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Sample records for nicardipine

  1. Cardiovascular pharmacology of nicardipine in animals

    PubMed Central

    Takenaka, T.; Asano, M.; Shiono, K.; Shibasaki, M.; Inagaki, O.

    1985-01-01

    1 The haemodynamic, antianginal and antihypertensive effects of nicardipine, a vascular selective calcium antagonist, were studied in experimental animals. 2 In the canine isolated coronary artery, nicardipine relaxed potassium-induced contraction and suppressed 3,4-diaminopyridine-induced rhythmic contractions more effectively than nifedipine, verapamil or diltiazem. 3 In anaesthetised rats, nicardipine prevented the elevation of ST segment induced by intracoronary injection of methacholine. 4 In anaesthetised dogs, nicardipine produced a greater vasodilatation in vertebral, carotid, and coronary vessels than in mesenteric, femoral, and renal vessels and did not affect myocardial oxygen consumption. 5 In conscious monkeys, nicardipine given intravenously lowered blood pressure and gave rise to reflex tachycardia but did not prolong the A-V conduction time. 6 Nicardipine given orally lowered blood pressure in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), and deoxycorticosterone acetate/salt hypertensive rats (DOCA/Salt), as well as in normotensive rats. 7 Long-term treatment with nicardipine given orally for 12 weeks effectively lowered high blood pressure in the three types of hypertensive rats, reduced cardiac hypertrophy in SHR and DOCA/Salt rats, and prevented mortality from stroke in DOCA/Salt rats. Combined treatment with nicardipine and a β-adrenoceptor blocking agent (indenolol) showed an antihypertensive effect similar to that obtained with nicardipine alone. 8 Conscious renal hypertensive dogs given repeated oral administration of nicardipine for 14 days did not develop tolerance to the hypotensive activity of nicardipine. Under the same conditions, tolerance to hydralazine developed within 4 days. PMID:4027153

  2. Nicardipine

    MedlinePlus

    ... vessels so the heart does not have to pump as hard. It controls chest pain by increasing ... medications such as beta-blockers, digoxin (Lanoxin), diuretics ('water pills'), and quinidine ; phenytoin (Dilantin); ranitidine (Zantac); theophylline ( ...

  3. Nicardipine and verapamil in essential hypertension

    PubMed Central

    Al-Khawaja, I. M.; Caruana, M. P.; Lahiri, A.; Whittington, J. R.; Lewis, J. G.; Raftery, E. B.

    1986-01-01

    1 Nicardipine 30 mg three times daily and verapamil 160 mg twice daily have been compared in 30 patients with essential hypertension using a two-period crossover clinical trial with 6 week treatment periods. 2 Blood pressure, heart rate and radionuclide left ventricular function were measured before and after exercise on both treatments. In addition to ejection fraction and ejection time, the left ventricular pressure volume ratio (P/V ratio) and left ventricular circumferential fibre shortening (VcF) were determined from the radionuclide scans. 3 Two patients were withdrawn from the trial during each of the treatment periods because of possible side-effects of therapy. Three patients were not analysed because of early crossover due to side-effects, leaving 23 completed studies. 4 Both treatments resulted in similar reductions in blood pressure, which were statistically significant with respect to the placebo-treated baseline. There was a significant difference between the effect of the two treatments on heart rate; both at rest and peak exercise, verapamil produced significant falls in heart rate but nicardipine produced little change. Neither treatment altered exercise capacity. 5 Both treatments produced similar increases in resting ejection fraction. Nicardipine resulted in a small decrease in ejection time and verapamil in a small increase (P < 0.001 between treatments). 6 Neither treatment produced significant change in resting P/V ratio. However, VcF improved significantly with nicradipine but was virtually unchanged with verapamil. 7 Nicardipine has a similar hypotensive efficacy to that of verapamil, but may be safer in the treatment of patients with depressed or compromised cardiac function.

  4. Myocardial protection by intracoronary nicardipine administration during percutaneous transluminal coronary angioplasty.

    PubMed

    Hanet, C; Rousseau, M F; Vincent, M F; Lavenne-Pardonge, E; Pouleur, H

    1987-05-01

    To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.

  5. Enantioselective high-performance liquid chromatographic determination of nicardipine in human plasma.

    PubMed

    Uno, T; Ohkubo, T; Sugawara, K

    1997-09-26

    A sensitive method for the enantioselective high-performance liquid chromatography (HPLC) determination of nicardipine in human plasma is described. (+)-Nicardipine, (-)-nicardipine and (+)-barnidipine as an internal standard are detected by an ultraviolet detector at 254 nm. Racemic nicardipine in human plasma was extracted by a rapid and simple procedure based on C18 bonded-phase extraction. The extraction samples were purified and concentrated on a pre-column using a C1 stationary phase and the enantiomers of nicardipine are quantitatively separated by HPLC on a Sumichiral OA-4500 column, containing a chemically modified Pirkle-type stationary phase. Determination of (+)- and (-)-nicardipine was possible in a concentration range of 5-100 ng ml(-1) and the limit of detection in plasma was 2.5 ng ml(-1). The recoveries of (+)- and (-)-nicardipine added to plasma were 91.4-98.4% and 93.3-96.7%, respectively, with coefficients of variation of less than 9.0 and 9.4% respectively. The method was applied to low level monitoring of (+)- and (-)-nicardipine in plasma from healthy volunteers.

  6. The Influence of Verapamil and Nicardipine on the Rate of Metabolism of Midazolam

    DTIC Science & Technology

    2000-10-01

    and vasodilation, verapamil and nicardipine are different in respect to structure and major effects. Verapamil is a non- dihydropyridine with strong...negative ionotropic and chronotropic properties. Nicardipine a dihydropyridine , on the other hand has greater effects upon vasodilation than on

  7. Effectiveness of Nicardipine for Blood Pressure Control in Patients with Subarachnoid Hemorrhage

    PubMed Central

    Kim, Sang Yong; Kim, Seong Min; Park, Moon Sun; Kim, Han Kyu; Park, Ki Seok

    2012-01-01

    Objective The purpose of the study is to determine the effectiveness and safety of nicardipine infusion for controlling blood pressure in patients with subarachnoid hemorrhage (SAH). Methods We prospectively evaluated 52 patients with SAH and treated with nicardipine infusion for blood pressure control in a 29 months period. The mean blood pressure of pre-injection, bolus injection and continuous injection period were compared. This study evaluated the effectiveness of nicardipine for each Fisher grade, for different dose of continuous nicardipine infusion, and for the subgroups of systolic blood pressure. Results The blood pressure measurement showed that the mean systolic blood pressure / diastolic blood pressure (SBP/DBP) in continuous injection period (120.9/63.0 mmHg) was significantly lower than pre-injection period (145.6/80.3 mmHg) and bolus injection period (134.2/71.3 mmHg), and these were statistically significant (p < 0.001). In each subgroups of Fisher grade and different dose, SBP/DBP also decreased after the use of nicardipine. These were statistically significant (p < 0.05), but there was no significant difference in effectiveness between subgroups (p > 0.05). Furthermore, controlling blood pressure was more effective when injecting higher dose of nicardipine in higher SBP group rather than injecting lower dose in lower SBP group, and it also was statistically significant (p < 0.05). During the infusion, hypotension and cardiogenic problems were transiently combined in five cases. However, patients recovered without any complications. Conclusion Nicardipine is an effective and safe agent for controlling acutely elevated blood pressure after SAH. A more systemic study with larger patients population will provide significant results and will bring solid evidence on effectiveness of nicardipine in SAH. PMID:23210033

  8. Sodium cromoglycate, verapamil and nicardipine antagonism to leukotriene D4 bronchoconstriction.

    PubMed Central

    Advenier, C.; Cerrina, J.; Duroux, P.; Floch, A.; Pradel, J.; Renier, A.

    1983-01-01

    1--The effects of nicardipine, verapamil and sodium cromoglycate (SCG) on the increase in pulmonary airway resistance(RAw) and decrease in pulmonary dynamic compliance (CDyn) induced by leukotriene D4 (LTD4) 0.5 micrograms kg-1 and acetylcholine (ACh) 3 micrograms kg-1 were investigated in anaesthetized guinea-pigs. The effects of these three agents on the contractile effects of LTD4 and ACh were tested on isolated tracheal preparations of the guinea-pig. 2--Nicardipine and verapamil (0.3 and 1 mg kg-1), as well as SCG (3 and 10 mg kg-1), partially but significantly inhibited the effects of LTD4 on RAw. Partial inhibition of the effect of LTD4 on CDyn was only observed with verapamil (0.3 and 1 mg kg-1). Nicardipine and verapamil had no effect on ACh-induced bronchoconstriction in vivo. 3--In concentrations higher than 10(-5) M, nicardipine and verapamil inhibited the contractile effects of LTD4 and ACh on guinea-pig isolated trachea. SCG had no effect on this preparation. 4--These results suggest that nicardipine, verapamil and SCG partially reduce the component of bronchoconstriction associated with stimulation of irritant receptors by LTD4. However, the site and mechanism of action of Ca2+-entry antagonists remain uncertain. PMID:6403095

  9. Acute vasoreactivity testing with nicardipine in patients with pulmonary arterial hypertension.

    PubMed

    Saito, Yukihiro; Nakamura, Kazufumi; Miyaji, Katsumasa; Akagi, Satoshi; Mizoguchi, Hiroki; Ogawa, Aiko; Fuke, Soichiro; Fujio, Hideki; Kiyooka, Takahiko; Nagase, Satoshi; Kohno, Kunihisa; Morita, Hiroshi; Kusano, Kengo F; Matsubara, Hiromi; Ohe, Tohru; Ito, Hiroshi

    2012-01-01

    Acute vasoreactivity testing for patients with pulmonary arterial hypertension (PAH) has been reported to be useful to identify patients with sustained beneficial response to oral calcium-channel blockers (CCBs), but there is a risk of exacerbation during the testing with oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine, a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testing with nicardipine in PAH patients. Acute vasoreactivity testing with nicardipine was performed in 65 PAH patients. Nicardipine was administered by short-time continuous infusion (1 μg·kg⁻¹·min⁻¹ for 5 min and 2 μg·kg⁻¹·min⁻¹ for 5 min) followed by bolus injection (5 μg/kg). Hemodynamic responses were continuously measured using a right heart catheter. Acute responders were defined as patients who showed a decrease in mean pulmonary artery pressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved or increased cardiac output. Two acute responders and sixty-three non-acute responders were identified. There was no hemodynamic instability requiring additional inotropic agents or death during the testing. Acute responders had good responses to long-term oral CCBs. The acute vasoreactivity testing with nicardipine might be safe and useful for identifying CCB responders in PAH patients.

  10. Comparative efficacy of nicardipine hydrochloride and atenolol in the treatment of chronic stable angina

    PubMed Central

    Logan, R. L.; Ikram, H.; Webster, M. W.; Guppy, W.

    1986-01-01

    1 The efficacy and safety of nicardipine, 30 mg three times a day, were compared with atenolol, 100 mg once daily in a randomised, double-blind, 11-week, crossover study of 46 patients with stable angina pectoris. 2 Both drugs significantly decreased the frequency of angina and improved total exercise time, time to angina, and time to 1 mm ST-segment depression. No statistically significant differences were observed between nicardipine and atenolol in clinical responses or treadmill performance. 3 At maximum workload, the double product decreased significantly in patients taking atenolol and did not change in those using nicardipine. 4 During treatment with atenolol, statistically significant decreases were observed in heart rate and QTc interval; these parameters increased minimally on nicardipine. 5 The incidence and severity of adverse experiences associated with each treatment were similar and did not interfere with the study. The two major adverse experiences, myocardial infarction and sudden death, occurred only in patients receiving atenolol. 6 Nicardipine therapy compared favourably with atenolol therapy in patients with angina pectoris.

  11. Treatment with nicardipine protects brain in an animal model of hypertension-induced damage.

    PubMed

    Amenta, Francesco; Tomassoni, Daniele

    2004-05-01

    Control of blood pressure protects from the development of cerebrovascular lesions and vascular dementia (VaD). This study has assessed the influence of treatment with the dihydropyridine-type Ca2+ antagonist nicardipine on brain microanatomical changes in spontaneously hypertensive rats (SHR). SHR were treated from 16th to 26th week of age with hypotensive (3 mg/Kg/day) or non-hypotensive (0.1 mg/Kg/day) doses of nicardipine, with the non-dihydropyridine-type vasodilator hydralazine (10 mg/kg/day) or with vehicle (control group). Untreated age-matched Wistar Kyoto (WKY) rats were used as a normotensive reference group. Brain volume, number of neurons, glial fibrillary-acidic protein (GFAP)-immunoreactive astrocytes and neurofilament 200 KDa (NFP)-immunoreactivity (IR) were assessed in frontal and occipital cortex, hippocampus and striatum. A decrease of volume and number of nerve cells and a loss of NFP-IR was found in the frontal and occipital cortex and in the CA1 subfield of hippocampus and in the striatum of SHR. Treatment with nicardipine countered microanatomical changes occurring in SHR, whereas hydralazine displayed a less pronounced effect. Comparatively, the non-hypotensive dose of nicardipine was less active than the hypotensive one. The observation that equihypotensive doses of nicardipine or hydralazine did not protect brain in the same way from hypertensive brain damage suggests that lowering blood pressure is per se not enough for affording neuroprotection. The demonstration of neuroprotective effect of nicardipine suggests an use of the compound in situations in which hypertension is accompanied by the risk of brain damage.

  12. The effect of nicardipine on the surgical pleth index during thyroidectomy under general anesthesia

    PubMed Central

    Won, Young Ju; Lim, Byung Gun; Yeo, Gwi Eun; Lee, Min Ki; Lee, Dong Kyu; Kim, Heezoo; Lee, Il Ok; Kong, Myoung Hoon

    2017-01-01

    Abstract Background: The effectiveness of surgical pleth index (SPI) for managing nociception-antinociception balance during general anesthesia with vasodilators, including nicardipine has not been demonstrated. We aimed to compare the time course during surgery in SPI values in patients receiving nicardipine or remifentanil infusion during thyroidectomy. Methods: Forty patients undergoing thyroidectomy were randomly assigned to receive nicardipine (group N; n = 19) or remifentanil (group R; n = 21) along with induction (propofol, fentanyl, and rocuronium) and maintenance (50% desflurane/nitrous oxide in oxygen) anesthesia (goal bispectral index [BIS] ∼50). The infusion of nicardipine or remifentanil was started before the 1st incision and adjusted to keep mean blood pressure (MBP) within ±20% of the preoperative value. SPI, BIS, end-tidal desflurane concentration (EtDes), MBP, and heart rate were recorded at 2.5 minute intervals from the 1st incision to the end of surgery. Extubation and recovery times, pain score/rescue ketorolac consumption, and adverse events in postanesthesia care unit (PACU) were recorded. Results: The trend of SPI during surgery was comparable between the 2 groups (P = 0.804), although the heart rates in group N were significantly higher than those in group R (P = 0.040). The patient characteristics, trends of BIS, EtDes, and MBP during surgery, extubation and recovery times, and incidence of nausea/vomiting were comparable between the groups. Group N had significantly lower pain scores and rescue ketorolac consumption at PACU. Conclusion: SPI was comparable between patients receiving nicardipine or remifentanil infusion during thyroidectomy under general anesthesia, which suggests that the administration of nicardipine may confound the interpretation of SPI values during general anesthesia. Clinical trial registration: This trial was registered in the UMIN clinical trials registry (unique trial number: UMIN000019058

  13. Direct inhibitory effect of nicardipine on basolateral K+ channels in human colonic crypts.

    PubMed

    Sandle, G I; Butterfield, I; Higgs, N B; Warhurst, G

    1999-03-01

    The most abundant basolateral K+ channels in human colonic crypt cells have a low conductance (23 pS), respond to increases in intracellular Ca2+ and cAMP, and have been implicated in intestinal electrogenic Cl- secretion. The effect of nicardipine on the activity of these K+ channels was examined by patch-clamp recording in the cell-attached and excised inside-out configurations from the basolateral membrane of single crypts isolated from biopsied samples of human distal colon. During cell-attached recordings, addition of 2 micromol/l nicardipine to crypts pretreated with 200 micromol/l dibutyryl cAMP decreased single-channel open probability by 87%, but in parallel studies nicardipine had no effect on the intracellular Ca2+ concentration. Using inside-out patches from crypts pretreated with dibutyryl cAMP (bathed in 1.2 mmol/l Ca2+), the addition of increasing concentrations of nicardipine (200 nmol/l, 2 micromol/l and 20 micromol/l) decreased single-channel open probability in a concentration-dependent manner (IC50 0.47 micromol/l). In additional experiments using stripped rat distal colonic mucosa mounted in conventional Ussing chambers, serosal addition of nicardipine at increasing concentrations (ranging from 200 nmol/l to 20 micromol/l) produced a concentration-dependent inhibition of dibutyryl-cAMP-stimulated electrogenic Cl- secretion (IC50 2 micromol/l). Taken together, these results indicate that nicardipine has a direct inhibitory action on 23-pS basolateral K+ channels in human intestinal crypt cells, which is likely to decrease cAMP-stimulated electrogenic Cl- secretion. These basolateral K+ channels may provide a focal point for the development of new strategies in the treatment of secretory diarrhoeal diseases.

  14. Protective effect of nicardipine treatment on cerebrovascular microanatomical changes in spontaneously hypertensive rats.

    PubMed

    Amenta, F; Ferrante, F; Ricci, A; Sabbatini, M

    1995-12-01

    1. The effect of long-term treatment with the dihydropyridine Ca2+ antagonist, nicardipine, on the morphology of different sized pial arteries was assessed in spontaneously hypertensive rats (SHR) using histological techniques associated with image analysis. 2. In control 20 week old SHR blood pressure values, the thickness of the tunica media, the media-to-lumen ratio and connective tissue content were significantly increased in comparison with reference normotensive Wistar-Kyoto (WKY) rats. 3. Treatment for 8 weeks with a daily dose of 3 mg/kg of nicardipine decreased blood pressure values in SHR and significantly reduced the area occupied by the tunica media and the media-to-lumen ratio. This effect was observed primarily in small sized pial arteries and to a lesser extent in medium sized pial arteries. Nicardipine administration was without effect on connective tissue content in the wall of cerebral arteries. 4. These results indicate that treatment with nicardipine reduces blood pressure elevation in SHR and exerts a protective effect on arteries controlling cerebrovascular resistance. The activity of the compound primarily on small sized pial arteries may protect the brain from generalized vasodilation which could cause cerebral hypoperfusion.

  15. The effect of acute and chronic nicardipine therapy on forearm arterial haemodynamics in essential hypertension

    PubMed Central

    Levenson, J.; Simon, A. Ch.; Bouthier, J.; Maarek, B. C.; Safar, M. E.

    1985-01-01

    1 By using simultaneous recording curves obtained with pulsed Doppler velocimetry and strain gauge mechanography, forearm arterial haemodynamics were studied in 26 patients with mild to moderate essential hypertension. Fifteen patients received a single oral dose of nicardipine 40 mg, and 11 patients were treated with nicardipine 30 mg three times daily for 3 months. 2 In both groups of patients there was a similar and significant (P < 0.001) reduction in mean, systolic, and diastolic pressures. There was a slight increase in heart rate (P < 0.05) after the single dose, but no change after 3 months of treatment. 3 The diameter, blood velocity, and blood flow of the brachial artery increased significantly in both treatment groups. The decrease in forearm vascular resistance was significant for both treatment groups. 4 Brachial artery compliance increased (P < 0.01) and characteristic impedance decreased (P < 0.01) after both single-dose and long-term therapy with nicardipine. 5 In patients who received nicardipine for 3 months, there were close correlations between the baseline serum calcium level and the percent change in vascular resistance (r = -0.73, P < 0.01), blood flow (r = 0.89, P < 0.001), and blood velocity (r = 0.91. P < 0.001) of the forearm. No correlation was found between the baseline serum calcium and the change in arterial pressure. 6 This study provided evidence that the blood-pressure-lowering effect of nicardipine was accompanied by a direct vasodilatory action in the small and large arteries of the forearm. An increase in peripheral blood flow with concomitant improvement of arterial compliance are the consequences of these arterial actions. PMID:4027144

  16. A radioreceptor assay for determination of nicardipine in human serum using 3H(+)PN 200-110 as radioligand

    SciTech Connect

    Gerbeau, C.; Barradas, J. )

    1990-01-01

    A radioreceptor assay for the determination of nicardipine in human serum using the active enantiomer 3H(+)PN 200-110 as radioligand is described. The assay is simple to perform, of low cost and requires only a small volume of serum. The standard curve permits measurements in the range 2.5 to 320 nM nicardipine (i.e. 1.2 to 153 ng/ml). The precision and the reproducibility of the method, evaluated from two different concentrations: 120 and 12 nM, show coefficients of variation for within and between assays, of 6% and 15% and 6% and 9%, respectively. Concentrations of nicardipine from 3 ng/ml could be measured with a satisfactory precision. The performances of the method permit the determination of nicardipine concentrations reached after therapeutic administration. Other dihydropyridine calcium channel antagonists may be measured using this assay if these compounds are used to generate the standard curves.

  17. Nicardipine-Induced Acute Pulmonary Edema: A Rare but Severe Complication of Tocolysis

    PubMed Central

    Serena, Claire; Begot, Emmanuelle; Cros, Jérôme; Hodler, Charles; Fedou, Anne Laure; Nathan-Denizot, Nathalie; Clavel, Marc

    2014-01-01

    We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative. PMID:25215245

  18. Nicardipine-induced acute pulmonary edema: a rare but severe complication of tocolysis.

    PubMed

    Serena, Claire; Begot, Emmanuelle; Cros, Jérôme; Hodler, Charles; Fedou, Anne Laure; Nathan-Denizot, Nathalie; Clavel, Marc

    2014-01-01

    We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative.

  19. Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris.

    PubMed

    Rousseau, M F; Vincent, M F; Cheron, P; van den Berghe, G; Charlier, A A; Pouleur, H

    1985-01-01

    The effects of intravenous nicardipine (2.5 mg) on the left ventricular (LV) inotropic state, LV metabolism, and coronary haemodynamics were analysed in 22 patients with angina pectoris. Measurements were made at fixed heart rate (atrial pacing), under basal state, and during a cold pressor test. After nicardipine, coronary blood flow and oxygen content in the coronary sinus increased significantly. The indices of inotropic state increased slightly, and the rate of isovolumic LV pressure fall improved. Myocardial oxygen consumption was unchanged despite the significant reduction in pressure-rate product, but LV lactate uptake increased, particularly during the cold pressor test. When nicardipine was administered after propranolol, the indices of inotropic state were unaffected. The lack of direct effect of nicardipine on LV inotropic state was further confirmed by intracoronary injection of 0.1 and 0.2 mg in a separate group of 10 patients. It is concluded that the nicardipine-induced coronary dilatation seems to improve perfusion and aerobic metabolism in areas with chronic ischaemia, resulting in reduced lactate production and augmented oxygen consumption.

  20. [Acute pulmonary edema occurred during tocolytic treatment using nicardipine in a twin pregnancy. Report of three cases].

    PubMed

    Philippe, H-J; Le Trong, A; Pigeau, H; Demeure, D; Desjars, P; Esbelin, J; Caroit, Y; Winer, N

    2009-02-01

    We report three cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in twin pregnancy patients with no previous heart problems. The three patients were admitted into our unit on account of the risk of premature birth after 29 to 32 weeks of amenorrhea. The treatment by intravenous tocolysis using nicardipine combined with glucocorticoids therapy had been undertaken in the previous maternity ward. The three patients presented symptoms of acute dyspnea 48 hours after the beginning of the treatment. Paraclinical examinations eliminated the diagnosis of pulmonary embolism. The patients'condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. There are currently few studies proving the benefits of nicardipine in tocolysis treatment. Few similar cases of acute pulmonary edema have been noted in twin pregnancy patients treated with nicardipine. Haemodynamic modifications specific to twin pregnancy, intravenous hydratation and glucocorticoid maturation may explain a part of this complication. Therefore, it is appropriated to limit the use of intravenous nicardipine in the sole indication of tocolysis in twin pregnancy, and to prefer the use of nifedipine and atosiban, that have proven their effectiveness in this indication.

  1. Systemic Nicardipine as an Adjunct to Combat Vasospasm after Prior Flap Failure

    PubMed Central

    Rajjoub, Samer; Johnson, T. Shane

    2013-01-01

    Summary: Unrecognized or untreated vasospasm in microsurgery can lead to flap hypoperfusion and failure. Numerous strategies have been explored for their efficacy in potentiating vasodilation. We present a case of unrecognized vasospasm leading to flap failure followed by a second free flap reconstruction in which severe vasospasm was treated with systemic nicardipine used as an adjunct to other more commonly employed antispasmodics. Although the literature investigating the use of systemic calcium channel blockade in microsurgery is limited, it should be considered an alternative when addressing arterial vasospasm. PMID:25289249

  2. Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells.

    PubMed

    Ochi, Masanori; Kawai, Yoshiko; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-02-01

    Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 μg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 μg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 μg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3-methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury.

  3. Formulation and evaluation of sustained release floating capsules of nicardipine hydrochloride.

    PubMed

    Moursy, N M; Afifi, N N; Ghorab, D M; El-Saharty, Y

    2003-01-01

    Nicardipine hydrochloride, a calcium channel blocker with significant vasodilating and antihypertensive activities, was formulated in this work as sustained release floating capsules. A hydrocolloid of high viscosity grade was used for the floating systems. The inclusion of sodium bicarbonate to allow evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release were included as coprecipitates with the drug and/or as additives in the formulated capsules. Both simple powder mixing of the ingredients and granule preparation via wet granulation were used. Seven capsule formulae were prepared. The prepared capsules were evaluated in vitro by testing drug dissolution, floating time and the kinetics of drug release. In vitro evaluation of a commercially available conventional 20 mg capsule of nicardipine hydrochloride, "Micard", was carried out for comparison. The hydrocolloid used succeeded in effecting capsule buoyancy. Floating time increased with increasing the proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. All of the seven floating capsule formulae prepared proved efficient in controlling drug release. The sustained release floating capsule formulation of choice was evaluated in vivo in comparison to "Micard" capsules using rabbits. Reversed phase HPLC with UV detection was used for drug determination in rabbit plasma. Plasma concentration time curves revealed a longer drug duration for administration in the sustained release formula than the conventional "Micard" capsule being 16 h in the former versus 8 h for the latter.

  4. Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination.

    PubMed Central

    Laurent-Kenesi, M A; Funck-Brentano, C; Poirier, J M; Decolin, D; Jaillon, P

    1993-01-01

    1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine

  5. Effects of nicardipine and nisoldipine on myocardial metabolism, coronary blood flow and oxygen supply in angina pectoris.

    PubMed

    Rousseau, M F; Vincent, M F; Van Hoof, F; Van den Berghe, G; Charlier, A A; Pouleur, H

    1984-12-01

    The effects of the calcium antagonists nicardipine and nisoldipine on left ventricular (LV) metabolism were analyzed in 32 patients with angina pectoris. Measurements were made at a fixed heart rate under the basal state and during a cold pressor test (CPT). After administration of the drugs, coronary blood flow increased significantly and the mean aortic pressure decreased by 10% (p less than 0.01) in the basal state and by 11% (p less than 0.01) during CPT. Despite the reduction in pressure-rate product, myocardial oxygen consumption was unchanged in the basal state (18 +/- 4 vs 19 +/- 4 ml/min, difference not significant) and during CPT (21 +/- 5 vs 21 +/- 5 ml/min, difference not significant); this discrepancy between a reduced pressure-rate product and an unchanged oxygen consumption was also noted when nicardipine was given after propranolol (0.1 mg/kg; 12 patients). Both agents also increased LV lactate uptake, particularly during CPT (+13 mumol/min, p less than 0.05 vs control CPT) and reduced LV glutamine production. In 10 patients in whom 14C-lactate was infused, the chemical LV lactate extraction ratio increased more than the 14C-lactate extraction ratio after administration of the drugs, indicating a reduction in LV lactate production. The data are consistent with the hypothesis that nicardipine and nisoldipine improve perfusion and aerobic metabolism in chronically ischemic areas, resulting in an augmented oxygen consumption and in a reduced lactate production.

  6. Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement.

    PubMed

    Aboofazeli, Reza; Zia, Hossein; Needham, Thomas E

    2002-01-01

    Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the

  7. Drug-induced vasodilation in an in vitro and in vivo study: the effects of nicardipine, papaverine, and lidocaine on the rabbit carotid artery.

    PubMed

    Evans, G R; Gherardini, G; Gürlek, A; Langstein, H; Joly, G A; Cromeens, D M; Sukumaran, A V; Williams, J; Kilbourn, R G; Wang, B; Lundeberg, T

    1997-11-01

    Extreme arterial vasoconstriction (vasospasm) is a common problem encountered in microvascular surgery. An ideal pharmacologic tool able to counteract ischemia during microsurgery should be easy to apply and exert its action both locally and distally in the microcirculation of the flap. We have compared in vitro and in vivo vascular properties of nicardipine, papaverine, and lidocaine in the rabbit carotid artery. In vitro, rings from the rabbit carotid artery (n = 7) were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7 to 4.2 g. The specimens were contracted with norepinephrine (1 microM), and a cumulative dose response curve was established. In vivo, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 35 animals using 9-0 nylon suture and standard microsurgical techniques. During and after the anastomoses, nicardipine (0.1, 0.01 mg topical, or 0.1 mg/hour IV), papaverine (30 mg/cc topical), and lidocaine (2% with and without epinephrine) were applied (blinded) at the anastomotic site in five rabbits each. Heparinized sodium chloride was used as topical irrigation for control and to clean the anastomosis. Blood flow changes were monitored continuously with the transonic Doppler for 30 minutes after the procedure. The systemic blood pressure was also monitored in a group of pilot experiments. A documented decrease in blood flow was noted in all animals after the microvascular anastomosis. Nicardipine and papaverine evoked a concentration-dependent relaxation to precontracted rings to norepinephrine. Nicardipine was greater than papaverine in inducing relaxation. Lidocaine demonstrated a biphasic response with low concentrations potentiating contraction. Systemic nicardipine and papaverine significantly increased the blood flow in the rabbit carotid artery. Topical application of nicardipine and lidocaine did not significantly alter the blood flow; however, the application of nicardipine

  8. Influence of long-term treatment with the dihydropyridine-type calcium antagonist nicardipine on renal microanatomical changes in spontaneously hypertensive rats.

    PubMed

    Amenta, F; Abbate, F; Cavallotti, C; Ciriaco, E; Ferrante, F; Sabbatini, M

    1995-12-01

    1. The influence of hypertension and treatment with the dihydropyridine-type Ca2+ antagonist, nicardipine, on the structure of the kidney was assessed in spontaneously hypertensive rats (SHR) of 12 weeks of age. Treatment went for 8 weeks with a daily oral dose of 1 mg/kg of nicardipine. 2. Control SHR exhibited hypertension and microanatomical vascular and glomerular changes. Vascular changes consisted of a thickening of the tunica media and decreased luminal area of medium- and small-sized intrarenal artery branches. Glomerular changes included glomerulosclerosis and atrophy of varying degrees. 3. Administration of nicardipine significantly reduced blood pressure. The drug also decreased the thickening of tunica media and luminal narrowing of renal artery branches as well as the degree of glomerular injury in SHR. 4. These data indicate that nicardipine treatment is able to control elevated blood pressure in SHR, and to counter hypertension-dependent microanatomical impairment of the kidney. This suggests that the compound exerts a protective effect on hypertensive kidney.

  9. Quantitative determination of amorphous nicardipine hydrochloride in long acting formula (NIC-LA) using light anhydrous silicic acid.

    PubMed

    Kohinata, Takeru; Fujii, Mitsuo; Nakamura, Souichiro; Hamada, Noritaka; Yonemochi, Etsuo; Terada, Katsuhide

    2004-12-01

    We investigated a method to quantitatively determine amorphous nicardipine hydrochloride (NIC) in the NIC-long acting formula (LA) model formulas prepared using NIC, light anhydrous silicic acid (LASA) and carboxymethylethylcellulose (CMEC). Consequently, since the quantity of total NIC in the formula can be determined by means of HPLC and crystal NIC can be determined by the differential scanning calorimetry (DSC) method because the heat of fusion (85.08 J/g) of NIC is constant and unaffected by excipients, we developed the HPLC-DSC method by which the quantity of amorphous NIC is calculated as the difference between the quantity of total NIC determined by HPLC and the quantity of crystal NIC determined by DSC. This practical HPLC-DSC method was confirmed to have good accuracy and reproducibility.

  10. A nicardipine-sensitive Ca2+ entry contributes to the hypotonicity-induced increase in [Ca2+]i of principal cells in rat cortical collecting duct.

    PubMed

    Komagiri, You; Nakamura, Kazuyoshi; Kubokawa, Manabu

    2011-01-01

    We examined the mechanisms involved in the [Ca(2+)](i) response to the extracellular hypotonicity in the principal cells of freshly isolated rat cortical collecting duct (CCD), using Fura-2/AM fluorescence imaging. Reduction of extracellular osmolality from 305 (control) to 195 mosmol/kgH(2)O (hypotonic) evoked transient increase in [Ca(2+)](i) of principal cells of rat CCDs. The [Ca(2+)](i) increase was markedly attenuated by the removal of extracellular Ca(2+)(.) The application of a P(2) purinoceptor antagonist, suramin failed to inhibit the hypotonicity-induced [Ca(2+)](i) increase. The [Ca(2+)](i) increase in response to extracellular hypotonicity was not influenced by application of Gd(3+) and ruthenium red. On the other hand, a voltage-gated Ca(2+) channel inhibitor, nicardipine, significantly reduced the peak amplitude of [Ca(2+)](i) increase in the principal cells. In order to assess Ca(2+) entry during the hypotonic stimulation, we measured the quenching of Fura-2 fluorescence intensity by Mn(2+). The hypotonic stimulation enhanced quenching of Fura-2 fluorescence by Mn(2+), indicating that a Ca(2+)-permeable pathway was activated by the hypotonicity. The hypotonicity-mediated enhancement of Mn(2+) quenching was significantly inhibited by nicardipine. These results strongly suggested that a nicardipine-sensitive Ca(2+) entry pathway would contribute to the mechanisms underlying the hypotonicity-induced [Ca(2+)](i) elevation of principal cells in rat CCD.

  11. Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.

    PubMed

    Ochi, Masanori; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-01-01

    Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

  12. Reconsideration of vascular selectivity of dihydropyridine calcium antagonists: comparison of cardiovascular profile of mepirodipine, a novel dihydropyridine consisting of a single stereoisomer with (+)-(S)-(S) conformation, with those of nifedipine and nicardipine.

    PubMed

    Motomura, S; Hashimoto, K

    1990-02-01

    The coronary vasodilator effect and negative chronotropic, inotropic and dromotropic effects of mepirodipine, the single stereoisomer of a novel dihydropyridine Ca antagonist, were compared with those of nifedipine and nicardipine using canine isolated, blood-perfused heart preparations. Drugs were injected into each nutrient artery. In the sinoatrial node preparation, the dose producing a 15% decrease in sinoatrial rate was 1.3, 6.5 and 2.5 micrograms for mepirodipine, nifedipine and nicardipine, respectively. In the papillary muscle preparation, the dose causing a 50% decrease in developed tension was 44, 6.5 and 54 micrograms for mepirodipine, nifedipine and nicardipine, respectively. The dose causing a 50% increase in blood flow through the anterior septal artery was 0.26, 0.18 and 2.0 micrograms for mepirodipine, nifedipine and nicardipine, respectively, while the time required for return to half maximum at the above dose was 13.1, 1.8 and 4.1 min, respectively. In the atrioventricular node preparation, the dose producing a 50% increase in AH interval was 1.6, 2.4 and 3.7 micrograms for mepirodipine, nifedipine and nicardipine, respectively. These results indicate that mepirodipine is a potent and long-lasting dihydropyridine Ca antagonist, whose vascular selectivity is highest against cardiac contractility, but less selective against sinoatrial node automaticity and atrioventricular nodal conduction, compared with nifedipine.

  13. Ranolazine enhances nicardipine-induced relaxation of alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta.

    PubMed

    Malavaki, Christina; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Stefanidis, Ioannis; Karatzaferi, Christina; Aidonidis, Isaac

    2015-04-01

    Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta.

  14. Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats.

    PubMed

    Konno, Yoshihiro; Sekimoto, Masashi; Nemoto, Kiyomitsu; Degawa, Masakuni

    2004-04-01

    Male and female of F344 rats were treated per os with nicardipine (Nic) and nifedipine (Nif), and changes in the levels of mRNA and protein of hepatic cytochrome P450 (P450) enzymes, CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP3A9, and CYP3A18 were examined. Furthermore, hepatic microsomal activities for pentoxyresorufin O-dealkylation (PROD) and nifedipine oxidation, which are mainly mediated by CYP2B and CYP3A subfamily enzymes, respectively, were measured. Analyses of RT-PCR and Western blotting revealed that Nic and Nif induced predominantly CYP3A and CYP2B enzymes, respectively. As for the gene activation of CYP2B enzymes, especially CYP2B1, Nif showed high capacity in both sexes of rats, whereas Nic did a definite capacity in the males but little in the females. Gene activations of CYP3A1, CYP3A2, and CYP3A18 by Nic occurred in both sexes of rats, although that of CYP3A9 did only in the male rats. Although gene activations of CYP3A1 and CYP3A2 by Nif were observed in both sexes of rats, a slight activation of the CYP3A9 gene occurred only in female rats, and the CYP3A18 gene activation, in neither male nor female rats. Thus, changes in levels of the mRNA or protein of CYP2B and CYP3A enzymes, especially CYP2B1 and CYP3A2, were closely correlated with those in hepatic PROD and nifedipine oxidation activities, respectively. The present findings demonstrate for the first time the sex difference in the Nic- and Nif-mediated induction of hepatic P450 enzymes in rats and further indicate that Nic and Nif show different specificities and sex dependencies in the induction of hepatic P450 enzymes.

  15. Pulmonary edema induced by calcium-channel blockade for tocolysis.

    PubMed

    Bal, Laurence; Thierry, Stéphane; Brocas, Elsa; Adam, Marie; Van de Louw, Andry; Tenaillon, Alain

    2004-09-01

    Nicardipine is used in the treatment of premature labor. There are no previous reports in the anesthesia literature of serious side effects associated with this drug. We report a case of pulmonary edema induced by nicardipine therapy for tocolysis in a pregnant 27-yr-old patient admitted to our hospital for preterm labor with intact membranes at 27 wk of gestation.

  16. Treatment of Essential Tremor

    MedlinePlus

    ... help treat limb tremor: • Amantadine • L-tryptophan/ • Olanzapine • Clonidine pyridoxine • Phenobarbital • Gabapentin • Metoprolol • Quetiapine • Glutethimide • Nicardipine • Theophylline ...

  17. A xanthine derivative denbufylline inhibits negative inotropic response to verapamil in guinea pig ventricular papillary muscles, independent of its phosphodiesterase inhibitory activity.

    PubMed

    Sanae, F; Ohmae, S; Takagi, K; Miyamoto, K

    1995-11-01

    A phosphodiesterase (PDE) III inhibitor, amrinone, inhibited both the negative inotropic actions of verapamil and nicardipine in guinea pig ventricular papillary muscle; this effect was canceled by the protein kinase A inhibitor H-89. The PDE IV inhibitor 1,3-di-n-butyl-7-(2'-oxopropyl)xanthine (denbufylline), which elicited a negative inotropic action by itself, attenuated the action of verapamil up to 10 microM, without any interaction with nicardipine. The attenuation by denbufylline was not influenced by H-89. This suggests that in the ventricular papillary muscle, denbufylline acts on some verapamil-sensitive site(s) in the membrane and interferes with the calcium channel function without involvement of its PDE inhibitory activity.

  18. Dihydropyridine Ca2+ channel antagonists and agonists block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells.

    PubMed

    Hatano, Noriyuki; Ohya, Susumu; Muraki, Katsuhiko; Giles, Wayne; Imaizumi, Yuji

    2003-06-01

    (1) We have determined the molecular basis of nicardipine-induced block of cardiac transient outward K(+) currents (I(to)). Inhibition of I(to) was studied using cloned voltage-dependent K(+) channels (Kv) channels, rat Kv4.3L, Kv4.2, and Kv1.4, expressed in human embryonic kidney cell line 293 (HEK293) cells. (2) Application of the dihydropyridine Ca(2+) channel antagonist, nicardipine, accelerated the inactivation rate and reduced the peak amplitude of Kv4.3L currents in a concentration-dependent manner (IC(50): 0.42 micro M). The dihydropyridine (DHP) Ca(2+) channel agonist, Bay K 8644, also blocked this K(+) current (IC(50): 1.74 micro M). (3) Nicardipine (1 micro M) slightly, but significantly, shifted the voltage dependence of activation and steady-state inactivation to more negative potentials, and also slowed markedly the recovery from inactivation of Kv4.3L currents. (4) Coexpression of K(+) channel-interacting protein 2 (KChIP2) significantly slowed the inactivation of Kv4.3L currents as expected. However, the features of DHP-induced block of K(+) current were not substantially altered. (5) Nicardipine exhibited similar block of Kv1.4 and Kv4.2 channels stably expressed in HEK293 cells; IC(50)'s were 0.80 and 0.62 micro M, respectively. (6) Thus, at submicromolar concentrations, DHP Ca(2+) antagonist and agonist inhibit Kv4.3L and have similar inhibiting effects on other components of cardiac I(to), Kv4.2 and Kv1.4.

  19. Differential sensitivities of CaV1.2 IIS5-S6 mutants to 1,4-dihydropyridine analogs.

    PubMed

    Hui, Kwokyin; Kwok, Trevor C Y; Kostelecki, Wojciech; Leen, Jessica; Roy, Peter John; Feng, Zhong-Ping

    2009-01-14

    1,4-Dihydropyridines (DHPs), L-type calcium channel (Ca(V)1) blockers, are known to interact with Ca(V)1.2 subunits through their binding site located at IIIS5-S6 and IVS6 regions. We recently identified two domain II residues (S666 and A752) critical for nifedipine blockade (Kwok et al., 2008). In this study, we examined the blockade effects of two DHP analogues, nemadipine and nicardipine, on wildtype, M1161A (in IIIS6), S666V (in IIS5) and A752T (in IIS6) mutants of the rat alpha(1C) subunit transiently expressed with beta(2a) and alpha(2)delta in cultured tsA201 cells. We found that the IC(50) ratio of the mutants to the wildtype channel was similar in S666V and M1161A mutants for both drugs, but in A752T it was lower for nemadipine than nicardipine (P<0.05). At saturating drug concentrations, not all the current was completely blocked in the mutants. The residual current recorded in 100 microM nemadipine was approximately 10% of the total current for the A752T channel, which was significantly higher than that in 100 microM nicardipine (approximately 2%). In wildtype, S666V and M1161A, there was no significant difference in residual current between nemadipine and nicardipine, although it was greater in S666V (approximately 15%) and M1161A approximately 30%) as compared to the wildtype channel (<5%). Taken together, our findings suggest that the domain II residues alter the DHP effect in a structure-specific manner and may be involved in a pathway downstream of DHP binding.

  20. Pharmacological characterization and autoradiographic localization of dihydropyridine-type calcium channels in the kidney of spontaneously hypertensive rats.

    PubMed

    Amenta, F; Liu, A; Sabbatini, M

    1995-12-01

    1. The pharmacological profile and the microanatomical localization of Ca2+ channels of the L-type were analysed in sections of the kidney of Wistar-Kyoto (WKY) rats and of spontaneously hypertensive rats (SHR) of different ages. 2. [3H]-Nicardipine was used as a ligand. It was bound to sections of rat kidney in a manner consistent with the labelling of Ca2+ channels of the L-type. The density of [3H]-nicardipine binding sites was similar in WKY rats of different ages and in SHR of 2 and 4 months, but was significantly increased in SHR of 6 months. 3. Light microscope autoradiography revealed the highest density of binding sites in the tubular portion of the nephron and to a lesser extent within smooth muscle of renal arteries and renal corpuscles. In SHR of 4 and 6 months the density of [3H]-nicardipine binding sites was increased within the epithelium of proximal tubules and of the loop of Henle and decreased in renal corpuscles in comparison with WKY rats or 2 month old SHR. 4. These results show that the density of Ca2+ channels of the L-type increases with the worsening of hypertension in SHR. The observation of a different sensitivity to hypertension of Ca2+ channels located in the various portions of the nephron indicates the usefulness of light microscope autoradiography for assessing hypertension-related changes of Ca2+ channels in the kidney.

  1. Nationwide survey of antihypertensive treatment for acute intracerebral hemorrhage in Japan.

    PubMed

    Koga, Masatoshi; Toyoda, Kazunori; Naganuma, Masaki; Kario, Kazuomi; Nakagawara, Jyoji; Furui, Eisuke; Shiokawa, Yoshiaki; Hasegawa, Yasuhiro; Okuda, Satoshi; Yamagami, Hiroshi; Kimura, Kazumi; Okada, Yasushi; Minematsu, Kazuo

    2009-09-01

    Acute hypertension is associated with hematoma enlargement and poor clinical outcomes in patients with intracerebral hemorrhage (ICH). However, the method of controlling blood pressure (BP) during the acute phase of ICH remains unknown. The aim of this study is to show current strategies about this issue in Japan. Questionnaires regarding antihypertensive treatment (AHT) strategies were sent to neurosurgeons, neurologists and others responsible for ICH management in 1424 hospitals. Of 600 respondents, 550 (92%) worked at hospitals wherein acute ICH patients are managed and 548 (99.6%) of them agreed with the application of AHT within 24 h of ICH onset. Most answered that the systolic BP threshold for starting AHT was 180 mm Hg (36%) or 160 mm Hg (31%), which differed significantly between neurosurgeons (median, 160 mm Hg) and neurologists/others (180 mm Hg, P<0.001). The goal of lowering systolic BP was to reach a maximum of 140, 150 or 160 mm Hg according to 448 respondents (82%) and 209 (38%) intensively lowered systolic BP to Nicardipine was the first choice of intravenous drug for 313 (57%) and the second choice for 146 respondents (27%). However, 141 (26%) thought that nicardipine is inappropriate mainly because of a conflict with a description of contraindications on the official Japanese label for this drug. In conclusion, the present Japanese respondents, especially neurosurgeons, lower BP more aggressively than recommended in domestic and Western guidelines for managing acute ICH patients. Nicardipine was the most frequent choice of antihypertensive agent.

  2. Analysis of responses to kava kava in the feline pulmonary vascular bed.

    PubMed

    Hoover, Jason M; Kaye, Alan D; Ibrahim, Ikhlass N; Fields, Aaron M; Richards, Todd A

    2006-01-01

    This study was designed to test the hypothesis that kava kava induces a depressor response in the pulmonary vascular bed of the cat and to identify the pathways involved in the mediation or modulation of these effects. In separate experiments, the effects of L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO), a nitric oxide synthase inhibitor, glibenclamide, an ATP-sensitive K+ channel blocker, meclofenamate, a nonselective cyclooxygenase inhibitor, nicardipine, a calcium channel blocker, bicuculline, a gamma-aminobutyric acid (GABA)A receptor antagonist, and saclofen, a GABAB antagonist, were investigated on pulmonary arterial responses to kava kava (kava), pinacidil, an ATP-sensitive K+ channel activator, bradykinin, an inducer of nitric oxide synthase, 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF-97541), a GABAB receptor agonist, and muscimol, a GABAA receptor agonist. Lobar arterial perfusion pressure and systemic pressure were continuously monitored, electronically averaged, and recorded. Under elevated tone conditions in the isolated left lower lobe of the feline vascular bed, kava induced a dose-dependent vasodepressor response that was not significantly altered after administration of L-NIO, glibenclamide, meclofenamate, or saclofen. Responses to kava were significantly reduced after administration of either nicardipine or bicuculline. When the calcium channel blocker nicardipine was administered in addition to the GABA blocker bicuculline, there was near complete attenuation of the kava-induced vasodepressor responses. The results of this investigation suggest that kava has potent vasodepressor activity in the feline lung bed and that this response is mediated or modulated by both a calcium channel- and GABA receptor-sensitive pathway.

  3. The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2.

    PubMed

    Shukla, Suneet; Robey, Robert W; Bates, Susan E; Ambudkar, Suresh V

    2006-07-25

    The human ATP-binding cassette transporter, ABCG2, confers resistance to multiple chemotherapeutic agents and also affects the bioavailability of different drugs. [(125)I]Iodoarylazidoprazosin (IAAP) and [(3)H]azidopine were used for photoaffinity labeling of ABCG2 in this study. We show here for the first time that both of these photoaffinity analogues are transport substrates for ABCG2 and that [(3)H]azidopine can also be used to photolabel both wild-type R482-ABCG2 and mutant T482-ABCG2. We further used these assays to screen for potential substrates or modulators of ABCG2 and observed that 1,4-dihydropyridines such as nicardipine and nifedipine, which are clinically used as antihypertensive agents, inhibited the photolabeling of ABCG2 with [(125)I]IAAP and [(3)H]azidopine as well as the transport of these photoaffinity analogues by ABCG2. Furthermore, [(3)H]nitrendipine and bodipy-Fl-dihydropyridine accumulation assays showed that these compounds are transported by ABCG2. These dihydropyridines also inhibited the efflux of the known ABCG2 substrates, mitoxantrone and pheophorbide-a, from ABCG2-overexpressing cells, and nicardipine was more potent in inhibiting this transport. Both nicardipine and nifedipine stimulated the ATPase activity of ABCG2, and the nifedipine-stimulated activity was inhibited by fumitremorgin C, suggesting that these agents might interact at the same site on the transporter. In addition, nontoxic concentrations of dihydropyridines increased the sensitivity of ABCG2-expressing cells to mitoxantrone by 3-5-fold. In aggregate, results from the photoaffinity labeling and efflux assays using [(125)I]IAAP and [(3)H]azidopine demonstrate that 1,4-dihydropyridines are substrates of ABCG2 and that these photolabels can be used to screen new substrates and/or inhibitors of this transporter.

  4. Prolonged neuromuscular block in a preeclamptic patient induced by magnesium sulfate

    PubMed Central

    Berdai, Mohamed Adnane; Labib, Smael; Harandou, Mustapha

    2016-01-01

    Recent large use of magnesium in the obstetric population should incite anesthesiologists to control its side effects and drugs interactions. We report a case of a 30-year-old woman, with severe preeclampsia and HELLP syndrome, receiving sulfate magnesium and nicardipine, who underwent a cesarean section under general anesthesia. She developed a prolonged and deep neuromuscular blockade, which was antagonized three hours later with neostigmine. In case of therapeutic hypermagnesaemia, non-depolarizing relaxants must be used in reduced doses, and at increased time intervals, with appropriate neuromuscular monitoring. PMID:28154698

  5. The effect of ionizing radiation of 1,4-dihydropyridine derivatives in the solid state.

    PubMed

    Naskrent, Marek; Mielcarek, Jadwiga

    2007-05-01

    Electron paramagnetic resonance (EPR) spectroscopy was used to investigate the gamma-radiation damage in the crystalline powder form of nine calcium channel blockers from the 1,4-dihydropyridine derivatives, which are in clinical use for treatment of arteria hypertension and ischemic heart disease. EPR studies have been carried out, showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals trapped. EPR spectra of isardipine and felodipine showed single EPR line. EPR spectra of nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine and nilvadipine reveal a broad anisotropic signal of hyperfine interaction. No EPR signal was observed from amlodipine.

  6. The effect of ionizing radiation of 1,4-dihydropyridine derivatives in the solid state

    NASA Astrophysics Data System (ADS)

    Naskrent, Marek; Mielcarek, Jadwiga

    2007-05-01

    Electron paramagnetic resonance (EPR) spectroscopy was used to investigate the gamma-radiation damage in the crystalline powder form of nine calcium channel blockers from the 1,4-dihydropyridine derivatives, which are in clinical use for treatment of arteria hypertension and ischemic heart disease. EPR studies have been carried out, showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals trapped. EPR spectra of isardipine and felodipine showed single EPR line. EPR spectra of nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine and nilvadipine reveal a broad anisotropic signal of hyperfine interaction. No EPR signal was observed from amlodipine.

  7. Stoichiometry and Physical Chemistry of Promiscuous Aggregate-Based Inhibitors

    PubMed Central

    Coan, Kristin E. D.

    2009-01-01

    Many false positives in early drug discovery owe to nonspecific inhibition by colloid-like aggregates of organic molecules. Despite their prevalence, little is known about aggregate concentration, structure, or dynamic equilibrium; the binding mechanism, stoichiometry with, and affinity for enzymes remain uncertain. To investigate the elementary question of concentration, we counted aggregate particles using flow cytometry. For seven aggregate-forming molecules, aggregates were not observed until the concentration of monomer crossed a threshold, indicating a “critical aggregation concentration” (CAC). Above the CAC, aggregate count increased linearly with added organic material, while the particles dispersed when diluted below the CAC. The concentration of monomeric organic molecule is constant above the CAC, as is the size of the aggregate particles. For two compounds that form large aggregates, nicardipine and miconazole, we measured particle numbers directly by flow cytometry, determining that the aggregate concentration just above the CAC ranged from 5 to 30 fM. By correlating inhibition of an enzyme with aggregate count for these two drugs, we determined that the stoichiometry of binding is about 10 000 enzyme molecules per aggregate particle. Using measured volumes for nicardipine and miconazole aggregate particles (2.1 × 1011 and 4.7 × 1010 Å3, respectively), computed monomer volumes, and the observation that past the CAC all additional monomer forms aggregate particles, we find that aggregates are densely packed particles. Finally, given their size and enzyme stoichiometry, all sequestered enzyme can be comfortably accommodated on the surface of the aggregate. PMID:18588298

  8. Investigation of calcium antagonist-L-type calcium channel interactions by a vascular smooth muscle cell membrane chromatography method.

    PubMed

    Du, Hui; He, Jianyu; Wang, Sicen; He, Langchong

    2010-07-01

    The dissociation equilibrium constant (K(D)) is an important affinity parameter for studying drug-receptor interactions. A vascular smooth muscle (VSM) cell membrane chromatography (CMC) method was developed for determination of the K(D) values for calcium antagonist-L-type calcium channel (L-CC) interactions. VSM cells, by means of primary culture with rat thoracic aortas, were used for preparation of the cell membrane stationary phase in the VSM/CMC model. All measurements were performed with spectrophotometric detection (237 nm) at 37 degrees C. The K(D) values obtained using frontal analysis were 3.36 x 10(-6) M for nifedipine, 1.34 x 10(-6) M for nimodipine, 6.83 x 10(-7) M for nitrendipine, 1.23 x 10(-7) M for nicardipine, 1.09 x 10(-7) M for amlodipine, and 8.51 x 10(-8) M for verapamil. This affinity rank order obtained from the VSM/CMC method had a strong positive correlation with that obtained from radioligand binding assay. The location of the binding region was examined by displacement experiments using nitrendipine as a mobile-phase additive. It was found that verapamil occupied a class of binding sites on L-CCs different from those occupied by nitrendipine. In addition, nicardipine, amlodipine, and nitrendipine had direct competition at a single common binding site. The studies showed that CMC can be applied to the investigation of drug-receptor interactions.

  9. Vascular pharmacology of mokuboito (mu-fang-yi-tang) and its constituents on the smooth muscle and the endothelium in rat aorta.

    PubMed

    Nishida, Seiichiro; Satoh, Hiroyasu

    2007-09-01

    Pharmacological actions of Mokuboito and its constituents (Sinomenium acutum and sinomenine) on rat aorta were examined. Mokuboito and S. acutum at lower concentrations (0.03-1 mg ml(-1)) contracted the non-loaded aorta, but at higher concentrations (1-3 mg ml(-1)), reversed to dilate it. The vasoconstriction was blocked by phentolamine (10 muM). Sinomenine failed to exhibit the vasoconstriction. On the other hand, Mokuboito and S. acutum dilated the NE (5 muM)-induced vasoconstriction: at 3 mg ml(-1), by 98.9 +/- 2.5% (n = 6, P < 0.01) and 97.0 +/- 4.8% (n = 6, P < 0.01). Vasorelaxation induced by Mokuboito and S. acutum was attenuated by indomethacin, L-NMMA and nicardipine. Propranolol decreased the vasorelaxation induced by Mokuboito, but not by S. acutum. Sinomenine also relaxed the constriction and at 100 muM, by 68.8 +/- 5.1% (n = 7, P < 0.01). This vasorelaxation was attenuated by indomethacin, L-NMMA and nicardipine, and also by propranolol. Therefore, these results indicate that Mokuboito and its constituents exert both vasodilating actions mediated by endothelium-dependent mechanisms (PGI(2) and NO from endothelium) and by endothelium-independent mechanisms (Ca(2+) influx control on smooth muscle cells). Simultaneously, Mokuboito and S. acutum cause the vasoconstrictions mediated through alpha-adrenoceptor stimulation, but not sinomenine. Also, Mokuboito and sinomenine possess beta-adrenoreceptor stimulating action, but not S. acutum.

  10. Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes.

    PubMed

    Furukawa, T; Yamakawa, T; Midera, T; Sagawa, T; Mori, Y; Nukada, T

    1999-11-01

    Some dihydropyridines (DHPs), such as amlodipine and cilnidipine, have been shown to block not only L-type but also N-type Ca(2+) channels; therefore, DHPs are no longer considered as L-type-specific Ca(2+) channel blockers. However, selectivity of DHPs for Ca(2+) channel subtypes including N-, P/Q-, and R-types are poorly understood. To address this issue at the molecular level, blocking effects of 10 DHPs (nifedipine, nilvadipine, barnidipine, nimodipine, nitrendipine, amlodipine, nicardipine, benidipine, felodipine, and cilnidipine) on four subtypes of Ca(2+) channels (L-, N-, P/Q-, and R-types) were investigated in the Xenopus oocyte expression system with the use of the two-microelectrode voltage-clamp technique. L-type Ca(2+) channels expressed as alpha(1C)alpha(2)beta(1a) combination were profoundly blocked by all DHPs examined, whereas blocking actions of these DHPs on R-type (alpha(1E)alpha(2)beta(1a)) channels were equally weak. In contrast, 5 of the 10 DHPs (amlodipine, benidipine, cilnidipine, nicardipine, and barnidipine) significantly blocked N-type (alpha(1B)alpha(2)beta(1a)) and P/Q-type (alpha(1A)alpha(2)beta(1a)) Ca(2+) channels. These selectivities of DHPs in blocking Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side effects and adverse effects.

  11. Antihypertensive and diuretic effects of YM-09730-5, a new calcium antagonist, in stroke-prone spontaneously hypertensive rats.

    PubMed

    Kawashima, K; Toda, H; Oohata, H; Fujimoto, K; Suzuki, T; Inagaki, O

    1991-01-01

    1. Effects of consecutive administration of YM-09730-5, (3S)-1-benzyl-3-pyrrolidinyl-methyl (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy lat e hydrochloride, a new calcium antagonist, for 9 wk on blood pressure and urinary excretion of electrolytes were studied in stroke-prone spontaneously hypertensive (SHRSP) rats. 2. YM-09730-5 (1 and 3 mg/kg per day, p.o.) prevented development of hypertension and produced a significant reduction in blood pressure from the first week of the experiment. Nicardipine (15 mg/kg per day, p.o.) produced almost the same degree of antihypertensive effect as YM-09730-5 at a dose of 3 mg/kg. 3. YM-09730-5 produced significant diuresis and increased urinary excretion of electrolytes throughout the experiment. 4. Chronic administration of YM-09730-5 (3 mg/kg) reduced the severity of glomerular lesions in the kidney and vasculitis in the mesenteric artery. 5. These results demonstrate that YM-09730-5 is a potential antihypertensive drug with a potency about 5 times higher than that of nicardipine.

  12. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    PubMed

    Contreras, E; Tamayo, L; Amigo, M

    1988-04-13

    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  13. [Management of arterial hypertension before 20weeks gestation in pregnant women].

    PubMed

    Seguro, Florent; Duly Bouhanick, Béatrice; Chamontin, Bernard; Amar, Jacques

    2016-01-01

    In the first 6 months of pregnancy, the primary goal of antihypertensive treatment is to prevent the complications of severe hypertension. Initiation of antihypertensive drug treatment is recommended in pregnant women with severe hypertension (blood pressure>160/110mmHg). Initiation of antihypertensive drug treatment should also be considered in pregnant women at high cardiovascular risk (diabetes, chronic kidney disease, personal history of cardiovascular disease) with moderate hypertension (blood pressure between 140-159/90-109mmHg). A systolic blood pressure goal<160 and a diastolic blood pressure goal between 85 and 100mmHg is recommended in pregnancy. Labetalol, nifedipine, nicardipine and alphamethyldopa should be considered preferential antihypertensive drugs in pregnancy. Salt restriction, physical exercise and weight loss have not demonstrated any effect in the prevention of preeclampsia and serious maternal complications of hypertension.

  14. Severe hypertension in children and adolescents: pathophysiology and treatment.

    PubMed

    Flynn, Joseph T; Tullus, Kjell

    2009-06-01

    Severe, symptomatic hypertension occurs uncommonly in children, usually only in those with underlying congenital or acquired renal disease. If such hypertension has been long-standing, then rapid blood pressure reduction may be risky due to altered cerebral hemodynamics. While many drugs are available for the treatment of severe hypertension in adults, few have been studied in children. Despite the lack of scientific studies, some agents, particularly continuous intravenous infusions of nicardipine and labetalol, are preferred in many centers. These agents generally provide the ability to control the magnitude and rapidity of blood pressure reduction and should--in conjunction with careful patient monitoring--allow the safe reduction of blood pressure and the avoidance of complications. This review provides a summary of the underlying causes and pathophysiology of acute severe hypertension in childhood as well as a detailed discussion of drug treatment and the optimal clinical approach to managing children and adolescents with acute severe hypertension.

  15. [Raynaud's phenomenon and calcium blocking agents. A preliminary open study with flunarizine].

    PubMed

    Centonze, V; Campanale, G; Vino, M; Caporaletti, P; Magrone, D; Russo, P; Di Bari, M; Loragno, V; Albano, O

    1991-04-30

    Raynaud's phenomenon (Raynaud's disease), an accessual vascular acrosyndrome characterised by an important constriction of distal arterioles, has still no specific pharmacological therapy. In the last years, the use of calcium-entry-blockers (nifedipine, diltiazem, verapamil, nicardipine), drugs able to control the contractility of the vessels, showed some positive results. Considering this data, we appraised the efficacy of flunarizine, another calcium-entry-blocker, in a preliminary study of 28 patients (23 females, 5 males, aged between 15 and 48 years) suffering from Raynaud's disease. Apart from a statistically insignificant improvement of subjective symptoms (i.e. acroparesthesias, cold extremities) flunarizine (10 mg/day for 1 month) did not have positive results. Finally, this drug caused some side-effects: drowsiness, increase of weight and appetite, but without a real necessity for withdrawal of therapy.

  16. Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

    DOE PAGES

    Veinberg, Stanislav L.; Johnston, Karen E.; Jaroszewicz, Michael J.; ...

    2016-06-08

    14N ultra-wideline (UW), 1H{15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. Here, a case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationarymore » samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R"NH+ and RR'NH2+) or other (i.e., RNH2 and RNO2) nitrogen environments.« less

  17. High and low affinity binding sites for endothelin on cultured rat glomerular mesangial cells.

    PubMed

    Badr, K F; Munger, K A; Sugiura, M; Snajdar, R M; Schwartzberg, M; Inagami, T

    1989-06-15

    Endothelin contracts glomerular mesangial cells, thereby influencing glomerular size and filtration rate. Here, we demonstrate the presence of two ET-specific binding sites on cultured rat mesangial cells with Kds of 0.76 and 44.70 nM, and maximal binding capacity (Bmax) values of 6.78 x 10(2) and 27.60 x 10(2) binding sites/cell, respectively. Binding of [125I]-ET was maximal at 120 min at 4 degrees C, stable for the subsequent 60 min, and selective. No competition for binding was observed with greater than 1000-fold concentrations of atrial natriuretic peptide, angiotensin II, arginine vasopressin, nicardipine, or nifedipine. The presence of specific receptors for ET on glomerular mesangial cells suggests a major role for this peptide in the regulation of glomerular filtration rate.

  18. Stability and Compatibility of Ceftazidime Administered by Continuous Infusion to Intensive Care Patients

    PubMed Central

    Servais, Hélène; Tulkens, Paul M.

    2001-01-01

    The stability and compatibility of ceftazidime have been examined in the context of its potential use in concentrated solutions for continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route. Ceftazidime stability in 4 to 12% solutions was found satisfactory (<10% degradation) for 24 h if kept at a temperature of 25°C (77°F) maximum. Studies mimicking the simultaneous administration of ceftazidime and other drugs as done in clinics showed physical incompatibilities with vancomycin, nicardipine, midazolam, and propofol and a chemical incompatibility with N-acetylcystein. Concentrated solutions (50 mg/ml) of erythromycin or clarithromycin caused the appearance of a precipitate, whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole, ketamine, sufentanil, valproic acid, furosemide, uradipil, and a standard amino acid solution were physically and chemically compatible. PMID:11502544

  19. Dexmedetomidine and remifentanil in the perioperative management of an adolescent undergoing resection of pheochromocytoma -A case report-

    PubMed Central

    Jung, Jae-Wook; Park, Jung Kyu; Jeon, Sang Yoon; Kim, Yong Han; Nam, So-Hyun; Choi, Young-Gyun

    2012-01-01

    A 15-year-old adolescent with unilateral multiple adrenal pheochromocytoma had an episode of subcortical intracerebral hemorrhage and seizure 6 weeks before the surgery. He was pretreated with terazosin, losartan, atenolol and levetiracetam for 2 weeks. Dexmedetomidine was started in the preoperative waiting area, and a combination of dexmedetomidine and remifentanil was continuously infused for most of anesthetic time. To control blood pressure, bolus injection of remifentanil and low-dose infusion of sodium nitroprusside, nicardipine, and esmolol were administered during three adrenergic crises. There was minimal post-resection hypotension, and his trachea was extubated safely 20 min after the surgery. He was discharged without noticeable complication. His catecholamine levels showed the steadily decreasing pattern during the operation in this case. Though a combination of dexmedetomidine and remifentanil may not prevent the hemodynamic instability impeccably during the tumor manipulation, this combination seems to be the way of interrupting release of catecholamines and minimizing hemodynamic fluctuations. PMID:23277819

  20. [Vasorelaxant activity of caffeic acid derivatives from Cichorium intybus and Equisetum arvense].

    PubMed

    Sakurai, Nobuko; Iizuka, Tohru; Nakayama, Shigeki; Funayama, Hiroko; Noguchi, Mariko; Nagai, Masahiro

    2003-07-01

    The vasorelaxant activities of chicoric acid (Compound 1) from Cichorium intybus and dicaffeoyl-meso-tartaric acid (Compound 2) from Equisetum arvense L. in isolated rat aorta strips were studied. Compound 1 is a diester composed of (S,S)-tartaric acid and caffeic acid, and 2 is composed of its meso type. Both 1 and 2 showed slow relaxation activity against norepinephrine (NE)-induced contraction of rat aorta with/without endothelium. These compounds did not affect contraction induced by a high concentration of potassium (60 mM K+), while they inhibited NE-induced vasocontraction in the presence of nicardipine. These results show that the inhibition by 1 and 2 of NE-induced vasocontraction is due to a decrease in calcium influx from the extracellular space caused by NE. In addition, dicaffeoyl tartaric acids showed vasorelaxant activity, regardless of their stereochemistry.

  1. Run-up to participation in ATACH II in Japan.

    PubMed

    Toyoda, K; Sato, S; Koga, M; Yamamoto, H; Nakagawara, J; Furui, E; Shiokawa, Y; Hasegawa, Y; Okuda, S; Sakai, N; Kimura, K; Okada, Y; Yoshimura, S; Hoshino, H; Uesaka, Y; Nakashima, T; Itoh, Y; Ueda, T; Nishi, T; Gotoh, J; Nagatsuka, K; Arihiro, S; Yamaguchi, T; Minematsu, K

    2012-08-01

    Intracerebral hemorrhage (ICH) is a major cause of morbidity and mortality in Japan. Seventeen Japanese institutions are participating in the Antihypertensive Treatment for Acute Cerebral Hemorrhage (ATACH) II Trial (ClinicalTrials.gov no. NCT01176565; UMIN 000006526). This phase III trial is designed to determine the therapeutic benefit of early intensive systolic blood pressure (BP) lowering for acute hypertension in ICH patients. This report explains the long run-up to reach the start of patient registration in ATACH II in Japan, including our preliminary study, a nationwide survey on antihypertensive treatment for acute ICH patients, a multicenter study for hyperacute BP lowering (the SAMURAI-ICH study), revision of the official Japanese label for intravenous nicardipine, and construction of the infrastructure for the trial.

  2. Antioxidant effects of calcium antagonists in rat brain homogenates.

    PubMed

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  3. Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients.

    PubMed

    Shimada, S; Nakajima, Y; Yamamoto, K; Sawada, Y; Iga, T

    1996-03-01

    The relationships between plasma drug concentration and antihypertensive effect of eight calcium channel antagonists (nicardipine, nifedipine, nilvadipine, benidipine, manidipine, barnidipine, nitrendipine and efonidipine) in Japanese essential hypertensive patients were analyzed. Based on the effect compartment model, we could explain the long duration of the pharmacological effect, and there was significant correlation (r = 0.876, p < 0.05) between estimated EC50 values and the dissociation constants (Kd) obtained from in vitro binding studies. We also developed the ion-channel binding model to understand the pharmacodynamics of long acting calcium antagonists. The model was also well fitted to antihypertensive effect data. A significant correlation between the apparent in vivo dissociation constants and in vitro Kd values was observed with a slope of 1.45 (r = 0.913), suggesting that the mechanism of long-lasting antihypertensive effect of newer developed calcium antagonists is due to their high binding affinity at ion-channel sites.

  4. Antibody to dihydropyridine calcium entry blockers

    SciTech Connect

    Thayer, S.; Minaskanian, G.; Fairhurst, A.

    1986-03-05

    Antibodies that recognize dihydropyridine calcium entry blockers were elicited from rabbits. A sensitive and specific radioimmunoassay for dihydropyridines was developed and its specificity compared to the DHP binding site in skeletal muscle membranes. The antibody bound (/sup 3/H)nitrendipine with a higher affinity (K/sub D/ = 0.155 nM) than did the DHP receptor of skeletal muscle (K/sub D/ = 1-3 nM). However, in contrast to the DHP receptor, the antibody recognized only those DHP drugs with meta-nitrophenyl substituents at the 4-position on the DHP ring, and thus reflected the meta position of the nitro group on the DHP hapten used as an antigen. Both the antibody and the receptor exhibited stereospecificity, with each site recognizing the (+) isomer of nicardipine as the more potent. This antibody should prove useful in the studies of some potentially irreversible DHP molecules and for use in the production of anti-idotype antibodies.

  5. Effects of isradipine and other calcium antagonists on arteriovenous-shunt flow in anesthetized rabbits and cats

    SciTech Connect

    Hof, R.P.

    1989-04-17

    The effects of vasodilators on arteriovenous (AV)-shunt flow was investigated in anesthetized cats and rabbits, using the tracer microsphere method. In cats, the calcium antagonist isradipine reduced AV-shunt flow; verapamil showed a similar tendency and nicardipine was without effect. Dihydralazine strongly increased, but nitroglycerin and dipyridamole decreased AV-shunt flow. In rabbits, the effects of isradipine and verapamil were similar to those seen in cats. Sodium nitroprusside had no effect, whereas prazosin, minoxidil, and the potassium-channel activator cromakalim increased AV-shunt flow. The contrasting effects of drugs sharing the same mechanism of action suggest that target-tissue selectivity is more important than the mechanism of action. An increase of AV-shunt flow is unlikely to be beneficial but could be associated with a number of undesirable side effects. It might negatively affect migraine sufferers and, if AV-shunt dilatation shows no tolerance development, it represents an unnecessary hemodynamic burden for the heart.

  6. Sympathetic nonadrenergic transmission contributes to autonomic dysreflexia in spinal cord-injured individuals.

    PubMed

    Groothuis, Jan T; Rongen, Gerard A; Deinum, Jaap; Pickkers, Peter; Danser, A H Jan; Geurts, Alexander C H; Smits, Paul; Hopman, Maria T E

    2010-03-01

    Autonomic dysreflexia is a hypertensive episode in spinal cord-injured individuals induced by exaggerated sympathetic activity and thought to be alpha-adrenergic mediated. alpha-Adrenoceptor antagonists have been a rational first choice; nevertheless, calcium channel blockers are primarily used in autonomic dysreflexia management. However, alpha-adrenoceptor blockade may leave a residual vasoconstrictor response to sympathetic nonadrenergic transmission unaffected. The aim was to assess the alpha-adrenergic contribution and, in addition, the role of supraspinal control to leg vasoconstriction during exaggerated sympathetic activity provoked by autonomic dysreflexia in spinal cord-injured individuals and by a cold pressure test in control individuals. Upper leg blood flow was measured using venous occlusion plethysmography during supine rest and during exaggerated sympathetic activity in 6 spinal cord-injured individuals and 7 able-bodied control individuals, without and with phentolamine (alpha-adrenoceptor antagonist) and nicardipine (calcium channel blocker) infusion into the right femoral artery. Leg vascular resistance was calculated. In spinal cord-injured individuals, phentolamine significantly reduced the leg vascular resistance increase during autonomic dysreflexia (8+/-5 versus 24+/-13 arbitrary units; P=0.04) in contrast to nicardipine (15+/-10 versus 24+/-13 arbitrary units; P=0.12). In controls, phentolamine completely abolished the leg vascular resistance increase during a cold pressure test (1+/-2 versus 18+/-14 arbitrary units; P=0.02). The norepinephrine increase during phentolamine infusion was larger (P=0.04) in control than in spinal cord-injured individuals. These results indicate that the leg vascular resistance increase during autonomic dysreflexia in spinal cord-injured individuals is not entirely alpha-adrenergic mediated and is partly explained by nonadrenergic transmission, which may, in healthy subjects, be suppressed by supraspinal

  7. Vascular Pharmacology of Mokuboito (Mu-Fang-Yi-Tang) and Its Constituents on the Smooth Muscle and the Endothelium in Rat Aorta

    PubMed Central

    Nishida, Seiichiro

    2007-01-01

    Pharmacological actions of Mokuboito and its constituents (Sinomenium acutum and sinomenine) on rat aorta were examined. Mokuboito and S. acutum at lower concentrations (0.03–1 mg ml−1) contracted the non-loaded aorta, but at higher concentrations (1–3 mg ml−1), reversed to dilate it. The vasoconstriction was blocked by phentolamine (10 μM). Sinomenine failed to exhibit the vasoconstriction. On the other hand, Mokuboito and S. acutum dilated the NE (5 μM)-induced vasoconstriction: at 3 mg ml−1, by 98.9 ± 2.5% (n = 6, P < 0.01) and 97.0 ± 4.8% (n = 6, P < 0.01). Vasorelaxation induced by Mokuboito and S. acutum was attenuated by indomethacin, L-NMMA and nicardipine. Propranolol decreased the vasorelaxation induced by Mokuboito, but not by S. acutum. Sinomenine also relaxed the constriction and at 100 μM, by 68.8 ± 5.1% (n = 7, P < 0.01). This vasorelaxation was attenuated by indomethacin, L-NMMA and nicardipine, and also by propranolol. Therefore, these results indicate that Mokuboito and its constituents exert both vasodilating actions mediated by endothelium-dependent mechanisms (PGI2 and NO from endothelium) and by endothelium-independent mechanisms (Ca2+ influx control on smooth muscle cells). Simultaneously, Mokuboito and S. acutum cause the vasoconstrictions mediated through α-adrenoceptor stimulation, but not sinomenine. Also, Mokuboito and sinomenine possess β-adrenoreceptor stimulating action, but not S. acutum. PMID:17965764

  8. [Drugs during preeclampsia. Fetal risks and pharmacology].

    PubMed

    Serreau, R

    2010-04-01

    During pregnancy, the maternal, placental and fetal physiological characteristics constantly evolve and thereby constantly alter drug bioavailability in the mother and feto-placental unit. Gastric emptying time is increased and bowel movements are reduced. Distribution in the maternal body is mainly influenced by body mass variations, water content and fat stores. Metabolic capacity of the liver appears unchanged but renal clearance of drugs is gradually increased. The placental transfer of most drugs mainly consists of passive diffusion between the maternal and fetal circulations, along their respective concentration gradients. Only the free, unbound and non-ionized fraction of the drug readily crosses the membranes. Four anti-hypertensive drugs have been granted a license for the treatment of PE since the year 2000: these are Clonidine (Catapressan), Nicardipine (Loxen+), Labetalol (Trandate), Dihydralazine (Nepressol). Dihydralazine, Labetalol and Nicardipine are not contraindicated in the breast feeding mother. The administration of a long acting Benzodiazepine during pregnancy can lead to new born intoxication of variable severity and duration. These symptoms may precede a withdrawal syndrome (hyper-excitability, tremor, gastro-intestinal upset, such as diarrhea or vomiting). Breast feeding by mothers using benzodiazepines (Nitrazepam and Midazolam) is not recommended. In France, the use of low molecular weight heparins is not recommended during pregnancy whereas in the United States, they are recommended as a prophylactic measure. Their high molecular weight prevents their diffusion across the placental membrane and therefore prevents any fetal or neonatal risk. Bromocriptine is used as an inhibitor of lactation. During the post-partum period, serious accidents have been described: these consist of systemic hypertension, fits, infarcts (cardiac and neurological). It is contraindicated in case of systemic hypertension.

  9. Characterization of a novel, hydrophilic dihydropyridine, NKY-722, as a Ca2+ antagonist in bovine cultured adrenal chromaffin cells.

    PubMed Central

    Ohue, T.; Lee, K.; Koshimura, K.; Miwa, S.

    1991-01-01

    1. To characterize NKY-722, a novel hydrophilic dihydropyridine derivative, as a Ca2+ antagonist, we examined its effects on 45Ca2+ influx, intracellular free Ca2+ concentrations [( Ca2+]i), and release of noradrenaline and adrenaline in bovine cultured adrenal chromaffin cells. 2. NKY-722 had little effect on basal 45Ca2+ influx into the resting cells, but inhibited high K+ (35.9 mM)-evoked 45Ca2+ influx in a concentration-dependent manner with an IC50 value of 5.2 nM. 3. NKY-722 inhibited high K(+)-evoked increases in [Ca2+]i in a concentration-dependent manner without effect on the resting [Ca2+]i. 4. NKY-722 had little effect on basal release of noradrenaline and adrenaline but inhibited high K(+)-evoked release of noradrenaline and adrenaline in a concentration-dependent manner with IC50 values of 5.0 nM and 4.8 nM, respectively. 5. Nicardipine, a prototype of NKY-722, also inhibited high K(+)-evoked 45Ca2+ influx and release of noradrenaline and adrenaline in a concentration-dependent manner: the IC50 value for high K(+)-evoked 45Ca2+ influx was 51 nM, and the values for high K(+)-evoked release of noradrenaline and adrenaline were 52 nM and 50 nM, respectively. 6. These results show that NKY-722 is a hydrophilic Ca2+ antagonist ten times more potent than nicardipine. PMID:1912977

  10. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

    PubMed Central

    Jaarin, Kamsiah; Foong, Wai Dic; Yeoh, Min Hui; Kamarul, Zaman Yusoff Nik; Qodriyah, Haji Mohd Saad; Azman, Abdullah; Zuhair, Japar Sidik Fadhlullah; Juliana, Abdul Hamid; Kamisah, Yusof

    2015-01-01

    OBJECTIVES This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration. RESULTS Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension. PMID:26602523

  11. Influence of acute or chronic calcium channel antagonists on the acquisition and consolidation of memory and nicotine-induced cognitive effects in mice.

    PubMed

    Biala, Grazyna; Kruk-Slomka, Marta; Jozwiak, Krzysztof

    2013-07-01

    Nicotinic cholinergic receptors (nAChRs) form a heterogeneous family of ligand-gated ion channels found in the nervous system. The main objective of our research was to investigate the interaction between cholinergic nicotinic system and calcium homeostasis in cognitive processes using the modified elevated plus maze memory model in mice. The time each mouse took to move from the open arm to either of the enclosed arms on the retention trial (transfer latency, TL2) was used as an index of memory. Our results showed that a single injection of nicotine (0.035 and 0.175 mg/kg) shortened TL2 values, improving memory-related processes. Similarly, L-type calcium channel antagonists (CCAs), i.e., flunarizine, verapamil, amlodipine, nimodipine, nifedipine, and nicardipine (at the range of dose 5-20 mg/kg) administered before or after training, decreased TL2 value improving memory acquisition and/or consolidation. Interestingly, at the subthresold doses, flunarizine, nicardipine, amlodipine, verapamil, and bupropion, a nAChR antagonist, significantly reversed the nicotine improvement of memory acquisition, while flunarizine, verapamil, and bupropion attenuated the improvement of memory consolidation provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). After subchronic administration (14 days, i.p.) of verapamil and amlodipine, two CCAs with the highest affinity for nAChRs, only verapamil (5 mg/kg) impaired memory acquisition and consolidation while both verapamil and amlodipine, at the subthresold, ineffective dose (2.5 mg/kg), significantly reversed the improvement of memory provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). Our findings can be useful to better understand the interaction between cholinergic nicotinic receptors and calcium-related mechanisms in memory-related processes.

  12. Effects of bradykinin B2 receptor antagonism on the hypotensive effects of ACE inhibition.

    PubMed Central

    Bouaziz, H; Joulin, Y; Safar, M; Benetos, A

    1994-01-01

    1. The aim of this study was to determine the participation of endogenous bradykinin (BK) in the antihypertensive effects of the angiotensin converting enzyme inhibitor (ACEI), perindoprilat, in the spontaneously hypertensive rat (SHR) on different salt diets. 2. Conscious SHRs receiving either a low or a high NaCl diet were used in order to evaluate the respective roles of angiotensin II suppression and bradykinin stimulation in the acute hypotensive effects of perindoprilat. Two different B2 receptor antagonists (B 4146 and Hoe 140) were used after bolus administration of 7 mg kg-1 of the ACEI, perindoprilat. In separate animals, Hoe 140 was administered before the injection of perindoprilat. In other experiments, the effects of Hoe 140 on the hypotensive effects of the calcium antagonist, nicardipine, were tested. 3. The different NaCl diets had no effect on baseline blood pressure. Hoe 140 injection before ACE inhibition did not modify blood pressure. Perindoprilat caused more marked hypotension in the low salt-fed rats than in the high salt animals (P < 0.01). Administration of Hoe 140 or B4146 after perindoprilat significantly reduced the antihypertensive effects of perindoprilat in the different groups, but this effect was more pronounced in high salt-fed rats. However, in SHRs receiving Hoe 140 before perindoprilat, the antihypertensive effect of perindoprilat was completely abolished in both high or low salt diet rats. In separate experiments we confirmed that Hoe 140 did not affect the hypotensive efficacy of the calcium antagonist, nicardipine. 4. Our study shows that inhibition of endogenous bradykinin degradation participates in the acute antihypertensive effects of perindoprilat in SHRs. The role of bradykinin is more pronounced following exposure to a high salt diet i.e., when the renin-angiotensin system is suppressed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858859

  13. Formation of DNA-damaging N-nitroso compounds from the interaction of calcium-channel blockers with nitrite.

    PubMed

    Martelli, Antonietta; Robbiano, Luigi; Grossi, Sarah; Mattioli, Francesca; Brambilla, Giovanni

    2007-09-05

    A large number of drugs have been shown to react with nitrite to give genotoxic-carcinogenic N-nitroso compounds (NOC). However, the majority of drugs remain to be examined in this respect, among which calcium-channel blockers, all theoretically nitrosatable and widely used in the therapy of hypertension and other cardiovascular diseases. In this preliminary investigation, seven calcium-channel blockers have been examined either for their in vitro nitrosation according to the procedure recommended by the WHO, or for occurrence of liver DNA fragmentation, as detected by the Comet assay, in rats given by gavage 1/2 LD50 of the drug and 80 mg/kg of sodium nitrite. After 6h incubation the yields of NOC formed in vitro from nicardipine, nifedipine, nimodipine and nitrendipine ranged from 37 to 45% of the theoretical one, whereas the yields of NOC formed from diltiazem, gallopamil and verapamil ranged from 2 to 5%. In vivo, as compared with the effect of the same dose of the drug alone, a significant increase of both tail length and tail moment, indicative of an increased frequency of DNA single-strand breaks and alkali-labile sites, was produced in rat liver DNA by the administration with nitrite of gallopamil, nifedipine, nimodipine and nitrendipine, the ratio [tail length of drug+NaNO(2)/tail length of drug alone] being 3.2 for nimodipine, 3.1 for gallopamil 2.2 for nifedipine, and 2.1 for nitrendipine. Even if present, the increase in the degree of DNA fragmentation did not reach the statistical significance in rats given with nitrite nicardipine, diltiazem and verapamil. Further studies should be performed to investigate the formation of NOC in conditions simulating those occurring in the stomach of humans treated with a therapeutic dose, and to quantitate their genotoxic potency.

  14. Five different profiles of dihydropyridines in blocking T-type Ca(2+) channel subtypes (Ca(v)3.1 (alpha(1G)), Ca(v)3.2 (alpha(1H)), and Ca(v)3.3 (alpha(1I))) expressed in Xenopus oocytes.

    PubMed

    Furukawa, Taiji; Nukada, Toshihide; Namiki, Yoshiko; Miyashita, Yoriko; Hatsuno, Kento; Ueno, Yasunari; Yamakawa, Takeshi; Isshiki, Takaaki

    2009-06-24

    1,4-dihydropyridine (DHP) Ca(2+) antagonists have recently been shown to block T-type Ca(2+) channels, which may render favorable actions on cardiovascular systems. However, this evaluation remains to be done systematically for each T-type Ca(2+) channel subtype except for the Ca(v)3.1 (alpha(1G)) subtype. To address this issue at the molecular level, blocking effects of 14 kinds of DHPs (amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine), which are clinically used for treatments of hypertension, on 3 subtypes of T-type Ca(2+) channels [Ca(v)3.2 (alpha(1H)), Ca(v)3.3 (alpha(1I)), and Ca(v)3.1 (alpha(1G))] were investigated in the Xenopus oocyte expression system using the two-microelectrode voltage-clamp technique. These 3 kinds (alpha(1H), alpha(1I) and alpha(1G)) of T-type channels were blocked by amlodipine, manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine and efonidipine significantly blocked alpha(1H) and alpha(1G), but not alpha(1I) channels, while nilvadipine and nimodipine apparently blocked alpha(1H) and alpha(1I), but not alpha(1G) channels. Moreover, aranidipine blocked only alpha(1H) channels. By contrast, cilnidipine, felodipine, nifedipine and nitrendipine had little effects on these subtypes of T-type channels. The result indicates that the blockade of T-type Ca(2+) channels by derivatives of DHP Ca(2+) antagonist was selective for the channel subtype. Therefore, these selectivities of DHPs in blocking T-type Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side-effects and adverse effects.

  15. Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression.

    PubMed

    Takara, Kohji; Sakaeda, Toshiyuki; Tanigawara, Yusuke; Nishiguchi, Kohshi; Ohmoto, Nobuko; Horinouchi, Masanori; Komada, Fusao; Ohnishi, Noriaki; Yokoyama, Teruyoshi; Okumura, Katsuhiko

    2002-08-01

    The effects of 12 Ca(2+) antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [(3)H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [(3)H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 microM), manidipine (4.65 microM) and benidipine (4.96 microM), followed by bepridil (10.6 microM), barnidipine (12.6 microM), efonidipine (13.0 microM), verapamil (13.2 microM) and nilvadipine (18.0 microM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [(3)H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca(2+) antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA.

  16. The visceromotor responses to colorectal distension and skin pinch are inhibited by simultaneous jejunal distension.

    PubMed

    Shafton, Anthony D; Furness, John B; Ferens, Dorota; Bogeski, Goce; Koh, Shir Lin; Lean, Nicholas P; Kitchener, Peter D

    2006-07-01

    Noxious stimuli that are applied to different somatic sites interact; often one stimulus diminishes the sensation elicited from another site. By contrast, inhibitory interactions between visceral stimuli are not well documented. We investigated the interaction between the effects of noxious distension of the colorectum and noxious stimuli applied to the jejunum, in the rat. Colorectal distension elicited a visceromotor reflex, which was quantified using electromyographic (EMG) recordings from the external oblique muscle of the upper abdomen. The same motor units were activated when a strong pinch was applied to the flank skin. Distension of the jejunum did not provoke an EMG response at this site, but when it was applied during colorectal distension it blocked the EMG response. Jejunal distension also inhibited the response to noxious skin pinch. The inhibition of the visceromotor response to colorectal distension was prevented by local application of tetrodotoxin to the jejunum, and was markedly reduced when nicardipine was infused into the local jejunal circulation. Chronic sub-diaphragmatic vagotomy had no effect on the colorectal distension-induced EMG activity or its inhibition by jejunal distension. The nicotinic antagonist hexamethonium suppressed phasic contractile activity in the jejunum, had only a small effect on the inhibition of visceromotor response by jejunal distension. It is concluded that signals that arise from skin pinch and colorectal distension converge in the central nervous system with pathways that are activated by jejunal spinal afferents; the jejunal signals strongly inhibit the abdominal motor activity evoked by noxious stimuli.

  17. Use of Continuous Infusion Hydralazine in a Pediatric Patient on Mechanical Circulatory Support

    PubMed Central

    Dillman, Nicholas O.; Anders, Marc M.

    2016-01-01

    Hydralazine is a direct peripheral arterial vasodilator used for acute hypertension. Usually administered as a bolus dose, continuous infusion has been described during pregnancy for preeclampsia and eclampsia and in limited reports in cardiac surgeries for afterload reduction. This case describes the use of continuous infusion hydralazine for afterload reduction in an infant receiving extracorporeal membrane oxygenation (ECMO) post–cardiac surgery. Postsurgery, the patient's mean arterial pressures (MAPs) could not be controlled despite escalating doses of vasodilatory medications including nitroprusside, nicardipine, and milrinone; hence, continuous infusion hydralazine was initiated. Although the initiation of a hydralazine infusion produced a decrease in MAP, the response was unsustainable. This case highlights an alternative method for managing systemic vascular resistance and cardiac output to allow for myocardial recovery after cardiac surgery and use of extracorporeal support. At the time of this writing, this is the first published case describing hydralazine administration via continuous infusion in pediatric patients. The use of continuous infusion hydralazine for afterload reduction provided a brief, non-sustained reduction in MAP in a post–cardiac surgery infant managed on ECMO support. PMID:27453704

  18. Calcium channels responsible for potassium-induced transmitter release at rat cerebellar synapses.

    PubMed Central

    Momiyama, A; Takahashi, T

    1994-01-01

    The effects of calcium channel blockers on potassium-induced transmitter release were studied in thin slices of cerebellum from neonatal rats using whole-cell patch clamp methods. Miniature inhibitory postsynaptic currents (mIPSCs) mediated by gamma-aminobutyric acid (GABA) were recorded from deep cerebellar nuclear neurones in the presence of tetrodotoxin. The frequency of mIPSCs was reproducibly increased by a brief application of high-potassium solution. In the presence of the L-type Ca2+ channel blocker nicardipine (10 microM), the potassium-induced increase in mIPSC frequency was suppressed by 49%. Neither the mean amplitude nor the time course of mIPSCs was affected by the blocker. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX, 3 microM) had no effect on the frequency of potassium-induced mIPSCs. The P-type Ca2+ channel blocker omega-Aga-IVA (200 nM) suppressed the potassium-induced increase in mIPSC frequency by 83% without affecting the mean amplitude or time course of mIPSCs. Comparing these data with previous studies of neurally evoked transmission, it is concluded that the Ca2+ channel subtypes responsible for potassium-induced transmitter release may be different from those mediating fast synaptic transmission. PMID:7913967

  19. Semiempirical Rules To Determine Drug Sensitivity and Ionization Efficiency in Secondary Ion Mass Spectrometry Using a Model Tissue Sample.

    PubMed

    Vorng, Jean-Luc; Kotowska, Anna M; Passarelli, Melissa K; West, Andrew; Marshall, Peter S; Havelund, Rasmus; Seah, Martin P; Dollery, Colin T; Rakowska, Paulina D; Gilmore, Ian S

    2016-11-15

    There is an increasing need in the pharmaceutical industry to reduce drug failure at late stage and thus reduce the cost of developing a new medicine. Since most drug targets are intracellular, this requires a better understanding of the drug disposition within a cell. Secondary ion mass spectrometry has been identified as a potentially important technique to do this, as it is label-free and allows imaging in 3D with subcellular resolution and recent studies have shown promise for amiodarone. An important analytical parameter is sensitivity, and we measure this in a bovine liver homogenate reference sample for 20 drugs representing important class types relevant to the pharmaceutical industry. We also measure the sensitivity for pure drug and show, for the first time, that the secondary ion mass spectrometry (SIMS) positive ionization efficiency for small molecules is a simple power-law relationship to the log P value. This discovery will be important for advancing the understanding of the SIMS ionization process in small molecules that has, until now, been elusive. This simple relationship is found to hold true for drug doped in the bovine liver homogenate reference sample, except for fluticasone, nicardipine, and sorafenib which suffer from severe matrix suppression. This relationship provides a simple semiempirical method to determine drug sensitivity for positive secondary ions. Furthermore, we show, on chosen models, how the use of different solvents during sample preparation can affect the ionization of analytes.

  20. Prolonged Infusion of Inhibitors of Calcineurin or L-Type Calcium Channels Does Not Block Mossy Fiber Sprouting in a Model of Temporal Lobe Epilepsy

    PubMed Central

    Ingram, Elizabeth A.; Toyoda, Izumi; Wen, Xiling; Buckmaster, Paul S.

    2008-01-01

    Purpose It would be useful to selectively block granule cell axon (mossy fiber) sprouting to test its functional role in temporal lobe epileptogenesis. Targeting axonal growth cones may be an effective strategy to block mossy fiber sprouting. L-type calcium channels and calcineurin, a calcium-activated phosphatase, are critical for normal growth cone function. Previous studies have provided encouraging evidence that blocking L-type calcium channels or inhibiting calcineurin during epileptogenic treatments suppresses mossy fiber sprouting. Methods Rats were treated systemically with pilocarpine to induce status epilepticus, which lasted at least 2 hours. Then, osmotic pumps and cannulae were implanted to infuse calcineurin inhibitors (FK506 or cyclosporin A) or an L-type calcium channel blocker (nicardipine) into the dorsal dentate gyrus. After 28 days of continuous infusion, extent of mossy fiber sprouting was evaluated with Timm-staining and stereological methods. Results Percentages of volumes of the granule cell layer + molecular layer that were Timm-positive were similar in infused and noninfused hippocampi. Conclusions These findings suggest inhibiting calcineurin or L-type calcium channels does not block mossy fiber sprouting in the pilocarpine-treated rat model of temporal lobe epilepsy. PMID:18616558

  1. Multiattribute evaluation in formulary decision making as applied to calcium-channel blockers.

    PubMed

    Schumacher, G E

    1991-02-01

    The use of multiattribute utility theory (MAUT) to make a formulary decision involving calcium-channel blockers (CCBs) is described. The MAUT method is a procedure for identifying, characterizing, and comparing the many variables that may affect a decision. Although applications in pharmacy have been infrequent, MAUT should be particularly appealing to formulary committees. The steps of the MAUT method are (1) determine the viewpoint of the decision makers, (2) identify the decision alternatives, (3) identify the attributes to be evaluated, (4) identify the factors to be used in evaluating the attributes, (5) establish a utility scale for scoring each factor, (6) transform the values for each factor to its utility scale, (7) determine weights for each attribute and factor, (8) calculate the total utility score for each decision alternative, (9) determine which decision alternative has the greatest total score, and (10) perform a sensitivity analysis. The viewpoint of a formulary committee in a health maintenance organization was simulated to develop a model for using the MAUT method to compare CCBs for single-agent therapy of chronic stable angina in ambulatory patients for one year. The attributes chosen were effectiveness, safety, patient acceptance, and cost and weighted 36%, 29%, 21%, and 14%, respectively, as contributions to the evaluation. The rank order of the decision alternatives was (1) generic verapamil, (2) brand-name verapamil, (3) diltiazem, (4) nicardipine, and (5) nifedipine. The MAUT method provides a standardized yet flexible format for comparing and selecting among formulary alternatives.

  2. Evaluation of the chiral recognition properties and the column performances of three chiral stationary phases based on cellulose for the enantioseparation of six dihydropyridines by high-performance liquid chromatography.

    PubMed

    Yu, Jia; Tang, Jing; Yuan, Xiaowei; Guo, Xingjie; Zhao, Longshan

    2017-03-28

    Separations of six dihydropyridine enantiomers on three commercially available cellulose-based chiral stationary phases (Chiralcel OD-RH, Chiralpak IB, and Chiralpak IC) were evaluated with high-performance liquid chromatography (HPLC). The best enantioseparation of the six chiral drugs was obtained with a Chiralpak IC (250 × 4.6 mm i.d., 5 μm) column. Then the influence of the mobile phase including an alcohol-modifying agent and alkaline additive on the enantioseparation were investigated and optimized. The optimal mobile phase conditions and maximum resolution for every analyte were as follows respectively: n-hexane/isopropanol (85:15, v/v) for nimodipine (R = 5.80) and cinildilpine (R = 5.65); n-hexane/isopropanol (92:8, v/v) for nicardipine (R = 1.76) and nisoldipine (R = 1.92); and n-hexane/isopropanol/ethanol (97:2:1, v/v/v) for felodipine (R = 1.84) and lercanidipine (R = 1.47). Relative separation mechanisms are discussed based on the separation results, and indicate that the achiral parts in the analytes' structure showed an important influence on the separation of the chiral column.

  3. Protection against adriamycin (doxorubicin)-induced toxicity in mice by several clinically used drugs.

    PubMed

    Shinozawa, S; Gomita, Y; Araki, Y

    1987-02-01

    Protective effects of clinically used drugs against adriamycin (ADM)-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.). The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg), 402.2% for dextran sulfate (MDS, 300 mg/kg), 121.6% for flavin adenine dinucleotide (20 mg/kg), 236.3% for adenosine triphosphate disodium (50 mg/kg), 213.7% for reduced glutathione (100 mg/kg), 121.6% for phytonadione (50 mg/kg), 155.2% for inositol nicotinate (Ino-N, 500 mg/kg), 335.5% for nicomol (1000 mg/kg), 157.5% for nicardipine (10 mg/kg) and 123.3% for dipyridamol (50 mg/kg). Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.

  4. Cardiovascular Pharmacology of Sinomenine: The Mechanical and Electropharmacological Actions

    PubMed Central

    Nishida, Seiichiro; Satoh, Hiroyasu

    2007-01-01

    Sinomenine is one of the alkaloids extracted from Chinese medical plant, Sinomenium acutum Rehder et Wilson. Sinomenine has been used for Rheumatoid arthritis as an anti-inflammatory and immunomodulative drugs. We have so far been investigated the cardiovascular pharmacological actions of sinomenine. Sinomenine dilated NE (5 μM)-, KCl (60 mM)- and PDB (300 nM)-induced vasoconstrictions. The pretreatment with nicardipine (0.1 μM), staurosporine (30 nM), L-NMMA (100 μM), indomethacin (10 μM) or propranolol significantly attenuated the sinomenine-induced vasorelaxation. Therefore, these results indicate that sinomenine causes the vasorelaxation by the involvement with the inhibitions of Ca2+ current (ICa) and PK-C, β-adrenoceptor stimulation, and the activation of NO and PGI2 syntheses in endothelium. On the other hand, in the ventricular cardiomyocytes of guinea pig, sinomenine inhibits ICa and simultaneously decreases the delayed rectifier K+ current (IK), resulting in the prolongation of action potential duration. Sinomenine also suppresses the dysrhysmias induced by triggered activities under the Ca2+ overload condition. Therefore, sinomenine may be expected as one of effective therapeutic drugs for heart failure and dysrhythmias, and may maintain the cardiovascular functions due to modulation of cardiac ionic channels and blood vessels. PMID:21901066

  5. Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury.

    PubMed

    Kawai, Yoshiko; Nakao, Takafumi; Kunimura, Naoshi; Kohda, Yuka; Gemba, Munekazu

    2006-01-01

    We investigated the involvement of reactive oxygen species (ROS) and intracellular calcium in nephrotoxicity related to an antitumor agent, cisplatin. In this study, we employed cultured renal epithelial cells (LLC-PK1). Cisplatin at 500 microM significantly increased the production of ROS 5 h and caused cell injury. This agent significantly increased the intracellular calcium level ([Ca2+]i) in a dose-dependent manner 1 h or more after exposure. DPPD (N,N'-diphenyl-p-phenylenediamine), an antioxidant, inhibited a cisplatin-related increase in active oxygen production and cell injury but did not inhibit an early increase in the [Ca2+]i level. An intracellular calcium-chelating compound BAPTA-AM (1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester) inhibited an increase in ROS production and cell injury induced by cisplatin. Furthermore, BAPTA-AM suppressed the rise of [Ca2+]i level in 1 h after exposure; however, an extracellular calcium chelator EGTA and a calcium antagonist nicardipine did not inhibit the rise in [Ca2+]i level in the early phase. An NADPH oxidase inhibitor inhibited a cisplatin-related increase in ROS production and cell disorder. These results suggest that cisplatin-related calcium release from the site of intracellular calcium storage in the early phase causes oxidative stress in renal tubular epithelial cells. Cisplatin may increase the intracellular production of ROS via NADPH oxidase.

  6. Cell membrane stretch activates intermediate-conductance Ca2+-activated K+ channels in arterial smooth muscle cells.

    PubMed

    Hayabuchi, Yasunobu; Nakaya, Yutaka; Mawatari, Kazuaki; Inoue, Miki; Sakata, Miho; Kagami, Shoji

    2011-01-01

    The aim of this study is to determine the signal transduction of membrane stretch on intermediate-conductance Ca(2+)-activated K(+) (IKca) channels in rat aorta smooth muscle cells using the patch-clamp technique. To stretch the cell membrane, both suction to the rear end of patch pipette and hypotonic shock were used. In cell-attached and inside-out patch configurations, the open probability of IKca channels increased when 20- to 45-mmHg suction was applied. Hyposmotic swelling efficiently increased IKca channel current. When the Ca(2+)-free solution was superfused, the activation of IKca current by the hyposmotic swelling was reduced. Furthermore, gadolinium (Gd(3+)) attenuated the activation of IKca channels induced by hyposmotic swelling, whereas nicardipine did not. In the experiments with Ca(2+)-free bath solution, pretreatment with GF109203X, a protein kinase C (PKC) inhibitor, completely abolished the stretch-induced activation of IKca currents. The stretch-induced activation of IKca channels was strongly inhibited by cytochalasin D, indicating a role for the F-actin in modulation of IKca channels by changes in cell stretching. These data suggest that cell membrane stretch activates IKca channels. In addition, the activation is associated with extracellular Ca(2+) influx through stretch-activated nonselective cation channels, and is also modulated by the F-actin cytoskeleton and the activation of PKC.

  7. Tonic regulation of vascular tone by nitric oxide and chloride ions in rat isolated small coronary arteries.

    PubMed

    Graves, J E; Greenwood, I A; Large, W A

    2000-12-01

    We have investigated the involvement of Cl(-) in regulating vascular tone in rat isolated coronary arteries mounted on a small vessel myograph. Mechanical removal of the endothelium or inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) led to contraction of rat coronary arteries, and these contractions were sensitive to nicardipine (10(-6) M). This suggests that release of NO tonically inhibits a contractile mechanism that involves voltage-dependent Ca(2+) channels. In arteries contracted with L-NAME, switching the bathing solution to physiological saline solution with a reduced Cl(-) concentration potentiated the contraction. DIDS (5 x 10(-6)-3 x 10(-4) M) caused relaxation of L-NAME-induced tension (IC(50) = 55 +/- 10 microM), providing evidence for a role of Cl(-). SITS (10(-5)-5 x 10(-4) M) did not affect L-NAME-induced tension, suggesting that DIDS is not acting by inhibition of anion exchange. Mechanical removal of the endothelium led to contraction of arteries, which was sensitive to DIDS (IC(50) = 50 +/- 8 microM) and was not affected by SITS. This study suggests that, in rat coronary arteries, NO tonically suppresses a contractile mechanism that involves a Cl(-) conductance.

  8. Role of neuronal and vascular Ca(2+)-channels in the ACTH-induced reversal of haemorrhagic shock.

    PubMed Central

    Guarini, S.; Bazzani, C.; Bertolini, A.

    1993-01-01

    1. In a rat model of volume-controlled haemorrhagic shock causing the death of all control (saline-treated) animals within 30 min, the intravenous (i.v.) bolus injection of ACTH-(1-24) at a dose of 160 micrograms kg-1 produced an impressive and sustained restoration of arterial pressure, pulse pressure and respiratory function, with 100% survival at the end of the observation period (2 h). 2. Both intracerebroventricular (i.c.v., 0.015-0.06 microgram kg-1) and i.v. (5 micrograms kg-1) pretreatment with the N-calcium channel blocker, omega-conotoxin GVIA, and i.v. (but not i.c.v.) pretreatment with the L-calcium channel blocker, nicardipine (125-500 micrograms kg-1) dose-dependently prevented the ACTH-induced shock reversal. 3. These results further indicate that the effect of ACTH in haemorrhagic shock may involve a neuronal link and the eventual restoration of vascular tone mediated by N- and L-type calcium channels, respectively. PMID:8395293

  9. Thyroid storm induced by TSH-secreting pituitary adenoma: a case report.

    PubMed

    Fujio, Shingo; Ashari; Habu, Mika; Yamahata, Hitoshi; Moinuddin, F M; Bohara, Manoj; Arimura, Hiroshi; Nishijima, Yui; Arita, Kazunori

    2014-01-01

    Thyroid stimulating hormone-secreting pituitary adenomas (TSHomas) are uncommon tumors of the anterior pituitary gland. Patients with TSHomas may present with hyperthyroidism, but the incidence of thyroid storm due to TSHomas has yet to be determined. We report a rare case of thyroid storm caused by TSHoma in a 54-year-old woman. Preoperatively she had symptoms of excessive sweating and palpitation. Blood tests showed inappropriate secretion of TSH with blood TSH 6.86 μ U/mL, fT3 19.8 pg/mL, and fT4 5.95 ng/dL. Magnetic resonance imaging (MRI) revealed a pituitary tumor with maximum diameter of 13 mm that was extirpated through transsphenoidal route. After operation the patient was stuporous and thyroid storm occurred presenting with hyperthermia, hypertension, and tachycardia. It was well managed with nicardipine, midazolam, steroids, and potassium iodide. Immunohistochemical staining of tumor specimen was positive for TSH and growth hormone (GH). One year after operation, fT3 and fT4 levels were still high. As her tumor was diagnosed to be GH- and TSH-producing adenoma, octreotide injection therapy was started, which normalized thyroid hormone levels. This is the second reported case with thyroid storm due to TSHoma and emphasizes the importance of strategies with interdisciplinary cooperation for prevention of such emergency conditions.

  10. Use of Continuous Infusion Hydralazine in a Pediatric Patient on Mechanical Circulatory Support.

    PubMed

    Dillman, Nicholas O; Anders, Marc M; Moffett, Brady S

    2016-01-01

    Hydralazine is a direct peripheral arterial vasodilator used for acute hypertension. Usually administered as a bolus dose, continuous infusion has been described during pregnancy for preeclampsia and eclampsia and in limited reports in cardiac surgeries for afterload reduction. This case describes the use of continuous infusion hydralazine for afterload reduction in an infant receiving extracorporeal membrane oxygenation (ECMO) post-cardiac surgery. Postsurgery, the patient's mean arterial pressures (MAPs) could not be controlled despite escalating doses of vasodilatory medications including nitroprusside, nicardipine, and milrinone; hence, continuous infusion hydralazine was initiated. Although the initiation of a hydralazine infusion produced a decrease in MAP, the response was unsustainable. This case highlights an alternative method for managing systemic vascular resistance and cardiac output to allow for myocardial recovery after cardiac surgery and use of extracorporeal support. At the time of this writing, this is the first published case describing hydralazine administration via continuous infusion in pediatric patients. The use of continuous infusion hydralazine for afterload reduction provided a brief, non-sustained reduction in MAP in a post-cardiac surgery infant managed on ECMO support.

  11. Hypertension in the elderly.

    PubMed

    Hansson, L

    1996-10-01

    TREATMENT OF ELDERLY HYPERTENSIVES: Treatment of hypertension in the elderly is nowadays an accepted and highly effective medical intervention following the positive reports on the benefits of lowering elevated arterial pressure in elderly patients. Most of the intervention studies an antihypertensive treatment in elderly patients have used diuretics or beta-blockers or the two in combination as the therapy by which blood pressure was lowered. However, from a theoretical point of view, novel therapies such as calcium antagonists could offer advantages that would translate into an even greater reduction in cardiovascular morbidity and mortality than has been obtained with the traditional antihypertensive therapies used so far. DATA ON CALCIUM ANTAGONISTS IN THE ELDERLY: Some of the studies in elderly hypertensives that are currently in progress are using calcium antagonists as one of the main therapies, e.g. the Swedish Trial in Old patients with hypertension (STOP-Hypertension)-2 study and the Systolic hypertension in Europe (Syst-Eur) study. Another source of information is a large database on nicardipine, a dihydropyridine-derived calcium antagonist, used in the treatment of elderly hypertensives.

  12. Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury.

    PubMed

    Hellmich, Helen L; Eidson, Kristine A; Capra, Bridget A; Garcia, Jeanna M; Boone, Deborah R; Hawkins, Bridget E; Uchida, Tatsuo; Dewitt, Douglas S; Prough, Donald S

    2007-01-05

    Hippocampal damage contributes to cognitive dysfunction after traumatic brain injury (TBI). We previously showed that Fluoro-Jade, a fluorescent stain that labels injured, degenerating brain neurons, quantifies the extent of hippocampal injury after experimental fluid percussion TBI in rats. Coincidentally, we observed that injured neurons in the rat hippocampus also stained with Newport Green, a fluorescent dye specific for free ionic zinc. Here, we show that, regardless of injury severity or therapeutic intervention, the post-TBI population of injured neurons in rat hippocampal subfields CA1, CA3 and dentate gyrus is indistinguishable, both in numbers and anatomical distribution, from the population of neurons containing high levels of zinc. Treatment with lamotrigine, which inhibits presynaptic release of glutamate and presumably zinc that is co-localized with glutamate, reduced numbers of Fluoro-Jade-positive and Newport Green-positive neurons equally as did treatment with nicardipine, which blocks voltage-gated calcium channels through which zinc enters neurons. To confirm using molecular techniques that Fluoro-Jade and Newport Green-positive neurons are equivalent populations, we isolated total RNA from 25 Fluoro-Jade-positive and 25 Newport Green-positive pyramidal neurons obtained by laser capture microdissection (LCM) from the CA3 subfield, linearly amplified the mRNA and used quantitative ribonuclease protection analysis to demonstrate similar expression of mRNA for selected TBI-induced genes. Our data suggest that therapeutic interventions aimed at reducing neurotoxic zinc levels after TBI may reduce hippocampal neuronal injury.

  13. Interactions of ethanol on the acute toxicity of cocaine in the rat

    SciTech Connect

    Trouve, R. ); Latour, C ); Nahas, G.G. Columbia Univ., New York, NY )

    1992-02-26

    Administration of 65 mg/kg in the awake rate, restrained and instrumented, is associated with cardiovascular toxicity, convulsions and lethality within 9 feet 44 inches {plus minus} 4 feet 56 inches. Such an outcome is prevented if selected Ca{sup 2+} antagonists are administered intraarterially 5 minutes following cocaine. Four additional groups of Sprague Dawley rats were studied. The first was administered I.P. ethanol 1.5-2.0 gr. Such doses were well tolerated only producing hypertension of 50 minutes duration and all animals survived without apparent ill effects. Second and third groups were first administered the same doses of ethanol and 15 minutes later 65 mg/kg of cocaine. Survival time was 5 feet 49 inches with 1.5 mg/kg ethanol and 5 feet 57 inches {plus minus} 1 foot 26 inches with 2 mg/kg, significantly less than after cocaine administration alone. In a fourth group, animals were treated intraarterially with nicardipine or flunarizine, 2 minutes after cocaine. Survival time was not different from saline control. Ethanol enhances significantly cocaine lethal toxicity in the rate and prevents the protective effects of antidotes to this alkaloid.

  14. Role of calcium influx through voltage-operated calcium channels and of calcium mobilization in the physiology of Schistosoma mansoni muscle contractions.

    PubMed

    Mendonça-Silva, D L; Novozhilova, E; Cobbett, P J R; Silva, C L M; Noël, F; Totten, M I J; Maule, A G; Day, T A

    2006-07-01

    We tested the hypothesis that voltage-operated Ca2+ channels mediate an extracellular Ca2+ influx in muscle fibres from the human parasite Schistosoma mansoni and, along with Ca2+ mobilization from the sarcoplasmic reticulum, contribute to muscle contraction. Indeed, whole-cell voltage clamp revealed voltage-gated inward currents carried by divalent ions with a peak current elicited by steps to +20 mV (from a holding potential of -70 mV). Depolarization of the fibres by elevated extracellular K+ elicited contractions that were completely dependent on extracellular Ca2+ and inhibited by nicardipine (half inhibition at 4.1 microM). However these contractions were not very sensitive to other classical blockers of voltage-gated Ca2+ channels, indicating that the schistosome muscle channels have an atypical pharmacology when compared to their mammalian counterparts. Futhermore, the contraction induced by 5 mM caffeine was inhibited after depletion of the sarcoplasmic reticulum either with thapsigargin (10 microM) or ryanodine (10 microM). These data suggest that voltage-operated Ca2+ channels do contribute to S. mansoni contraction as does the mobilization of stored Ca2+, despite the small volume of sarcoplasmic reticulum in schistosome smooth muscles.

  15. Endothelin- and oxytocin-induced calcium signaling in cultured human myometrial cells.

    PubMed Central

    Maher, E; Bardequez, A; Gardner, J P; Goldsmith, L; Weiss, G; Mascarina, M; Aviv, A

    1991-01-01

    The demonstration that endothelin (ET) induces rat uterine contraction, coupled with the observation that ET is present in human amniotic fluid, suggests that the myometrium may be an important target organ for this hormone. We show that in quiescent human myometrial cells ET produced a dose-dependent increase in cytosolic free Ca2+ (Cai2+), which was markedly attenuated when the cells were studied in Ca2(+)-free media. Preincubation with nicardipine, diltiazem, or verapamil reduced the ET-evoked Cai2+ transient by 30, 40, and 65%, respectively. The presence of voltage sensitive Ca2+ channels was demonstrated by Mn2+ quenching of fura-2. Activation of the Na+/H+ antiport could not be demonstrated with ET stimulation. In nonquiescent cells, the ET-evoked Cai2+ transient was significantly reduced, while the response to oxytocin was retained. This is at least partially explained by a reduction in Bmax (maximal binding capacity) for ET (mean +/- SEM) from 3,506 +/- 268 binding sites/cell in quiescent cells to 2,411 +/- 300 binding sites/cell, as well as 72% increase in Kd (equilibrium dissociation constant), in the nonquiescent cells. We conclude that, in human myometrial cells, ET and oxytocin modulate Cai2+ through independent receptors and propose that ET, like oxytocin, is an important endogenous modulator of uterine contractility. Images PMID:1849147

  16. [Rapid detection of four antipertensive chemicals adulterated in traditional Chinese medicine for hypertension using TLC-SERS].

    PubMed

    Zhu, Qing-Xia; Cao, Yong-Bing; Cao, Ying-Ying; Lu, Feng

    2014-04-01

    A novel facile method for on-site detection of antipertensive chemicals (e. g. nicardipine hydrochloride, doxazosin mesylate, propranolol hydrochloride, and hydrochlorothiazide) adulterated in traditional Chinese medicine for hypertension using thin layer chromatography (TLC) combined with surface enhanced Raman spectroscopy (SERS) was reported in the present paper. Analytes and pharmaceutical matrices was separated by TLC, then SERS method was used to complete qualitative identification of trace substances on TLC plate. By optimizing colloidal silver concentration and developing solvent, as well as exploring the optimal limits of detection (LOD), the initially established TLC-SERS method was used to detect real hypertension Chinese pharmaceuticals. The results showed that this method had good specificity for the four chemicals and high sensitivity with a limit of detection as lower as to 0.005 microg. Finally, two of the ten antipertensive drugs were detected to be adulterated with chemicals. This simple and fast method can realize rapid detection of chemicals illegally for doping in antipertensive Chinese pharmaceuticals, and would have good prospects in on-site detection of chemicals for doping in Chinese pharmaceuticals.

  17. [Anesthetic Management of a Parturient with Eclampsia, Posterior Reversible Encephalopathy Syndrome and Pulmonary Edema due to Pregnancy-induced Hypertension].

    PubMed

    Aida, Junko; Okutani, Hiroai; Oda, Yutaka; Okutani, Ryu

    2015-08-01

    A 27-year-old woman with mental retardation was admitted to a nearby hospital for an abrupt onset of seizure. Physical examination revealed remarkable hypertension and pregnancy with estimated gestational age of 28th week. Severe pulmonary edema and hypoxia led to a diagnosis of pregnancy-induced hypertension (PIH) accompanied by eclampsia. She was orotracheally intubated because of refractory seizure and hypoxemia, and transferred to our hospital for further treatment. Besides severe hypoxia and hypercapnea, an enhanced lesion was detected in the left posterior cerebrum by brain MRI. No abnormal findings were detected in the fetus, with heart rate of 150 beats x min. She was diagnosed with posterior reversible encephalopathy syndrome (PRES) caused by PIH and emergency cesarean section under general anesthesia was scheduled. A male newborn was delivered with Apgar score of 1/4 (1/5 min), followed by starting continuous infusion of nicardipine for controlling hypertension. Chest X-P on completion of surgery revealed remarkably alleviated pulmonary edema. She received intensive treatment and continued positive pressure ventilation for four days after delivery. She recovered with no neurological deficits and her child was well without any complications.

  18. Calcium channel receptor sites for (+)-[3H]PN 200-110 in coronary artery.

    PubMed

    Yamada, S; Kimura, R; Harada, Y; Nakayama, K

    1990-01-01

    The receptor sites for 1,4-dihydropyridine (DHP) Ca++ channel antagonists in porcine coronary artery were identified and characterized by a binding assay using (+)-[3H]PN 200-110 as a radioligand. Specific (+)-[3H]PN 200-110 binding in porcine coronary artery was saturable, reversible and of high affinity (Kd = 0.24 nM) and it showed a pharmacological specificity as well as stereoselectivity which characterized the receptor sites for DHP Ca++ channel antagonists. DHP antagonists competed for the (+)-[3H]PN 200-110 binding in order: PN 200-110 greater than mepirodipine greater than nisoldipine greater than nicardipine greater than nitrendipine greater than nimodipine greater than nifedipine greater than (-)-PN 200-110. (+)-PN 200-110 was approximately 140 times as potent as the (-)-isomer. The potencies (PKi) of these eight DHP Ca++ channel antagonists in competing for (+)-[3H]PN 200-110 binding sites in porcine coronary artery correlated well with their pharmacological potencies. Specific (+)-[3H]PN 200-110 binding in the coronary artery was enhanced by d-cis-diltiazem and was inhibited incompletely by verapamil and D-600. In EDTA-pretreated coronary artery, the maximal number of binding sites for specific (+)-[3H]PN 200-110 binding was reduced (80%) markedly, and it was restored to the untreated level by the addition of Ca++ and Mg++.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Effect of barnidipine on blood flow to major organs and renal function in anaesthetized dogs and spontaneously hypertensive rats.

    PubMed

    Saitoh, M; Kasai, C; Ishikawa, J; Masaki, K; Asano, M

    1995-12-01

    1. The effects of barnidipine on blood flow to major organs and on renal function were investigated in anaesthetized dogs and conscious spontaneously hypertensive rats (SHR), and the results were compared with those for nicardipine, nitrendipine, nisoldipine, manidipine and amlodipine. 2. In anaesthetized dogs, barnidipine (0.3-3 mu g/kg i.v.) dose-dependently decreased blood pressure and increased or preserved blood flow in the vertebral, coronary, femoral and renal arteries. The effect of barnidipine on blood flow was the most potent of the compounds tested. In conscious SHR, barnidipine (0.3-3 mg/kg p.o.) produced a dose-dependent antihypertensive effect and decreased renal vascular resistance. Barnidipine also dose-dependently increased urinary volume. The antihypertensive and diuretic effects of barnidipine were the most potent of the drugs tested. 3. In summary, barnidipine was shown to preserve or increase blood flow to major organs and to produce diuretic activity with a decrease in blood pressure. These findings suggest that barnidipine maintains or promotes renal function at antihypertensive doses.

  20. Relationship between lipophilicities of 1,4-dihydropyridine derivatives and pharmacokinetic interaction strengths with grapefruit juice.

    PubMed

    Uesawa, Yoshihiro; Mohri, Kiminori

    2008-01-01

    It is well known fact that the strengths of drug interactions with grapefruit juice (GFJ) differ greatly depending on the 1,4-dihydropyridine calcium channel antagonist (DHP) used. However, there are no available data on the relationship between interactions with GFJ and its physicochemical attributes. Therefore we endeavored to study the correlation between calculated logP values, indicating lipophilicity, from chemical structures of DHPs as well as water diffusion, molecular volume, molecular polarization, molecular density, refractive index, topologic polar surface area, and calculated molar refractivity. Thirteen forms of DHP, amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and pranidipine were analyzed due to clinical trials performed with GFJ and these agents. The pharmacokinetic interaction strengths were defined in common logarithmic values of increasing ratios of area under the plasma concentration-time curve (AUC) with GFJ intake compared with controls. Physicochemical properties including three categories of predicted logP values were calculated from the structures of DHPs and their estimated relationship with the interactions. As a result, the logP values indicated significant positive correlations with the interaction strengths. This finding suggests that lipophilicity is an important factor in the strengths of pharmacokinetic interactions of DHPs with GFJ intake.

  1. Anti-leishmanial and anti-trypanosomal activities of 1,4-dihydropyridines: In vitro evaluation and structure-activity relationship study.

    PubMed

    Reimão, Juliana Q; Scotti, Marcus T; Tempone, André G

    2010-11-15

    Leishmaniasis and Chagas' disease constitute a relevant health and socio-economic problem in Latin America, Africa, and Asia. The therapeutic interventions rely on inefficient and highly toxic drugs with systemic side effects in patients. Considering the multiple biological activities of the calcium channel blockers and the high versatility of 1,4-dihydropyridines, eight clinically used 1,4-dihydropyridines (azelnidipine, amlodipine, cilnidipine, lercanidipine, nicardipine, nifedipine, nimodipine and nitrendipine) were in vitro tested against Leishmania and Trypanosoma cruzi parasites, and their cytotoxicity was tested against mammalian cells. In addition, a QSAR study was performed in order to delineate further structural requirements for the anti-protozoan activity and to predict the biological potency of 1,4-dihydropyridines. The tested compounds were effective against Leishmania (L.) amazonensis, Leishmania (V.)braziliensis, Leishmania (L.) chagasi, and Leishmania (L.) major promastigotes, L. (L.) chagasi intracellular amastigotes and T. cruzi trypomastigotes with 50% inhibitory concentration (IC(50)) values in the range of 2.6-181μM. The QSAR provided useful information about the structural features of the anti-protozoan activities, including diphenylpropyl and diphenylmethylazetidin groups at position 4 of the 1,4-dihydropyridine ring, allowing the prediction of two novel potential anti-protozoan analogs.

  2. Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

    SciTech Connect

    Veinberg, Stanislav L.; Johnston, Karen E.; Jaroszewicz, Michael J.; Kispal, Brianna M.; Mireault, Christopher R.; Kobayashi, Takeshi; Pruski, Marek; Schurko, Robert W.

    2016-06-08

    14N ultra-wideline (UW), 1H{15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. Here, a case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationary samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R"NH+ and RR'NH2+) or other (i.e., RNH2 and RNO2) nitrogen environments.

  3. A novel impedance-based cellular assay for the detection of anti-calcium channel autoantibodies in type 1 diabetes.

    PubMed

    Jackson, Michael W; Gordon, Tom P

    2010-09-30

    We have recently postulated that functional autoantibodies (Abs) against L-type voltage-gated calcium channels (VGCCs) contribute to autonomic dysfunction in type 1 diabetes (T1D). Previous studies based on whole-organ assays have proven valuable in establishing the mechanism of anti-VGCC Ab activity, but are complex and unsuitable for screening large patient cohorts. In the current study, we used real-time dynamic monitoring of cell impedance to demonstrate that anti-VGCC Abs from patients with T1D inhibit the adherence of Rin A12 cells. The functional effect of the anti-VGCC Abs was mimicked by the dihydropyridine agonist, Bay K8644, and reversed by the antagonist, nicardipine, providing a pharmacological link to the whole-organ studies. IVIg neutralized the effect on cell adhesion of the anti-VGCC Abs, consistent with the presence of anti-idiotypic Abs in IVIg that may prevent the emergence of pathogenic Abs in healthy individuals. The cell impedance assay can be performed in a 96 well plate format, and represents a simple method for detecting the presence of anti-VGCC activity in patient immunoglobulin (IgG). The new cell assay should prove useful for further studies to determine the prevalence of the Ab and its association with symptoms of autonomic dysfunction in patients with T1D.

  4. Systematic approach to optimize a pretreatment method for ultrasensitive liquid chromatography with tandem mass spectrometry analysis of multiple target compounds in biological samples.

    PubMed

    Togashi, Kazutaka; Mutaguchi, Kuninori; Komuro, Setsuko; Kataoka, Makoto; Yamazaki, Hiroshi; Yamashita, Shinji

    2016-08-01

    In current approaches for new drug development, highly sensitive and robust analytical methods for the determination of test compounds in biological samples are essential. These analytical methods should be optimized for every target compound. However, for biological samples that contain multiple compounds as new drug candidates obtained by cassette dosing tests, it would be preferable to develop a single method that allows the determination of all compounds at once. This study aims to establish a systematic approach that enables a selection of the most appropriate pretreatment method for multiple target compounds without the use of their chemical information. We investigated the retention times of 27 known compounds under different mobile phase conditions and determined the required pretreatment of human plasma samples using several solid-phase and liquid-liquid extractions. From the relationship between retention time and recovery in a principal component analysis, appropriate pretreatments were categorized into several types. Based on the category, we have optimized a pretreatment method for the identification of three calcium channel blockers in human plasma. Plasma concentrations of these drugs in a cassette-dose clinical study at microdose level were successfully determined with a lower limit of quantitation of 0.2 pg/mL for diltiazem, 1 pg/mL for nicardipine, and 2 pg/mL for nifedipine.

  5. Therapeutic Interchange of Clevidipine For Sodium Nitroprusside in Cardiac Surgery

    PubMed Central

    Cruz, Joseph E.; Thomas, Zachariah; Lee, David; Moskowitz, David M.; Nemeth, Jeff

    2016-01-01

    Background: Generic price inflation has resulted in rising acquisition costs for sodium nitroprusside (SNP), an agent historically described as the drug of choice for the treatment of perioperative hypertension in cardiac surgery. Purpose: To describe the implementation and cost avoidance achieved by utilizing clevidipine as an alternative to SNP in cardiac surgery patients at a 520-bed community teaching hospital that performs more than 300 cardiac surgeries each year. Methods: A multidisciplinary team inclusive of anesthesiologists, intensivists, pharmacists, and surgeons collaborated to develop a therapeutic interchange for SNP in cardiac surgery patients. Consistent with current guidelines for therapeutic interchange, the goal was to encourage a less expensive alternative that was demonstrated to be at least therapeutically equivalent to SNP based on data derived from clinical trials published in peer-reviewed literature. A comprehensive literature review identified clevidipine as an alternative to SNP for perioperative hypertension in cardiac surgery. Nicardipine was considered as well, but was not chosen as a substitute due to lack of strong evidence and comparative data with SNP. Results: Clevidipine was implemented successfully in our cardiac surgery patients and will result in a net cost avoidance of approximately $300,000 in 2016. This is thought to be driven largely by the difference in acquisition cost between clevidipine and SNP. The operating room in our institution no longer keeps SNP stocked in anesthesia trays as a result of the success of our interchange. No requests have been made to return to the SNP standard. Conclusion: Through effective communication and multidisciplinary collaboration, our institution was able to develop an evidence-based and effective therapeutic interchange program for SNP. PMID:27757002

  6. Method development and validation for the simultaneous determination of cinnarizine and co-formulated drugs in pharmaceutical preparations by capillary electrophoresis.

    PubMed

    Abdelal, A A; Kitagawa, S; Ohtani, H; El-Enany, N; Belal, F; Walash, M I

    2008-02-13

    Rapid and simple capillary electrophoresis (CE) methods were developed for the simultaneous determinations of cinnarizine and domperidone (CN/DOM) and cinnarizine and nicergoline (CN/NIC) in their co-formulated tablets. The optimized CE conditions were as follows: running buffer, methanol-acetate buffer (pH 3.0, 10 mM) (80:20 and 85:15 (v/v) for CN/DOM and CN/NIC, respectively); applied voltage, 20 kV; UV detection wavelengths, 215 and 227 nm for CN/DOM and CN/NIC, respectively; hydrodynamic injection was performed at a height of 25 mm for 30 s. Quinine hydrochloride and nicardipine hydrochloride were used as internal standards for the determination of CN/DOM and CN/NIC, respectively. Calibration curves were linear over the ranges 0.25-20/0.375-15 microg/ml (CN/DOM) and 0.25-25/0.4-10 microg/ml (CN/NIC) in each optimized condition. Detection limits were 0.074/0.119 microg/ml and 0.072/0.116 microg/ml for CN/DOM and CN/NIC, respectively. The proposed methods were successfully applied for the simultaneous determination of both CN/DOM and CN/NIC in their co-formulated tablets without interfering peaks due to the excipients present in the pharmaceutical tablets. The estimated amounts of CN/DOM and CN/NIC were almost identical with the certified values, and their percentage relative standard deviation values (%R.S.D.) were found to be < or =2.34% (n=3).

  7. pH-Dependent Liquid-Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs.

    PubMed

    Indulkar, Anura S; Box, Karl J; Taylor, Robert; Ruiz, Rebeca; Taylor, Lynne S

    2015-07-06

    Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid-liquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson-Hasselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds-clotrimazole, nicardipine, and atazanavir-was determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson-Hasselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a

  8. LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

    PubMed Central

    Wang, Weiwei; Townes-Anderson, Ellen

    2015-01-01

    Purpose Rod photoreceptors retract their axon terminals and develop neuritic sprouts in response to retinal detachment and reattachment, respectively. This study examines the role of LIM kinase (LIMK), a component of RhoA and Rac pathways, in the presynaptic structural remodeling of rod photoreceptors. Methods Phosphorylated LIMK (p-LIMK), the active form of LIMK, was examined in salamander retina with Western blot and confocal microscopy. Axon length within the first 7 hours and process growth after 3 days of culture were assessed in isolated rod photoreceptors treated with inhibitors of upstream regulators ROCK and p21-activated kinase (Pak) (Y27632 and IPA-3) and a direct LIMK inhibitor (BMS-5). Porcine retinal explants were also treated with BMS-5 and analyzed 24 hours after detachment. Because Ca2+ influx contributes to axonal retraction, L-type channels were blocked in some experiments with nicardipine. Results Phosphorylated LIMK is present in rod terminals during retraction and in newly formed processes. Axonal retraction over 7 hours was significantly reduced by inhibition of LIMK or its regulators, ROCK and Pak. Process growth was reduced by LIMK or Pak inhibition especially at the basal (axon-bearing) region of the rod cells. Combining Ca2+ channel and LIMK inhibition had no additional effect on retraction but did further inhibit sprouting after 3 days. In detached porcine retina, LIMK inhibition reduced rod axonal retraction and improved retinal morphology. Conclusions Thus structural remodeling, in the form of either axonal retraction or neuritic growth, requires LIMK activity. LIM kinase inhibition may have therapeutic potential for reducing pathologic rod terminal plasticity after retinal injury. PMID:26658506

  9. Intercellular communication within the rat anterior pituitary gland. XV. Properties of spontaneous and LHRH-induced Ca2+ transients in the transitional zone of the rat anterior pituitary in situ.

    PubMed

    Hattori, Kazuki; Shirasawa, Nobuyuki; Suzuki, Hikaru; Otsuka, Takanobu; Wada, Ikuo; Yashiro, Takashi; Herbert, Damon C; Soji, Tsuyoshi; Hashitani, Hikaru

    2013-01-01

    In the transitional zone of the rat anterior pituitary, spontaneous and LHRH-induced Ca(2+) dynamics were visualized using fluo-4 fluorescence Ca(2+) imaging. A majority of cells exhibited spontaneous Ca(2+) transients, while small populations of cells remained quiescent. Approximately 70% of spontaneously active cells generated fast, oscillatory Ca(2+) transients that were inhibited by cyclopiazonic acid (10 μm) but not nicardipine (1 μm), suggesting that Ca(2+) handling by endoplasmic reticulum, but not Ca(2+) influx through voltage-dependent L-type Ca(2+) channels, plays a fundamental role in their generation. In the adult rat anterior pituitary, LHRH (100 μg/ml) caused a transient increase in the Ca(2+) level in a majority of preparations taken from the morning group rats killed between 0930 h and 1030 h. However, the second application of LHRH invariably failed to elevate Ca(2+) levels, suggesting that the long-lasting refractoriness to LHRH stimulation was developed upon the first challenge of LHRH. In contrast, LHRH had no effect in most preparations taken from the afternoon group rats euthanized between 1200 h and 1400 h. In the neonatal rat anterior pituitary, LHRH caused a suppression of spontaneous Ca(2+) transients. Strikingly, the second application of LHRH was capable of reproducing the suppression of Ca(2+) signals, indicating that the refractoriness to LHRH had not been established in neonatal rats. These results suggest that responsiveness to LHRH has a long-term refractoriness in adult rats, and that the physiological LHRH surge may be clocked in the morning. Moreover, LHRH-induced excitation and associated refractoriness appear to be incomplete in neonatal rats and may be acquired during development.

  10. Autoregulation of cerebral blood flow to changes in arterial pressure in mild Alzheimer's disease.

    PubMed

    Zazulia, Allyson R; Videen, Tom O; Morris, John C; Powers, William J

    2010-11-01

    Studies in transgenic mice overexpressing amyloid precursor protein (APP) demonstrate impaired autoregulation of cerebral blood flow (CBF) to changes in arterial pressure and suggest that cerebrovascular dysfunction may be critically important in the development of pathological Alzheimer's disease (AD). Given the relevance of such a finding for guiding hypertension treatment in the elderly, we assessed autoregulation in individuals with AD. Twenty persons aged 75±6 years with very mild or mild symptomatic AD (Clinical Dementia Rating 0.5 or 1.0) underwent (15)O-positron emission tomography (PET) CBF measurements before and after mean arterial pressure (MAP) was lowered from 107±13 to 92±9 mm Hg with intravenous nicardipine; (11)C-PIB-PET imaging and magnetic resonance imaging (MRI) were also obtained. There were no significant differences in mean CBF before and after MAP reduction in the bilateral hemispheres (-0.9±5.2 mL per 100 g per minute, P=0.4, 95% confidence interval (CI)=-3.4 to 1.5), cortical borderzones (-1.9±5.0 mL per 100 g per minute, P=0.10, 95% CI=-4.3 to 0.4), regions of T2W-MRI-defined leukoaraiosis (-0.3±4.4 mL per 100 g per minute, P=0.85, 95% CI=-3.3 to 3.9), or regions of peak (11)C-PIB uptake (-2.5±7.7 mL per 100 g per minute, P=0.30, 95% CI=-7.7 to 2.7). The absence of significant change in CBF with a 10 to 15 mm Hg reduction in MAP within the normal autoregulatory range demonstrates that there is neither a generalized nor local defect of autoregulation in AD.

  11. Lysophosphatidylcholine potentiates vascular contractile responses by enhancing vasoconstrictor-induced increase in cytosolic free Ca2+ in rat aorta.

    PubMed

    Suenaga, H; Kamata, K

    1998-11-20

    We investigated the effects of palmitoyl-L-alpha-lysophosphatidylcholine on the contractile responses of the endothelium-denuded rat aorta to high K+, noradrenaline, UK14,304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) (a selective alpha2 adrenoceptor agonist) and phorbol 12-myristate 13-acetate (PMA). Lysophosphatidylcholine at concentrations from 10(-6) M to 10(-4) M did not contract aortic strips. However, lysophosphatidylcholine strongly potentiated the UK14,304-induced contraction. High K+ - and PMA-induced contractions were also potentiated. In contrast, the noradrenaline-induced contraction was only slightly potentiated by 10(-5) M lysophosphatidylcholine. In fura PE-3-loaded aortic strips, lysophosphatidylcholine (10(-5) M) markedly augmented the increase in both cytosolic free Ca2+ ([Ca2+]i) and contractile tension induced by UK14,304, high K+ and PMA. Nicardipine (10(-7) M) and 10(-6) M Ro-31-8220 (¿1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H-++ +indoyl-3-yl)-maleimide-methane sulfate) strongly inhibited the increase in [Ca2+]i and contractile tension induced by UK14,304 and in the presence of these inhibitors, the enhancing effects of lysophosphatidylcholine were attenuated. However, the enhancing effect on high K+ -induced contraction was not affected by Ro-31-8220. These results suggest that lysophosphatidylcholine may cause an augmentation of the increase in [Ca2+]i induced by UK14,304 which response is depend on protein kinase C activation and in this way potentiate contractile responses in the rat aorta. Protein kinase C independent mechanisms may also be involved in the enhancing effect of lysophosphatidylcholine on smooth muscle contraction.

  12. Mechanisms of strain-mediated mesenchymal stem cell apoptosis.

    PubMed

    Kearney, E M; Prendergast, P J; Campbell, V A

    2008-12-01

    Mechanical conditioning of mesenchymal stem cells (MSCs) has been adopted widely as a biophysical signal to aid tissue engineering applications. The replication of in vivo mechanical signaling has been used in in vitro environments to regulate cell differentiation, and extracellular matrix synthesis, so that both the chemical and mechanical properties of the tissue-engineered construct are compatible with the implant site. While research in these areas contributes to tissue engineering, the effects of mechanical strain on MSC apoptosis remain poorly defined. To evaluate the effects of uniaxial cyclic tensile strain on MSC apoptosis and to investigate mechanotransduction associated with strain-mediated cell death, MSCs seeded on a 2D silicone membrane were stimulated by a range of strain magnitudes for 3 days. Mechanotransduction was investigated using the stretch-activated cation channel blocker gadolinium chloride, the L-type voltage-activated calcium channel blocker nicardipine, the c-jun NH(2)-terminal kinase (JNK) blocker D-JNK inhibitor 1, and the calpain inhibitor MDL 28170. Apoptosis was assessed through DNA fragmentation using the terminal deoxynucleotidyl transferase mediated-UTP-end nick labeling method. Results demonstrated that tensile strains of 7.5% or greater induce apoptosis in MSCs. L-type voltage-activated calcium channels coupled mechanical stress to activation of calpain and JNK, which lead to apoptosis through DNA fragmentation. The definition of the in vitro boundary conditions for tensile strain and MSCs along with a proposed mechanism for apoptosis induced by mechanical events positively contributes to the development of MSC biology, bioreactor design for tissue engineering, and development of computational methods for mechanobiology.

  13. G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.

    PubMed

    Menon-Johansson, A S; Berrow, N; Dolphin, A C

    1993-11-01

    High-voltage-activated (HVA) calcium channel currents (IBa) were recorded from acutely replated cultured dorsal root ganglion (DRG) neurons. IBa was irreversibly inhibited by 56.9 +/- 2.7% by 1 microM omega-conotoxin-GVIA (omega-CTx-GVIA), whereas the 1,4-dihydropyridine antagonist nicardipine was ineffective. The selective gamma-aminobutyric acidB (GABAB) agonist, (-)-baclofen (50 microM), inhibited the HVA IBa by 30.7 +/- 5.4%. Prior application of omega-CTx-GVIA completely occluded inhibition of the HVA IBa by (-)-baclofen, indicating that in this preparation (-)-baclofen inhibits N-type current. To investigate which G protein subtype was involved, cells were replated in the presence of anti-G protein antisera. Under these conditions the antibodies were shown to enter the cells through transient pores created during the replating procedure. Replating DRGs in the presence of anti-G(o) antiserum, raised against the C-terminal decapeptide of the G alpha o subunit, reduced (-)-baclofen inhibition of the HVA IBa, whereas replating DRGs in the presence of the anti-Gi antiserum did not. Using anti-G alpha o antisera (1:2000) and confocal laser microscopy, G alpha o localisation was investigated in both unreplated and replated neurons. G alpha o immunoreactivity was observed at the plasma membrane, neurites, attachment plaques and perinuclear region, and was particularly pronounced at points of cell-to-cell contact. The plasma membrane G alpha o immunoreactivity was completely blocked by preincubation with the immunising G alpha o undecapeptide (1 microgram.ml-1) for 1 h at 37 degrees C. A similar treatment also blocked recognition of G alpha o in brain membranes on immunoblots.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Effects of 5-hydroxytryptamine on human isolated placental chorionic arteries and veins.

    PubMed Central

    Reviriego, J.; Marín, J.

    1989-01-01

    1. Effects of 5-hydroxytrypamine (5-HT) on cylindrical segments of human chorionic arteries and veins were investigated. Concentrations of 5-HT (up to 3 x 10(-6) M) produced concentration-dependent contractions; higher concentrations induced a reduction of the maximal response. These responses were antagonized by methysergide and ketanserin in a non-competitive manner. The contractions elicited by low 5-HT concentrations were more affected by methysergide (10(-7) M) than by ketanserin (10(-7) M). Ketanserin apparently increased the responses to high 5-HT concentrations in veins. Arteries appeared to be more sensitive to both drugs than veins. Single concentrations of 5-HT elicited transient contractions in both kinds of vessel. 2. Marked tachyphylaxis was seen in segments exposed to high concentrations of 5-HT or in which a concentration-response curve was determined. 3. Contractions induced by 5-HT were reduced in a Ca2+-free medium. Veins were more affected by the Ca2+ antagonists, nifedipine (10(-7) M), nicardipine (10(-5) M) and diltiazem (10(-5) M) than arteries. 4. 5-HT (10(-6) M) enhanced 45Ca2+ uptake in those vessels in which a concentration-response curve had not been previously determined. In veins, this increase was reduced by the three Ca2+ antagonists. 5. The results indicate that 5-HT responses in these vessels were greatly dependent on extracellular Ca2+. A type of 5-HT1-receptor may mediate responses to low 5-HT concentrations, while higher concentrations may activate 5-HT2-receptors. 5-HT may desensitize the latter by interconversion between a high affinity and low affinity state, as suggested by others, a change prevented in part by ketanserin. PMID:2743086

  15. Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.

    PubMed

    Kadono, Keitaro; Akabane, Takafumi; Tabata, Kenji; Gato, Katsuhiko; Terashita, Shigeyuki; Teramura, Toshio

    2010-07-01

    This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.

  16. Calcium homeostasis and protein kinase/phosphatase balance participate in nicotine-induced memory improvement in passive avoidance task in mice.

    PubMed

    Michalak, Agnieszka; Biala, Grazyna

    2017-01-15

    Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca(2+)/calmodulin concentration. LTP results from Ca(2+) influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca(2+) influx, leads to activation of Ca(2+)/calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes. Nicotine, which is one of the most common addictive drugs, manifests its memory effects through nicotinic acetylcholine receptors (nAChRs). Because nAChRs may also gate Ca(2+), it is suggested that calcium signaling pathways are involved in nicotine-induced memory effects. Within the scope of the study was to evaluate the importance of calcium homeostasis and protein kinase/phosphatase balance in nicotine-induced short- and long-term memory effects. To assess memory function in mice passive avoidance test was used. The presented results confirm that acute nicotine (0.1mg/kg) improves short- and long-term memory. Pretreatment with L-type VGCC blockers (amlodipine, nicardipine verapamil) increased nicotine-induced memory improvement in the context of short- and long-term memory. Pretreatment with FK-506 (a potent CaN inhibitor) enhanced short- but not long-term memory effects of nicotine, while SL-327 (a selective MAPK/ERK kinase inhibitor) attenuated both nicotine-induced short- and long-term memory improvement. Acute nicotine enhances both types of memory via L-type VGCC blockade and via ERK1/2 activation. Only short- but not long-term memory enhancement induced by nicotine is dependent on CaN inhibition.

  17. Zinc modulation of calcium activity at the photoreceptor terminal: a calcium imaging study.

    PubMed

    Anastassov, Ivan; Shen, Wen; Ripps, Harris; Chappell, Richard L

    2013-07-01

    There is abundant experimental evidence that zinc ions (Zn(2+)) are present in the synaptic vesicles of vertebrate photoreceptors, and that they are co-released with glutamate. Here we show that increasing the concentration of extracellular zinc (2 μM-2 mM) suppresses the entry of calcium into the synaptic terminals of isolated salamander double cones. The resultant dose-dependent curve was fit by an inverse Hill equation having an IC50 of 38 μM, and Hill coefficient of 1.1. Because there is currently no reliable way to measure the concentration of extracellular zinc, it is not known whether the zinc released under normal circumstances is of physiological significance. In an attempt to circumvent this problem we used zinc chelators to reduce the available pool of endogenous zinc. This enabled us to determine how the absence of zinc affected calcium entry. We found that when intra- or extra-cellular zinc was chelated by 250 μM of membrane-permeable TPEN or 500 μM of membrane-impermeable histidine, there was a significant rise in the depolarization-induced intracellular calcium level within photoreceptor terminals. This increase in internal [Ca(2+)] will undoubtedly lead to a concomitant increase in glutamate release. In addition, we found that blocking the L-type calcium channels that are expressed on the synaptic terminals of photoreceptors with 50 μM nicardipine or 100 μM verapamil abolished the effects of zinc chelation. These findings are a good indication that, when released in vivo, the zinc concentration is sufficient to suppress voltage-gated calcium channels, and reduce the rate of glutamate release from photoreceptor terminals.

  18. GTP gamma S causes contraction of skinned frog skeletal muscle via the DHP-sensitive Ca2+ channels of sealed T-tubules.

    PubMed

    Somasundaram, B; Tregear, R T; Trentham, D R

    1991-03-01

    We have investigated the involvement of G-proteins in excitation-contraction coupling of fast-twitch skeletal muscle, using a fibre preparation designed to retain intact T-tubules and sarcoplasmic reticulum. The nonhydrolysable analogue of guanosine triphosphate, GTP gamma S (50-500 microM) caused a strong, transient isometric contraction in this preparation. Reduction of ethylene-bis(oxonitrilo)tetraacete (EGTA) in the sealed T-tubules from 5 mM to 0.1 mM lowered the threshold to GTP gamma S and removal of sodium reversibly raised it. The dihydropyridine (DHP) calcium channel antagonists nicardipine and nifedipine allowed a first contraction and then blocked subsequent GTP gamma S action. The phenylalkylamine methoxyverapamil (D-600) did likewise, reversibly, at 10 degrees C. The guanosine diphosphate analogue, GDP beta S, and procaine reversibly blocked the action of GTP gamma S; pertussis toxin also blocked it. Photolytic release of 40-100 microM GTP gamma S within 0.1 s from S-caged GTP gamma S caused contraction after a latent period of 0.3-20 s. We conclude that GTP gamma S can activate contraction in frog skeletal muscle via a route requiring both the integrity of the T-tubular DHP-sensitive calcium channel (DHPr) and the presence of sodium in the sealed T-tubules. We propose that in this preparation GTP gamma S activates a G-protein, which in turn activates the DHPr as a calcium channel and releases stored calcium from within the sealed T-tubule. Implications of these results for the excitation-contraction coupling mechanism in skeletal muscle are discussed.

  19. Airway hyperresponsiveness induced by repeated esophageal infusion of HCl in guinea pigs.

    PubMed

    Cheng, Yan-Mei; Cao, Ai-Li; Zheng, Jian-Pu; Wang, Hong-Wei; Sun, Yong-Shun; Liu, Chun-Fang; Zhang, Bei-Bei; Wang, Yi; Zhu, Sheng-Liang; Wu, Da-Zheng

    2014-11-01

    Gastroesophageal reflux is a common disorder closely related to chronic airway diseases, such as chronic cough, asthma, chronic bronchitis, and chronic obstructive disease. Indeed, gastroesophageal acid reflux into the respiratory tract causes bronchoconstriction, but the underlying mechanisms have still not been clarified. This study aimed to elucidate functional changes of bronchial smooth muscles (BSMs) isolated from guinea pigs in an animal model of gastroesophageal reflux. The marked airway inflammation, hyperresponsiveness and remodeling were observed after guinea pigs were exposed to intraesophageal HCl infusion for 14 days. In addition, contractile responses to acetylcholine (ACh), KCl, electrical field stimulation, and extracellular Ca(2+) were greater in guinea pigs infused with HCl compared with control groups. The L-type voltage-dependent Ca(2+) channels (L-VDCC) blocker, nicardipine, significantly inhibited ACh- and Ca(2+)-enhanced BSM contractions in guinea pigs infused with HCl. The Rho-kinase inhibitor, Y27632, attenuated ACh-enhanced BSM contractions in guinea pigs infused with HCl. Moreover, mRNA and protein expressions for muscarinic M2 and M3 receptors, RhoA, and L-VDCC in BSM were detected by real-time PCR and Western blot. Expressions of mRNA and protein for muscarinic M3 receptors, RhoA, and L-VDCC were greater than in BSM of HCl-infused guinea pigs, whereas levels of muscarinic M2 receptors were unchanged. We demonstrate that acid infusion to the lower esophagus and, subsequently, microaspiration into the respiratory tract in guinea pigs leads to airway hyperresponsiveness and overactive BSM. Functional and molecular results indicate that overactive BSM is the reason for enhancement of extracellular Ca(2+) influx via L-VDCC and Ca(2+) sensitization through Rho-kinase signaling.

  20. Long-term anti-hypertensive therapy with benidipine improves arterial stiffness over blood pressure lowering.

    PubMed

    Kita, Toshihiro; Suzuki, Yoshihiko; Eto, Tanenao; Kitamura, Kazuo

    2005-12-01

    Pulse wave velocity (PWV) reflects arterial stiffness and is an independent predictor of cardiovascular mortality and morbidity. However, because it is closely related to blood pressure (BP), PWV is an imperfect measure for evaluating the effects of anti-hypertensive drugs on arterial wall properties. To clarify the effect of benidipine on arterial properties, we first derived the regression line between BP and PWV changes in a short-term experiment. Using this line, we evaluated the long-term effect of benidipine on PWV changes. In the short-term experiment, 29 participants were intravenously administered nicardipine for 90 min. Maximum decreases of brachial-ankle PWV (baPWV) were plotted against the corresponding decreases in BP. In the long-term experiment, 9 hypertensive patients were treated with benidipine for 1 year, during which BP and baPWV were monitored. After 1 year, benidipine was suspended for 2 weeks, and BP and baPWV were reevaluated. In the short-term experiment, PWV was dependent on BP only, and the equation of the regression line was deltaPWV (cm/s) =10.114 x deltaMBP (mmHg) (r=0.913) or deltaPWV (%) =0.719 x deltaMBP (%) (r=0.926). In the long-term therapy, benidipine treatment achieved stable BP control within 3 months; the real PWV decreases (r-PWV) were almost identical to the PWV decrease estimated (e-PWV) from BP lowering at 3 months. However, r-PWV exceeded e-PWV after 6 months. Relative BP and PWV improvements compared to the control were maintained 2 weeks after suspension of benidipine. In conclusion, long-term benidipine administration improves arterial wall properties beyond what can be accounted for by changes in BP.

  1. Cytochrome P450 3A Conjugation to Ubiquitin in a Process Distinct from Classical Ubiquitination Pathway

    SciTech Connect

    Zangar, Richard C. ); Kimzey, Amy L.; Okita, Janice R.; Wunschel, David S. ); Edwards, Robert J.; Kim, Hyesook; Okita, Richard T.

    2001-12-01

    We characterize a novel microsome system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not alter CYP4A or most other microsomal proteins. The formation of the HMM bands was observed in hepatic microsomes isolated from rats treated 1 week or more with high doses (50 mg/kg/day) of nicardipine, clotrimazole, or pregnenolone 16alpha-carbonitrile, but not microsomes from control, dexamethasone-, nifedipine-, or diltiazem-treated rats. Extensive washing of the microsomes to remove loosely attached proteins or cytosolic contaminants did not prevent the conjugation reaction. In contrast to prototypical ubiquitination pathways, this reaction did not require addition of ubiquitin, ATP, Mg(2+), or cytosol. Addition of cytosol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteasome inhibitors. Immunoprecipitated CYP3A contained HMM ubiquitin. Even so, mass spectrometric analysis of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a diffuse pool of ubiquitinated proteins already present in the microsomes. Addition of CYP3A substrates inhibited the formation of the HMM CYP3A and the cytosol-dependent degradation of HMM CYP3A. These results suggest that after extended periods of elevated CYP3A expression, microsomal factors are induced that catalyze the formation of HMM CYP3A conjugates that contain ubiquitin. This conjugation reaction, however, seems to be distinct from the classical ubiquitination pathway but may be related to the substrate-dependent stabilization of CYP3A observed in vivo.

  2. Role of eicosanoids in alteration of membrane electrical properties in isolated mesenteric arteries of salt-loaded, Dahl salt-sensitive rats

    PubMed Central

    Fujii, Koji; Onaka, Uran; Ohya, Yusuke; Ohmori, Susumu; Tominaga, Mitsuhiro; Abe, Isao; Takata, Yutaka; Fujishima, Masatoshi

    1997-01-01

    The role of eicosanoids in altered membrane electrical properties of Dahl salt-sensitive (DS) rats was investigated, by use of conventional microelectrodes technique, in isolated superior mesenteric arteries of DS rats and Dahl salt-resistant (DR) rats fed either a high or low salt diet.The membrane was significantly depolarized in salt-loaded DS rats compared with the other three groups. In addition, the arteries of salt-loaded DS rats exhibited spontaneous electrical activity.Spontaneous electrical activity in salt-loaded DS rats was inhibited by the following: indomethacin, a cyclo-oxygenase inhibitor; ONO-3708, a prostaglandin H2/thromboxane A2 receptor antagonist; OKY-046, a thromboxane A2 synthase inhibitor; nicardipine, a Ca2+-channel antagonist and by Ca2+-free solution. In addition, spontaneous electrical activity was enhanced by a thromboxane A2 analogue and by prostaglandin H2. Spontaneous electrical activity was unaffected by phentolamine, atropine and tetrodotoxin.Membrane potential in arteries of salt-loaded DS rats was not affected by either indomethacin or ONO-3708.Spontaneous contraction, sensitive to indomethacin, was present, and contractile sensitivity to high potassium solution was enhanced in arteries of salt-loaded DS rats.These findings suggest that eicosanoid action, together with membrane depolarization, may lead to the activation of voltage-dependent Ca2+-channels, thereby causing spontaneous electrical activity in mesenteric arteries of salt-loaded DS rats. In addition, tension data suggest that these changes in membrane properties are related to enhanced contractile activities in salt-loaded DS rats. Mechanisms of depolarization remain to be determined. PMID:9105694

  3. The first intestinal motility patterns in fetal mice are not mediated by neurons or interstitial cells of Cajal.

    PubMed

    Roberts, Rachael R; Ellis, Melina; Gwynne, Rachel M; Bergner, Annette J; Lewis, Martin D; Beckett, Elizabeth A; Bornstein, Joel C; Young, Heather M

    2010-04-01

    In mature animals, neurons and interstitial cells of Cajal (ICC) are essential for organized intestinal motility. We investigated motility patterns, and the roles of neurons and myenteric ICC (ICC-MP), in the duodenum and colon of developing mice in vitro. Spatiotemporal mapping revealed regular contractions that propagated in both directions from embryonic day (E)13.5 in the duodenum and E14.5 in the colon. The propagating contractions, which we termed ripples, were unaffected by tetrodotoxin and were present in the intestine of embryonic Ret null mutant mice, which lack enteric neurons. Neurally mediated motility patterns were first observed in the duodenum at E18.5. To examine the possible role of ICC-MP, three approaches were used. First, intracellular recordings from the circular muscle of the duodenum did not detect slow wave activity at E16.5, but regular slow waves were observed in some preparations of E18.5 duodenum. Second, spatiotemporal mapping revealed ripples in the duodenum of E13.5 and E16.5 W/W(v) embryos, which lack KIT+ ICC-MP and slow waves. Third, KIT-immunoreactive cells with the morphology of ICC-MP were first observed at E18.5. Hence, ripples do not appear to be mediated by ICC-MP and must be myogenic. Ripples in the duodenum and colon were abolished by cobalt chloride (1 mm). The L-type Ca(2+) channel antagonist nicardipine (2.5 microm) abolished ripples in the duodenum and reduced their frequency and size in the colon. Our findings demonstrate that prominent propagating contractions (ripples) are present in the duodenum and colon of fetal mice. Ripples are not mediated by neurons or ICC-MP, but entry of extracellular Ca(2+) through L-type Ca(2+) channels is essential. Thus, during development of the intestine, the first motor patterns to develop are myogenic.

  4. Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis.

    PubMed

    Yoshimoto, K; Saima, S; Nakamura, Y; Nakayama, M; Kubo, H; Kawaguchi, Y; Nishitani, H; Nakamura, Y; Yasui, A; Yokoyama, K; Kuriyama, S; Shirai, D; Kugiyama, A; Hayano, K; Fukui, H; Horigome, I; Amagasaki, Y; Tsubakihara, Y; Kamekawa, T; Ando, R; Tomura, S; Okamoto, R; Miwa, S; Koyama, T; Echizen, H

    1998-08-01

    We previously reported that manidipine, a new dihydropyridine type calcium channel blocker, produced chylous peritoneal dialysate being visually indistinguishable from infective peritonitis in 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [Yoshimoto et al. 1993]. To study whether such an adverse drug reaction would also be elicited by other commonly prescribed calcium channel blockers in CAPD patients, we have conducted postal inquiry to 15 collaborating hospitals and an institutional survey in International Medical Center of Japan as to the possible occurrence of calcium channel blocker-associated non-infective, turbid peritoneal dialysate in CAPD patients. Our diagnostic criteria for drug-induced turbidity of dialysate as a) it developed within 48 h after the administration of a newly introduced calcium channel blocker to the therapeutic regimen, b) absence of clinical symptoms of peritoneal inflammation (i.e., pyrexia, abdominal pain, nausea or vomiting), c) the fluid containing normal leukocyte counts and being negative for bacterial and fungal culture of the fluid, and d) it disappeared shortly after the withdrawal of the assumed causative agent. Results showed that 19 out of 251 CAPD patients given one of the calcium channel blockers developed non-infective turbid peritoneal dialysis that fulfilled all the above criteria. Four calcium channel blockers were suspected to be associated with the events: benidipine [2 out of 2 (100%) patients given the drug], manidipine [15 out of 36 (42%) patients], nisoldipine [1 out of 11 (9%) patients] and nifedipine [1 out of 159 (0.6%)] in descending order of frequency. None of the patients who received nicardipine, nilvadipine, nitrendipine, barnidipine and diltiazem (25, 7, 2, 1 and 8 patients, respectively) exhibited turbid dialysate. In conclusion, we consider that certain dihydropyridine type calcium channel blockers would cause turbid peritoneal dialysate being similar to that observed in

  5. Differential blocking action of dihydropyridine Ca2+ antagonists on a T-type Ca2+ channel (alpha1G) expressed in Xenopus oocytes.

    PubMed

    Furukawa, Taiji; Nukada, Toshihide; Miura, Reiko; Ooga, Kyoji; Honda, Mituyoshi; Watanabe, Suguru; Koganesawa, Satoshi; Isshiki, Takaaki

    2005-03-01

    Recent reports show that efonidipine, a dihydropyridine Ca2+ antagonist, has blocking action on T-type Ca2+ channels, which may produce favorable actions on cardiovascular systems. However, the effects of other dihydropyridine Ca2+ antagonists on T-type Ca2+ channels have not been investigated yet. Therefore, in this study, we examined the effects of dihydropyridine compounds clinically used for treatment of hypertension on a T-type Ca2+ channel subtype, alpha1G, expressed in Xenopus oocytes. These effects were compared with those on T-type Ca2+ channel. Rabbit L-type (alpha1Calpha2/deltabeta1a) or rat T-type (alpha1G) Ca2+ channel was expressed in Xenopus oocytes by injection of cRNA for each subunit. The Ba currents through expressed channels were measured by conventional 2-microelectrode voltage-clamp methods. Twelve DHPs (amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine, felodipine, nifedipine, nilvadipine, minodipine, and nitrendipine had little effect on the T-type channel. The blocks by drugs at 10 microM were less than 10% at a holding potential of -100 mV. The remaining 6 drugs had blocking action on the T-type channel comparable to that on the L-type channel. The blocking actions were also comparable to that by mibefradil. These results show that many dihydropyridine Ca2+ antagonists have blocking action on the alpha1G channel subtype. The action of dihydropyridine Ca2+ antagonists in clinical treatment should be evaluated on the basis of subtype selectivity.

  6. The receptor occupation and plasma concentration of NKY-722, a water-soluble dihydropyridine-type calcium antagonist, in spontaneously hypertensive rats.

    PubMed Central

    Uchida, S; Yamada, S; Ohkura, T; Heshikiri, M; Yoshimi, A; Shirahase, H; Kimura, R

    1995-01-01

    1. The occupation in vivo by NKY-722 of 1,4-dihydropyridine (DHP) calcium antagonist receptors in myocardium, aorta and cerebral cortex was investigated. At 1 and 3 h after oral administration of NKY-722 (3 mg kg-1) in spontaneously hypertensive rats (SHR), there was a significant (44 and 41%, respectively) decrease in the number of myocardial (+)-[3H]-PN 200-110 binding sites (Bmax) compared to control values. A greater reduction of Bmax values was observed at 1 (86%), 3 (88%), 6 (63%) and 12 (46%) h later by a higher dose (10 mg kg-1) of this drug. The occupation of myocardial 1,4-DHP calcium antagonist receptors after oral administration of NKY-722 correlated significantly with its plasma concentration. There was a significant decrease in cerebral cortical (+)-[3H]-PN 200-110 binding (Bmax) at 1 and 3 h after oral administration of NKY-722 (10 mg kg-1). 2. Oral administration of nicardipine (10 mg kg-1) in SHR caused a significant reduction of Bmax values for (+)-[3H]-PN 200-110 binding in myocardium at 1 and 3 h later and in cerebral cortex at 1 h later. 3. The in vivo specific binding of (+)-[3H]-PN 200-110 in particulate fractions of aorta of SHR was significantly (79 and 83%, respectively) reduced at 1 and 6 h after oral administration of NKY-722 (3 mg kg-1), while myocardial (+)-[3H]-PN 200-110 binding was decreased by 52% only at 1 h later.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7712021

  7. Molecular Mechanism of Dihydropyridine Ca(2+) Channel Blockers in Pulmonary Hypertension.

    PubMed

    Yamamura, Aya

    2016-01-01

     Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca(2+) channel blockers are only effective in very few patients with IPAH (<10%). It is unclear why dihydropyridine Ca(2+) channel blockers are not therapeutically effective in a majority of IPAH patients. We have previously shown that extracellular Ca(2+)-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, and it contributes to enhanced [Ca(2+)]cyt responses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca(2+) channel blockers on [Ca(2+)]cyt responses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca(2+)]cyt in IPAH-PASMCs, but not in PASMCs from normal subjects. Nicardipine (dihydropyridines) and Bay K 8644 (a dihydropyridine Ca(2+) channel activator) also augmented the CaSR-mediated [Ca(2+)]cyt increase in IPAH-PASMCs. In contrast, non-dihydropyridine Ca(2+) channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca(2+)]cyt response in IPAH-PASMCs. Finally, in monocrotaline-induced pulmonary hypertensive rats, nifedipine caused further increase in right ventricular systolic pressure and thus right ventricular hypertrophy. In conclusion, dihydropyridine Ca(2+) channel blockers could exacerbate symptoms of pulmonary hypertension in IPAH patients with upregulated CaSR in PASMCs.

  8. Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption

    NASA Technical Reports Server (NTRS)

    Miyauchi, A.; Hruska, K. A.; Greenfield, E. M.; Duncan, R.; Alvarez, J.; Barattolo, R.; Colucci, S.; Zambonin-Zallone, A.; Teitelbaum, S. L.; Teti, A.

    1990-01-01

    The mechanisms of Ca2+ entry and their effects on cell function were investigated in cultured chicken osteoclasts and putative osteoclasts produced by fusion of mononuclear cell precursors. Voltage-gated Ca2+ channels (VGCC) were detected by the effects of membrane depolarization with K+, BAY K 8644, and dihydropyridine antagonists. K+ produced dose-dependent increases of cytosolic calcium ([Ca2+]i) in osteoclasts on glass coverslips. Half-maximal effects were achieved at 70 mM K+. The effects of K+ were completely inhibited by dihydropyridine derivative Ca2+ channel blocking agents. BAY K 8644 (5 X 10(-6) M), a VGCC agonist, stimulated Ca2+ entry which was inhibited by nicardipine. VGCCs were inactivated by the attachment of osteoclasts to bone, indicating a rapid phenotypic change in Ca2+ entry mechanisms associated with adhesion of osteoclasts to their resorption substrate. Increasing extracellular Ca2+ ([Ca2+]e) induced Ca2+ release from intracellular stores and Ca2+ influx. The Ca2+ release was blocked by dantrolene (10(-5) M), and the influx by La3+. The effects of [Ca2+]e on [Ca2+]i suggests the presence of a Ca2+ receptor on the osteoclast cell membrane that could be coupled to mechanisms regulating cell function. Expression of the [Ca2+]e effect on [Ca2+]i was similar in the presence or absence of bone matrix substrate. Each of the mechanisms producing increases in [Ca2+]i, (membrane depolarization, BAY K 8644, and [Ca2+]e) reduced expression of the osteoclast-specific adhesion structure, the podosome. The decrease in podosome expression was mirrored by a 50% decrease in bone resorptive activity. Thus, stimulated increases of osteoclast [Ca2+]i lead to cytoskeletal changes affecting cell adhesion and decreasing bone resorptive activity.

  9. Quantitative structure-interaction relationship analysis of 1,4-dihydropyridine drugs in concomitant administration with grapefruit juice.

    PubMed

    Uesawa, Y; Mohri, K

    2012-03-01

    Quantitative structure-interaction relationship (QSIR) analyses of 1,4-dihydropyridine drugs were performed on grapefruit juice interaction potentials to characterize the interaction and evaluate drugs not yet tested in clinical research. AUC ratios of drugs with and without grapefruit juice ingestion were estimated as grapefruit juice interaction potentials from clinical studies on dihydropyridine drugs such as amlodipine, azelnidipine, benidipine, cilnidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and pranidipine. The minimal energy conformation in each dihydropyridine drug was searched for using Merck Molecular Force Field (MMFFaq), and then geometry optimization was performed by density-functional-theory (DFT) calculation (B3LYP/6-31G**). The geometric, electronic, and physicochemical features including molecular size, dipole moment, total energy, HOMO/LUMO energies, and logP values were then obtained. Dragon descriptors were also calculated by optimized 3D-structures. The relation between the potentials and over 1000 of the molecular properties was investigated using statistical techniques including partial least squares analysis with genetic algorithm (GA-PLS) to a variable subset selection. Some PLS regression equations including logP values and dragon descriptors as explanatory variables were constructed in which the maximal contribution coefficient was 94%. These models could be applied to estimate the interaction potentials of other dihydropyridine drugs that have gone unreported in interactions with drugs such as aranidipine, barnidipine, clevidipine, lemildipine, lercanidipine, niguldipine, niludipine, and nilvadipine. In the assessment of major dihydropyridines, amlodipine was found to be the safest drug to avoid interactions among the drugs investigated in the present study.

  10. Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats.

    PubMed

    Briede, Janīna; Stivriņa, Māra; Stoldere, Dzintra; Bisenieks, Egīls; Uldriķis, Jānis; Poikāns, Jānis; Makarova, Natālija; Duburs, Gunārs

    2004-01-01

    Analysis of the effect of several 1,4-DHP Ca(2+) channel antagonists on experimental and clinical diabetes shows that structurally similar Ca(2+) channel antagonists can exert opposite effects on Ca(2+) influx, glucose homeostasis and insulin secretion. The influence of the Ca(2+) channel antagonists on pancreatic beta cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure-function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF(2) group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg x kg(-1), p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats.

  11. Hypertensive emergencies. Etiology and management.

    PubMed

    Tuncel, Meryem; Ram, Venkata C S

    2003-01-01

    Although systemic hypertension is a common clinical disorder, hypertensive emergencies are unusual in clinical practice. Situations that qualify as hypertensive emergencies include accelerated or malignant hypertension, hypertensive encephalopathy, acute left ventricular failure, acute aortic dissection, pheochromocytoma crisis, interaction between tyramine-containing foods or drugs and monoamine oxidase inhibitors, eclampsia, drug-induced hypertension and possibly intracranial hemorrhage. It is important to recognize these conditions since immediate lowering of systemic blood pressure is indicated. The diagnosis of hypertensive emergencies depends on the clinical manifestations rather than on the absolute level of the blood pressure. Depending on the target organ that is affected, the manifestations of hypertensive emergencies can be quite expressive, yet variable. Thus, the physician has to make the clinical diagnosis urgently in order to render appropriate therapy. Several parenteral drugs can quickly and effectively lower the blood pressure in hypertensive emergencies. Intravenous fenoldopam, a selective dopamine (DA1) receptor agonist, offers the advantage of improving renal blood flow and causing natriuresis. Intravenous nicardipine may be beneficial in reserving tissue perfusion in patients with ischemic disorders. Whereas trimethaphan camsilate is the drug of choice for managing acute aortic dissection, hydralazine remains the drug of choice for the treatment of eclampsia. The alpha-adrenoceptor, phentolamine, is useful in patients with pheochromocytoma crisis. Enalaprilat is the only ACE inhibitor available for parenteral use and may be particularly useful in treating hypertensive emergencies in patients with heart failure. However, ACE inhibitors may cause a precipitous fall in blood pressure in patients who are hypovolemic. Although useful as adjunctive therapy in hypertensive crises, diuretics should be used with caution in these patients because prior

  12. Signaling Pathways Linked to Serotonin-Induced Superoxide Anion Production: A Physiological Role for Mitochondria in Pulmonary Arteries

    PubMed Central

    Genet, Nafiisha; Billaud, Marie; Rossignol, Rodrigue; Dubois, Mathilde; Gillibert-Duplantier, Jennifer; Isakson, Brant E.; Marthan, Roger; Savineau, Jean-Pierre; Guibert, Christelle

    2017-01-01

    Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion (O2•_) is commonly associated to cellular damages due to O2•_ overproduction, we previously demonstrated that, in physiological conditions, O2•_ also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to O2•_ production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced O2•_ production was inhibited by ketanserin (1 μM—an inhibitor of the 5-HT2 receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone—100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM—an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced O2•_ production. O2•_ levels were also increased by α-methyl-5-HT (10 μM—a 5-HT2 receptors agonist) whereas GR127935 (1 μM—an antagonist of the 5-HT1B/D receptor) and citalopram (1 μM—a 5-HT transporter inhibitor) had no effect on the 5-HT-induced O2•_ production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and O2•_ levels, which were both abrogated in absence of extracellular calcium. Mitochondrial O2•_ levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas in the absence of extracellular calcium the mitochondrial membrane depolarisation was delayed and sustained in

  13. A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells.

    PubMed Central

    Guo, J; Ono, K; Noma, A

    1995-01-01

    1. After blocking both the hyperpolarization-activated current and the membrane K+ conductance, depolarizations from -80 mV to between -70 and -50 mV induced a sustained current in sino-atrial node cells. We have tentatively designated this current Ist. 2. Ist was blocked by both organic and inorganic Ca2+ channel blockers, but was insensitive to tetrodotoxin (30 microM). Isoprenaline increased Ist. 3. The peak of Ist (at about -50 mV) was increased to 149 +/- 13% (n = 8, P < 0.01) by lowering the external Ca2+ concentration ([Ca2+]o) from 1.8 to 0.1 mM, in contrast to the marked depression of the L-type Ca2+ current. In 0.1 mM [Ca2+]o solution, the nicardipine-sensitive current-voltage relation showed the peak amplitude at about -50 mV and a reversal potential of +37.4 +/- 4.4 mV (n = 5). The isoprenaline-sensitive component also showed a reversal potential of about +30 mV. 4. Reducing [Na+]o from 140 to 70 mM in 0.1 mM [Ca2+]o decreased Ist to 53 +/- 5% (n = 7, P < 0.01). Increasing [Ca2+]o or [Mg2+]o decreased the amplitude of Ist. The half-maximum concentration of Mg2+ inhibition was 2.2 mM. 5. At 1.8 mM [Ca2+]o, Ist was inactivated by clamping for 5s at -10 mV, and gradually recovered after repolarization to -80 mV with a half-time of 1.36 +/- 0.4 s (n = 6). 6. The transitional sino-atrial node cell had minimal amplitude of Ist. 7. These characteristics of Ist are qualitatively comparable to those of the monovalent cation conductance of the L-type Ca2+ channel induced by depleting external divalent cations to the micromolar range. We conclude that Ist is generated by a novel subtype of L-type Ca2+ channel. PMID:7776225

  14. Protection against methoxyacetic-acid-induced spermatocyte apoptosis with calcium channel blockers in cultured rat seminiferous tubules: possible mechanisms.

    PubMed

    Li, L H; Wine, R N; Miller, D S; Reece, J M; Smith, M; Chapin, R E

    1997-05-01

    A calcium-mediated mechanism underlying spermatocyte apoptosis induced by 2-methoxyethanol (2-ME) has been previously proposed. This hypothesis was tested in vitro in the present study using cultured juvenile (25 days old) and adult rat seminiferous tubules (JRST and ARST, respectively) with methoxyacetic acid (MAA, the active metabolite of 2-ME). In JRST, spermatocyte degeneration was morphologically obvious 19 hr after a 5-hr exposure to 5 mM MAA. The lesion was unaffected by the presence or absence of extratubular Ca2+. However, MAA-induced cell death was significantly prevented by cotreatment with the dihydropyridines (DHP) nifedipine (50 microM) and nicardipine (20 microM), as well as verapamil (50 microM) and TMB-8 (50 microM), all of which are able to inhibit calcium movement through plasma membranes. However, neither ryanodine, dantrolene, nor cyclosporin A and ruthenium red, which inhibit Ca2+ mobilization from intracellular stores (endoplasmic reticulum and mitochondria), affected the MAA-induced cell death. Inhibition of calcium mobilization through IP3-sensitive pathways by blocking the product of IP3 with manoalide, neomycin, and U73122 did not block the MAA-induced lesion. The protective effects of 50 microM nifedipine and 50 microM TMB-8 were also observed in ARSTs treated with 10 mM MAA for 5 hr. However, when rat testicular sections were immunohistochemically stained with monoclonal antibodies specific for the alpha 1 (the DHP receptor) or the alpha 2 subunits of DHP-sensitive calcium channels, no positive staining was found. Finally, in an attempt to see whether the intracellular free calcium concentrations ([Ca2+]i) in germ cells were increased after the MAA treatment, intact seminiferous tubules were loaded with indo-1 and were measured using laser-scanning confocal microscopy. No detectable increase in the signal in MA A-sensitive spermatocytes was observed, while a 34-54% increase in the signal could be detected in the same cell types when

  15. Analysis of the effects of graded levels of hypoxia on noradrenaline-evoked contraction in the rat iliac artery in vitro.

    PubMed

    Bartlett, Iain S; Marshall, Janice M

    2002-03-01

    In rings of rat iliac artery, contractions were evoked by noradrenaline (NA), the selective alpha(1) adrenoceptor agonist phenylephrine (PE), and K(+), which causes depolarisation-induced contraction. There was no evidence of alpha(2) adrenoceptor-evoked contraction. Hypoxia, induced by reducing P(O(2)) in the bath from 100 mmHg to 70, 55 or 40 mmHg, had similar effects on rings with (E+) and without (E-) endothelium. In E- rings, the NA concentration-response curve was biphasic, whereas that for PE was monophasic. Hypoxia reduced maximum contractions in response to NA and PE (NA(max) and PE(max), respectively) without affecting the concentrations that evoked 50 % of maximum contraction (EC(50)). At P(O(2)) of 70 mmHg, NA(max) of the high affinity alpha(1) receptor for NA (NA(maxh)) and PE(max) were reduced by approximately 15 %, but at P(O(2)) of 55 and 40 mmHg, NA(maxh) was severely attenuated while PE(max) fell by 45 and 75 %, respectively. Similarly, the Ca(2+) channel blocker nicardipine depressed NA(maxh) and PE(max), but P(O(2)) of 55 mmHg further reduced NA(max) and PE(max). Hypoxia also reduced contractions evoked by NA, PE or K(+) at the concentrations required to produce 80 % of the maximum contraction (EC(80)), receptor-mediated contractions being more affected. Ca(2+)-free conditions reduced the contractions evoked by NA and PE, at the EC(80), to approximately 10 % of control. The K(+) channel inhibitors glibenclamide and tetraethylammonium did not prevent hypoxia-induced depression of PE-evoked contraction. Thus, contractions evoked in iliac artery by the high affinity subtype of alpha(1) adrenoceptor for NA, which may respond to circulating levels of NA, and by the single alpha(1) adrenoceptor subtype for PE, are especially vulnerable to P(O(2)) levels less-than-or-equal 55 mmHg. We propose that this reflects hypoxia-induced inhibition of Ca(2+) influx through L-type and receptor-operated Ca(2+) channels; K(+) channel opening makes little

  16. An Appraisal of Drug-Drug Interactions with Green Tea (Camellia sinensis).

    PubMed

    Albassam, Ahmed A; Markowitz, John S

    2017-01-24

    This review summarizes published in vitro, animal, and clinical studies investigating the effects of green tea (Camellia sinensis) extract and associated catechins on drug-metabolizing enzymes and drug transporters. In vitro studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine. Conversely, green tea extract and/or (-)-epigallocatechin-3-gallate reduce the bioavailability of quetiapine, sunitinib, clozapine, and nadolol. Of the few clinical studies available for review, it appears neither green tea extract nor (-)-epigallocatechin-3-gallate inhibit any major cytochrome P450 enzyme. Regarding drug transporters, in vitro studies indicate P-glycoprotein, organic anion transporting polypeptide 1A1, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, organic anion transporting polypeptide 2B1, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion 1, and multidrug and toxin extrusion 2-K are potentially inhibited by green tea extract. A clinical study indicates the organic anion transporting polypeptide 1A1 transporter is inhibited by (-)-epigallocatechin-3-gallate while P-glycoprotein is unaffected. In conclusion, the ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on major cytochrome P450 or uridine 5'-diphospho-glucuronosyltransferase enzyme substrates or drugs serving as substrates of P-glycoprotein. However, some caution is advised in the consumption of significant amounts of green tea beverages or green

  17. Gintonin facilitates catecholamine secretion from the perfused adrenal medulla

    PubMed Central

    Na, Seung-Yeol; Kim, Ki-Hwan; Choi, Mi-Sung; Ha, Kang-Su

    2016-01-01

    The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M1 receptor antagonist), Ki14625 (10 µM, an LPA1/3 receptor antagonist), amiloride (1 mM, an inhibitor of Na+/Ca2+ exchanger), a nicardipine (1 µM, a voltage-dependent Ca2+ channel blocker), TMB-8 (1 µM, an intracellular Ca2+ antagonist), and perfusion of Ca2+-free Krebs solution with 5mM EGTA (a Ca2+chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor). Interestingly, LPA (0.3~3 µM, an LPA receptor agonist) also dose-dependently enhanced the CA secretion from the adrenal medulla, but this facilitatory effect of LPA was greatly inhibited in the presence of Ki 14625 (10 µM). Moreover, acetylcholine (AC)-evoked CA secretion was greatly potentiated during the perfusion of gintonin (3 µg/ml). Taken together, these results demonstrate the first evidence that gintonin increases the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. This facilitatory effect of gintonin seems to be associated with activation of LPA- and cholinergic-receptors, which are relevant to the cytoplasmic Ca2+ increase by stimulation of the Ca2+ influx as well as by the inhibition of Ca2+ uptake into the cytoplasmic Ca2+ stores, without the increased nitric oxide (NO). Based on these results, it is thought that gintonin, one of ginseng components, can elevate the CA secretion from adrenal medulla by regulating the Ca2+ mobilization for exocytosis, suggesting

  18. Ca2+ influx in resting rat sensory neurones that regulates and is regulated by ryanodine-sensitive Ca2+ stores

    PubMed Central

    Usachev, Yuriy M; Thayer, Stanley A

    1999-01-01

    Store-operated, voltage-independent Ca2+ channels are activated by depletion of intracellular Ca2+ stores and mediate Ca2+ influx into non-excitable cells at resting membrane potential. We used microfluorimetry, patch-clamp and Mn2+-quench techniques to explore the possibility that a similar mechanism exists in rat dorsal root ganglion (DRG) neurones in primary culture. Following caffeine-induced depletion, ryanodine-sensitive Ca2+ stores refilled with Ca2+ at resting membrane potential. The refilling process required extracellular Ca2+, was blocked by 2 mM Ni2+, and was facilitated by membrane hyperpolarization from −55 to −80 mV, indicating a key role for Ca2+ influx. This influx of Ca2+ was not affected by the voltage-operated Ca2+ channel (VOCC) antagonists nicardipine (10 μM), nimodipine (10 μm) or ω-grammotoxin SIA (1 μm). When ryanodine-sensitive Ca2+ stores were depleted in Ca2+-free media, a return to 2 mM external Ca2+ resulted in a pronounced [Ca2+]i overshoot, indicating an increased permeability to Ca2+. Depletion of Ca2+ stores also produced a 2-fold increase in the rate of Mn2+ influx. The [Ca2+]i overshoot and Mn2+ entry were both inhibited by Ni2+, but not by VOCC antagonists. Caffeine induced periodic Ca2+ release from, and reuptake into, ryanodine-sensitive stores. The [Ca2+]i oscillations were arrested by removal of extracellular Ca2+ or by addition of Ni2+, but they were not affected by VOCC antagonists. Hyperpolarization increased the frequency of this rhythmic activity. These data suggest the presence of a Ca2+ entry pathway in mammalian sensory neurones that is distinct from VOCCs and is regulated by ryanodine-sensitive Ca2+ stores. This pathway participates in refilling intracellular Ca2+ stores and maintaining [Ca2+]i oscillations and thus controls the balance between intra- and extracellular Ca2+ reservoirs in resting DRG neurones. PMID:10432343

  19. Defining the role of calcium channel antagonists in heart failure due to systolic dysfunction.

    PubMed

    Mahé, Isabelle; Chassany, Olivier; Grenard, Anne-Sophie; Caulin, Charles; Bergmann, Jean-François

    2003-01-01

    Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations. Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure. There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a 'class b' effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents. Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized

  20. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes.

    PubMed

    Pichard, L; Fabre, I; Fabre, G; Domergue, J; Saint Aubert, B; Mourad, G; Maurel, P

    1990-01-01

    detected as potential competitive inhibitors included: triacetyloleandomycin, erythromycin, josamycin, midecamycin, ketoconazole, miconazole, midazolam, nifedipin, diltiazem, verapamil, nicardipine, ergotamine, dihydroergotamine, glibenclamide, bromocriptine, ethynylestradiol, progesterone, cortisol, prednisone, prednisolone, and methylprednisolone. Finally, cefoperazone, cefotaxime, ceftazidime, isoniazide, doxycycline, spiramycin, sulfamethoxazole, norfloxacin, pefloxacin, vancocin, trimethoprim, amphotericin B, valproic acid, quinidine, cimetidine, ranitidine, omeprazole, diclofenac, aspirin, paracetamol, debrisoquine, guanoxan, captopril, furosemide, acetazolamide, sparteine, gliclazide, and imipramine were found not to interfere with the hepatic metabolism of CsA.

  1. Signaling Pathways Linked to Serotonin-Induced Superoxide Anion Production: A Physiological Role for Mitochondria in Pulmonary Arteries.

    PubMed

    Genet, Nafiisha; Billaud, Marie; Rossignol, Rodrigue; Dubois, Mathilde; Gillibert-Duplantier, Jennifer; Isakson, Brant E; Marthan, Roger; Savineau, Jean-Pierre; Guibert, Christelle

    2017-01-01

    Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion ([Formula: see text]) is commonly associated to cellular damages due to [Formula: see text] overproduction, we previously demonstrated that, in physiological conditions, [Formula: see text] also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to [Formula: see text] production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced [Formula: see text] production was inhibited by ketanserin (1 μM-an inhibitor of the 5-HT2 receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone-100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM-an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced [Formula: see text] production. [Formula: see text] levels were also increased by α-methyl-5-HT (10 μM-a 5-HT2 receptors agonist) whereas GR127935 (1 μM-an antagonist of the 5-HT1B/D receptor) and citalopram (1 μM-a 5-HT transporter inhibitor) had no effect on the 5-HT-induced [Formula: see text] production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and [Formula: see text] levels, which were both abrogated in absence of extracellular calcium. Mitochondrial [Formula: see text] levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas

  2. [Significance of endogenous sulfur dioxide in the regulation of cardiovascular system].

    PubMed

    Jin, Hong Fang; DU, Shu Xu; Zhao, Xia; Zhang, Su Qing; Tian, Yue; Bu, Ding Fang; Tang, Chao Shu; DU, Jun Bao

    2007-08-18

    increased to 721.98+/-30.11 micromol/L at the end of 30 seconds, while the blood pressure was decreased to the lowest point 65.0+/- 4.9 mm Hg at the end of 1 minute. The above results showed that endogenous SO(2) might be involved in the maintenance of blood pressure and normal vascular structure. In spontaneous hypertensive rat (SHR) animal model, exogenous supplement of SO(2) donor decreased the BP, the media cross-sectional area, and pressure of the media and the ratio of wall thickness to lumen radius in the SHR. Moreover, the proliferative index of aortic smooth muscle cells was decreased in the SHR treated with SO(2) donor compared with that in SHR. The above data showed that SO(2) could prevent the aortic structural remodeling by inhibiting the proliferation of aortic smooth muscle cells. The authors observed the direct vasorelaxant effects of SO(2) on the aortic ring pre-treated with norepinephrine (NE). SO(2) donor at a concentration of 25-100 micromol/L relaxed the aortic ring temporarily and slightly, but SO(2) donor at a concentration of 1-12 mmol/L induced relaxation of the ring in a concentration-dependent manner. Administration with nicardipine, an L-type calcium channel blocker other than glibenclamide, an ATP sensitive potassium channel (K(ATP) channel) blocker or removal of vascular endothelium could decrease the SO(2)-induced vasorelaxation. In hypoxic pulmonary hypertension animal model, SO(2) donor decreased the mean pulmonary artery pressure and the systolic pulmonary artery pressure (P<0.01), respectively as compared with hypoxic group, and alleviated obviously the hypoxic pulmonary vascular structural remodeling. The percentage of muscularized arteries of small pulmonary vessels was significantly decreased in hypoxia+SO(2) donor-treated rats compared with that of hypoxic rats (P<0.01), while the percentage of non-muscularized vessels was obviously higher in hypoxia with SO(2) donor-treated rats than that of hypoxic rats (P<0.01). Similarly, SO(2

  3. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

    PubMed

    Qureshi, Adnan I; Palesch, Yuko Y; Barsan, William G; Hanley, Daniel F; Hsu, Chung Y; Martin, Renee L; Moy, Claudia S; Silbergleit, Robert; Steiner, Thorsten; Suarez, Jose I; Toyoda, Kazunori; Wang, Yongjun; Yamamoto, Haruko; Yoon, Byung-Woo

    2016-09-15

    Background Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. Methods We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Results Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events

  4. [Historical sketch of modern pharmaceutical science and technology (Part 4). Post World War II 50 years].

    PubMed

    Yamakawa, K

    1995-01-01

    ethical drugs and re-evaluation of drugs. Many facilities were built for the purpose of ensuring efficacy and safety, as shwon in Table 1. 6. Problems of Intellectual Property and followed the revisionist line of research and development for new ethical drugs. In 1976, Japanese pharmaceutical companies ceased to be an imitation industry, and increased research for the development of new drugs. 7. Pharmaceutical science and technology innovation (After 1985). Many of the pharmaceutical innovations during this period were as follows: 7.1) Technology innovation for evaluation of drug efficacy; 7.2) 1st to 3rd medical diagnostic technology innovations; 7.3) medical analytical methods and spectrometry technologies; 7.4) Computer-aided drug-design technology and drug information technology innovation; and 7.5) Drug delivery system and treatment drugs. 8. Recent research and development of new ethical drugs in Japan (1970 to 1995). Cephalosporine type beta-lactams (cefazolin, cefametazole, furomoxef, cefdinir), new quinolones (norfloxcin, ofloxacin, tosfloxcin), H1-Blockers (famotidine), Ca-antagonists (diltiazem, nicardipine), and other new drugs (pravastatine, taclolimus, leuprine) etc. came onto the market. 9. International Harmonization Age and Review toward 21 century. The rapid development and globalization of the pharmaceutical market has promoted international harmonization and rationalization of pharmaceutical regulatory affairs. In 1990, the Japan Pharmaceutical Manufacturers Association published a report toward 21 century, which described practical plans.

  5. Caffeine-dependent stimulus-triggered oscillations in the CA3 region of hippocampal slices from rats chronically exposed to lead.

    PubMed

    He, Shui-Jin; Xiao, Cheng; Wu, Zhi-Yuan; Ruan, Di-Yun

    2004-12-01

    M nicardipine), L-type and N-type voltage-dependent calcium channels (100 microM Cd2)), and T-type Ca2+ channels (100 microM Ni2+). Previous studies have demonstrated that expression and function of NMDA and AMPA receptors are altered in the hippocampus of chronic lead-exposed rats. We propose that caffeine-dependent stimulus-induced oscillations in CA3 area of hippocampus from chronic lead-exposed rats are mainly mediated by the entry of extracellular Ca2+ through NMDA and non-NMDA receptors, without participation of GABAA receptors. Additionally, the underlying mechanisms are also discussed.

  6. Effects of endothelin on the mechanical activity and cytosolic calcium level of various types of smooth muscle.

    PubMed Central

    Sakata, K.; Ozaki, H.; Kwon, S. C.; Karaki, H.

    1989-01-01

    1. Effects of porcine/human endothelin (endothelin-1), a novel vasoconstrictor peptide, on various smooth muscles were examined. 2. In rat aorta, endothelin (1 pM-30nM) induced contraction in a concentration-dependent manner. Removal of endothelium shifted the concentration-response curve to the left. When added during the sustained contraction induced by 0.1 microM noradrenaline, endothelin (1 nM) induced a relaxation that was inhibited by removing endothelium or by methylene blue. 3. In rat aorta without endothelium, endothelin (1-30 nM) increased cytosolic Ca2+ level [( Ca2+]cyt) followed by contraction. Endothelin induced less contraction than high K+ at a given [Ca2+] cyt when the concentration of endothelin was lower (1-3nm) and/or during the early phase of the contraction (less than 10 min). In contrast, endothelin induced a greater contraction than KCl after prolonged exposure to high concentrations (greater than 10 nM). 4. The increase in [Ca2+]cyt due to endothelin was strongly inhibited by 10 microM verapamil or 0.3 microM nicardipine although muscle contraction was only partially inhibited. 5.In Ca2+ -free solution, endothelin (30 nM) induced a transient increase in [Ca2+] cyt and a slow increase in muscle tension. After a prolonged incubation in Ca2+-free solution, endothelin (30 nM) still induced a slow increase in tension without changing [Ca2+]cyt. This contraction was inhibited by 1 microM sodium nitropusside or 10 microM forskolin. 6. In canine trachea and guinea-pig uterus, endothelin (30 nM) induced sustained contraction with an increase in [Ca2+]cyt. In the absence of external Ca2+, endothelin (30 nM) induced a sustained contraction in canine trachea without changing [Ca2+]cyt. In guinea-pig vas deferens, taenia caeci and ileal longitudinal muscle, endothelin induced small increases in [Ca2+]cyt and tension. 7. In permeabilized smooth muscles, endothelin (30 nM) did not change the muscle tone. 8. These results suggest that endothelin acts on

  7. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage

    PubMed Central

    Qureshi, Adnan I.; Palesch, Yuko Y.; Barsan, William G.; Hanley, Daniel F.; Hsu, Chung Y.; Martin, Renee L.; Moy, Claudia S.; Silbergleit, Robert; Steiner, Thorsten; Suarez, Jose I.; Toyoda, Kazunori; Wang, Yongjun; Yamamoto, Haruko; Yoon, Byung-Woo

    2017-01-01

    Background Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. Methods We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm3) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Results Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within

  8. Treatment for calcium channel blocker poisoning: A systematic review

    PubMed Central

    Dubé, P.-A.; Gosselin, S.; Guimont, C.; Godwin, J.; Archambault, P. M.; Chauny, J.-M.; Frenette, A. J.; Darveau, M.; Le sage, N.; Poitras, J.; Provencher, J.; Juurlink, D. N.; Blais, R.

    2014-01-01

    Context Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in

  9. Pharmacokinetic drug–drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management

    PubMed Central

    Zhou, Yi-Ting; Yu, Lu-Shan; Zeng, Su; Huang, Yu-Wen; Xu, Hui-Min; Zhou, Quan

    2014-01-01

    Background Coadministration of 1,4-dihydropyridine calcium channel blockers (DHP-CCBs) with statins (or 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) is common for patients with hypercholesterolemia and hypertension. To reduce the risk of myopathy, in 2011, the US Food and Drug Administration (FDA) Drug Safety Communication set a new dose limitation for simvastatin, for patients taking simvastatin concomitantly with amlodipine. However, there is no such dose limitation for atorvastatin for patients receiving amlodipine. The combination pill formulation of amlodipine/atorvastatin is available on the market. There been no systematic review of the pharmacokinetic drug–drug interaction (DDI) profile of DHP-CCBs with statins, the underlying mechanisms for DDIs of different degree, or the corresponding management of clinical risk. Methods The relevant literature was identified by performing a PubMed search, covering the period from January 1987 to September 2013. Studies in the field of drug metabolism and pharmacokinetics that described DDIs between DHP-CCB and statin or that directly compared the degree of DDIs associated with cytochrome P450 (CYP)3A4-metabolized statins or DHP-CCBs were included. The full text of each article was critically reviewed, and data interpretation was performed. Results There were three circumstances related to pharmacokinetic DDIs in the combined use of DHP-CCB and statin: 1) statin is comedicated as the precipitant drug (pravastatin–nimodipine and lovastatin–nicardipine); 2) statin is comedicated as the object drug (isradipine–lovastatin, lacidipine–simvastatin, amlodipine–simvastatin, benidipine-simvastatin, azelnidipine– simvastatin, lercanidipine–simvastatin, and amlodipine–atorvastatin); and 3) mutual interactions (lercanidipine–fluvastatin). Simvastatin has an extensive first-pass effect in the intestinal wall, whereas atorvastatin has a smaller intestinal first-pass effect. The interaction