ to study the structures and energies associated with the binding. We used the implicit Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method to estimate the free energies of binding for the phenyl based compound/ERRγ systems. The addition of hydroxyl groups to the aromatic ring had only a minor effect on binding structures and a significant effect on ligand/protein binding energy in an aqueous solution. Free binding energies of BPA-D to the ERRγ were found to be considerably less than those of BPA-A and BPA-C to the ERRγ. These results are well correlated with those from experiments where no binding affinities were determined in the BPA-D/ERRγ complex. No conformational change was observed for the helix 12 (H-12) of ERRγ upon binding of these compounds preserving an active transcriptional conformation state. PMID:25098505

Probing the binding of flavonoids to catalase by molecular spectroscopy

NASA Astrophysics Data System (ADS)

Zhu, Jingfeng; Zhang, Xia; Li, Daojin; Jin, Jing

2007-10-01

The binding of flavonoids (quercetin and myricetin) to catalase was investigated by fluorescence and circular dichroism (CD) techniques under physiological conditions. The binding parameters and binding mode between flavonoids and catalase were determined, and the results of synchronous fluorescence spectra and CD indicated a conformational change of catalase with addition of flavonoids. The effect of both Cu 2+ and vitamin C on the binding constant of flavonoid-catalase was also examined. The experiment data show that the difference of the structure characteristics of quercetin and myricetin has a significant effect on their binding affinity for catalase.

Carboxyl‐terminal Heparin‐binding Fragments of Platelet Factor 4 Retain the Blocking Effect on the Receptor Binding of Basic Fibroblast Growth Factor

PubMed Central

Waki, Michinori; Ohno, Motonori; Kuwano, Michihiko; Sakata, Toshiie

1993-01-01

Platelet factor 4 (PF‐4) blocks the binding of basic fibroblast growth factor (bFGF) to its receptor. In the present study, we constructed carboxyl‐terminal fragments, which represent the heparin‐binding region of the PF‐4 molecule, and examined whether these synthetic peptides retain the blocking effects on the receptor binding of bFGF. Synthetic peptides inhibited the receptor binding of bFGF. Furthermore, they inhibited the migration and tube formation of bovine capillary endothelial cells in culture (these phenomena are dependent on endogenous bFGF). PMID:8320164

Comparison of Effects of Separate and Combined Sugammadex and Lipid Emulsion Administration on Hemodynamic Parameters and Survival in a Rat Model of Verapamil Toxicity.

PubMed

Tulgar, Serkan; Kose, Halil Cihan; Demir Piroglu, Isılay; Karakilic, Evvah; Ates, Nagihan Gozde; Demir, Ahmet; Gergerli, Ruken; Guven, Selin; Piroglu, Mustafa Devrim

2016-03-25

Toxicity of calcium channel blockers leads to high patient mortality and there is no effective antidote. The benefit of using 20% lipid emulsion and sugammadex has been reported. The present study measured the effect of sugammadex and 20% lipid emulsion on hemodynamics and survival in a rat model of verapamil toxicity. In this single-blinded randomized control study, rats were separated into 4 groups of 7 rats each: Sugammadex (S), Sugammadex plus 20% lipid emulsion (SL), 20% lipid emulsion (L), and control (C). Heart rates and mean arterial pressures were monitored and noted each minute until death. Average time to death was 21.0±9.57 minutes for group C, 35.57±10.61 minutes for group S, 37.14±16.6 minutes for group L and 49.86±27.56 minutes for group SL. Time to death was significantly longer in other groups than in the control group (p<0.05). Verapamil overdose is has a comparatively high mortality rate and there is no effective antidote. Treatment generally involves gastric decontamination and symptomatic treatment to counteract the drug's negative effects. In animal studies sugammadex and lipid emulsion had a positive effect on survival in patients with calcium channel blocker toxicity. Sugammadex and intralipid increased survival in a rat model of verapamil toxicity. The combination of both drugs may decrease cardiotoxicity. Sugammadex alone or combined with 20% lipid emulsion reduce the need for inotropic agents. The mechanism requires clarification with larger studies.

Comparison of Effects of Separate and Combined Sugammadex and Lipid Emulsion Administration on Hemodynamic Parameters and Survival in a Rat Model of Verapamil Toxicity

PubMed Central

Tulgar, Serkan; Kose, Halil Cihan; Piroglu, Isılay Demir; Karakilic, Evvah; Ates, Nagihan Gozde; Demir, Ahmet; Gergerli, Ruken; Guven, Selin; Piroglu, Mustafa Devrim

2016-01-01

Background Toxicity of calcium channel blockers leads to high patient mortality and there is no effective antidote. The benefit of using 20% lipid emulsion and sugammadex has been reported. The present study measured the effect of sugammadex and 20% lipid emulsion on hemodynamics and survival in a rat model of verapamil toxicity. Material/Methods In this single-blinded randomized control study, rats were separated into 4 groups of 7 rats each: Sugammadex (S), Sugammadex plus 20% lipid emulsion (SL), 20% lipid emulsion (L), and control (C). Heart rates and mean arterial pressures were monitored and noted each minute until death. Results Average time to death was 21.0±9.57 minutes for group C, 35.57±10.61 minutes for group S, 37.14±16.6 minutes for group L and 49.86±27.56 minutes for group SL. Time to death was significantly longer in other groups than in the control group (p<0.05). Conclusions Verapamil overdose is has a comparatively high mortality rate and there is no effective antidote. Treatment generally involves gastric decontamination and symptomatic treatment to counteract the drug’s negative effects. In animal studies sugammadex and lipid emulsion had a positive effect on survival in patients with calcium channel blocker toxicity. Sugammadex and intralipid increased survival in a rat model of verapamil toxicity. The combination of both drugs may decrease cardiotoxicity. Sugammadex alone or combined with 20% lipid emulsion reduce the need for inotropic agents. The mechanism requires clarification with larger studies. PMID:27012816

Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes.

PubMed

Li, Qince; Pogwizd, Steven M; Prabhu, Sumanth D; Zhou, Lufang

2014-01-01

Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na+/K+ ATPase (NKA), which raises [Na+]i and attenuates Ca2+ extrusion via the Na+/Ca2+ exchanger (NCX), causing [Ca2+]i elevation. The resulting [Ca2+]i accumulation further enhances Ca2+-induced Ca2+ release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias via impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca2+ retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na+/Ca2+ exchanger, but not enhancing of Ca2+ uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca2+ transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.

Cognitive and neuropsychological underpinnings of relational and conjunctive working memory binding across age.

PubMed

van Geldorp, Bonnie; Parra, Mario A; Kessels, Roy P C

2015-01-01

The ability to form associations (i.e., binding) is critical for memory formation. Recent studies suggest that aging specifically affects relational binding (associating separate features) but not conjunctive binding (integrating features within an object). Possibly, this dissociation may be driven by the spatial nature of the studies so far. Alternatively, relational binding may simply require more attentional resources. We assessed relational and conjunctive binding in three age groups and we included an interfering task (i.e., an articulatory suppression task). Binding was examined in a working memory (WM) task using non-spatial features: shape and colour. Thirty-one young adults (mean age = 22.35), 30 middle-aged adults (mean age = 54.80) and 30 older adults (mean age = 70.27) performed the task. Results show an effect of type of binding and an effect of age but no interaction between type of binding and age. The interaction between type of binding and interference was significant. These results indicate that aging affects relational binding and conjunctive binding similarly. However, relational binding is more susceptible to interference than conjunctive binding, which suggests that relational binding may require more attentional resources. We suggest that a general decline in WM resources associated with frontal dysfunction underlies age-related deficits in WM binding.

Timing of vasopressor initiation and mortality in septic shock: a cohort study

PubMed Central

2014-01-01

Introduction Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock. Methods Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis. Results In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P <0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors. Conclusion Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock. PMID:24887489

Toxic Shock Syndrome within 24 H of an Office Hysteroscopy.

PubMed

Bhagat, Nanak; Karthikeyan, Akilandeshwari; Kalkur, Sanjaya

2017-01-01

Office hysteroscopy is now a common procedure performed to look at the endometrial cavity and is relatively free of serious complications. A 68-year-old lady, previously fit and well, presented with abdominal pain, rigors, sweats, and vomiting within 24 h of an outpatient hysteroscopy for postmenopausal bleeding. She was diagnosed with streptococcal toxic shock syndrome (STSS) due to Group A beta-hemolytic streptococci. She was managed in the Intensive Care Unit, with inotropic and antibiotic support. She recovered eventually and was discharged home with oral antibiotics. Toxic shock syndrome due to Streptococci is an unusual occurrence, whose incidence has been slowly increasing over the years. However, this appears to be the first case of STSS manifesting within 24 h following an outpatient hysteroscopy.

[Monitoring and Modern Hemodynamic Concepts in Cardiac Anesthesia].

PubMed

Heringlake, Matthias; Schmidt, Christian; Brandt, Sebastian

2018-05-01

Patients undergoing cardiac surgery are growing older, present with more comorbidities, and are frequently scheduled for more complex and prolonged surgical procedures. Routine application of neurological as well as extended hemodynamic monitoring combined with goal-directed perioperative hemodynamic optimization, targeting optimization of systemic and cerebral oxygen balance, show promise to reduce postoperative complications and to improve mortality in this high risk population. Expert recommendations suggest to avoid synthetic colloids for fluid optimization. Additionally, pathophysiological reasoning and results from recent trials suggest to start inotropic and vasoactive therapy primarily with non-adrenergic drugs like levosimendan and vasopressin and to add classical catecholamines like dobutamine and noradrenalin only if necessary to accomplish hemodynamic goals. Georg Thieme Verlag KG Stuttgart · New York.

Therapy of stress (takotsubo) cardiomyopathy: present shortcomings and future perspectives.

PubMed

Brunetti, Natale Daniele; Santoro, Francesco; De Gennaro, Luisa; Correale, Michele; Kentaro, Hayashi; Gaglione, Antonio; Di Biase, Matteo

2016-09-01

Several therapeutic options are available for the treatment of the acute phase of stress cardiomyopathy, pharmacological (β-blockers, diuretics, anticoagulants, antiarrhythmics, noncatecholamine inotropics [levosimendan]), and nonpharmacological (intra-aortic balloon pumping, extracorporeal membrane oxygenation), according to the wide possible clinical presentation and course of the disease. However, there is a gap in evidence, and very few data come from randomized and adequately powered studies. Some evidence supports the use of β-blockers, in particular with a short half-life, in the case of left ventricular outflow tract obstruction, and angiotensin-converting enzyme inhibitors in secondary prevention. Future perspectives include the study of genetic basis of stress cardiomyopathy, role of miRNA and neurovegetative modulation. Randomized studies, however, are surely warranted.

[Cardiogenic shock associated with inappropriate nutritional regimen: refeeding syndrome].

PubMed

Campos-Ferrer, C; Cervera-Montes, M; Romero, A; Borrás, S; Gómez, E; Ricart, C

2004-01-01

Situations of cardiac arrest have been reported in under-nourished patients with protein and calorie deficits when the provision of nutrients was initiated in an uncontrolled manner. The recognition of the association between the provision of food in these circumstances and the serious clinical consequences, generally heartbeat disorders, has led this condition to be described as "re-feeding syndrome". The case presented here is of severe acute respiratory failure and cardiogenic shock in a 44-year-old female patient with severe protein and calorie malnutrition associated with the start of hyperproteic nutritional support. Treatment with inotropic-vasoactive drugs and diuretics together with a progressive nutritional programme brought about the complete reversal of her heart failure and the concomitant endocrine-metabolic syndrome.

[Effect of calcium and magnesium ions on the interaction of corticosterone with the cytosol receptor(s) in the rat brain].

PubMed

Ueda, M

1981-01-01

The effects of calcium and magnesium ions on the corticosterone binding to rat brain cytosol receptor protein(s) were investigated. The increasing amounts of CaCl2 or MgCl2 up to 5.0 mM were added, the specific [3H] corticosterone binding increased 1.3-fold and 1.5 respectively. The addition of MnCl2 and KCl did not affect this binding. The binding of corticosterone with rat brain cytosol receptor(s) were decreased by increasing amounts of EDTA and complete inhibition was observed at concentration equal to and greater than 2.5 mM. Inhibition of this binding by EDTA was less than by EGTA. Either theophylline or dibutyryl cyclic AMP had no effect on this binding.

Binding Isotope Effects for para-Aminobenzoic Acid with Dihydropteroate Synthase from Staphylococcus aureus and Plasmodium falciparum.

PubMed

Stratton, Christopher F; Namanja-Magliano, Hilda A; Cameron, Scott A; Schramm, Vern L

2015-10-16

Dihydropteroate synthase is a key enzyme in folate biosynthesis and is the target of the sulfonamide class of antimicrobials. Equilibrium binding isotope effects and density functional theory calculations indicate that the substrate binding sites for para-aminobenzoic acid on the dihydropteroate synthase enzymes from Staphylococcus aureus and Plasmodium falciparum present distinct chemical environments. Specifically, we show that para-aminobenzoic acid occupies a more sterically constrained vibrational environment when bound to dihydropteroate synthase from P. falciparum relative to that of S. aureus. Deletion of a nonhomologous, parasite-specific insert from the plasmodial dihydropteroate synthase abrogated the binding of para-aminobenzoic acid. The loop specific to P. falciparum is important for effective substrate binding and therefore plays a role in modulating the chemical environment at the substrate binding site.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Honda, T.; Adachi, H.; Noguchi, M.

The authors have examined the effect of carbamylcholine on the binding of cholecystokinin (CCK) to dispersed acini from rat pancreas. The CCK receptor on pancreatic acini possesses two classes of binding sites. Simultaneous addition of carbamylcholine inhibited binding of CCK binding sites. Atropine prevented the inhibitory effect of carbamylcholine, whereas calcium ionophore A23187 did not alter binding of CCK. 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited binding of CCK in the same manner as carbamylcholine. Inhibition by carbamylcholine was reversible and the recovery was time dependent. By contrast, inhibition of binding of CCK by TPA did not reverse after a 60-min incubation without themore » agent. These findings, at least in part, account for the inhibition of the CCK-induced stimulation of amylase secretion by carbamylcholine. The action of TPA on binding of CCK suggests the possible involvement of the activation of protein kinase C in the inhibition of binding.« less

Dissociation of binding and learning processes.

PubMed

Moeller, Birte; Frings, Christian

2017-11-01

A single encounter of a stimulus together with a response can result in a short-lived association between the stimulus and the response [sometimes called an event file, see Hommel, Müsseler, Aschersleben, & Prinz, (2001) Behavioral and Brain Sciences, 24, 910-926]. The repetition of stimulus-response pairings typically results in longer lasting learning effects indicating stimulus-response associations (e.g., Logan & Etherton, (1994) Journal of Experimental Psychology: Learning, Memory, and Cognition, 20, 1022-1050]. An important question is whether or not what has been described as stimulus-response binding in action control research is actually identical with an early stage of incidental learning (e.g., binding might be seen as single-trial learning). Here, we present evidence that short-lived binding effects can be distinguished from learning of longer lasting stimulus-response associations. In two experiments, participants always responded to centrally presented target letters that were flanked by response irrelevant distractor letters. Experiment 1 varied whether distractors flanked targets on the horizontal or vertical axis. Binding effects were larger for a horizontal than for a vertical distractor-target configuration, while stimulus configuration did not influence incidental learning of longer lasting stimulus-response associations. In Experiment 2, the duration of the interval between response n - 1 and presentation of display n (500 ms vs. 2000 ms) had opposing influences on binding and learning effects. Both experiments indicate that modulating factors influence stimulus-response binding and incidental learning effects in different ways. We conclude that distinct underlying processes should be assumed for binding and incidental learning effects.

Penicillin-binding site on the Escherichia coli cell envelope

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amaral, L.; Lee, Y.; Schwarz, U.

The binding of /sup 35/S-labeled penicillin to distinct penicillin-binding proteins (PBPs) of the cell envelope obtained from the sonication of Escherichia coli was studied at different pHs ranging from 4 to 11. Experiments distinguishing the effect of pH on penicillin binding by PBP 5/6 from its effect on beta-lactamase activity indicated that although substantial binding occurred at the lowest pH, the amount of binding increased with pH, reaching a maximum at pH 10. Based on earlier studies, it is proposed that the binding at high pH involves the formation of a covalent bond between the C-7 of penicillin and freemore » epsilon amino groups of the PBPs. At pHs ranging from 4 to 8, position 1 of penicillin, occupied by sulfur, is considered to be the site that establishes a covalent bond with the sulfhydryl groups of PBP 5. The use of specific blockers of free epsilon amino groups or sulfhydryl groups indicated that wherever the presence of each had little or no effect on the binding of penicillin by PBP 5, the presence of both completely prevented binding. The specific blocker of the hydroxyl group of serine did not affect the binding of penicillin.« less

Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes.

PubMed

Subasinghe, Supundi; Unabia, Sharon; Barrow, Colin J; Mok, Su San; Aguilar, Marie-Isabel; Small, David H

2003-02-01

Accumulation of beta amyloid (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease. Abeta can bind to membrane lipids and this binding may have detrimental effects on cell function. In this study, surface plasmon resonance technology was used to study Abeta binding to membranes. Abeta peptides bound to synthetic lipid mixtures and to an intact plasma membrane preparation isolated from vascular smooth muscle cells. Abeta peptides were also toxic to vascular smooth muscle cells. There was a good correlation between the toxic effect of Abeta peptides and their membrane binding. 'Ageing' the Abeta peptides by incubation for 5 days increased the proportion of oligomeric species, and also increased toxicity and the amount of binding to lipids. The toxicities of various Abeta analogs correlated with their lipid binding. Significantly, binding was influenced by the concentration of cholesterol in the lipid mixture. Reduction of cholesterol in vascular smooth muscle cells not only reduced the binding of Abeta to purified plasma membrane preparations but also reduced Abeta toxicity. The results support the view that Abeta toxicity is a direct consequence of binding to lipids in the membrane. Reduction of membrane cholesterol using cholesterol-lowering drugs may be of therapeutic benefit because it reduces Abeta-membrane binding.

Effect of binding in cyclic phosphorylation-dephosphorylation process and in energy transformation.

PubMed

Sarkar, A; Beard, D A; Franza, B R

2006-07-01

The effects of binding on the phosphorylation-dephosphorylation cycle (PDPC) - one of the key components of the signal transduction processes - is analyzed based on a mathematical model. The model shows that binding of proteins, forming a complex, diminishes the ultrasensitivity of the PDPC to the differences in activity between kinase and phosphatase in the cycle. It is also found that signal amplification depends upon the strength of the binding affinity of the protein (phosphorylated or dephosphorylated) to other proteins . It is also observed that the amplification of signal is not only dependent on phosphorylation potential but also on binding properties and resulting adjustments in binding energies.

Novel soluble, high-affinity gastrin-releasing peptide binding proteins in Swiss 3T3 fibroblasts.

PubMed

Kane, M A; Portanova, L B; Kelley, K; Holley, M; Ross, S E; Boose, D; Escobedo-Morse, A; Alvarado, B

1994-01-01

Swiss 3T3 cells contained substantial amounts of soluble and specific [125I]GRP binders. Like the membrane-associated GRP receptor, they were of high affinity, saturable, bound to GRP(14-27) affinity gels, and exhibited specificity for GRP(14-27) binding. They differed in that acid or freezing destroyed specific binding, specific binding exhibited different time and temperature effects, no detergent was required for their solubilization, ammonium sulfate fractionation yielded different profiles, the M(rs) were lower, GRP(1-16) also blocked binding, and a polyclonal anti-GRP receptor antiserum did not bind on Western blots. The isolated, soluble GRP binding protein(s) rapidly degraded [125I]GRP. These soluble GRP binding proteins may play a role in the regulation of the mitogenic effects of GRP on these cells.

The gammaPE complex contains both SATB1 and HOXB2 and has positive and negative roles in human gamma-globin gene regulation.

PubMed

Case, S S; Huber, P; Lloyd, J A

1999-11-01

A large nuclear protein complex, termed gammaPE (for gamma-globin promoter and enhancer binding factor), binds to five sites located 5' and 3' of the human y-globin gene. Two proteins, SATB1 (special A-T-rich binding protein 1) and HOXB2, can bind to yPE binding sites. SATB1 binds to nuclear matrix-attachment sites, and HOXB2 is a homeodomain protein important in neural development that is also expressed during erythropoiesis. The present work showed that antisera directed against either SATB1 or HOXB2 reacted specifically with the entire gammaPE complex in electrophoretic mobility shift assays (EMSAs), suggesting that the two proteins can bind to the gammaPE binding site simultaneously. When SATB1 or HOXB2 was expressed in vitro, they could bind independently to gammaPE binding sites in EMSA. Interestingly, the proteins expressed in vitro competed effectively with each other for the gammaPE binding site, suggesting that this may occur under certain conditions in vivo. Transient cotransfections of a HOXB2 cDNA and a y-globin-luciferase reporter gene construct into cells expressing SATB1 suggested that SATB1 has a positive and HOXB2 a negative regulatory effect on transcription. Taking into account their potentially opposing effects and binding activities, SATB1 and HOXB2 may modulate the amount of gamma-globin mRNA expressed during development and differentiation.

Simultaneous effects of pressure and temperature on donor binding energy in Pöschl-Teller quantum well

NASA Astrophysics Data System (ADS)

Hakimyfard, Alireza; Barseghyan, M. G.; Duque, C. A.; Kirakosyan, A. A.

2009-12-01

In the frame of the variational method and the effective-mass approximation, the effects of hydrostatic pressure and temperature on the binding energy for donor impurities in the Pöschl-Teller quantum well are studied. The binding energy dependencies on the width of the quantum well, the hydrostatic pressure, the impurity position, the temperature, and the parameters of the confining potential are reported. The results show that the binding energy increases (decreases) with the increasing of the hydrostatic pressure (temperature). It is also found that, associated with the symmetry breaking in the Pöschl-Teller quantum well, and depending on the impurity position, the binding energy can increase or decrease.

External electric field effect on the binding energy of a hydrogenic donor impurity in InGaAsP/InP concentric double quantum rings

NASA Astrophysics Data System (ADS)

Hu, Min; Wang, Hailong; Gong, Qian; Wang, Shumin

2018-04-01

Within the framework of effective-mass envelope-function theory, the ground state binding energy of a hydrogenic donor impurity is calculated in the InGaAsP/InP concentric double quantum rings (CDQRs) using the plane wave method. The effects of geometry, impurity position, external electric field and alloy composition on binding energy are considered. It is shown that the peak value of the binding energy appears in two rings with large gap as the donor impurity moves along the radial direction. The binding energy reaches the peak value at the center of ring height when the donor impurity moves along the axial direction. The binding energy shows nonlinear variation with the increase of ring height. With the external electric field applied along the z-axis, the binding energy of the donor impurity located at zi ≥ 0 decreases while that located at zi < 0 increases. In addition, the binding energy decreases with increasing Ga composition, but increases with the increasing As composition.

Effects of salts on protein-surface interactions: applications for column chromatography.

PubMed

Tsumoto, Kouhei; Ejima, Daisuke; Senczuk, Anna M; Kita, Yoshiko; Arakawa, Tsutomu

2007-07-01

Development of protein pharmaceuticals depends on the availability of high quality proteins. Various column chromatographies are used to purify proteins and characterize the purity and properties of the proteins. Most column chromatographies require salts, whether inorganic or organic, for binding, elution or simply better recovery and resolution. The salts modulate affinity of the proteins for particular columns and nonspecific protein-protein or protein-surface interactions, depending on the type and concentration of the salts, in both specific and nonspecific manners. Salts also affect the binding capacity of the column, which determines the size of the column to be used. Binding capacity, whether equilibrium or dynamic (under an approximation of a slow flow rate), depends on the binding constant, protein concentration and the number of the binding site on the column as well as nonspecific binding. This review attempts to summarize the mechanism of the salt effects on binding affinity and capacity for various column chromatographies and on nonspecific protein-protein or protein-surface interactions. Understanding such salt effects should also be useful in preventing nonspecific protein binding to various containers. Copyright 2007 Wiley-Liss, Inc.

Regulation of RYR1 activity by Ca(2+) and calmodulin

NASA Technical Reports Server (NTRS)

Rodney, G. G.; Williams, B. Y.; Strasburg, G. M.; Beckingham, K.; Hamilton, S. L.

2000-01-01

The skeletal muscle calcium release channel (RYR1) is a Ca(2+)-binding protein that is regulated by another Ca(2+)-binding protein, calmodulin. The functional consequences of calmodulin's interaction with RYR1 are dependent on Ca(2+) concentration. At nanomolar Ca(2+) concentrations, calmodulin is an activator, but at micromolar Ca(2+) concentrations, calmodulin is an inhibitor of RYR1. This raises the question of whether the Ca(2+)-dependent effects of calmodulin on RYR1 function are due to Ca(2+) binding to calmodulin, RYR1, or both. To distinguish the effects of Ca(2+) binding to calmodulin from those of Ca(2+) binding to RYR1, a mutant calmodulin that cannot bind Ca(2+) was used to evaluate the effects of Ca(2+)-free calmodulin on Ca(2+)-bound RYR1. We demonstrate that Ca(2+)-free calmodulin enhances the affinity of RYR1 for Ca(2+) while Ca(2+) binding to calmodulin converts calmodulin from an activator to an inhibitor. Furthermore, Ca(2+) binding to RYR1 enhances its affinity for both Ca(2+)-free and Ca(2+)-bound calmodulin.

High-affinity binding of laurate to naturally occurring mutants of human serum albumin and proalbumin.

PubMed

Kragh-Hansen, U; Pedersen, A O; Galliano, M; Minchiotti, L; Brennan, S O; Tárnoky, A L; Franco, M H; Salzano, F M

1996-12-15

Binding of laurate (n-dodecanoate) to genetic variants of albumin or its proprotein and to normal albumin isolated from the same heterozygous carriers was studied by a kinetic dialysis technique at physiological pH. The first stoichiometric association constant for binding to proalbumin Lille (Arg-2-->His) and albumin (Alb) Roma (Glu321-->Lys) was increased to 126% and 136% respectively compared with that for binding to normal albumin, whereas the constant for Alb Maku (Lys541-->Glu) was decreased to 80%. In contrast, normal laurate-binding properties were found for as many as nine other albumin variants with single amino acid substitutions. Because the net charges of all these mutants were different from that of normal albumin, the results suggest that the examples of modified laurate binding are not caused by long-range electrostatic effects. Rather, the three positions mentioned are located close to different binding sites for the fatty acid anion. The most pronounced effect was observed for the glycosylated Alb Casebrook, the binding constant of which was decreased to 20%. Binding to the glycosylated Alb Redhill was also decreased, but to a smaller extent (68%). These decreases in binding are caused by partial or total blocking of the high-affinity site by the oligosaccharides, by the negative charges of the oligosaccharides, and/or by conformational changes induced by these bulky moieties. Laurate binding to two chain-termination mutants (Alb Catania and Alb Venezia) was normal, indicating that the C-terminus of albumin is not important for binding. By using different preparations of normal albumin as controls in the binding experiments, it was also possible to compare the effect of various methods for isolation and defatting on laurate binding.

[THE ROLE PLEIOTROPIC EFFECTS OF CALCIUM CHANNEL BLOCKER LERCANIDIPINE IN PERIOPERATIVE THERAPY OF ARTERIAL HYPERTENSION.

PubMed

Melnik, M V; Afonicheva, I I; Beloborodova, A V

2016-09-01

This review presents the data of assessing antihypertensive efficacy and tolerability vasoselective high-lipophilic the 3d generations calcium channel blocker lercanidpine. The inhibition of the calcium ions flow through the membranes of smooth muscle cells of blood vessels causes peripheral, cerebral, renal and coronary vasodilation decreasing total peripheral vascular resistance and, consequently, blood pressure (BP) lowering and improve regional circulation. During reception of lercanidipine the level of norepinephrine remains the same even when using high doses of the drug. Negative inotropic effect does not occur therefore, lercanidipine can be used in the treatment of myocardial ischemia. Renal protection properties slow down the development and progression ofchronic renalfailure (CRF). The drug can be successfully used in patients with arterial hypertension, chronic renalfailure, diabetic and non-diabetic nephropathy. Lercanidpine also may be effectively used in the treatment of hypertension with associated clinical conditions: bronchial asthma, chronic obstructive pulmonary disease, bradiarrythmias, atrioventricular blockade 2-3 degree, sinus node dysfunction, peripheral arteries deseases with symptoms of the extremities ischemia, sleep disturbance, depression, dystonia, asthenic and cephalgic syndme in the frame of the cerebrovascular insufficiency manifestations. Therapy with lercanidpine, in addition to lowering blood pressure, can help to nephroprotection, neuroprotection, antianginal effect, the regression of left ventricular hypertrophy, improvement of lipid metabolism and glucose tolerance. With over 30 years experience in the application and modification of the molecular structure, slow the onset of action and superior long-lasting effect reception of letranidipine well-tolerated and provides a high adherence ofpatients to the treatment of hypertension.

A forskolin derivative, colforsin daropate hydrochloride, inhibits the decrease in cortical renal blood flow induced by noradrenaline or angiotensin II in anesthetized rats.

PubMed

Ogata, Junichi; Minami, Kouichiro; Segawa, Kayoko; Uezono, Yasuhito; Shiraishi, Munehiro; Yamamoto, Chikako; Sata, Takeyoshi; Sung-Teh, Kim; Shigematsu, Akio

2004-01-01

A forskolin derivative, colforsin daropate hydrochloride (CDH), acts directly on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate levels which produce a positive inotropic effect and a lower blood pressure. However, little is known about the effects of CDH on the renal function. We used laser Doppler flowmetry to measure the cortical renal blood flow (RBF) in male Wistar rats given a continuous intravenous infusion of CDH and evaluated the effects of CDH on the noradrenaline (NA) and angiotensin II (AngII) induced increases in blood pressure and reductions in RBF. Continuous intravenous administration of CDH at 0.25 microg/kg/min did not affect the mean arterial pressure (MAP), but increased heart rate and RBF. Continuous intravenous administration of CDH at high doses (0.5-0.75 microg/kg/min) decreased the MAP, with little effect on the RBF. The administration of exogenous NA (1.7 microg/kg) increased the MAP and decreased the RBF. However, a bolus injection of NA did not decrease the RBF during continuous intravenous administration of CDH, and CDH did not affect the NA-induced increase in MAP. The administration of exogenous AngII (100 ng/kg) increased MAP and decreased RBF and heart rate, but a bolus injection of AngII did not decrease RBF during continuous intravenous administration of CDH. These results suggest that CDH plays a protective role against the pressor effects and the decrease in RBF induced by NA or AngII. Copyright 2004 S. Karger AG, Basel

Cardiac transplantation: candidate identification, evaluation, and management.

PubMed

McCalmont, Vicki; Ohler, Linda

2008-01-01

For more than 40 years, cardiac transplantation has been a treatment option for patients with severe heart failure in whom optimal medical management is no longer effective. Critical care nurses are integrally involved in the care of patients with severe heart failure who may benefit from cardiac transplantation and are in a special position to recognize potential candidates for transplantation. Understanding patient selection criteria, the evaluation process, and how patients are managed while awaiting transplantation is key to the knowledge and skills required. It is also important to understand the allocation of donor hearts as part of this process. The waiting period for a suitable donor heart can be long and a patient's condition may deteriorate, requiring an increase in pharmacologic bridges with intravenous inotropic agents or mechanical bridges with circulatory assist devices. Critical care nurses become important as a personal bridge to transplantation through their education of patients and families and helping them cope with their fears during the waiting period. Critical care nurses who possess knowledge of patient selection and organ allocation processes along with the skills of caring for this complex patient population can contribute to better outcomes for patients with heart failure who may be candidates for cardiac transplantation.

Milrinone Dosing Issues in Critically Ill Children With Kidney Injury: A Review.

PubMed

Gist, Katja M; Goldstein, Stuart L; Joy, Melanie S; Vinks, Alexander A

2016-02-01

Milrinone is an inotropic drug used in a variety of clinical settings in adults and children. The efficacy of milrinone in pediatric low-cardiac output syndrome after cardiac surgery is reported. Its primary route of removal from the body is through the kidney as unchanged drug in the urine. Milrinone is not known to be efficiently removed by extracorporeal dialytic therapies and thus has the potential to cause serious adverse effects and potentially worsens renal function in patients experiencing acute kidney injury (AKI). AKI is an important public health issue that is associated with increased morbidity, mortality, and cost. It is a known risk factor for the development of chronic kidney disease. There are no specific therapies to mitigate AKI once it has developed, and interventions are focused on supportive care and dose adjustment of medications. Estimating glomerular filtration rate based on height and serum creatinine is the most commonly used clinical method for assessing kidney function and modification of medication doses. The purpose of this review is to discuss our current understanding of milrinone pharmacokinetics and pharmacodynamics in children with AKI and to describe the potential use of urinary biomarkers to guide therapeutic decision making for milrinone dosing.

Anoxia and Acidosis Tolerance of the Heart in an Air-Breathing Fish (Pangasianodon hypophthalmus).

PubMed

Joyce, William; Gesser, Hans; Bayley, Mark; Wang, Tobias

2015-01-01

Air breathing has evolved repeatedly in fishes and may protect the heart during stress. We investigated myocardial performance in the air-breathing catfish Pangasianodon hypophthalmus, a species that can withstand prolonged exposure to severe hypoxia and acidosis. Isometric ventricular preparations were exposed to anoxia, lactic acidosis, hypercapnic acidosis, and combinations of these treatments. Ventricular preparations were remarkably tolerant to anoxia, exhibiting an inotropic reduction of only 40%, which fully recovered during reoxygenation. Myocardial anoxia tolerance was unaffected by physiologically relevant elevations of bicarbonate concentration, in contrast to previous results in other fishes. Both lactic acidosis (5 mM; pH 7.10) and hypercapnic acidosis (10% CO2; pH 6.70) elicited a biphasic response, with an initial and transient decrease in force followed by overcompensation above control values. Spongy myocardial preparations were significantly more tolerant to hypercapnic acidosis than compact myocardial preparations. While ventricular preparations were tolerant to the isolated effects of anoxia and acidosis, their combination severely impaired myocardial performance and contraction kinetics. This suggests that air breathing may be a particularly important myocardial oxygen source during combined anoxia and acidosis, which may occur during exercise or environmental stress.

Chemical compositions and properties of Schinus areira L. essential oil on airway inflammation and cardiovascular system of mice and rabbits.

PubMed

Bigliani, María C; Rossetti, Víctor; Grondona, Ezequiel; Lo Presti, Silvina; Paglini, Patricia M; Rivero, Virginia; Zunino, María P; Ponce, Andrés A

2012-07-01

The main purpose was to investigate the effects of essential plant-oil of Schinus areira L. on hemodynamic functions in rabbits, as well as myocardial contractile strength and airways inflammation associated to bacterial endotoxin lipopolysaccharide (LPS) in mice. This study shows the important properties of the essential oil (EO) of S. areira studied and these actions on lung with significant inhibition associated to LPS, all of which was assessed in mice bronchoalveolar lavage fluid and evidenced by stability of the percentage of alveolar macrophages, infiltration of polymorphonuclear leukocytes and tumor necrosis factor-α concentration, and without pathway modifications in conjugated dienes activity. Clinical status (morbidity or mortality), macroscopic morphology and lung/body weight index were unaffected by the administration of the EO S. areira. Furthermore, the ex vivo analysis of isolated hearts demonstrated the negative inotropic action of the EO of S. areira in a mice model, and in rabbits changes in the hemodynamic parameters, such as a reduction of systolic blood pressure. We conclude that EO S. areira could be responsible for modifications on the cardiovascular and/or airway parameters. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Catecholamine therapy in cardiogenic shock: helpful, useless or dangerous?].

PubMed

Schwertz, H; Müller-Werdan, U; Prondzinsky, R; Werdan, K; Buerke, M

2004-09-10

Cardiogenic shock is characterized by inadequate organ and tissue perfusion, due to cardiac dysfunction, predominantly following acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain high, ranging from 50-70 % despite effective therapy. Rapid diagnostics, aggressive therapeutic approach (invasive or surgical revascularisation) and pharmacological support are currently used to improve the clinical outcome and survival. In the first line commonly sympathomimetics like dopamine, dobutamine, epinephrine and norepinephrine are used for the pharmacological treatment. They have a high affinity for alpha- and beta adrenergic receptors, leading to a positive inotropic cardiac function, an increase in heart rate, oxygen enhanced demand, and an increase in vasoconstriction. However, there are also some disadvantages in the use of sympathomimetics in patients with cardiogenic shock. Clearly, metabolic acidosis due to the increased oxygen demand can be observed. Vasoconstriction induced by sympathomimetics can lead to perfusion mismatch or even deficit within the microcirculation. Additionally, in some studies which give evidence that the use of sympathomimetics can directly lead to enhanced systemic inflammatory response due to an increased IL-6 expression. However, sympathomimetics are still first line therapeutics for treatment of cardiogenic shock -- with respect to dosage and duration of treatment.

Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRα.

PubMed

Fang, Changming; Filipp, Fabian V; Smith, Jeffrey W

2012-04-01

Ursodeoxycholic acid (UDCA, ursodiol) is used to prevent damage to the liver in patients with primary biliary cirrhosis. The drug also prevents the progression of colorectal cancer and the recurrence of high-grade colonic dysplasia. However, the molecular mechanism by which UDCA elicits its beneficial effects is not entirely understood. The aim of this study was to determine whether ileal bile acid binding protein (IBABP) has a role in mediating the effects of UDCA. We find that UDCA binds to a single site on IBABP and increases the affinity for major human bile acids at a second binding site. As UDCA occupies one of the bile acid binding sites on IBABP, it reduces the cooperative binding that is often observed for the major human bile acids. Furthermore, IBABP is necessary for the full activation of farnesoid X receptor α (FXRα) by bile acids, including UDCA. These observations suggest that IBABP may have a role in mediating some of the intestinal effects of UDCA.

Simultaneous effects of temperature and pressure on the donor binding energy in a V-groove quantum wire

NASA Astrophysics Data System (ADS)

Khordad, R.

2010-03-01

The influence of temperature and pressure, simultaneously, on the binding energy of a hydrogenic donor impurity in a ridge GaAs/Ga 1- xAl xAs quantum wire is studied using a variational procedure within the effective mass approximation. The subband energy and the binding energy of the donor impurity in its ground state as a function of the wire bend width and impurity location at different temperatures and pressures are calculated. The results show that, when the temperature increases, the donor binding energy decreases for a constant applied pressure for all wire bend widths. Also, the binding energy increases by increasing the pressure for a constant temperature for all wire bend widths. In addition, when the temperature and pressure are applied simultaneously the binding energy decreases as the quantum wire bend width increases. On the whole, it is deduced that the temperature and pressure have important effects on the donor binding energy in a V-groove quantum wire.

Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRα[S

PubMed Central

Fang, Changming; Filipp, Fabian V.; Smith, Jeffrey W.

2012-01-01

Ursodeoxycholic acid (UDCA, ursodiol) is used to prevent damage to the liver in patients with primary biliary cirrhosis. The drug also prevents the progression of colorectal cancer and the recurrence of high-grade colonic dysplasia. However, the molecular mechanism by which UDCA elicits its beneficial effects is not entirely understood. The aim of this study was to determine whether ileal bile acid binding protein (IBABP) has a role in mediating the effects of UDCA. We find that UDCA binds to a single site on IBABP and increases the affinity for major human bile acids at a second binding site. As UDCA occupies one of the bile acid binding sites on IBABP, it reduces the cooperative binding that is often observed for the major human bile acids. Furthermore, IBABP is necessary for the full activation of farnesoid X receptor α (FXRα) by bile acids, including UDCA. These observations suggest that IBABP may have a role in mediating some of the intestinal effects of UDCA. PMID:22223860

Rate constants for proteins binding to substrates with multiple binding sites using a generalized forward flux sampling expression

NASA Astrophysics Data System (ADS)

Vijaykumar, Adithya; ten Wolde, Pieter Rein; Bolhuis, Peter G.

2018-03-01

To predict the response of a biochemical system, knowledge of the intrinsic and effective rate constants of proteins is crucial. The experimentally accessible effective rate constant for association can be decomposed in a diffusion-limited rate at which proteins come into contact and an intrinsic association rate at which the proteins in contact truly bind. Reversely, when dissociating, bound proteins first separate into a contact pair with an intrinsic dissociation rate, before moving away by diffusion. While microscopic expressions exist that enable the calculation of the intrinsic and effective rate constants by conducting a single rare event simulation of the protein dissociation reaction, these expressions are only valid when the substrate has just one binding site. If the substrate has multiple binding sites, a bound enzyme can, besides dissociating into the bulk, also hop to another binding site. Calculating transition rate constants between multiple states with forward flux sampling requires a generalized rate expression. We present this expression here and use it to derive explicit expressions for all intrinsic and effective rate constants involving binding to multiple states, including rebinding. We illustrate our approach by computing the intrinsic and effective association, dissociation, and hopping rate constants for a system in which a patchy particle model enzyme binds to a substrate with two binding sites. We find that these rate constants increase as a function of the rotational diffusion constant of the particles. The hopping rate constant decreases as a function of the distance between the binding sites. Finally, we find that blocking one of the binding sites enhances both association and dissociation rate constants. Our approach and results are important for understanding and modeling association reactions in enzyme-substrate systems and other patchy particle systems and open the way for large multiscale simulations of such systems.

The Glycine Synaptic Receptor: Evidence That Strychnine Binding Is Associated with the Ionic Conductance Mechanism

PubMed Central

Young, Anne B.; Snyder, Solomon H.

1974-01-01

The ability of a series of anions to inhibit [3H]strychnine binding to spinal cord synaptic membranes correlates closely with their neurophysiologic capacity to reverse inhibitory postsynaptic potentials in the mammalian spinal cord. Seven neurophysiologically active anions are also effective inhibitors of [3H]strychnine binding with mean effective doses ranging from 160 to 620 mM. Seven other anions that are ineffective neurophysiologically also fail to alter strychnine binding. Chloride inhibits strychnine binding in a noncompetitive fashion. Hill plots of the displacement of [3H]strychnine by chloride give coefficients of 2.3-2.7. The inhibition of strychnine binding by these anions suggests that strychnine binding is closely associated with the ionic conductance mechanism for chloride in the glycine receptor. PMID:4372600

Aspects of Protein, Chemistry, Part II: Oxygen-Binding Proteins

ERIC Educational Resources Information Center

Nixon, J. E.

1977-01-01

Compares differences in function and behavior of two oxygen-binding proteins, myoglobin found in muscle and hemoglobin found in blood. Describes the mechanism of oxygen-binding and allosteric effect in hemoglobin; also describes the effect of pH on the affinity of hemoglobin for oxygen. (CS)

Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

PubMed

Foti, M; Omichinski, J G; Stahl, S; Maloney, D; West, J; Schweitzer, B I

1999-02-05

We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.

Arousal-Enhanced Location Memory for Pictures

PubMed Central

Mather, Mara; Nesmith, Kathryn

2008-01-01

Four experiments revealed arousal-enhanced location memory for pictures. After an incidental encoding task, participants were more likely to remember the locations of positive and negative arousing pictures than the locations of non-arousing pictures, indicating better binding of location to picture. This arousal-enhanced binding effect did not have a cost for the binding of nearby pictures to their locations. Thus, arousal can enhance binding of an arousing picture’s content to its location without interfering with picture-location binding for nearby pictures. In addition, arousal-enhanced picture-location memory binding is not just a side effect of enhanced memory for the picture itself, as it occurs both when recognition memory is good and when it is poor. PMID:19190722

Selective enrichment of metal-binding proteins based on magnetic core/shell microspheres functionalized with metal cations.

PubMed

Fang, Caiyun; Zhang, Lei; Zhang, Xiaoqin; Lu, Haojie

2015-06-21

Metal binding proteins play many important roles in a broad range of biological processes. Characterization of metal binding proteins is important for understanding their structure and biological functions, thus leading to a clear understanding of metal associated diseases. The present study is the first to investigate the effectiveness of magnetic microspheres functionalized with metal cations (Ca(2+), Cu(2+), Zn(2+) and Fe(3+)) as the absorbent matrix in IMAC technology to enrich metal containing/binding proteins. The putative metal binding proteins in rat liver were then globally characterized by using this strategy which is very easy to handle and can capture a number of metal binding proteins effectively. In total, 185 putative metal binding proteins were identified from rat liver including some known less abundant and membrane-bound metal binding proteins such as Plcg1, Acsl5, etc. The identified proteins are involved in many important processes including binding, catalytic activity, translation elongation factor activity, electron carrier activity, and so on.

Effects of ionic compositions of the medium on monosodium glutamate binding to taste epithelial cells.

PubMed

Hayashi, Y; Tsunenari, T; Mori, T

1999-03-01

Monosodium glutamate and nucleotides are umami taste substances in animals and have a synergistic effect on each other. We studied the ligand-binding properties of the glutamate receptors in taste epithelial cells isolated from bovine tongue. Specific glutamate binding was observed in an enriched suspension of taste receptor cells in Hanks' balanced salt solution, while no specific glutamate binding was apparent in the absence of divalent ions or when the cells had been depolarized by a high content of potassium in Hanks' balanced salt solution. There was no significant difference between the release of glutamate under depolarized or divalent ion-free conditions and under normal conditions. However, glutamate was easily released from the depolarized cells in the absence of divalent ions. These data suggest that the binding of glutamate to receptors depends on divalent ions, which also have an effect on maintaining binding between glutamate and receptors.

Minimized virus binding for tests of barrier materials.

PubMed Central

Lytle, C D; Routson, L B

1995-01-01

Viruses are used to test the barrier properties of materials. Binding of virus particles during passage through holes in the material may yield misleading test results. The choices of challenge virus and suspending medium may be important for minimizing confounding effects that might arise from such binding. In this study, different surrogate viruses, as well as different support media, were evaluated to determine optimal test parameters. Two membranes with high-binding properties (nitrocellulose and cationic polysulfone) were used as filters to compare binding activities of different surrogate challenge viruses (MS2, phi X174, T7, PRD1, and phi 6) in different media. The media consisted of buffered saline with surfactants, serum, or culture broth as additives. In addition, elution rates of viruses that bound to the membranes were determined. The results suggest that viruses can bind by hydrophobic and electrostatic interactions, with phi X174 displaying the lowest level of binding by either process. The nonionic detergents Triton X-100 and Tween 80 (0.1%) equally minimized hydrophobic interactions. Neither anionic nor cationic surfactants were as effective at nontoxic levels. Serum was effective at reducing both hydrophobic and electrostatic binding, with 2% being sufficient for eliminating binding under our test conditions. Thus, phi X174 remains the best choice as a surrogate virus to test barrier materials, and Triton X-100 (0.1%) remains a good choice for reducing hydrophobic binding. In addition, binding of viruses by barrier materials is unlikely to prevent passage of blood-borne pathogens. PMID:7574603

Retinoid Pathway and Cancer Therapeutics

PubMed Central

Bushue, Nathan; Wan, Yu-Jui Yvonne

2010-01-01

The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid × receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with the emphasis on the application of retinoids in cancer treatment and prevention. PMID:20654663

Identification of new 2,5-diketopiperazine derivatives as simultaneous effective inhibitors of αβ-tubulin and BCRP proteins: Molecular docking, Structure-Activity Relationships and virtual consensus docking studies

NASA Astrophysics Data System (ADS)

Fani, Najmeh; Sattarinezhad, Elham; Bordbar, Abdol-Khalegh

2017-06-01

In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure-activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity.

Myotropic Effects of Cholinergic Muscarinic Agonists and Antagonists in the Beetle Tenebrio molitor L.

PubMed

Chowanski, Szymon; Rosinski, Grzegorz

2017-01-01

In mammals, the cholinergic nervous system plays a crucial role in neuronal regulation of physiological processes. It acts on cells by two types of receptors - nicotinic and muscarinic receptors. Both signal transmission pathways also operate in the central and peripheral cholinergic nervous system of insects. In our pharmacological experiments, we studied the effects of two muscarinic agonists (carbachol, pilocarpine) and two muscarinic antagonists (atropine, scopolamine) on the muscle contractile activity of visceral organs in the beetle, Tenebrio molitor. Both antagonists, when injected to haemolymph at concentration 10-5 M, caused delayed and prolonged cardioinhibitory effects on heart contractility in ortho- and antidromic phases of heart activity in T. molitor pupa what was observed as negative chrono- and inotropic effects. Agonist of muscarinic receptors - carbachol evoked opposite effect and increased contraction rate but only in antidromic phase. Pilocarpine, the second agonist induced weak negative chronotropic effects in the antiand orthodromic phases of heart activity. However, neither agonists had an effect on semi-isolated beetle heart in vitro. Only atropine at the highest tested concentrations slightly decreased the frequency of myocardial contractions. These suggest the regulation of heart activity by muscarinic system indirectly. The tested compounds also affected the contractility of the oviduct and hindgut, but the responses of these organs were varied and depended on the concentration of the applied compounds. These pharmacological experiments suggest the possible modulation of insect visceral muscle contractility by the cholinergic nervous system and indirectly indicate the presence of muscarinic receptor(s) in the visceral organs of the beetle T. molitor. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development of a Fluorescence Assay for the Characterization of Brevenal Binding to Rat Brain Synaptosomes

PubMed Central

2015-01-01

The marine dinoflagellate Karenia brevis produces a family of neurotoxins known as brevetoxins. Brevetoxins elicit their effects by binding to and activating voltage-sensitive sodium channels (VSSCs) in cell membranes. K. brevis also produces brevenal, a brevetoxin antagonist, which is able to inhibit and/or negate many of the detrimental effects of brevetoxins. Brevenal binding to VSSCs has yet to be fully characterized, in part due to the difficulty and expense of current techniques. In this study, we have developed a novel fluorescence binding assay for the brevenal binding site. Several fluorescent compounds were conjugated to brevenal to assess their effects on brevenal binding. The assay was validated against the radioligand assay for the brevenal binding site and yielded comparable equilibrium inhibition constants. The fluorescence-based assay was shown to be quicker and far less expensive and did not generate radioactive waste or need facilities for handling radioactive materials. In-depth studies using the brevenal conjugates showed that, while brevenal conjugates do bind to a binding site in the VSSC protein complex, they are not displaced by known VSSC site specific ligands. As such, brevenal elicits its action through a novel mechanism and/or currently unknown receptor site on VSSCs. PMID:25226846

Physiological and pharmacological features of the novel gasotransmitter: Hydrogen sulfide

PubMed Central

Mancardi, Daniele; Penna, Claudia; Merlino, Annalisa; Del Soldato, Piero; Wink, David A.; Pagliaro, Pasquale

2012-01-01

Hydrogen sulfide (H2S) has been known for hundreds of years because of its poisoning effect. Once the basal bio-production became evident its pathophysiological role started to be investigated in depth. H2S is a gas that can be formed by the action of two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, both involved in the metabolism of cysteine. It has several features in common with the other two well known “gasotransmitters” (nitric oxide and carbon monoxide) in the biological systems. These three gasses share some biological targets; however, they also have dissimilarities. For instance, the three gases target heme-proteins and open KATP channels; H2S as NO is an antioxidant, but in contrast to the latter molecule, H2S does not directly form radicals. In the last years H2S has been implicated in several physiological and pathophysiological processes such as long term synaptic potentiation, vasorelaxation, pro- and anti-inflammatory conditions, cardiac inotropism regulation, cardioprotection, and several other physiological mechanisms. We will focus on the biological role of H2S as a molecule able to trigger cell signaling. Our attention will be particularly devoted on the effects in cardiovascular system and in cardioprotection. We will also provide available information on H2S-donating drugs which have so far been tested in order to conjugate the beneficial effect of H2S with other pharmaceutical properties. PMID:19285949

Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension

PubMed Central

Yoshiyuki, Rieko; Tanaka, Ryo; Fukushima, Ryuji; Machida, Noboru

2016-01-01

The present study aimed to evaluate the preventive effect of sildenafil treatment on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. Fifty-four 12-week-old male Sprague–Dawley rats were injected with MCT or saline solution (MCT-injected rats: n=36; saline: n=18). Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed at 2, 4 and 6 weeks after the injection. After injection of MCT, rats received oral sildenafil (MCT/sildenafil group: n=18) or no treatment (MCT group: n=18) until undergoing echocardiography and cardiac catheterization. RVSP in the MCT/sildenafil group was lower than that in the MCT group at 4 (P<0.001) and 6 weeks (P<0.001). The septal curvature was improved in the MCT/sildenafil group compared with the MCT group. This finding showed that sildenafil prevented flattening of the interventricular septum because of right ventricular pressure overload. The ratio of peak trans-tricuspid early diastolic wave velocity to active filling with atrial systolic velocity showed that sildenafil improved diastolic function. Tricuspid annular plane systolic excursion and tricuspid annular systolic velocity in the MCT/sildenafil group did not show preserved myocardial contraction after administration of sildenafil. Administration of sildenafil leads to a reduction in RVSP and improvement in cardiac function in rats with PH induced by MCT. The vasodilatory action of sildenafil improves right ventricular diastolic function, but the intrinsic, positive, inotropic effect of sildenafil is minimal. PMID:26876436

Severe ranitidine-induced anaphylaxis: a case report and literature review.

PubMed

Aouam, K; Bouida, W; Ben Fredj, N; Chaabane, A; Boubaker, H; Boukef, R; Boughattas, N A; Nouira, S

2012-08-01

Ranitidine is a generally well-tolerated drug, and serious side effects are rare. However, ranitidine-induced anaphylaxis has been reported on rare occasions. We report on such a case and review other cases reported in the literature. A 36-year-old man with no history of other medications, illnesses or allergic diseases, especially to drugs, consulted our emergency department because of renal colic and epigastric discomfort. He was given 50 mg of ranitidine as a slow intravenous bolus and 20 mg of piroxicam intramuscularly. Within the first minute, the patient developed a cold sweat, trembling, dyspnoea and deterioration of his consciousness. The condition was considered as an anaphylactic shock, and cardiopulmonary resuscitation and inotropic support were immediately commenced. Two days later, he was weaned off the ventilator as he was haemodynamically stable. He was discharged after 7 days. Four weeks later, skin prick tests to ranitidine and piroxicam were performed on the forearm of the patient. He reacted strongly to ranitidine about 10 min later but not to piroxicam. To assess cross-reactivity to other H2- and H1-receptor antagonists in our patient, we subsequently performed prick tests to famotidine, cimetidine and desloratadine and all were negative. We re-emphasize a potentially serious, albeit very rare, adverse effect of ranitidine and summarize other reported cases. This case demonstrates that commonly used, generally safe drugs may on occasions cause serious adverse effects. © 2011 Blackwell Publishing Ltd.

Insecticide imidacloprid influences cognitive functions and alters learning performance and related gene expression in a rat model.

PubMed

Kara, Murat; Yumrutas, Onder; Demir, Caner F; Ozdemir, Hasan Huseyin; Bozgeyik, Ibrahim; Coskun, Salih; Eraslan, Ersen; Bal, Ramazan

2015-10-01

The potential toxic effects of several pesticides, including imidacloprid on non-target organisms have not been clearly established. Also, the chronic effects of non-toxic doses on cognitive function in mammals are unknown. In this study, the effects of different doses of imidacloprid on learning and memory of infant and adult rats were evaluated, and the expressions of genes synthesizing proteins known to be associated with learning in brain tissues were also documented. 0.5, 2 and 8 mg/kg doses of imidacloprid were administered to newborn infant and adult Wistar albino rats by gavage. Their learning activities were evaluated, and the expression levels of the inotropic glutamate receptor GRIN1, synoptophysin, growth-associated protein 43 and the muscarinic receptor M1 in hippocampus were determined by real-time PCR method. Learning activities were diminished significantly at 2 and 8 mg/kg doses in the infant model groups and at 8 mg/kg dose in adult rats. Also, expression levels of GRIN1, SYP and GAP-43 were found to be insignificantly altered. Only the expression of M1 were significantly changed in high doses of adult group. Thus imidacloprid in high doses causes deterioration in cognitive functions particularly in infant rats, and this deterioration may be associated with changes in the expressions of related genes. © 2015 The Authors. International Journal of Experimental Pathology © 2015 International Journal of Experimental Pathology.

High-mobility group (HMG) protein HMG-1 and TATA-binding protein-associated factor TAF(II)30 affect estrogen receptor-mediated transcriptional activation.

PubMed

Verrier, C S; Roodi, N; Yee, C J; Bailey, L R; Jensen, R A; Bustin, M; Parl, F F

1997-07-01

The estrogen receptor (ER) belongs to a family of ligand-inducible nuclear receptors that exert their effects by binding to cis-acting DNA elements in the regulatory region of target genes. The detailed mechanisms by which ER interacts with the estrogen response element (ERE) and affects transcription still remain to be elucidated. To study the ER-ERE interaction and transcription initiation, we employed purified recombinant ER expressed in both the baculovirus-Sf9 and his-tagged bacterial systems. The effect of high-mobility group (HMG) protein HMG-1 and purified recombinant TATA-binding protein-associated factor TAF(II)30 on ER-ERE binding and transcription initiation were assessed by electrophoretic mobility shift assay and in vitro transcription from an ERE-containing template (pERE2LovTATA), respectively. We find that purified, recombinant ER fails to bind to ERE in spite of high ligand-binding activity and electrophoretic and immunological properties identical to ER in MCF-7 breast cancer cells. HMG-1 interacts with ER and promotes ER-ERE binding in a concentration- and time-dependent manner. The effectiveness of HMG-1 to stimulate ER-ERE binding in the electrophoretic mobility shift assay depends on the sequence flanking the ERE consensus as well as the position of the latter in the oligonucleotide. We find that TAF(II)30 has no effect on ER-ERE binding either alone or in combination with ER and HMG-1. Although HMG-1 promotes ER-ERE binding, it fails to stimulate transcription initiation either in the presence or absence of hormone. In contrast, TAF(II)30, while not affecting ER-ERE binding, stimulates transcription initiation 20-fold in the presence of HMG-1. These results indicate that HMG-1 and TAF(II)30 act in sequence, the former acting to promote ER-ERE binding followed by the latter to stimulate transcription initiation.

Ventricular ectopy in patients with left ventricular dysfunction: should it be treated?

PubMed

Chen, Taibo; Koene, Ryan; Benditt, David G; Lü, Fei

2013-01-01

Ventricular premature complexes (VPCs) are commonly encountered in patients with congestive heart failure (CHF). Frequent ventricular ectopy can be associated with deterioration of cardiac function and may lead to VPC-induced cardiomyopathy. VPC-induced inter- and/or intraventricular dyssynchrony has been postulated as the main mechanism underlying VPC-induced left ventricular dysfunction. For risk stratification, VPCs in the setting of CHF can not be regarded to be a benign arrhythmia as in an apparently healthy subject. However, any potential survival benefits to be derived from suppression of VPCs or nonsustained ventricular tachycardia in CHF may be offset by the negative inotropic and proarrhythmic effects of antiarrhythmic drugs and may be masked by the risk of death that is already high in this subgroup of patients. β-Blockers are currently considered to be the first-line therapy, with amiodarone as a back-up. Catheter ablation, although invasive and not without procedural risk, avoids the common adverse effects of currently available antiarrhythmic medications. From a standpoint of preventing or reversing left ventricular dysfunction, frequent VPCs should be treated earlier regardless of their site of origin or the presence of associated symptoms, such as palpitations. Catheter ablation may be the preferable approach in selected patients, particularly when β-blocker therapy has been ineffective or not tolerated. Copyright © 2013 Elsevier Inc. All rights reserved.

Dissection of the Effects of Quercetin on Mouse Myocardium.

PubMed

Santos, Michel Santana; Oliveira, Evaleide Diniz; Santos-Miranda, Artur; Cruz, Jader Santos; Gondim, Antônio Nei Santana; Menezes-Filho, José Evaldo Rodrigues; Souza, Diego Santos; Pinho-da-Silva, Leidiane; Jesus, Itamar Couto Guedes; Roman-Campos, Danilo; Guatimosim, Silvia; Lara, Aline; Conde-Garcia, Eduardo Antônio; Vasconcelos, Carla Maria Lins

2017-06-01

Quercetin is a plant flavonoid with several biological activities. This study aimed to describe quercetin effects on contractile and electrophysiological properties of the cardiac muscle as well as on calcium handling. Quercetin elicited positive inotropism that was significantly reduced by propranolol indicating an involvement of the sympathetic nervous system. In cardiomyocytes, 30 μM quercetin increased I Ca,L at 0 mV from -0.95 ± 0.01 A/F to -1.21 ± 0.08 A/F. The membrane potential at which 50% of the channels are activated (V 0.5 ) shifted towards more negative potentials from -13.06 ± 1.52 mV to -19.26 ± 1.72 mV and did not alter the slope factor. Furthermore, quercetin increased [Ca 2+ ] i transient by 28% when compared to control. Quercetin accelerated [Ca 2+ ] i transient decay time, which could be attributed to SERCA activation. In resting cardiomyocytes, quercetin did not change amplitude or frequency of Ca 2+ sparks. In isolated heart, quercetin increased heart rate and decreased PRi, QTc and duration of the QRS complex. Thus, we showed that quercetin activates β-adrenoceptors, leading to increased L-type Ca 2+ current and cell-wide intracellular Ca 2+ transient without visible changes in Ca 2+ sparks. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Short term effects of milrinone on biomarkers of necrosis, apoptosis, and inflammation in patients with severe heart failure

PubMed Central

Lanfear, David E; Hasan, Reema; Gupta, Ramesh C; Williams, Celeste; Czerska, Barbara; Tita, Cristina; Bazari, Rasha; Sabbah, Hani N

2009-01-01

Introduction Inotropes are associated with adverse outcomes in heart failure (HF), raising concern they may accelerate myocardial injury. Whether biomarkers of myocardial necrosis, inflammation and apoptosis change in response to acute milrinone administration is not well established. Methods Ten patients with severe HF and reduced cardiac output who were to receive milrinone were studied. Blood samples were taken just before initiation of milrinone and after 24 hours of infusion. Dosing was at the discretion of the patient's attending physician (range 0.25–0.5 mcg/kg/min). Plasma measurements of troponin, myoglobin, N-terminal-pro-BNP, interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand were performed at both time points. Results Troponin was elevated at baseline in all patients (mean 0.1259 ± 0.17 ng/ml), but there was no significant change after 24 hours of milrinone (mean 0.1345 ± 0.16 ng/ml, p = 0.44). There were significant improvements in interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand (all p < 0.05) indicative of reduced inflammatory and apoptotic signaling compared to baseline. Conclusion In conclusion, among patients with severe HF and low cardiac output, ongoing myocardial injury is common, and initiation of milrinone did not result in exacerbation of myocardial injury but instead was associated with salutary effects on other biomarkers. PMID:19640280

The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism.

PubMed

Reiffel, James A; Camm, A John; Belardinelli, Luiz; Zeng, Dewan; Karwatowska-Prokopczuk, Ewa; Olmsted, Ann; Zareba, Wojciech; Rosero, Spencer; Kowey, Peter

2015-10-01

Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety. HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone's negative inotropic effect-see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated. HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled. ClinicalTrials.gov; Unique identifier: NCT01522651. © 2015 American Heart Association, Inc.

Effect of intraoperative dobutamine on splanchnic tissue perfusion and outcome after Whipple surgery.

PubMed

Reyad, Amal Rashad; Elkharboutly, Walaa; Wahba, Ashraf; Elmorshedi, Mohamed; Hasaneen, Nadia A

2013-08-01

Splanchnic hypoperfusion during abdominal surgery contributes to postoperative gut sepsis and mortality. Dobutamine is an inotrope with vasodilator properties that improve hepatosplanchnic perfusion. The aim of this study was to examine the effect of intraoperative dobutamine infusion during Whipple surgery on splanchnic perfusion, hemodynamic, and overall postoperative outcome. Sixty patients were randomly allocated to receive intraoperatively (3 μg/kg per minute or 5 μg/kg per minute) doses of dobutamine or saline. Baseline measurements included hemodynamic parameters, gastric tonometric parameters, and arterial and mixed venous gases. These patients had a follow-up for development for in-hospital morbidity and mortality. Intraoperative use of dobutamine increased oxygen-derived parameters as evidenced by increased mixed venous oxygen saturation. Tonometered gastric mucosal pH, a surrogate for splanchnic perfusion, increased in patients who received intraoperative dobutamine. Patients in the dobutamine groups demonstrated significant higher heart rates, premature ventricular contraction arrhythmias, and electrocardiographic signs of ischemia. Mean arterial blood pressure demonstrated no significant difference among groups. The overall incidence of postoperative complications was higher in control group 70 % vs 20% to 40% in dobutamine groups. Intraoperative use of dobutamine improved global oxygen delivery, splanchnic perfusion, and postoperative outcome after Whipple surgery. These findings may be of clinical importance when the therapeutic goal is to improve gut perfusion. Copyright © 2013 Elsevier Inc. All rights reserved.

The effectiveness of prestorage leukocyte-reduced red blood cell transfusion on perioperative inflammatory response with a miniaturized biocompatible bypass system.

PubMed

Miyaji, Kagami; Miyamoto, Takashi; Kohira, Satoshi; Itatani, Kei-ichi; Tomoyasu, Takahiro; Sato, Hajime; Ohara, Kuniyoshi

2010-06-01

Since 2007, the Japanese Red Cross Blood Center has provided prestorage leukocyte-reduced red blood cell concentrates in which the leukocytes were reduced soon after collection. We have established a miniaturized bypass system (140 mL) to reduce the perioperative inflammatory responses. This study was designed to reveal the effectiveness of leukocyte-reduced red blood cell concentrate transfusion on perioperative inflammatory responses in pediatric cardiac surgery. Between May 2006 and June 2008, 50 consecutive patients weighing less than 5 kg who underwent a surgical procedure with red blood cell concentrate transfusion using a miniaturized bypass system were reviewed retrospectively. Twenty-five patients before 2007 received stored red blood cell concentrate in which leukocytes were reduced with a filter just before transfusion (group A). After 2007, 25 patients received the prestorage leukocyte-reduced red blood cell concentrate transfusion (group B). The postoperative peak C-reactive protein level, peak white blood cell count, peak neutrophil count, percentage body weight gain, inotrope score, plasma lactate concentration, postoperative mechanical ventilation time, and length of intensive care unit stay were compared as the perioperative inflammatory response and morbidity for both groups. There were no significant differences in peak white blood cell count, peak neutrophil count, percentage body weight gain, and inotrope score between the groups. The peak C-reactive protein level in group A was significantly greater than that in group B (6.7 +/- 4.7 vs 4.2 +/- 3.6 mg/dL, P < .05). The lactate concentration at 12 and 24 hours after surgical intervention in group A was significantly greater than that in group B (3.1 +/- 2.5 vs 1.9 +/- 1.1 mmol/L [P < .05] and 2.2 +/- 0.2 vs 1.4 +/- 0.2 mmol/L [P < .05], respectively). The postoperative mechanical ventilation time and intensive care unit stay in group A were significantly greater than those in group B (5.9 +/- 7.4 vs 2.1 +/- 2.0 days [P < .05] and 9.8 +/- 7.9 vs 5.0 +/- 2.1 days [P < 0.05], respectively). Multivariate analyses showed that the leukocyte-reduced red blood cell concentrate transfusion reduced the peak C-reactive protein level (in milligrams per deciliter; coefficient, -2.95; 95% confidence interval [CI], -4.66 to -0.93; P = .003), postoperative mechanical ventilation time (in days; coefficient, -3.41; 95% CI, -6.07 to -0.74; P = .013), and intensive care unit stay (in days; coefficient, -4.51; 95% CI, -7.37 to -1.64; P = .003). Our study revealed that in neonates and small infants, compared with transfusions with stored red blood cell concentrate, transfusion of leukocyte-reduced red blood cell concentrates was associated with reduced perioperative inflammatory responses and improved clinical outcomes. Copyright 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor.

PubMed

Matulis, Daumantas; Kranz, James K; Salemme, F Raymond; Todd, Matthew J

2005-04-05

ThermoFluor (a miniaturized high-throughput protein stability assay) was used to analyze the linkage between protein thermal stability and ligand binding. Equilibrium binding ligands increase protein thermal stability by an amount proportional to the concentration and affinity of the ligand. Binding constants (K(b)) were measured by examining the systematic effect of ligand concentration on protein stability. The precise ligand effects depend on the thermodynamics of protein stability: in particular, the unfolding enthalpy. An extension of current theoretical treatments was developed for tight binding inhibitors, where ligand effect on T(m) can also reveal binding stoichiometry. A thermodynamic analysis of carbonic anhydrase by differential scanning calorimetry (DSC) enabled a dissection of the Gibbs free energy of stability into enthalpic and entropic components. Under certain conditions, thermal stability increased by over 30 degrees C; the heat capacity of protein unfolding was estimated from the dependence of calorimetric enthalpy on T(m). The binding affinity of six sulfonamide inhibitors to two isozymes (human type 1 and bovine type 2) was analyzed by both ThermoFluor and isothermal titration calorimetry (ITC), resulting in a good correlation in the rank ordering of ligand affinity. This combined investigation by ThermoFluor, ITC, and DSC provides a detailed picture of the linkage between ligand binding and protein stability. The systematic effect of ligands on stability is shown to be a general tool to measure affinity.

"Rigor mortis" in a live patient.

PubMed

Chakravarthy, Murali

2010-03-01

Rigor mortis is conventionally a postmortem change. Its occurrence suggests that death has occurred at least a few hours ago. The authors report a case of "Rigor Mortis" in a live patient after cardiac surgery. The likely factors that may have predisposed such premortem muscle stiffening in the reported patient are, intense low cardiac output status, use of unusually high dose of inotropic and vasopressor agents and likely sepsis. Such an event may be of importance while determining the time of death in individuals such as described in the report. It may also suggest requirement of careful examination of patients with muscle stiffening prior to declaration of death. This report is being published to point out the likely controversies that might arise out of muscle stiffening, which should not always be termed rigor mortis and/ or postmortem.

Severe bradycardia and prolonged hypotension in ciguatera.

PubMed

Chan, Thomas Yan Keung

2013-06-01

Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed.

Fatal Primary Capillary Leak Syndrome in a Late Preterm Newborn.

PubMed

Kulihova, Katarina; Prochazkova, Martina; Semberova, Jana; Janota, Jan

2016-10-01

Primary capillary leak syndrome is a rare disease of unknown etiology, characterized by episodes of vascular collapse and plasma extravasation, which may lead to multiple organ failure. Primary capillary leak is extremely rare in children. The authors report a case of a late preterm newborn with fatal capillary leak syndrome of unknown etiology, manifesting as hypotension unresponsive to treatment, extravasation leading to generalised edema, disseminated intravascular coagulation and finally, multiple organ dysfunction syndrome. Aggressive volumotherapy and a combination of inotropes and high doses of terlipressin did not influence systemic vascular collapse and plasma extravasation. The newborn developed multiple organ failure and died on day 27 of life. Investigations performed failed to reveal any specific cause of capillary leak. This is the first report of a fatal primary capillary leak syndrome in a newborn.

Case Report: Bilateral reexpansion pulmonary edema following treatment of a unilateral hemothorax

PubMed Central

de Wolf, Steven P; Deunk, Jaap; Cornet, Alexander D; Elbers, Paul WG

2014-01-01

Bilateral re-expansion pulmonary edema (RPE) is an extremely rare entity. We report the unique case of bilateral RPE following a traumatic, unilateral hemopneumothorax in a young healthy male. Bilateral RPE occurred only one hour after drainage of a unilateral hemopneumothorax. The patient was treated with diuretics and supplemental oxygen. Diagnosis was confirmed by excluding other causes, using laboratory findings, chest radiography, pulmonary and cardiac ultrasound and high resolution computed tomography. His recovery was uneventful. The pathophysiology of bilateral RPE is not well known. Treatment is mainly supportive and consists of diuretics, mechanical ventilation, inotropes and steroids. In case of a pulmonary deterioration after the drainage of a traumatic pneumothorax, bilateral RPE should be considered after exclusion of more common causes of dyspnea. PMID:25713699

The role of Pyruvate Dehydrogenase Complex in cardiovascular diseases.

PubMed

Sun, Wanqing; Liu, Quan; Leng, Jiyan; Zheng, Yang; Li, Ji

2015-01-15

The regulation of mammalian myocardial carbohydrate metabolism is complex; many factors such as arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue play a role in regulating mammalian myocardial carbohydrate metabolism. The Pyruvate Dehydrogenase Complex (PDHc), a mitochondrial matrix multienzyme complex, plays an important role in energy homeostasis in the heart by providing the link between glycolysis and the tricarboxylic acid (TCA) cycle. In TCA cycle, PDHc catalyzes the conversion of pyruvate into acetyl-CoA. This review determines that there is altered cardiac glucose in various pathophysiological states consequently causing PDC to be altered. This review further summarizes evidence for the metabolism mechanism of the heart under normal and pathological conditions including ischemia, diabetes, hypertrophy and heart failure. Copyright © 2014 Elsevier Inc. All rights reserved.

The Gratton effect remains after controlling for contingencies and stimulus repetitions

PubMed Central

Blais, Chris; Stefanidi, Aikaterini; Brewer, Gene A.

2014-01-01

Highlights: The conflict monitoring hypothesis signals the need for cognitive controlThe Gratton effect is a key result attributed to the conflict monitoring hypothesisSome argue that controlling binding confounds eliminates the Gratton effect A Gratton effect remains in a vocal Stroop task after eliminating confounds The Gratton effect, the observation that the size of the Stroop effect is larger following a congruent trial compared to an incongruent trial, is one pivotal observation in support of the conflict-monitoring hypothesis. Previous reports have demonstrated that non-conflict components, such as feature binding, also contribute to this effect. Critically, Schmidt and De Houwer (2011) report a flanker task and a button-press Stroop task suggesting that there is no conflict adaptation in the Gratton effect; it is entirely caused by feature binding. The current investigation attempts to replicate and extend this important finding across two experiments using a canonical four-choice Stroop task with vocal responses. In contrast to Schmidt and De Houwer, we observe reliable conflict adaptation after controlling for feature binding. We argue that the overall strength of conflict is critical for determining whether a conflict adaptation component will remain in the Gratton effect after explaining binding components. PMID:25386151

Oligomycin frames a common drug-binding site in the ATP synthase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Symersky, Jindrich; Osowski, Daniel; Walters, D. Eric

We report the high-resolution (1.9 {angstrom}) crystal structure of oligomycin bound to the subunit c10 ring of the yeast mitochondrial ATP synthase. Oligomycin binds to the surface of the c10 ring making contact with two neighboring molecules at a position that explains the inhibitory effect on ATP synthesis. The carboxyl side chain of Glu59, which is essential for proton translocation, forms an H-bond with oligomycin via a bridging water molecule but is otherwise shielded from the aqueous environment. The remaining contacts between oligomycin and subunit c are primarily hydrophobic. The amino acid residues that form the oligomycin-binding site are 100%more » conserved between human and yeast but are widely different from those in bacterial homologs, thus explaining the differential sensitivity to oligomycin. Prior genetics studies suggest that the oligomycin-binding site overlaps with the binding site of other antibiotics, including those effective against Mycobacterium tuberculosis, and thereby frames a common 'drug-binding site.' We anticipate that this drug-binding site will serve as an effective target for new antibiotics developed by rational design.« less

An investigation on the effect of impurity position on the binding energy of quantum box under electric field with pressure and temperature

NASA Astrophysics Data System (ADS)

Yilmaz, S.; Kirak, M.

2018-05-01

In the present study, we have studied theoretically the influences of donor impurity position on the binding energy of a GaAs cubic quantum box structure. The binding energy is calculated as functions of the position of impurity, electric field, temperature and hydrostatic pressure. The variational method is employed to obtain the energy eigenvalues of the structure in the framework of the effective mass approximation. It has been found that the impurity positions with electric field, pressure and temperature have an important effect on the binding energy of structure considered. The results can be used to manufacture semiconductor device application by manipulating the binding energy with the impurity positions, electric field, pressure and temperature.

Allosteric Effect of Adenosine Triphosphate on Peptide Recognition by 3'5'-Cyclic Adenosine Monophosphate Dependent Protein Kinase Catalytic Subunits.

PubMed

Kivi, Rait; Solovjova, Karina; Haljasorg, Tõiv; Arukuusk, Piret; Järv, Jaak

2016-12-01

The allosteric influence of adenosine triphosphate (ATP) on the binding effectiveness of a series of peptide inhibitors with the catalytic subunit of 3'5'-cyclic adenosine monophosphate dependent protein kinase was investigated, and the dependence of this effect on peptide structure was analyzed. The allosteric effect was calculated as ratio of peptide binding effectiveness with the enzyme-ATP complex and with the free enzyme, quantified by the competitive inhibition of the enzyme in the presence of ATP excess, and by the enzyme-peptide complex denaturation assay, respectively It was found that the principle "better binding-stronger allostery" holds for interactions of the studied peptides with the enzyme, indicating that allostery and peptide binding with the free enzyme are governed by the same specificity pattern. This means that the allosteric regulation does not include new ligand-protein interactions, but changes the intensity (strength) of the interatomic forces that govern the complex formation in the case of each individual ligand. We propose that the allosteric regulation can be explained by the alteration of the intrinsic dynamics of the protein by ligand binding, and that this phenomenon, in turn, modulates the ligand off-rate from its binding site as well as the binding affinity. The positive allostery could therefore be induced by a reduction in the enzyme's overall intrinsic dynamics.

Ethylene Receptor 1 (ETR1) Is Sufficient and Has the Predominant Role in Mediating Inhibition of Ethylene Responses by Silver in Arabidopsis thaliana*

PubMed Central

McDaniel, Brittany K.; Binder, Brad M.

2012-01-01

Ethylene influences many processes in Arabidopsis thaliana through the action of five receptor isoforms. All five isoforms use copper as a cofactor for binding ethylene. Previous research showed that silver can substitute for copper as a cofactor for ethylene binding activity in the ETR1 ethylene receptor yet also inhibit ethylene responses in plants. End-point and rapid kinetic analyses of dark-grown seedling growth revealed that the effects of silver are mostly dependent upon ETR1, and ETR1 alone is sufficient for the effects of silver. Ethylene responses in etr1-6 etr2-3 ein4-4 triple mutants were not blocked by silver. Transformation of these triple mutants with cDNA for each receptor isoform under the promoter control of ETR1 revealed that the cETR1 transgene completely rescued responses to silver while the cETR2 transgene failed to rescue these responses. The other three isoforms partially rescued responses to silver. Ethylene binding assays on the binding domains of the five receptor isoforms expressed in yeast showed that silver supports ethylene binding to ETR1 and ERS1 but not the other isoforms. Thus, silver may have an effect on ethylene signaling outside of the ethylene binding pocket of the receptors. Ethylene binding to ETR1 with silver was ∼30% of binding with copper. However, alterations in the Kd for ethylene binding to ETR1 and the half-time of ethylene dissociation from ETR1 do not underlie this lower binding. Thus, it is likely that the lower ethylene binding activity of ETR1 with silver is due to fewer ethylene binding sites generated with silver versus copper. PMID:22692214

Distinct roles of beta1 metal ion-dependent adhesion site (MIDAS), adjacent to MIDAS (ADMIDAS), and ligand-associated metal-binding site (LIMBS) cation-binding sites in ligand recognition by integrin alpha2beta1.

PubMed

Valdramidou, Dimitra; Humphries, Martin J; Mould, A Paul

2008-11-21

Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

Effect of exercise, heat stress and dehydration on myocardial performance.

PubMed

Fehling, P C; Haller, J M; Lefferts, W K; Hultquist, E M; Wharton, M; Rowland, T W; Smith, D L

2015-06-01

Myocardial dysfunction is a well-documented outcome of extended periods of high cardiac output. Whether similar effects occur during firefighting, an occupation characterized by repeated periods of work compounded by dehydration and heat stress, is uncertain. To investigate the independent and combined effects of moderate heat stress and dehydration on indicators of myocardial performance following intermittent, submaximal treadmill exercise while wearing personal protective equipment (PPE). Twelve aerobically fit young men (age 21.5±2.6 years; maximal oxygen uptake [VO2max] 60.3±4.4ml kg(-1) min(-1)) performed intermittent treadmill walking exercise consisting of three 20min bouts at an intensity of ~40% VO2max separated by two periods of rest in four different conditions in random order: (i) no heat stress-euhydrated, (ii) heat stress-euhydrated (heat stress created by wearing PPE, (iii) no heat stress-dehydrated and (iv) heat stress-dehydrated. We measured core temperature by a telemetric gastrointestinal pill. We determined cardiac variables by standard echocardiographic techniques immediately before and ~30min after exercise. We recorded no significant changes in markers of systolic (ejection fraction, shortening fraction, tissue Doppler-S) or diastolic (mitral peak E velocity, tissue Doppler-E' and E/E') function following exercise in any of the four conditions. In this model of exercise designed to mimic the work, heat stress and dehydration associated with firefighting activities, we observed no negative effects on myocardial inotropic or lusitropic function. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.