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Sample records for nicardipine

  1. Nicardipine

    MedlinePlus

    ... organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other ... doctor if you have or have ever had heart failure, or heart, liver, or kidney disease.tell your ...

  2. Nicardipine in models of myocardial infarction

    PubMed Central

    Alps, B. J.; Calder, C.; Wilson, A.

    1985-01-01

    1 In a dog model of partial myocardial ischaemia, superimposed ST segment elevations in epicardial ECGs were inhibited by nicardipine over a cumulative i.v. dose range of 1-20 μg kg-1. 2 Over the cumulative i.v. dose range of 0.5-166.5 μg kg-1, nicardipine had little overall effect on gross cardiac conduction, at spontaneous heart rate. 3 Dogs that received oral 1-2 mg kg-1 nicardipine daily for 16 weeks and then survived 1 week occlusion of the left anterior descending coronary artery (LAD) developed a superior coronary collateral circulation compared with untreated animals. 4 Nicardipine given by three different dosing schedules to baboons markedly limited myocardial infarction over a 6 h period of LAD occlusion. 5 Compared with a group of completely untreated dogs, there was protection of the myocardium in the animals given nicardipine that survived 3 months occlusion of the LAD. ImagesFigure 7 PMID:4027150

  3. The distribution of intravenous nicardipine in rat brain after subarachnoid hemorrhage

    SciTech Connect

    Tsukahara, T.; Arista, A.; Kassell, N.F. )

    1989-09-01

    The distribution of intravenously injected nicardipine in rat brain was investigated, as well as the influence of subarachnoid hemorrhage on its distribution. Autoradiographic studies demonstrated the accumulation of {sup 3}H-nicardipine only in the ventricles and subarachnoid spaces around pial vessels in normal brains. Thirty minutes after subarachnoid hemorrhage, the concentration of {sup 3}H-nicardipine was higher in the ventricles and in the subarachnoid space than that found in normal brains. It is concluded that nicardipine penetrates into the subarachnoid spaces and ventricles from pial vessels and/or choroid plexus, and that subarachnoid hemorrhage increases the penetration of nicardipine from vessels into the subarachnoid space.

  4. Effects of nicardipine on ventriculo-arterial coupling in humans.

    PubMed

    Tanaka, K; Oshita, S; Kitahata, H; Kimura, H; Kawahito, S; Park, Y C; Sakabe, T

    1998-08-01

    The ratio of effective arterial elastance (Ea) to left ventricular elastance (Ees) is an indicator of the coupling between ventricular properties and arterial load properties. Another criterion for the coupling between an energy source and its load is the principle of economical fuel consumption, or mechanical efficiency, which is defined as the ratio of stroke work (SW) to myocardial oxygen consumption per beat (MVO2). It has been revealed that SW of ventricular contraction is maximized when Ea/Ees = 1, while mechanical efficiency is maximized when Ea/Ees = 0.5. The purpose of the present study was to investigate the ventriculo-arterial coupling during hypertension, and the effects of nicardipine on this relationship in surgical patients using Ea/Ees and SW/MVO2 as indicators. Anaesthesia was maintained with isoflurane, nitrous oxide, and fentanyl. Radial artery pressure was displayed on a polygraph, and left ventricular end-systolic and end-diastolic volumes were determined by use of transoesophageal echocardiography. Ees was calculated as MAP/(ESVI-4), where MAP is mean arterial pressure and ESVI is end-systolic volume index. Ea was calculated as the ratio of MAP to stroke volume index (SVI). Stroke work index (SWI) was calculated as the product of MAP and SVI. MVO2 was assessed by estimating the ventricular pressure-volume area index (PVAI), which is expressed as the sum of SWI and the end-systolic potential energy index. Before (baseline), and 3, 10, 20, and 30 min after i.v. nicardipine (30 micrograms kg-1), Ea/Ees and SWI/PVAI were determined in 14 surgical patients with intraoperative hypertension. Before nicardipine (during hypertension), Ea was almost equal to Ees, whereas Ea/Ees was significantly reduced to about 0.5-0.6 at 3, 10, and 20 min after nicardipine. SWI/PVAI was maximized and significantly greater than the baseline value at 3 min after nicardipine. These results suggest that, during hypertension, ventricular and arterial properties were so

  5. Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

    PubMed Central

    Huang, Bor-Ren; Chang, Pei-Chun; Yeh, Wei-Lan; Lee, Chih-Hao; Tsai, Cheng-Fang; Lin, Chingju; Lin, Hsiao-Yun; Liu, Yu-Shu; Wu, Caren Yu-Ju; Ko, Pei-Ying; Huang, Shiang-Suo; Hsu, Horng-Chaung; Lu, Dah-Yuu

    2014-01-01

    Background/Objective Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved. Methodology/Principal Findings In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo. Conclusion/Significance The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases. PMID:24621589

  6. Effects of nicardipine on cardiac volume at rest and during exercise-induced angina

    PubMed Central

    Silke, B.; Verma, S. P.; Frais, M. A.; Hafizullah, M.; Taylor, S. H.

    1985-01-01

    1 The action of nicardipine on cardiac volume, both at rest and during exercise-induced angina, was evaluated in 12 patients with angiographically-proven coronary artery disease. 2 Nicardipine given to patients at rest reduced systemic vascular resistance and mean arterial pressure and increased heart rate and cardiac index. The left ventricular filling pressure, ejection fraction (EF), end-diastolic and end-systolic volumes were unchanged. 3 During supine bicycle exercise, the reduction in systemic arterial blood pressure following nicardipine increased cardiac and stroke index and attenuated the rise in left ventricular filling pressure observed in the control exercise. 4 The effects of nicardipine on EF, end-diastolic and end-systolic cardiac volumes were dependent on the baseline cardiac reserve. In patients with EF < 50%, nicardipine improved EF and left ventricular exercise volumes. PMID:2862901

  7. A systematic review of nicardipine vs labetalol for the management of hypertensive crises.

    PubMed

    Peacock, W Frank; Hilleman, Daniel E; Levy, Phillip D; Rhoney, Denise H; Varon, Joseph

    2012-07-01

    Hypertensive emergencies are acute elevations in blood pressure (BP) that occur in the presence of progressive end-organ damage. Hypertensive urgencies, defined as elevated BP without acute end-organ damage, can often be treated with oral agents, whereas hypertensive emergencies are best treated with intravenous titratable agents. However, a lack of head-to-head studies has made it difficult to establish which intravenous drug is most effective in treating hypertensive crises. This systematic review presents a synthesis of published studies that compare the antihypertensive agents nicardipine and labetalol in patients experiencing acute hypertensive crises. A MEDLINE search was conducted using the term "labetalol AND nicardipine AND hypertension." Conference abstracts were searched manually. Ultimately, 10 studies were included, encompassing patients with hypertensive crises across an array of indications and practice environments (stroke, the emergency department, critical care, surgery, pediatrics, and pregnancy). The results of this systematic review show comparable efficacy and safety for nicardipine and labetalol, although nicardipine appears to provide more predictable and consistent BP control than labetalol. PMID:21908132

  8. Penetration enhancing effect of menthol on the percutaneous flux of nicardipine hydrochloride through excised rat epidermis from hydroxypropyl cellulose gels.

    PubMed

    Krishnaiah, Y S R; Satyanarayana, V; Karthikeyan, R S

    2002-01-01

    The aim of the present investigation is to study the penetration enhancing effect of menthol on the percutaneous flux of nicardipine hydrochloride through the excised rat epidermis from 2% w/w hydroxypropyl cellulose (HPC) gel system. The HPC gel formulations containing nicardipine hydrochloride and selected concentrations of menthol (0-12% w/w) were prepared, and evaluated for in vitro permeation of the drug through excised rat abdominal epidermis. The percutaneous flux of nicardipine hydrochloride across rat epidermis was enhanced markedly by the addition of menthol to the HPC gels. A maximum flux of nicardipine hydrochloride (227.70 +/- 1.30 micrograms cm-2 hr-1) was observed with an enhancement ratio of 7.12 when menthol was incorporated at a concentration of 8% w/w in a reservoir HPC system. The differential scanning calorimetry and Fourier transform-infrared spectroscopy data indicated that menthol increased the percutaneous flux of nicardipine hydrochloride through the rat skin by partial extraction of lipids in the stratum corneum. The results suggest that menthol may be useful for increasing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir. PMID:12229262

  9. 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. PMID:25215245

  10. 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

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

    PubMed Central

    Rousseau, M. F.; Vincent, M. F.; Cheron, P.; Van Den Berghe, G.; Charlier, A. A.; Pouleur, H.

    1985-01-01

    1 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. 2 Measurements were made at fixed heart rate (atrial pacing), under basal state, and during a cold pressor test. 3 After nicardipine, coronary blood flow and oxygen content in the coronary sinus increased significantly. 4 The indices of inotropic state increased slightly, and the rate of isovolumic LV pressure fall improved. 5 Myocardial oxygen consumption was unchanged despite the significant reduction in pressure-rate product, but LV lactate uptake increased, particularly during the cold pressor test. 6 When nicardipine was administered after propranolol, the indices of inotropic state were unaffected. 7 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. 8 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. PMID:2862900

  12. Evaluation of the efficacy and safety of oral nicardipine in treatment of urgent hypertension: a multicenter, randomized, double-blind, parallel, placebo-controlled clinical trial.

    PubMed

    Habib, G B; Dunbar, L M; Rodrigues, R; Neale, A C; Friday, K J

    1995-05-01

    This study was a prospective, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of oral nicardipine for the treatment of urgent hypertension in the emergency department. Of 57 patients with urgent hypertension 53 patients were enrolled: 36 men and 17 women, 43 black and 10 white, age range 48 +/- 11 years, and diastolic blood pressure 128 +/- 7 mm Hg. Patients were randomly assigned to receive 30 mg nicardipine or placebo in blind fashion followed by 30 mg open-label nicardipine in nonresponders. Responders to one or two doses of nicardipine received 30 or 40 mg nicardipine three times a day for 1 week after discharge from the emergency department. Adequate blood pressure reduction, defined as a reduction of diastolic blood pressure to less than 100 mm Hg or by at least 20 mm Hg, was achieved in 65% and 22% of patients who received 30 mg nicardipine or placebo (p = 0.002). Adequate blood pressure reduction after administration of open-label nicardipine occurred in 76% of the nonresponders to placebo. Blood pressure reductions were maintained at 1 week after discharge. The drug was well tolerated, and no significant adverse events occurred. We conclude that oral nicardipine is a safe and effective drug for the initial treatment of urgent hypertension. PMID:7732981

  13. Comparison of haemodynamic responses to cilnidipine and nicardipine in an experimental model of acute congestive heart failure.

    PubMed

    Noguchi, K; Matsuzaki, T; Koyama, T; Itomine, T; Sakanashi, M

    1998-01-01

    1. The haemodynamic effects of cilnidipine, a new calcium channel blocker, were examined in a canine model of acute congestive heart failure and were compared with those of nicardipine at equihypotensive doses. 2. The model was prepared by injections of saponin into coronary arteries of anaesthetized open-chest dogs followed by volume loading and continuous i.v. infusion of methoxamine. After the treatment, aortic blood flow (AoF) and left ventricular dP/dt markedly decreased, while left ventricular end-diastolic pressure (LVEDP), right atrial pressure and systemic vascular resistance (SVR) increased. Cilnidipine (0.3, 1.0 and 3.0 micrograms/kg per min), nicardipine (0.3, 1.0 and 3.0 micrograms/kg per min) or the respective vehicle was given i.v. after accomplishment of heart failure. 3. These drugs both produced a comparable reduction in aortic pressure and an increase in AoF associated with profound decreases in LVEDP, SVR and coronary vascular resistance. In contrast, administration of nicardipine was associated with significant increases in heart rate and cardiac contractility but that of cilnidipine was not. 4. These results indicate that cilnidipine as well as nicardipine can exert beneficial haemodynamic effects in a model of acute heart failure probably through lessening afterload and cilnidipine may moderate reflex-induced sympathetic stimulation. PMID:9673425

  14. Does a single dose of intravenous nicardipine or nimodipine affect the bispectral index following rapid sequence intubation?

    PubMed Central

    Lee, Jeong Jin; Ahn, Hyun Joo; Kim, Jin-Kyoung; Yang, Mikyung; Choi, Soo Joo; Kim, Hyun-Soo; Yang, Soo Hyun

    2010-01-01

    Background Theoretically, L-type calcium channel blockers could modulate anesthetic effects. Nicardipine does not affect the bispectral index (BIS), but nimodipine, which can penetrate the blood-brain barrier, has not been studied. The aim of this study was to evaluate whether a single dose of intravenous nicardipine or nimodipine could affect BIS following rapid sequence intubation. Methods This study was done in a double-blind, randomized fashion. Anesthesia was induced with fentanyl 2 µg/kg, thiopental sodium 5 mg/kg, and 100% oxygen. After loss of consciousness, patients received rocuronium 1.0 mg/kg and either a bolus of 20 µg/kg nicardipine, nimodipine, or a comparable volume of normal saline (n = 20). Intubation was performed 1 min after study drug administration. BIS, mean blood pressure (MBP), and heart rate (HR) were measured before anesthetic induction, after loss of consciousness, before intubation, during intubation, and 1, 2 and 5 min after intubation. Results BIS dropped rapidly after induction but increased to 60 before intubation in all groups irrespective of study drug. In nimodipine, the increase in BIS during intubation was not significant compared to pre-intubation, in contrast to the other two groups, but there was no difference in BIS during intubation. HR significantly increased, but MBP just rose to pre-induction values after intubation in nicardipine and nimodipine groups. BIS, MBP, and HR following intubation increased in control group. Conclusions A single dose of intravenous nicardipine or nimodipine could attenuate blood pressure increases but not affect BIS increases in rapid sequence intubation. PMID:21057615

  15. Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

    PubMed

    Krishnaiah, Y S R; Satyanarayana, V; Bhaskar, P

    2003-05-01

    A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form. PMID:12754008

  16. 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

  17. 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. PMID:26148375

  18. Protection by nicorandil against the dysfunction of the central vagal baroreflex system following transient global cerebral ischaemia in dogs.

    PubMed Central

    Kurihara, J.; Ochiai, N.; Kato, H.

    1993-01-01

    1. A possible cerebroprotective effect of nicorandil was investigated in a canine model of 5 min global cerebral ischaemia, and compared with protective effects of nitroglycerin and nicardipine. 2. Cerebral ischaemia was produced by occlusion of the left subclavian and the brachiocephalic arteries with preceding ligation of the intercostal arteries. The decrease in baroreflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, was used to assess the cerebroprotective effect. 3. Nicorandil (10 or 30 micrograms kg-1 min-1, i.v.), nitroglycerin (3 micrograms kg-1 min-1, i.v.) or nicardipine (0.3 micrograms kg-1 min-1, i.v.) were infused for 60 min just before ischaemia. Nitroglycerin and nicardipine decreased mean arterial blood pressure to an extent similar to that induced by the lower dose of nicorandil. Blood flow in the dorsal medulla oblongata was increased by nicorandil and nicardipine, but not by nitroglycerin. 4. Nicorandil at both doses and nitroglycerin prevented the post-ischaemic decrease in BRS. In these cases, bilateral vagotomy during the reperfusion period decreased BRS, indicating that the vagal component of BRS was protected from ischaemia. On the other hand, nicardipine failed to exert a cerebroprotective effect. 5. The present study suggests that nicorandil may possess a direct cerebroprotective effect and that its property as a nitrate might, at least in part, be important for the observed cerebral protection. PMID:8401937

  19. [Effect of efonidipine hydrochloride, a calcium channel blocker, on the experimental cerebral ischemia/anoxia].

    PubMed

    Matsumura, T; Furuichi, H; Izumi, J; Suda, H; Ito, S; Takei, M; Nishi, N; Mori, T; Tanaka, Y; Kurimoto, T

    1995-06-01

    The anti-ischemic and anti-anoxic effects of efonidipine, a dihydropyridine calcium antagonist, were studied in several models for cerebral ischemia and anoxia in mice and rats, and the effects were compared with those of nicardipine and flunarizine. Both efonidipine and flunarizine showed protective effects in the models of KCN-induced anoxia and complete ischemia induced by decapitation in mice 6 hr after the treatment, while nicardipine did not show such a long-lasting effect. Efonidipine (1 mg/kg, i.p.), but not nicardipine and flunarizine, prolonged the tolerance times in the asphyxic anoxia model. In mice, efonidipine (4 mg/kg, i.p.) significantly reduced the cumulative mortality rate after bilateral carotid artery ligation. The survival rates at 20 hr after bilateral carotid artery ligation were 33% in the group treated with efonidipine, significantly higher than that in the control group, 0%. On the other hand, the treatment with nicardipine or flunarizine did not increase the rates at 20 hr after the ligation. Moreover, efonidipine attenuated the disturbance of cerebral energy metabolism induced by decapitation in rats. These effects of efonidipine observed in this study were on the whole superior to those of the reference drugs, strongly suggesting the improving effect of efonidipine on cerebral ischemia and anoxia. PMID:7557732

  20. Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

    PubMed Central

    Tjia, J F; Back, D J; Breckenridge, A M

    1989-01-01

    The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine. PMID:2789931

  1. Effect of pinaverium and other calcium channel blockers on contraction of isolated gastric antral smooth muscle cells caused by gastrointestinal hormones.

    PubMed

    Bobo, M H; Magous, R; Christen, M O; Bali, J P

    1994-01-01

    Gastrointestinal hormones, gastrin, cholecystokinin (CCK), and motilin, are known to induce contraction of digestive smooth muscle cells from various species. In this paper, we studied the effect of calcium channel blockers, diltiazem, nicardipine, and pinaverium on the hormone-dependent contraction of smooth muscle cells isolated from rabbit antrum. Gastrin, CCK-8, and motilin caused dose-dependent contraction with EC-50 values in the physiological range (10-100 pM). This contractile effect was dependent upon extracellular calcium for gastrin and CCK-8 but not for motilin. When used alone, calcium channel blockers diltiazem, nicardipine, but not pinaverium, caused a weak but significant contraction of the cells. Pinaverium inhibited both gastrin- and CCK-8-induced contractions with IC-50 values of 1 nM and it was much less potent in the inhibition of motilin-induced contractions (IC-50 = 25 nM). The effect of pinaverium was equivalent to that of diltiazem in the inhibition of CCK-8- or gastrin-induced contractions. Both drugs were slightly more potent than nicardipine (IC-50 = 10 nM versus 1 nM for pineaverium and 5 nM for diltiazem). In contrast, diltiazem and pinaverium were less potent against motilin stimulation, diltiazem being 5 times more potent than pinaverium. In conclusion, it appears that since Ca2+ antagonists pinaverium, diltiazem and nicardipine inhibited contraction of smooth muscle cells stimulated by gastrointestinal hormones, "L-type" calcium channels of the plasma membrane might also be regulated through occupation of gastrin or CCK receptors. PMID:8201843

  2. Vasodilator effects of flunarizine on retinal blood vessels in anesthetized rats.

    PubMed

    Noguchi, Masahiro; Mori, Asami; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2009-12-01

    The aim of this study was to investigate the effects of intravenous administration of flunarizine on the diameter of retinal blood vessels and blood pressure in anesthetized rats and to compare the effects of this antagonist with those of nicardipine and nifedipine. Retinal vascular images were captured with a fundus camera system for small animals and the diameter of retinal blood vessels contained in the images was measured using image-processing softwares on a personal computer. Blood pressure was continuously measured. Flunarizine [1-30 microg/kg, intravenously (i.v.)] dose-dependently increased the diameter of retinal blood vessels without significantly changing systemic blood pressure. Nicardipine (1-30 microg/kg, i.v.) increased the retinal blood vessel diameter but decreased blood pressure in a dose-dependent manner. Nifedipine (10-100 microg/kg, i.v.) failed to dilate the retinal blood vessels, although it produced comparable depressor responses as those to nicardipine. These results suggest that flunarizine selectively acts on the retinal blood vessels rather than on the peripheral resistance vessels. Flunarizine could therefore be considered as a candidate for therapeutic drugs to treat diseases associated with disorders of retinal circulation without severe cardiovascular side-effects. PMID:19952431

  3. Blockade of intracellular actions of calcium may protect against ischaemic damage to the gerbil brain.

    PubMed Central

    Asano, T.; Ikegaki, I.; Satoh, S.; Mochizuki, D.; Hidaka, H.; Suzuki, Y.; Shibuya, M.; Sugita, K.

    1991-01-01

    1. The brain cytoprotective effects of a putative calcium-associated protein kinase inhibitor, HA1077, as well as a calcium entry blocker nicardipine were evaluated in models of cerebral ischaemia in Mongolian gerbils. Morphological changes characterizing delayed neuronal death of selectively vulnerable CA1 pyramidal neurones in the hippocampus of the Mongolian gerbil brain occurred 7 days after transient bilateral occlusion of the common carotid arteries. 2. A single injection of HA1077 (1 and 3 mg kg-1, i.p.) 5 min after the occlusion led to a dose-dependent protection of the CA1 neurones. Repeated administrations of HA1077 (1 and 3 mg kg-1, i.p., twice daily for 7 days post-ischaemia) revealed an increase in the number of normal cells, compared to findings with a single administration. 3. In contrast to HA1077, nicardipine (0.3 and 1 mg kg-1, i.p.) did not reduce neuronal degeneration. 4. HA1077 did not interact with the ion channel within which MK-801 binds, as determined by receptor binding. 5. The calcium ionophore, A23187, caused a tonic contraction in canine cerebral arterial strips. HA1077, but not nicardipine, relaxed the A23187-induced contraction, concentration-dependently. 6. These results suggest that blockade of the intracellular actions of calcium may provide protection against ischaemic damage in the brain. Images Figure 1 PMID:1912980

  4. Effects of calcium entry blockers on calcium-dependent contractions of rat portal vein.

    PubMed Central

    Dacquet, C.; Mironneau, C.; Mironneau, J.

    1987-01-01

    1 The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200-110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high-K+ solutions, noradrenaline, acetylcholine and caffeine. 2 The rank order of potency was PN 200-110 greater than nicardipine = nifedipine = D888 greater than D600 greater than diltiazem from experiments on spontaneous contractions and high-K+ induced contractions. With depolarized preparations, the concentration-response curves for nicardipine, PN 200-110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage-dependent inhibitory properties. This effect was not significant with D888 and diltiazem. 3 All the calcium entry blockers strongly reduced the noradrenaline (NA)- and acetylcholine (ACh)-induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine-induced contractions. 4 In Ca2+-free, EGTA-containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug-sensitive calcium store. The filling of the calcium store was maximal after 10-12 min of calcium loading in 2.1 mM Ca2+, while the depletion was complete after 4-6 min of perfusion in Ca2+-free solution. 5 At concentrations which abolished spontaneous contractions, PN 200-110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+-free solutions by ACh, NA and caffeine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2959345

  5. Preparation of polymeric microspheres by the solvent evaporation method using sucrose stearate as a droplet stabilizer.

    PubMed

    Yüksel, N; Baykara, T

    1997-01-01

    Polymeric microspheres containing nicardipine hydrochloride (HCl) as a reference drug were prepared with the acrylic polymers Eudragit RS and L by the solvent evaporation method. Different concentrations of sucrose stearate as a droplet stabilizer were used. Sucrose stearate affected the diffusion rate of the solvent from the preliminary emulsion droplets to the outer phase for the formation of microspheres. Increasing concentrations of sucrose stearate in the formulations caused increasing porosity on the surface of the microspheres. However, a correlation between the concentrations of sucrose stearate and diameters of microspheres could not be assessed. From this point of view, during processing, applied stirring rate was important. PMID:9394253

  6. Calcium balance in pea root statocytes under both clinorotation and Ca2+ channel blockers' influence

    NASA Astrophysics Data System (ADS)

    Belyavskaya, Ninel A.; Tsarik, Nina P.

    We have previously demonstrated that space flight and clinorotation conditions increase cytoplasmic Ca^2+ level in pea root statocytes. A rise in [Ca^2+]_i may be a serious problem for plants in microgravity environment. It is hypothesized that involvement of Ca^2+ channel blockers in the growth medium may rescue a plant from abundance of Ca^2+ ions. Indeed, combination of clinorotation (2 rpm, 5 days) and any Ca^2+ channel blocker (1 μm D600 or nicardipine, 12 hr) causes decreasing the Ca^2+ concentration in pea root statocytes in comparison with clinorotation alone. Redistribution of Ca^2+-ATPase activities observed under clinorotation comes to normal after D600 application whereas following by nicardipine action the pattern of the cytochemical staining is intermediate between those in stationary control and under clinorotation. Our data support the hypothesis that Ca^2+ channel blockers may act as protectors for plants against rise in [Ca^2+]i. The role for Ca^2+ channels in graviperception and in microgravity effects as well as ways for stabilization of Ca^2+ balance in plant cells in space flights are discussed.

  7. Intracellular calcium store filling by an L-type calcium current in the basolateral amygdala at subthreshold membrane potentials

    PubMed Central

    Power, John M; Sah, Pankaj

    2005-01-01

    The long-term changes that underlie learning and memory are activated by rises in intracellular Ca2+ that activate a number of signalling pathways and trigger changes in gene transcription. Ca2+ rises due to influx via L-type voltage-dependent Ca2+ channels (L-VDCCs) and release from intracellular Ca2+ stores have been consistently implicated in the biochemical cascades that underlie the final changes in memory formation. Here, we show that pyramidal neurones in the basolateral amygdala express an L-VDCC that is active at resting membrane potentials. Subthreshold depolarization of neurones either by current injection or summating synaptic potentials led to a sustained rise in cytosolic Ca2+ that was blocked by the dihydropyridine nicardipine. Activation of metabotropic receptors released Ca2+ from intracellular Ca2+ stores. At hyperpolarized potentials, metabotropic-evoked store release ran down with repeated stimulation. Depolarization of cells to −50 mV, or maintaining them at the resting membrane potential, restored release from intracellular Ca2+ stores, an effect that was blocked by nicardipine. These results show that Ca2+ influx via a low-voltage-activated L-type Ca2+ current refills inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores, and maintains Ca2+ release and wave generation by metabotropic receptor activation. PMID:15550460

  8. Cyclodextrin-polyhydrazine degradable gels for hydrophobic drug delivery.

    PubMed

    Jalalvandi, Esmat; Cabral, Jaydee; Hanton, Lyall R; Moratti, Stephen C

    2016-12-01

    An injectable and biocompatible hydrogel system was designed for hydrophobic drug delivery. This hydrogel consisted of degradable polymers with cyclodextrin (CD) moieties. CD groups were used to increase the solubility of a hydrophobic molecule (nicardipine) in an aqueous solution through the formation of the inclusion complex. Two sets of gels were prepared by mixing oxidized dextran (DA) and CD functionalized polyhydrazine (PH) at physiological conditions and different level of crosslinking via hydrazone bonds. Cytotoxicity studies on the gels and their components confirmed the biocompatibility of these materials. Gel-30 with higher crosslinking density showed a two week degradation period whereas this period was 10days for gel-10, with lower crosslinking density, to complete degradation. The results from swelling tests and rheological measurements were also found to be dependent on crosslinking density of the hydrogels. Release profile of the hydrogel displayed a sustained release of nicardipin up to 6days for gel-30 and a 4day release with initial burst release for gel-10. PMID:27612699

  9. Neurotrophic effect of isoquinoline derivatives in primary cortical culture.

    PubMed

    Ueda, Y; Nakanishi, H; Yoshida, K

    1999-01-01

    Recent studies indicate that the N-methyl-D-aspartate (NMDA) antagonist, (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (FR 115427), enhanced neuronal survival in primary culture of cortical neurons from mouse embryos. In the present study isoquinoline derivatives were examined for the neurotrophic activity in primary culture of cortical neurons and were also examined for anti-NMDA activity. In spite of varying level of anti-NMDA activity, isoquinoline derivatives enhanced neuronal survival at the concentration of 10 microM. To elucidate of the mechanisms of neurotrophic activity in primary cortical culture, nicardipine and flunarizine, known calcium channel blockers, were also tested. Neither nicardipine nor flunarizine showed neurotrophic activity up to the doses causing toxicity in cultured neurons. NBQX, an AMPA receptor antagonist, was also tested for neurotrophic activity. However no enhancement of neuronal survival was observed. These data suggest that one of the mechanisms to promote neuronal survival may depend on the structure of isoquinoline ring. Moreover neurotrophic activity observed in our culture systems might not relate on anti-NMDA activity, blockade of voltage dependent L-type calcium channels and antagonization of AMPA receptor. PMID:10530799

  10. Evaluation of the long-lasting antihypertensive action of 7-O-ethylfangchinoline.

    PubMed

    Kato, T; Noguchi, K; Sakanashi, M

    1994-09-01

    The antihypertensive effect of 7-O-ethylfangchinoline (TJN-220) was analyzed in an experimental model of hypertensive rats under the conscious condition. Single oral administration of TJN-220 (25 and 50 mg/kg) produced a progressive and long-lasting fall of mean blood pressure in spontaneously hypertensive rats (SHRs), deoxycorticosterone acetate (DOCA)-salt hypertensive rats and renal hypertensive rats until 72 hr after the drug administration, but affected neither the heart rate in these hypertensive rats nor the hemodynamic parameters in normotensive rats. In SHRs implanted with a telemetry transmitter, TJN-220 (50 mg/kg, p.o.) produced falls of systolic and diastolic blood pressures and diminished the difference in blood pressure between the dark period and the light period for 3 days, particularly by suppressing the increasing phase of blood pressure during the dark period without influencing heart rate or locomotor activity. On the other hand, nicardipine (10 mg/kg, p.o.) produced a transient fall of blood pressure associated with a tachycardia during the light period on the first day alone. Clonidine (0.3 mg/kg, p.o.) diminished the increasing phases of blood pressure and heart rate during the dark period on the first day alone. Thus, the antihypertensive action of TJN-220 was much longer than those of nicardipine and clonidine. The present results suggest that TJN-220 may have potential for use as a beneficial antihypertensive drug. PMID:7861666

  11. The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities.

    PubMed

    El-Kattan, A F; Asbill, C S; Kim, N; Michniak, B B

    2001-03-14

    Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P -0.99 +/- 0.1, hydrocortisone log P 1.43 +/- 0.47, carbamazepine log P 2.67 +/- 0.38, and tamoxifen log P 7.87 +/- 0.75). The enhancing activities of four terpene enhancers (fenchone log P 2.13 +/- 0.30, thymol log P 3.28 +/- 0.20, D-limonene log P 4.58 +/- 0.23, and nerolidol log P 5.36 +/- 0.38) were tested in vitro across full thickness hairless mouse skin with each of the evaluated drugs formulated in hydroxypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ER(flux)) of the drugs when coadministered with the enhancers were examined using linear regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increased by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-fold, and tamoxifen 2-fold. The lowest increase in the flux was observed with fenchone. Linear relationships were generated between the ER(flux) of nicardipine hydrochloride, hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [r = 0.951, (P = 0.049), r = 0.977, (P = 0.023), r = 0.942, (P = 0.057), and r = 0.874, (P = 0.126), respectively]. Furthermore, the four terpene enhancers produced linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs rather than lipophilic drugs r=-0.824 (P=0.176) for fenchone, r = -0.891 (P = 0.109) for thymol, r = -0.846 (P = 0.154) for limonene, and r = -0.769 (P = 0.232) for nerolidol. PMID:11250108

  12. Natural abundance (14)N and (15)N solid-state NMR of pharmaceuticals and their polymorphs.

    PubMed

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

    2016-06-29

    (14)N ultra-wideline (UW), (1)H{(15)N} indirectly-detected HETCOR (idHETCOR) and (15)N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of (14)N 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. 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 (14)N 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. Directly-excited (14)N NMR spectra were acquired using the WURST-CPMG pulse sequence, which incorporates WURST (wideband, uniform rate, and smooth truncation) pulses and a CPMG (Carr-Purcell Meiboom-Gill) refocusing protocol. In certain cases, spectra were acquired using (1)H → (14)N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion - cross polarization) pulse sequence. These spectra provide (14)N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The (1)H{(15)N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide (1)H-(15)N chemical shift correlations for all nitrogen environments, except for two sites in acebutolol and nicardipine. One of these two sites (RR'NH2(+) in acebutolol) was successfully detected using the DNP-enhanced (15)N{(1)H} CP/MAS measurement, and one (RNO2 in nicardipine) remained elusive due to the absence of

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

    DOE PAGESBeta

    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 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

  14. Effects of calcium antagonists in the treatment of ophthalmic postherpetic neuralgia.

    PubMed

    Famà, F; Santamaria, S; Castagna, I; Genovese, F R; Ferreri, G

    1995-01-01

    Postherpetic neuralgia is one of the most common, but also one of the most difficult conditions to treat. This condition mainly involves trigeminal, intercostal and sciatic nerves and the brachial plexus area. It mostly appears in patients older than 60 years. Although pain is a transient condition, the pain of postherpeutic neuralgia may become intractable, disabling an may decrease the quality of the patient's life. We studied 30 patients affected by ophthalmic postherpetic neuralgia, appearing, some months after fronto-orbital cutaneous eruption. All patients received nicardipine retard, decreasing gradually, 40 mg/day for 2 weeks. The monitoring of pain was performed using the visual analogue score of Scott-Huskissonn. The results show an improvement in 'pain relief'. PMID:8570150

  15. Micellar modified spectrophotometric determination of nitrobenzenes based upon reduction with tin(II), diazotisation and coupling with the Bratton-Marshall reagent.

    PubMed

    Escrig-Tena, I; Alvarez Rodríguez, L; Esteve-Romero, J; García-Alvarez-Coque, M C

    1998-09-01

    Nitrobenzenes, such as the antibiotic chloramphenicol, the vasodilator nicardipine, and the herbicides dinitramin, dinobuton, fenitrothion, methylparathion, oxyfluorfen, parathion, pendimethalin, quintozene, and trifluralin, were determined by using a spectrophotometric method in the visible region (540 nm). The method was based on the reduction of the nitrobenzenes to arylamines with tin(II) chloride, diazotisation of the arylamines and coupling of the diazonium ions with the Bratton-Marshall reagent. The two latter reactions were performed in a micellar medium of sodium dodecyl sulphate. The linear calibration range was 2x10(-6) to 7x10(-5) M (r>0.999), with limits of detection in the 10(-7) M level, which is 2-6 fold lower with respect to the corresponding spectrophotometric procedure in non-micellar medium. The procedure was applied to the analysis of the compounds in commercial preparations (pharmaceuticals and herbicide formulations) and in water samples, with good recoveries. PMID:18967301

  16. A Case of Isolated Celiac Artery Dissection Accompanied by Splenic Infarction Detected by Ultrasonography in the Emergency Department

    PubMed Central

    Emori, Kazumasa; Takeuchi, Nobuhiro; Soneda, Junichi

    2016-01-01

    A 46-year-old male with a history of hypertension visited the emergency department (ED) by ambulance complaining of sudden pain in the left side of his back. Ultrasonography (USG) performed at ED revealed splenic infarction along with occlusion and dissection of the celiac and splenic arteries without abdominal artery dissection. Contrast enhanced computed tomography (CT) revealed the same result. Consequently, spontaneous isolated celiac artery dissection (SICAD) was diagnosed. Because his blood pressure was high (159/70 mmHg), antihypertensive medicine was administered (nicardipine and carvedilol). After his blood reached optimal levels (130/80 mmHg), symptoms disappeared. Follow-up USG and contrast enhanced CT performed 8 days and 4 months after onset revealed amelioration of splenic infarction and improvement of the narrowed artery. Here, we report a case of SICAD with splenic infarction presenting with severe left-sided back pain and discuss the relevance of USG in an emergency setting. PMID:27148460

  17. ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia

    PubMed Central

    Joseph, Elizabeth K.; Green, Paul G.; Levine, Jon D.

    2014-01-01

    Endothelin-1 acts on endothelial cells to enhance mechanical stimulation-induced release of ATP, which in turn can act on sensory neurons innervating blood vessels to contribute to vascular pain, a phenomenon we have referred to as stimulus-dependent hyperalgesia (SDH). In the present study we evaluated the role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis, plasma membrane associated ATP synthase, ATP-Binding Cassette (ABC) transporters, and ion channels. Inhibitors of vesicular exocytosis (i.e., monensin, brefeldin A and bafilomycin), plasma membrane associated ATPase (i.e., oligomycin and pigment epithelium-derived factor-derived peptide 34-mer) and connexin ion channels (carbenoxolone and flufenamic acid), but not ABC transporters (i.e., dipyridamole, nicardipine or CFTRinh-172) attenuated stimulus-dependent hyperalgesia. These studies support a role of ATP in SDH, and suggest novel targets for the treatment of vascular pain syndromes. PMID:24793242

  18. A Case of Isolated Celiac Artery Dissection Accompanied by Splenic Infarction Detected by Ultrasonography in the Emergency Department.

    PubMed

    Emori, Kazumasa; Takeuchi, Nobuhiro; Soneda, Junichi

    2016-01-01

    A 46-year-old male with a history of hypertension visited the emergency department (ED) by ambulance complaining of sudden pain in the left side of his back. Ultrasonography (USG) performed at ED revealed splenic infarction along with occlusion and dissection of the celiac and splenic arteries without abdominal artery dissection. Contrast enhanced computed tomography (CT) revealed the same result. Consequently, spontaneous isolated celiac artery dissection (SICAD) was diagnosed. Because his blood pressure was high (159/70 mmHg), antihypertensive medicine was administered (nicardipine and carvedilol). After his blood reached optimal levels (130/80 mmHg), symptoms disappeared. Follow-up USG and contrast enhanced CT performed 8 days and 4 months after onset revealed amelioration of splenic infarction and improvement of the narrowed artery. Here, we report a case of SICAD with splenic infarction presenting with severe left-sided back pain and discuss the relevance of USG in an emergency setting. PMID:27148460

  19. [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. PMID:27554460

  20. Calcium antagonist flunarizine hydrochloride affects striatal D2 dopamine receptors in the young adult and aged rat brain.

    PubMed

    Asanuma, M; Ogawa, N; Haba, K; Hirata, H; Mori, A

    1991-01-01

    The calcium (Ca) antagonist flunarizine hydrochloride (FNZ) has been reported to induce parkinsonism, especially in the elderly. The effects of FNZ on dopamine receptors in rat striatal membranes, especially in aged rats, were studied using radiolabeled receptor assay. Similar displacing potencies in [(3)H]spiperone bindings were exhibited for FNZ and the Ca antagonists verapamil and nicardipine. FNZ was found to directly and competitively effect D2 receptors (D2-Rs) as an antagonist, without effecting D1 receptors. Furthermore, the washing of preoccupied membranes revealed that FNZ has a long-acting potent effect on D2-Rs. The comparative study of FNZ and sulpiride in young-adult and aged rats showed that the effect of FNZ on D2-Rs was more marked in aged rats. These results might be related to FNZ-induced parkinsonism and its high incidence in the elderly. PMID:15374420

  1. Photoalteration of calcium channel blockade in the cardiac Purkinje fiber.

    PubMed

    Sanguinetti, M C; Kass, R S

    1984-05-01

    Organic compounds that block calcium channel current (calcium antagonists) are important tools for the characterization of this channel. However, the practically irreversible nature of this block restricts the usefulness of this group of drugs. In this paper, we investigate the influence of light on calcium channel blockade by several organic compounds. Our results show that inhibition of calcium channel current by two dihydropyridine derivatives that contain an o-nitro moiety (nisoldipine and nifedipine) can be rapidly reversed by illumination. The energy range important to this reaction is for light wavelengths between 320 and 450 nm. Calcium channel inhibition by two other dihydropyridine derivatives (nicardipine and nitrendipine) as well as by D600, is not modulated by illumination. These results indicate that the photosensitivity of certain dihydropyridine calcium channel blockers make these compounds useful as reversible blockers of this channel. PMID:6329345

  2. 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.

  3. 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

  4. 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

  5. Risk Factors and Prevention of Guiding Catheter-induced Vasospasm in Neuroendovascular Treatment

    PubMed Central

    ISHIHARA, Hideaki; ISHIHARA, Shoichiro; NIIMI, Jun; NEKI, Hiroaki; KAKEHI, Yoshiaki; UEMIYA, Nahoko; KOHYAMA, Shinya; YAMANE, Fumitaka; KATO, Hiroshi

    2015-01-01

    Mechanically-induced vasospasm often occurs during guiding catheter insertion, occasionally preventing catheter advancement to the desired location. Delicate manipulation would be impossible without the proper positioning of guiding catheters, and vasospasm-induced cerebral hypoperfusion may cause thrombotic complications. From June 2012 to December 2013, we prospectively analyzed 150 endovascular treatment cases, excluding acute cases, for the frequency of vasospasm, risk factors, and countermeasures. The associated risk factors such as the Japanese-style State-Trait Anxiety Inventory (STAI) score; anatomy and devices; and the efficacies of warm compresses, intra-arterial lidocaine/nicardipine, and tranquilizers were analyzed. Groups 1, 2, and 3 comprised 50 patients each with controls, tranquilizer administration, and prophylactic warm compresses/intra-arterial drug injection, respectively. Moderate or severe vasospasm was seen in approximately 40% patients in each group; however, severe vasospasm was absent in Group 3. Mild vasospasm-induced cerebral infarction occurred in one patient each in Groups 1 and 2. Vasospasm during diagnostic angiography [odds ratio (OR) = 10.63; P = 0.01], many ≥ 30° vessel curves [OR = 4.21; P = 0.01], and the high STAI score [OR = 1.84; P = 0.01] were risk factors for severe vasospasm. Although the relationship between anxiety and sympathetic tone remained unclear, tranquilizer administration relieved vasospasm. Warm compresses and the intra-arterial drug infusion were also useful for relieving vasospasm. Prophylactic measures such as a tranquilizer and warm compresses are expected to alleviate vasospasm; in addition, countermeasures such as the intra-arterial injection of lidocaine/nicardipine are effective. PMID:25739431

  6. Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: comparison of tolbutamide and gliclazide and a potential role for EPAC activation of a 2-APB-sensitive Ca2+ influx.

    PubMed

    Jarrard, Rachel E; Wang, Yuchen; Salyer, Amy E; Pratt, Evan P S; Soderling, Ian M; Guerra, Marcy L; Lange, Allison M; Broderick, Hilary J; Hockerman, Gregory H

    2013-01-01

    Tolbutamide and gliclazide block the K(ATP) channel K(ir)6.2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells. We examined the ability of the EPAC-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it. Insulin secretion stimulated by both 200 μM tolbutamide and 20 μM gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 μM) or the L-type Ca(2+) channel blocker nicardipine (2 μM) and was potentiated by 8-pCPT-2'-O-Me-cAMP-AM at concentrations ≥2 μM in INS-1 cells. Ca(2+) transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-2'-O-Me-cAMP-AM at 5 μM but not 1 μM. Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K(ATP) channels, and this activity was partially inhibited by pertussis toxin. 8-pCPT-2'-O-Me-cAMP-AM alone (5 μM) did not stimulate insulin secretion, but did increase intracellular Ca(2+) concentration significantly, and this activity was inhibited by 25 μM 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca(2+). 8-pCPT-2'-O-Me-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 μM) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 μM). Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-2'-O-Me-cAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-2'-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca(2+) influx. PMID:23071106

  7. Cannabinoid receptor activation in the juvenile rat brain results in rapid biomechanical alterations: Neurovascular mechanism as a putative confounding factor.

    PubMed

    Chatelin, Simon; Humbert-Claude, Marie; Garteiser, Philippe; Ricobaraza, Ana; Vilgrain, Valérie; Van Beers, Bernard E; Sinkus, Ralph; Lenkei, Zsolt

    2016-05-01

    We have recently reported cannabinoid-induced rapid changes in the structure of individual neurons. In order to investigate the presence of similar effects at the regional level, measures of brain tissue biomechanics are required. However, cannabinoids are known to alter cerebral blood flow (CBF), putatively resulting in presently unexplored changes in cerebral tissue biomechanics. Here we used magnetic resonance elastography (MRE) and flow-sensitive alternating inversion recovery (FAIR) imaging to measure in vivo alterations of mechanical properties and CBF, respectively, in the rat hippocampus, a brain region with a high density of type-1 cannabinoid receptors (CB1R). Systemic injection of the cannabinoid agonist CP55,940 (0.7 mg/kg) induced a significant stiffness decrease of 10.5 ± 1.2% at 15 minutes. FAIR imaging indicated a comparable decrease (11.3 ± 1.9%) in CBF. Both effects were specific to CB1R activation, as shown by pretreatment with the CB1R-specific antagonist AM251. Strikingly, similar rapid parallel changes of brain elasticity and CBF were also observed after systemic treatment with the hypotensive drug nicardipine. Our results reveal important drug-induced parallel changes in CBF and brain mechanical characteristics, and show that blood flow-dependent tissue softening has to be considered as an important putative confounding factor when cerebral viscoelastic changes are investigated. PMID:26661178

  8. Suppression of cytochrome P450 3A protein levels by proteasome inhibitors.

    SciTech Connect

    Zangar, Richard C. ); Kocarek, Thomas A.; Shen, Shang; Bollinger, Nikki ); Dahn, Michael S.; Lee, Donna W.

    2003-06-01

    We have previously reported that CYP3A cross-links with polyubiquitinated proteins in microsomes from nicardipine-treated rats in a process that is distinct from classical polyubiquitination. To further examine the role of the proteasome in CYP3A degradation, we investigated the effects of proteasome inhibitors lactacystin, MG132, proteasome inhibitor 1, and hemin in primary cultures of rat and human hepatocytes. With the exception of hemin, these agents increased the total pool of ubiquitinated proteins in microsomes isolated from rat hepatocytes, indicating that lactacystin, MG132, and proteasome inhibitor 1 effectively inhibited the proteasome in these cells. All four agents caused a reduction in the amount of the major approximately 55-kDa CYP3A band, opposite to what would be expected if the ubiquitin-proteasome pathway degraded CYP3A. Only hemin treatment caused an increase in high molecular mass (HMM) CYP3A bands. Because hemin treatment did not alter levels of ubiquitin in CYP3 A immunoprecipitates, the HMM CYP3A bands formed in response to hemin treatment clearly were not due to proteasome inhibition. Rather, because hemin treatment also caused an increase in HMM CYP3A in the detergent-insoluble fraction of the 10,000g pellet, the HMM CYP3A seems to represent a large protein complex that is unlikely to primarily represent ubiquitination.

  9. 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.

  10. An overdose of extended-release guanfacine.

    PubMed

    Fein, Daniel M; Hafeez, Zoabe F; Cavagnaro, Christopher

    2013-08-01

    Extended-release guanfacine is a centrally acting α2-adrenergic agonist that was recently approved for treatment of attention-deficit/hyperactivity disorder. The following is a case discussion of a 12-year-old boy with attention-deficit/hyperactivity disorder and Tourette syndrome, who presented 18 hours after ingestion of 3 times his usual dose of extended-release guanfacine. On presentation, he was lethargic, bradycardic, and hypertensive with an otherwise nonfocal neurological examination. He remained hypertensive until administration of an intravenous antihypertensive agent (nicardipine) 24 hours after ingestion. After cessation of the calcium-channel blocker, he continued to have intermittent episodes of symptomatic hypotension for the next 2½ days. This extremely protracted course of hypertension followed by prolonged symptomatic hypotension is rare with ingestions of centrally acting α2-adrenergic agonists. As this drug is increasingly prescribed for treatment of a disease with increasing prevalence, it is imperative that emergency physicians become familiar with the varying presentations of its toxicity. PMID:23925253

  11. Cerebral Vasospasm in Critically III Patients with Aneurysmal Subarachnoid Hemorrhage: Does the Evidence Support the Ever-Growing List of Potential Pharmacotherapy Interventions?

    PubMed Central

    Kiser, Tyree H.

    2014-01-01

    The occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a significant event resulting in decreased cerebral blood flow and oxygen delivery. Prevention and treatment of cerebral vasospasm is vital to avert neurological damage and reduced functional outcomes. A variety of pharmacotherapy interventions for the prevention and treatment of cerebral vasospasm have been evaluated. Unfortunately, very few large randomized trials exist to date, making it difficult to make clear recommendations regarding the efficacy and safety of most pharmacologic interventions. Considerable debate exists regarding the efficacy and safety of hypervolemia, hemodilution, and hypertension (triple-H therapy), and the implementation of each component varies substantially amongst institutions. There is a new focus on euvolemic-induced hypertension as a potentially preferred mechanism of hemodynamic augmentation. Nimodipine is the one pharmacologic intervention that has demonstrated favorable effects on patient outcomes and should be routinely administered unless contraindications are present. Intravenous nicardipine may offer an alternative to oral nimodipine. The addition of high-dose magnesium or statin therapy has shown promise, but results of ongoing large prospective studies are needed before they can be routinely recommended. Tirilazad and clazosentan offer new pharmacologic mechanisms, but clinical outcome results from prospective randomized studies have largely been unfavorable. Locally administered pharmacotherapy provides a targeted approach to the treatment of cerebral vasospasm. However, the paucity of data makes it challenging to determine the most appropriate therapy and implementation strategy. Further studies are needed for most pharmacologic therapies to determine whether meaningful efficacy exists. PMID:25477565

  12. [Effect of Ca-antagonists on pulmonary blood flow during single-lung ventilation in the dog].

    PubMed

    Minami, T; Inoue, H; Ogawa, J; Shohtsu, A

    1993-10-01

    Experiments were conducted in 21 adult mongrel dogs to clarify the effects of Ca-antagonist (nifedipine sublingual administration 2.5 mg or 5 mg, or nicardipine intravenous administration 30 micrograms/kg or 60 micrograms/kg) on pulmonary blood flow under the condition of collapsed lung on the side of thoracotomy. Under anesthesia, an endotracheal tube with a movable blocker was used to intubate the trachea and the thoracotomized lung was collapsed. Subsequently, a Ca-antagonist was given and the ratio of the left main pulmonary artery/ascending thoracic aorta blood flow was used as an index of hypoxic pulmonary vasoconstriction (HPV). The following results were obtained. 1. Ca-antagonist administration under lung-collapse on the thoracotomy side resulted in inhibition of HPV of the collapsed lung, whereas, arterial blood oxygen tension (PaO2) remained in the acceptable range. 2. The maintenance of the lowered PaO2 within the acceptable range may have been due to the increase in cardiac output and the elevation of mixed venous blood oxygen tension resulting from Ca-antagonist administration, as well as the residual HPV even after administration of the Ca-antagonist. PMID:8271651

  13. 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. PMID:25132171

  14. Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism.

    PubMed Central

    Shaw, P M; Barnes, T S; Cameron, D; Engeset, J; Melvin, W T; Omar, G; Petrie, J C; Rush, W R; Snyder, C P; Whiting, P H

    1989-01-01

    A form of human hepatic microsomal cytochrome P-450 (P450hA7) with subunit Mr 50,400 has been purified from an epileptic who had been receiving long-term treatment with anticonvulsant drugs. P450hA7 metabolized the immunosuppressant drug cyclosporin A and the dihydropyridine calcium channel antagonist nifedipine, but did not metabolize a similar dihydropyridine drug, nicardipine, nor a series of alkoxyresorufin model substrates. The hepatic microsomal concentration of P450hA7 was higher in five individuals who had been receiving long-term anticonvulsant treatment than in any of 21 individuals who had not been similarly treated. The mean P450hA7 concentration in the treated individuals was 5-fold higher than the mean concentration in the untreated individuals. It is concluded that P450hA7 is a member of the cytochrome P450III family which is induced by anticonvulsant drugs in man. Images Fig. 1. Fig. 4. Fig. 5. Fig. 6. PMID:2688634

  15. FMRFamide-like peptides (FLPs) enhance voltage-gated calcium currents to elicit muscle contraction in the human parasite Schistosoma mansoni.

    PubMed

    Novozhilova, Ekaterina; Kimber, Michael J; Qian, Hai; McVeigh, Paul; Robertson, Alan P; Zamanian, Mostafa; Maule, Aaron G; Day, Tim A

    2010-01-01

    Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca(2+) influx through sarcolemmal voltage operated Ca(2+) channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 microM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31-8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 microM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca(2+) influx through VOCC currents using a PKC-dependent pathway. PMID:20706630

  16. Interactions of phospholipase D and cytochrome P450 protein stability

    SciTech Connect

    Zangar, Richard C.; Fan, Yang-Yi; Chapkin, Robert S.

    2004-08-01

    Previous studies have suggested a relationship between cytochrome P450 (P450) 3A (CYP3A) conformation and the phospholipid composition of the associated membrane. In this study, we utilized a novel microsomal incubation system that mimics many of the characteristics of CYP3A degradation pathway that have been observed in vivo and in cultured cells to study the effects of phospholipid composition on protein stability. We found that addition of phosphatidylcholine-specific phospholipase D (PLD) stabilized CYP3A in this system, but that phosphatidylinositol-specific phospholipase C (PLC) was without effect. Addition of phosphatidic acid also stabilized CYP3A protein in the microsomes. The use of 1,10-phenanthroline (phenanthroline), an inhibitor of PLD activity, decreased CYP3A stability in incubated microsomes. Similarly, 6-h treatment of primary cultures of rat hepatocytes with phenanthroline resulted in nearly complete loss of CYP3A protein. Treatment of rats with nicardipine or dimethylsulfoxide (DMSO), which have been shown to affect CYP3A stability, altered the phospholipid composition of hepatic microsomes. It did not appear, though, that the changes in phospholipid composition that resulted from these in vivo treatments accounted for the change in CYP3A stability observed in hepatic microsomes from these animals.

  17. Unexpected flagellar movement patterns and epithelial binding behavior of mouse sperm in the oviduct.

    PubMed

    Chang, Haixin; Suarez, Susan S

    2012-05-01

    In order to better understand how sperm movement is regulated in the oviduct, we mated wild-type female mice with Acr-EGFP males that produce sperm with fluorescent acrosomes. The fluorescence improved our ability to detect sperm within the oviduct. Oviducts were removed shortly before or after ovulation and placed in chambers on a warm microscope stage for video recording. Hyperactivated sperm in the isthmic reservoir detached frequently from the epithelium and then reattached. Unexpectedly, most sperm found in the ampulla remained bound to epithelium throughout the observation period of several minutes. In both regions, most sperm produced deep flagellar bends in the direction opposite the hook of the sperm head. This was unexpected, because mouse sperm incubated under capacitating conditions in vitro primarily hyperactivate by producing deep flagellar bends in the same direction as the hook of the head. In vitro, sperm that are treated with thimerosal to release Ca(2+) from internal stores produce deep anti-hook bends; however, physical factors such as viscous oviduct fluid could also have influenced bending in oviductal sperm. Some sperm detached from epithelium in both the ampulla and isthmus during strong contractions of the oviduct. Blockage of oviduct contractions with nicardipine, however, did not stop sperm from forming a storage reservoir in the isthmus or prevent sperm from reaching the ampulla. These observations indicate that sperm continue to bind to oviductal epithelium after they leave the isthmic reservoir and that sperm motility is crucial in the transport of sperm to the fertilization site. PMID:22337334

  18. Isolated rat cardiac myocytes as an experimental model to study calcium overload: the effect of calcium-entry blockers.

    PubMed

    Donck, L V; Pauwels, P J; Vandeplassche, G; Borgers, M

    1986-03-01

    Calcium overload and the effect of a series of calcium-entry blockers were studied in isolated adult cardiac myocytes from the rat challenged with veratrine. The isolation procedure resulted in a high yield of individual rod shaped, calcium tolerant myocytes. After incubation with veratrine, an alkaloid which induces both sodium and calcium influx, 93% of the myocytes became calcium intolerant: the quiescent rod shaped cells vigorously contracted after 30 sec of contact with veratrine and contracture (round cells) ensued within 1 min. Exposure for 30 min to various doses of calcium-entry blockers prior to veratrine addition resulted in the prevention of contracture, the degree of protection depending on the type and the concentration of calcium-entry blocker. Among the different calcium-entry blockers tested, the diarylalkylpiperazines lidoflazine, cinnarizine and flunarizine were protective from the 10(-7) M concentration onwards. Nicardipine was protective at the 10(-6) M and 10(-5) M concentrations, verapamil at 10(-5)M only while other blockers of the "slow channel" type (diltiazem and nifedipine) were not protective in the concentration range tested. This study shows that isolated myocytes represent a valid model for pharmacological investigations. The results with the calcium-entry blockers stress the heterogeneity of the different series of calcium-entry blockers. PMID:3951332

  19. [A Case of Undiagnosed Extra-adrenal Pheochromocytoma in an Adult Patient with Single Ventricle Circulation after the Bidirectional Glenn Operation].

    PubMed

    Kohno, Masaki; Nagamine, Yusuke; Goto, Takahisa

    2015-09-01

    We experienced a case of undiagnosed extra-adrenal pheochromocytoma in an adult patient with single ventricle circulation after the bidirectional Glenn operation. A 32-year-old woman was scheduled for open abdominal surgery for incidental retroperitoneal tumor. She had undergone the bidirectional Glenn operation for complex congenital heart disease consisting of double outlet right ventricle, ventricular septal defect, and pulmonary artery stenosis. She had not undergone the Fontan operation because of insufficient development of pulmonary circulation. Her physical status was New York Heart Association (NYHA) functional class II, and her oxygen saturation was 80% in room air. She reported no symptoms for the abdominal tumor preoperatively. The surgery was performed under general and epidural anesthesia. After induction of general anesthesia, she developed hypertension and tachycardia, and the manipulation of the tumor worsened them. Landiolol, a short acting beta blocker, and nicardipine were administrated. After the resection of the tumor, hypotension refractory to volume replacement emerged, and we administrated low dose noradrenaline. She was extubated in'the operating room and was transferred to the intensive care unit. The histopathological examination of the tumor revealed extra-adrenal pheochromocytoma (paraganglioma). Catecholamine release from pheochromocytoma can be dangerous in patients with single ventricular circulation because it may elevate pulmonary resistance and thereby decrease cardiac output. Thorough preoperative examination is desirable. PMID:26466501

  20. Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome.

    PubMed

    Khajuria, Bhavik; Khajuria, Mansi; Agrawal, Yashwant

    2016-01-01

    A 29-year-old woman presented with diffuse anasarca and shortness of breath. Workup revealed a creatinine of 3.3 and a glomerular filtration rate of 17. The patient was also found to be pancytopenic with evidence of hemolytic anemia. A renal biopsy showed evidence of stage IV lupus nephritis with rapidly progressive glomerulonephritis. Her lupus was further classified as ANA negative and anti-dsDNA positive. Mycophenolate and triweekly hemodialysis were started along with a steroid burst of methylprednisolone 1 g for 3 days followed by prednisone 60 mg daily. Four days after discharge, the patient represented with a witnessed 3-minute seizure involving bowel incontinence, altered mental status, and tongue biting. She was given 2 mg intravenous lorazepam and loaded with 1000 mg levetiracetam for seizure prophylaxis. Magnetic resonance imaging of the head revealed bilateral posterior hemispheric subcortical edema, and the diagnosis of posterior reversible encephalopathy syndrome was made. Mycophenolate was immediately discontinued and replaced with cyclophosphamide. Strict blood pressure control below 140/90 mm Hg was maintained initially with intravenous nicardipine drip and then transitioned to oral nifedipine, clonidine, losartan, and minoxidil. A repeat head magnetic resonance imaging 8 days later showed resolved subcortical edema consistent with the patient's improved mental status. No permanent neurologic sequelae were recorded as a result of this hospital episode. PMID:25933141

  1. Contractile properties of synthetic cationic polypeptides in guinea-pig isolated trachea.

    PubMed Central

    Spina, D.; Goldie, R. G.

    1994-01-01

    1. The synthetic polypeptides, poly-L-arginine, poly-L-lysine and poly-D-lysine contract guinea-pig isolated trachea in a concentration-dependent, epithelium-independent manner. Indomethacin augmented the contractile response to poly-L-arginine. 2. The contractile response to poly-L-arginine was not significantly inhibited by nicardipine, a selective L-type calcium channel blocker or by the histamine H1-receptor antagonist, mepyramine nor significantly augmented by the neutral endopeptidase inhibitor, phosphoramidon. 3. The contractile response to poly-L-arginine was inhibited in a concentration-dependent manner by prior incubation of guinea-pig tracheal rings with a number of anionic polypeptides including, low molecular weight heparin, poly-L-aspartic acid and bovine serum albumin. 4. In vitro capsaicin-induced desensitization failed to attenuate the contractile response to poly-L-arginine, suggesting little, if any role for sensory neuropeptides in the functional response in the guinea-pig. 5. Synthetic polypeptides induce an epithelium-independent, charge-dependent contraction of guinea-pig isolated trachea. PMID:8012709

  2. Management of hypertension emergencies.

    PubMed

    Elliott, William J

    2003-12-01

    Although they have become less common, hypertensive emergencies occur with an incidence of approximately 1 to 2/100,000 people per year. Our knowledge about this problem, its pathophysiology, risk factors, and appropriate treatment options has expanded during the past decade. A hypertensive emergency can be declared when an elevated blood pressure is associated with acute target-organ damage. Rapid evaluation and treatment (typically with an intravenously administered agent) should be instituted, usually in an intensive care unit setting, and the patient should be observed carefully during acute blood-pressure lowering. When properly treated, the prognosis for these patients is not nearly as dismal as it was more than 60 years ago, and the initial level of function of target organs (brain, heart, kidneys) is more indicative of an emergency than the actual level of blood pressure. Therapeutic options include the time-tested sodium nitroprusside (which has toxic metabolic products and is contraindicated in pregnancy, tobacco amblyopia, and Leber's optic atrophy); fenoldopam mesylate; and nicardipine. When properly treated, "malignant hypertension" need be considered malignant no longer. PMID:14594569

  3. [Acute blood pressure elevations].

    PubMed

    Chamontin, B; Amar, J; Chollet, F; Rouge, P; Bonetti-d'Esteve, L; Guittard, J; Salvador, M

    2000-11-01

    Blood pressure (BP) elevations may correspond to different clinical situations. Hypertensives emergencies are situations that require immediate reduction in BP because of acute or rapidly progressing target organ damage: accelerated malignant hypertension, hypertensive encephalopathy, acute myocardial infarction, acute aortic dissection, acute left ventricular failure, and eclampsia. Hypertensive urgencies are those with marked elevated BP in which it is desirable to reduce BP progressively within few hours, such as severe hypertension, progressive target organ damage, perioperative hypertension. Cerebrovascular accidents have to be individualized. In most patients in the immediate post-stroke period, BP should not be lowered. Caution is advised in lowering BP in these patients because excessive falls may precipitate cerebral ischemia. In situations without symptoms or progressive target organ it is necessary to exclude proximate causes of elevated BP such as pain and elevated BP alone rarely requires antihypertensive treatment. Among parenteral antihypertensive (AH) drugs labetalol, nicardipine, urapidil, and nitroprussiate are generally used, and the choice of AH drug depends on the clinical situation. It is not required to normalize BP immediately but to reduce mean BP no more than 25%, then toward 160/100 mmHg as recommended by JNC VI, in order to avoid an impairment of renal, cerebral or coronary ischemia. Oral long-acting dihydropyridines are often subsequently administrated, except in myocardial ischemia. Therapeutic attitudes vary considerably according to the clinical situation: abstention, immediate decrease or progressive decrease in BP have to be decided. PMID:11190294

  4. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

    PubMed Central

    Lee, Hyang-Ae; Hyun, Sung-Ae; Park, Sung-Gurl

    2016-01-01

    Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (ICa) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (IKr, IKs) and voltage-gated Na+ channel current (INa). The concentration-dependent inhibition of Ca2+ channel currents (ICa) was examined in rat cardiomyocytes; these CCBs have similar potency on ICa channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 µM whereas NIC and AML shortened APD50 but not APD90 up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited IKr and IKs while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of INa was similarly observed in the three CCBs. Since the IKr and IKs mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of ICa. PMID:26807031

  5. Inhibition of 3H-nitrendipine binding in rat aortic and cerebral cortex membranes by the new dihydropyridine calcium antagonist benidipine hydrochloride.

    PubMed

    Ishii, A

    1989-12-01

    Effects of a new calcium antagonist, benidipine hydrochloride (+/-)-(R*)-3-[(R*)-1-benzyl-3-piperidyl]methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedi carboxylate hydrochloride, KW-3049), on the 3H-nitrendipine binding in the rat aortic microsomes and cerebral cortex membranes were examined. The equilibrium dissociation constant (Kd) and the binding capacity (Bmax) were 0.32 nmol/l and 59.0 fmol/mg protein, respectively, in the rat aorta and 0.17 nmol/l and 450 fmol/mg protein, respectively, in the rat cortex. In both types of membranes, the specific binding was inhibited completely and concentration-dependently by six calcium antagonists such as benidipine, nicardipine, nisoldipine, nitrendipine, nifedipine and flunarizine. Diltiazem enhanced concentration-dependently the 3H-nitrendipine binding in the aortic and cortex membranes. Benidipine had the highest affinity for specific 3H-nitrendipine binding sites in the aorta (Ki = 0.063 nmol/l) and in the cortex membranes (0.043 nmol/l). The decreasing order of binding affinity of the isomers of benidipine for 3H-nitrendipine binding sites was S-S, benidipine, S-R, R-R and R-S. Presumed metabolites had a weak affinity for 3H-nitrendipine binding sites. PMID:2624603

  6. Kinetic Spectrofluorometric Determination of Certain Calcium Channel Blockers via Oxidation with Cerium (IV) in Pharmaceutical Preparations.

    PubMed

    Walash, M I; Belal, F; El-Enany, N; Abdelal, A A

    2009-06-01

    A simple and sensitive kinetic spectrofluorometric method was developed for the determination of some calcium channel blockers namely, verapamil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride and flunarizine. The method is based upon oxidation of the studied drugs with cerium (IV) ammonium sulphate in acidic medium. The fluorescence of the produced Ce (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plots were rectilinear for all the studied compounds over the concentration range of 0.01 to 0.12 μg mL(-1). The limits of detections for the studied compounds ranged from 2.93 × 10(-3) to 0.012 μg mL(-1) and limits of quantification from 9.76 × 10(-3) to 0.04 μg mL(-1) were obtained. The method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained with reference methods. PMID:23675129

  7. Kinetic Spectrofluorometric Determination of Certain Calcium Channel Blockers via Oxidation with Cerium (IV) in Pharmaceutical Preparations

    PubMed Central

    Walash, M. I.; Belal, F.; El-Enany, N.; Abdelal, A. A.

    2009-01-01

    A simple and sensitive kinetic spectrofluorometric method was developed for the determination of some calcium channel blockers namely, verapamil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride and flunarizine. The method is based upon oxidation of the studied drugs with cerium (IV) ammonium sulphate in acidic medium. The fluorescence of the produced Ce (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plots were rectilinear for all the studied compounds over the concentration range of 0.01 to 0.12 μg mL-1. The limits of detections for the studied compounds ranged from 2.93 × 10-3 to 0.012 μg mL-1 and limits of quantification from 9.76 × 10-3 to 0.04 μg mL-1 were obtained. The method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained with reference methods. PMID:23675129

  8. Pre-surgical regional blocks in orthognathic surgery: prospective study evaluating their influence on the intraoperative use of anaesthetics and blood pressure control.

    PubMed

    Chen, Y A; Rivera-Serrano, C M; Chen, C; Chen, Y R

    2016-06-01

    In orthognathic surgery, maxillary (CNV2) and mandibular (CNV3) divisions of the trigeminal nerve can be blocked successfully prior to surgery. In this study, it was hypothesized that regional blocks (nerve block over a particular region: bilateral CNV2 and CNV3 divisions of the trigeminal nerve) would decrease the total requirement for intraoperative anaesthetic agents and facilitate the process of hypotensive anaesthesia. Local anaesthesia containing 1/100,000 epinephrine and 10ml 0.5% levobupivacaine was injected into the planned incisions in 50 patients. Twenty-five patients (group A) underwent orthognathic surgery without regional blocks and another 25 patients (group B) underwent surgery with regional blocks. The anaesthetic protocol was the same in both groups and administered by a single anaesthesiologist. The mean arterial pressure was recorded at several points throughout the operation, as well as all the medications used. The blood loss and the amounts of medications administered were lower in group B than in group A. In patients receiving regional blocks, the amounts of fentanyl and nicardipine required were significantly lower. The use of pre-emptive anaesthesia in orthognathic surgery may reduce the overall amounts of medications required for hypotensive anaesthesia, facilitate the intraoperative control of blood pressure, and decrease intraoperative blood loss. PMID:26811189

  9. Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil

    SciTech Connect

    Safa, A.R. )

    1988-10-01

    Verapamil, a phenylalkylamine calcium channel blocker, has been shown to reverse multidrug resistance in tumor cells, possibly by increasing drug retention through interaction with an outward drug transporter of the resistant cells. In this study two photoactive radioactive analogs of verapamil, N-(p-azido(3,5-{sup 3}H)benzoyl)aminomethyl verapamil and N-(p-azido(3-{sup 125}I)salicyl)aminomethyl verapamil, were synthesized and used to identify the possible biochemical target(s) for verapamil in multidrug-resistance DC-3F/VCRd-5L Chinese hamster lung cells selected for resistance to vincristine. The results show that a specifically labeled 150- to 180-kDa membrane protein in resistant cells was immunoprecipitated with a monoclonal antibody specific for P-glycoprotein. Phenylalkylamine binding specificity was established by competitive blocking of specific photolabeling with the nonradioactive photoactive analogs as well as with verapamil. Photoaffinity labeling was also inhibited by 50 {mu}M concentrations of the calcium channel blockers nimodipine, nifedipine, nicardipine, azidopine, bepridil, and diltiazem and partially by prenylamine. Moreover, P-glycoprotein labeling was inhibited in a dose-dependent manner by vinblastine with half-maximal inhibition at 0.2 {mu}M compared to that by verapamil at 8 {mu}M. These data provide direct evidence that P-glycoprotein has broad drug recognition capacity and that it serves as a molecular target for calcium channel blocker action in reversing multidrug resistance.

  10. Effects of hypercapnia on membrane potential and intracellular calcium in rat carotid body type I cells.

    PubMed Central

    Buckler, K J; Vaughan-Jones, R D

    1994-01-01

    1. An acid-induced rise in the intracellular calcium concentration ([Ca2+]i) of type I cells is thought to play a vital role in pH/PCO2 chemoreception by the carotid body. In this present study we have investigated the cause of this rise in [Ca2+]i in enzymatically isolated, neonatal rat type I cells. 2. The rise in [Ca2+]i induced by a hypercapnic acidosis was inhibited in Ca(2+)-free media, and by 2 mM Ni2+. Acidosis also increased Mn2+ permeability. The rise in [Ca2+]i is dependent, therefore, upon a Ca2+ influx from the external medium. 3. The acid-induced rise in [Ca2+]i was attenuated by both nicardipine and methoxyverapamil (D600), suggesting a role for L-type Ca2+ channels. 4. Acidosis depolarized type I cells and often (approximately 50% of cells) induced action potentials. These effects coincided with a rise in [Ca2+]i. When membrane depolarization was prevented by a voltage clamp, acidosis failed to evoke a rise in [Ca2+]i. The acid-induced rise in [Ca2+]i is a consequence, therefore, of membrane depolarization. 5. Acidosis decreased the resting membrane conductance of type I cells. The reversal potential of the acid-sensitive current was about -75 mV. 6. A depolarization (30 mM [K+]o)-induced rise in [Ca2+]i was blocked by either the removal of extracellular Ca2+ or the presence of 2 mM Ni2+, and was also substantially inhibited by nicardipine. Under voltage-clamp conditions, [Ca2+]i displayed a bell-shaped dependence on membrane potential. Depolarization raises [Ca2+]i, therefore, through voltage-operated Ca2+ channels. 7. Caffeine (10 mM) induced only a small rise in [Ca2+]i (< 10% of that induced by 30 mM extracellular K+). Ca(2+)-induced Ca2+ release is unlikely, therefore, to contribute greatly to the rise in [Ca2+]i induced by depolarization. 8. Although the replacement of extracellular Na+ with N-methyl-D-glucamine (NMG), but not Li+, inhibited the acid-induced rise in [Ca2+]i, this was due to membrane hyperpolarization and not to the inhibition

  11. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine.

    PubMed

    Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don; Sanders, Kenton M

    2014-04-01

    Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca(2+) entry mechanism with the signature of a T-type Ca(2+) conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage-activated current. The latter was of smaller current density and blocked by nicardipine. Ni(2+) (30 μM) or mibefradil (1 μM) blocked the low voltage-activated current. Replacement of extracellular Ca(2+) with Ba(2+) did not affect the current, suggesting that either charge carrier was equally permeable. Half-activation and half-inactivation occurred at -36 and -59 mV, respectively. Temperature sensitivity of the Ca(2+) current was also characterized. Increasing temperature (20-30°C) augmented peak current from -7 to -19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h(-/-) mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h(-/-) mice, and Ni(2+) or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks. PMID:24477235

  12. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine

    PubMed Central

    Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don

    2014-01-01

    Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca2+ entry mechanism with the signature of a T-type Ca2+ conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage-activated current. The latter was of smaller current density and blocked by nicardipine. Ni2+ (30 μM) or mibefradil (1 μM) blocked the low voltage-activated current. Replacement of extracellular Ca2+ with Ba2+ did not affect the current, suggesting that either charge carrier was equally permeable. Half-activation and half-inactivation occurred at −36 and −59 mV, respectively. Temperature sensitivity of the Ca2+ current was also characterized. Increasing temperature (20–30°C) augmented peak current from −7 to −19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h−/− mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h−/− mice, and Ni2+ or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks. PMID:24477235

  13. Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest?

    PubMed

    Al-Hashimi, Sara; Zaman, Mahvash; Waterworth, Paul; Bilal, Haris

    2013-08-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest (DHCA)? Altogether, more than 62 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Four of the seven papers used thiopental alongside other neuroprotective methods and agents. The methods included the use of ice packs to the head and core systemic hypothermia. Agents used alongside thiopental included nicardipine and mannitol. Thiopental was found to have the ability to lower oxygen consumption, where oxygen consumption was measured using the phosphocreatinine and adenosine triphosphate ratio. The neuroprotective effect of thiopental was evaluated by assessing the electrical activity of the brain during circulatory arrest, by which it was shown to be advantageous. However, other trials suggested that adding thiopental during circulatory arrest did not provide any extra protection to the brain. The timing of thiopental administration is of importance in order to gain positive outcomes, as it's ability to lower the cerebral energy state may result in unfavourable results if added before hypothermic circulatory arrest, where this may lead to an ischaemic event. We conclude that the use of thiopental during deep hypothermic circulatory arrest is beneficial, but if administered too early, it may replete the cerebral energy state before arrest and prove to be detrimental. PMID:23644730

  14. Smooth muscle NOS, colocalized with caveolin-1, modulates contraction in mouse small intestine

    PubMed Central

    El-Yazbi, Ahmed F; Cho, Woo Jung; Cena, Jonathan; Schulz, Richard; Daniel, Edwin E

    2008-01-01

    Neuronal nitric oxide synthase (nNOS) in myenteric neurons is activated during peristalsis to produce nitric oxide which relaxes intestinal smooth muscle. A putative nNOS is also found in the membrane of intestinal smooth muscle cells in mouse and dog. In this study we studied the possible functions of this nNOS expressed in mouse small intestinal smooth muscle colocalized with caveolin-1(Cav-1). Cav-1 knockout mice lacked nNOS in smooth muscle and provided control tissues. 60 mM KCl was used to increase intracellular [Ca2+] through L-type Ca2+ channel opening and stimulate smooth muscle NOS activity in intestinal tissue segments. An additional contractile response to LNNA (100 μM, NOS inhibitor) was observed in KCl-contracted tissues from control mice and was almost absent in tissues from Cav-1 knockout mice. Disruption of caveolae with 40 mM methyl-β cyclodextrin in tissues from control mice led to the loss of Cav-1 and nNOS immunoreactivity from smooth muscle as shown by immunohistochemistry and a reduction in the response of these tissues to N-ω-nitro-L-arginine (LNNA). Reconstitution of membrane cholesterol using water soluble cholesterol in the depleted segments restored the immunoreactivity and the response to LNNA added after KCl. Nicardipine (1 μM) blocked the responses to KCl and LNNA confirming the role of L-type Ca2+ channels. ODQ (1 μM, soluble guanylate cyclase inhibitor) had the same effect as inhibition of NOS following KCl. We conclude that the activation of nNOS, localized in smooth muscle caveolae, by calcium entering through L-type calcium channels triggers nitric oxide production which modulates muscle contraction by a cGMP-dependent mechanism. PMID:18400048

  15. [Traumatic rupture of the aortic isthmus in a patient with severe head injury].

    PubMed

    Lassié, P; Tentillier, E; Thicoïpé, M; Pinaquy, C; Laborde, N

    1993-01-01

    A 32-year-old man sustained a severe head injury in a road traffic accident. On admission, he was in deep coma (6 on the Glasgow coma scale). The aortic knuckle was difficult to identify on a plain chest film. Twenty hours after admission, the aortic knuckle had completely disappeared and the mediastinal shadow had become enlarged. The diagnosis of a ruptured aortic isthmus was confirmed by angiography. Surgical repair of this lesion may be carried out either with simple aortic cross-clamping, or by using cardiopulmonary bypass (CPB). Either technique may worsen other injuries, especially head injury, by initiating severe arterial hypertension or coagulation disturbances. In this patient, the technique chosen was aortic cross-clamping with permanent monitoring of the intracranial and cerebral perfusion pressures. Anaesthesia was obtained with 5 mg.kg-1 of thiopentone, 30 mg.kg-1 x h-1 of sodium gamma hydroxybutyrate and 8 micrograms.kg-1 x h-1 of fentanyl. Surgery lasted for 90 min, with 33 min of aortic clamping. The increase in arterial blood pressure was controlled with 0.25 mg.kg-1 x h-1 of thiopentone and nicardipine which was stopped 8 min before unclamping. The postoperative course was uneventful. Sedation was stopped after 8 days, and the patient regained consciousness two days later. These remained a paraplegia with no sensory deficit, which had totally receded 15 months later. Carrying out this emergency surgery without CPB means that the intracranial pressure must imperatively be monitored during surgery. Any intracranial hypertension should delay the surgery. PMID:8338263

  16. The role of myogenic mechanisms in human cerebrovascular regulation

    PubMed Central

    Tan, Can Ozan; Hamner, J W; Taylor, J Andrew

    2013-01-01

    Although myogenic mechanisms have been hypothesized to play a role in cerebrovascular regulation, previous data from both animals and humans have not provided an unequivocal answer. However, cerebral autoregulation is explicitly non-linear and most prior work relied on simple linear approaches for assessment, potentially missing important changes in autoregulatory characteristics. Therefore, we examined cerebral blood flow responses to augmented arterial pressure oscillations with and without calcium channel blockade (nicardipine) during blood pressure fluctuations (oscillatory lower body negative pressure, OLBNP) across a range of frequencies in 16 healthy subjects. Autoregulation was characterized via a robust non-linear method (projection pursuit regression, PPR). Blockade resulted in significant tachycardia, a modest but significant elevation in mean arterial pressure, and reductions in mean cerebral blood flow and end-tidal CO2 during OLBNP. The reductions in flow were directly related to the reductions in CO2 (r= 0.57). While linear cross-spectral analysis showed that the relationship between pressure–flow fluctuations was preserved after blockade, PPR showed that blockade significantly altered the non-linearity between pressure and flow, particularly at the slowest fluctuations. At 0.03 Hz, blockade reduced the range of pressure fluctuations that can be buffered (7.5 ± 1.0 vs. 3.7 ± 0.8 mmHg) while increasing the autoregulatory slope (0.10 ± 0.05 vs. 0.24 ± 0.08 cm s−1 mmHg−1). Furthermore, the same rate of change in pressure elicited a change in flow more than twice as large as at baseline. Thus, our results show that myogenic mechanisms play a significant role in cerebrovascular regulation but this may not be appreciated without adequately characterizing the non-linearities inherent in cerebrovascular regulation. PMID:23959681

  17. 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

  18. Efficacy and safety of intravenous nimodipine administration for treatment of hypertension in patients with intracerebral hemorrhage

    PubMed Central

    Li, Yuqian; Fang, Wei; Tao, Lei; Li, Min; Yang, Yanlong; Gao, Yafei; Ge, Shunnan; Gao, Li; Zhang, Bin; Li, Zhihong; Zhou, Wei; Wang, Boliang; Li, Lihong

    2015-01-01

    Background Nicardipine (NC) is the most commonly used antihypertensive drug in neurological patients with hypertension. Although nimodipine (NM) is widely used to treat cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage, trials exploring its antihypertensive effect after intravenous administration in subjects with intracerebral hemorrhage (ICH) are scarce. Methods A retrospective study was carried out to compare the safety and efficacy of NC and NM administered intravenously in patients with ICH. Therapeutic responses were assessed by achievement of goal blood pressure (BP); use of additional medications for BP control; proportion of time spent within goal; variability in BP; time to goal BP; number of dose adjustments; variability in ICH volume, Glasgow Coma Scale score, and intracranial pressure; and drug-related complications. Results A total of 87 patients were eligible for analysis (n=46 [NC]; n=41 [NM]), and baseline characteristics between groups were similar. Both agents were effective in achieving goal BP during infusion, with 93.5% and 87.8% patients in the NC and NM groups achieving goal, respectively. Fewer additional medications were needed to control BP in the NC group. BP variability was similar and no differences were observed in the mean time to goal BP and mean numbers of dose adjustments between both groups. Interestingly, intracranial pressure declined (P=0.048) during NC administration but increased (P=0.066) after NM treatment. Finally, the incidences of hematoma expansion, neurological deterioration, and adverse drug events were similar in both groups. Conclusion NM is effective and safe for BP control in patients with ICH. PMID:26056454

  19. Modulatory effects of static magnetic fields on blood pressure in rabbits.

    PubMed

    Okano, H; Ohkubo, C

    2001-09-01

    Acute effects of locally applied static magnetic fields (SMF) on pharmacologically altered blood pressure (BP) in a central artery of the ear lobe of a conscious rabbit were evaluated. Hypotensive and vasodilator actions were induced by a Ca(2+) channel blocker, nicardipine (NIC). Hypertensive and vasoconstrictive actions were induced by a nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). The hemodynamic changes in the artery exposed to SMF were measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, BP changes in a central artery contralateral to that of the exposed ear lobe were monitored. SMF intensity was 1 mT and the duration of exposure was 30 min. A total of 180 experimental trials were carried out in 34 healthy adult male rabbits weighing 2.6-3.8 kg. Six experimental procedures were chosen at random: (1) sham exposure without pharmacological treatment; (2) SMF exposure alone; (3) decreased BP induced by a single intravenous (iv) bolus injection of NIC (100 microM/kg) without SMF exposure; (4) decreased BP induced by injection of NIC with SMF exposure; (5) increased BP induced by a constant iv infusion of L-NAME (10 mM/kg/h) without SMF exposure; (6) increased BP induced by infusion of L-NAME with SMF exposure. The results demonstrated that SMF significantly reduced the vasodilatation with enhanced vasomotion and antagonized the reduction of BP via NIC-blocked Ca(2+) channels in vascular smooth muscle cells. In addition, SMF significantly attenuated the vasoconstriction and suppressed the elevation of BP via NOS inhibition in vascular endothelial cells and/or central nervous system neurons. These results suggest that these modulatory effects of SMF on BP might, in part, involve a feedback control system for alteration in NOS activity in conjunction with modulation of Ca(2+) dynamics. PMID:11536282

  20. 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) PMID:8309795

  1. Sodium-calcium exchanger and R-type Ca(2+) channels mediate spontaneous [Ca(2+)]i oscillations in magnocellular neurones of the rat supraoptic nucleus.

    PubMed

    Kortus, Stepan; Srinivasan, Chinnapaiyan; Forostyak, Oksana; Zapotocky, Martin; Ueta, Yoichi; Sykova, Eva; Chvatal, Alexandr; Verkhratsky, Alexei; Dayanithi, Govindan

    2016-06-01

    Isolated supraoptic neurones generate spontaneous [Ca(2+)]i oscillations in isolated conditions. Here we report in depth analysis of the contribution of plasmalemmal ion channels (Ca(2+), Na(+)), Na(+)/Ca(2+) exchanger (NCX), intracellular Ca(2+) release channels (InsP3Rs and RyRs), Ca(2+) storage organelles, plasma membrane Ca(2+) pump and intracellular signal transduction cascades into spontaneous Ca(2+) activity. While removal of extracellular Ca(2+) or incubation with non-specific voltage-gated Ca(2+) channel (VGCC) blocker Cd(2+) suppressed the oscillations, neither Ni(2+) nor TTA-P2, the T-type VGCC blockers, had an effect. Inhibitors of VGCC nicardipine, ω-conotoxin GVIA, ω-conotoxin MVIIC, ω-agatoxin IVA (for L-, N-, P and P/Q-type channels, respectively) did not affect [Ca(2+)]i oscillations. In contrast, a specific R-type VGCC blocker SNX-482 attenuated [Ca(2+)]i oscillations. Incubation with TTX had no effect, whereas removal of the extracellular Na(+) or application of an inhibitor of the reverse operation mode of Na(+)/Ca(2+) exchanger KB-R7943 blocked the oscillations. The mitochondrial uncoupler CCCP irreversibly blocked spontaneous [Ca(2+)]i activity. Exposure of neurones to Ca(2+) mobilisers (thapsigargin, cyclopiazonic acid, caffeine and ryanodine); 4-aminopyridine (A-type K(+) current blocker); phospholipase C and adenylyl cyclase pathways blockers U-73122, Rp-cAMP, SQ-22536 and H-89 had no effect. Oscillations were blocked by GABA, but not by glutamate, apamin or dynorphin. In conclusion, spontaneous oscillations in magnocellular neurones are mediated by a concerted action of R-type Ca(2+) channels and the NCX fluctuating between forward and reverse modes. PMID:27052156

  2. Efficacy of Raynaud's phenomenon and digital ulcer pharmacological treatment in systemic sclerosis patients: a systematic literature review.

    PubMed

    García de la Peña Lefebvre, Paloma; Nishishinya, María Betina; Pereda, Claudia Alejandra; Loza, Estíbaliz; Sifuentes Giraldo, Walter Alberto; Román Ivorra, José Andrés; Carreira, Patricia; Rúa-Figueroa, Iñigo; Pego-Reigosa, Jose María; Muñoz-Fernández, Santiago

    2015-09-01

    To evaluate the efficacy of current treatments for the Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc), a systematic literature search was performed using Medline, EMBASE, and Cochrane Central Register of Controlled Trials (from 1961 to October 2011). We included meta-analyses, systematic reviews, clinical trials, and high-quality cohort studies published in English or Spanish. Patient populations had to include adults diagnosed with limited cutaneous or diffuse SSc who had associated RP and/or digital ulcers under pharmacological treatment. Efficacy of treatments was evaluated based on: number of RP episodes, RP severity, episode-free time, ulcer improvement/healing, and appearance of new ulcers. We used the Jadad scale of methodological quality to evaluate the quality of randomized clinical trials, and the 2009 Oxford Centre for Evidence-Based Medicine classification for other studies. Of a total of 1617 studies identified, only 27 fulfilled inclusion criteria. Drugs received the following grade recommendations: Grade A for nifedipine, nicardipine, quinapril, IV iloprost, bosentan, tadalafil, and MQx-503; Grade B for beraprost, cicaprost, DMSO, cyclofenil, and atorvastatin; and Grade C for misoprostol, prazosin, OPC-2826, enalapril, sildenafil, antioxidant, and stanazolol. Calcium channel blockers, prostanoids, tadalafil, and bosentan received the highest recommendation level for their effectiveness. However, most systematic reviews reviewed just a handful of studies with small sample sizes and short follow-ups. Our review shows that the existing evidence on the efficacy of RP treatment in SSc patients is inconclusive which calls for further research, especially in the form of prospective studies of high quality with long-term follow-ups. PMID:25824427

  3. 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.

  4. 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.

  5. Hypertensive crisis during pregnancy and postpartum period.

    PubMed

    Too, Gloria T; Hill, James B

    2013-08-01

    Hypertension affects 10% of pregnancies, many with underlying chronic hypertension, and approximately 1-2% will undergo a hypertensive crisis at some point during their lives. Hypertensive crisis includes hypertensive urgency and emergency; the American College of Obstetricians and Gynecologists describes a hypertensive emergency in pregnancy as persistent (lasting 15 min or more), acute-onset, severe hypertension, defined as systolic BP greater than 160 mmHg or diastolic BP >110 mmHg in the setting of pre-eclampsia or eclampsia. Pregnancy may be complicated by hypertensive crisis, with lower blood pressure threshold for end-organ damage than non-pregnant patients. Maternal assessment should include a thorough history. Fetal assessment should include heart rate tracing, ultrasound for growth and amniotic assessment, and Doppler evaluation if growth restriction is suspected. Initial management of hypertensive emergency (systolic BP >160 mmHg or diastolic BP >110 mmHg in the setting of pre-eclampsia or eclampsia) generally includes the rapid reduction of blood pressure through the use of intravenous antihypertensive medications, with goal systolic blood pressure between 140 mmHg and 150 mmHg and diastolic pressure between 90 mmHg and 100 mmHg. First-line intravenous drugs include labetalol and hydralazine, but other agents may be used, including esmolol, nicardipine, nifedipine, and, as a last resort, sodium nitroprusside. Among patients with hypertensive urgency, slower blood pressure reduction can be provided with oral agents. The objective of this article is to review the current understanding, diagnosis, and management of hypertensive crisis during pregnancy and the postpartum period. PMID:23916027

  6. Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features.

    PubMed

    Mazza, Alberto; Armigliato, Michela; Marzola, Maria Cristina; Schiavon, Laura; Montemurro, Domenico; Vescovo, Giorgio; Zuin, Marco; Chondrogiannis, Sotirios; Ravenni, Roberta; Opocher, Giuseppe; Colletti, Patrick M; Rubello, Domenico

    2014-04-01

    Pheochromocytoma (PH) and paraganglioma (PG) are neuroendocrine neoplasms arising from chromaffin cells of the adrenal medulla and the sympathetic ganglia, respectively. Although are unusual cause of hypertension (HT) accounting for at most 0.1-0.2 % of cases, they may lead to severe and potentially lethal hypertensive crisis due to the effects of the released catecholamines. However, both PH and PG may be asymptomatic as ~30 % of subjects are normotensive or have orthostatic hypotension and in these cases the 24 h ambulatory blood pressure (BP) monitoring is an important toll to diagnose and treat HT. HT treatment may be difficult when PH or PG occurs in pregnancy or in the elderly subjects and in these cases a multidisciplinary team is required. When surgical excision is mandatory the perioperative management requires the administration of selective α1-adrenergic blocking agents (i.e., doxazosin, prazosin or terazosin) followed by a β-adrenergic blockade (i.e., propranolol, atenolol). This latter should never be started first because blockade of vasodilatory peripheral β-adrenergic receptors with unopposed α-adrenergic receptor stimulation can lead to a further elevation of BP. Although labetalol is traditionally considered the ideal agent due to its α- and β-adrenergic antagonism, experimental studies do not support its use in this clinical setting. As second regimen, the administration of vasodilators as calcium channel blockers (i.e., nicardipine, nifedipine) may be required to control BP. Oral and sublingual short-acting nifedipine are potentially dangerous in patients with hypertensive emergencies and are not recommend. The latest evidences into the diagnosis and treatment of hypertensive crisis due to PH and PG are reviewed here. PMID:23817839

  7. 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. PMID:20354105

  8. Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers

    PubMed Central

    Wang, Yi-Chun; Hsieh, Tsung-Cheng; Chou, Chu-Lin; Wu, Jung-Lun; Fang, Te-Chao

    2016-01-01

    Abstract Some statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug–drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwan's National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription. In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non-CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35–3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36–6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16–2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08–1.68) than those who received non-CYP3A4-metabolized statins. This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP

  9. Comparison of the Ca2+ entry channels responsible for mechanical responses of guinea-pig aorta to noradrenaline and thapsigargin using SK&F 96365 and LOE 908.

    PubMed

    Tanaka, Y; Imai, T; Igarashi, T; Takayanagi, K; Otsuka, K; Yamaki, F; Tanaka, H; Shigenobu, K

    2000-08-01

    Noradrenaline (NA) produces sustained contractions in conduit arteries such as aorta isolated from various animal species. In guinea-pig aorta, NA-produced sustained contraction is largely dependent upon the influx of extracellular Ca2+, but is refractory to the treatment with organic Ca2+ entry blockers. In the present study, we attempted to characterize pharmacologically the Ca2+ entry channel responsible for NA-produced sustained contraction of guinea-pig aorta using SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imi dazole) and LOE 908 ((R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2- (2,3,4-trimethoxyphenyl)ethyl]-acetamide), both of which block voltage-independent Ca2+ channels. The effects of SK&F 96365 and LOE 908 on NA-produced contraction were compared with those on extracellular Ca2+-dependent contractile and endothelium-dependent relaxant responses to thapsigargin (TSG), an inhibitor of Ca2+-pump Ca2+-ATPase. NA (3x10(-6) M)-produced sustained contraction of guinea-pig aorta without endothelium exhibited a strong dependency on the extracellular Ca2+. Nicardipine (10(-7) M), diltiazem (10(-5) M) and verapamil (10(-5) M) did not show any appreciable inhibitory effects on NA-produced sustained contraction. SK&F 96365 concentration-dependently (10(-6)-10(-4) M) attenuated the NA-produced sustained contraction whereas LOE 908 did not affect it at concentrations up to 10(-4) M. Similarly, extracellular Ca2+-dependent contraction of guinea-pig aorta without endothelium in response to TSG was also diminished by SK&F 96365 but was unaffected by LOE 908. In fura-PE3-loaded vascular preparations, SK&F 96365 decreased both cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension elevated by NA and TSG. Both SK&F 96365 and LOE 908 did not affect an endothelium-dependent relaxation of guinea-pig aorta in response to TSG. These findings suggest that in guinea-pig aortic smooth muscle cells, NA activates Ca2+ influx across

  10. Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression.

    PubMed

    Overstreet, D H; Pucilowski, O; Rezvani, A H; Janowsky, D S

    1995-09-01

    Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these "therapeutic" effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal

  11. Propagation of pacemaker activity in the guinea-pig antrum

    PubMed Central

    Hennig, G W; Hirst, G D S; Park, K J; Smith, C B; Sanders, K M; Ward, S M; Smith, T K

    2004-01-01

    Cyclical periods of depolarization (slow waves) underlie peristaltic contractions involved in mixing and emptying of contents in the gastric antrum. Slow waves originate from a myenteric network of interstitial cells of Cajal (ICC-MY). In this study we have visualized the sequence and propagation of Ca2+ transients associated with pacemaker potentials in the ICC network and longitudinal (LM) and circular muscle (CM) layers of the isolated guinea-pig gastric antrum. Gastric antrum was dissected to reveal the ICC-MY network, loaded with Fluo-4 AM and activity was monitored at 37°C. Ca2+ waves propagated throughout the ICC-MY network at an average velocity of 3.24 ± 0.12 mm s−1 at a frequency of 4.87 ± 0.16 cycles min−1 (n = 4). The propagation of the Ca2+ wave often appeared ‘step-like’, with separate regions of the network being activated after variable delays. The direction of propagation was highly variable (Δ angle of propagation 44.3 ± 10.9 deg per cycle) and was not confined to the axes of the longitudinal or circular muscle. Ca2+ waves appeared to spread out radially from the site of initiation. The initiating Ca2+ wave in ICC-MY was correlated to secondary Ca2+ waves in intramuscular interstial cells of Cajal, ICC-IM, and smooth muscle cells, and the local distortion (contraction) in a field of view. TTX (1 μm) had little effect on slow wave or pacemaker potential activity, but 2-APB (50 μm) blocked all Ca2+ waves, indicating a pivotal role for intracellular Ca2+ stores. Nicardipine (2 μm) eliminated the Ca2+ transient generated by smooth muscle, but did not affect the fast upstroke associated with ICC-MY. These results indicate that slow waves follow a sequence of activation, beginning with the ICC-MY and ICC-IM network, followed later by a sustained Ca2+ transient in the muscle layers that is responsible for contraction. PMID:14754999

  12. Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers: A Nationwide Population-Based Study.

    PubMed

    Wang, Yi-Chun; Hsieh, Tsung-Cheng; Chou, Chu-Lin; Wu, Jung-Lun; Fang, Te-Chao

    2016-01-01

    Some statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug-drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwan's National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription.In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non-CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35-3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36-6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16-2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08-1.68) than those who received non-CYP3A4-metabolized statins.This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP3A4-metabolized

  13. Effects of extracellular pH on receptor-mediated Ca2+ influx in A7r5 rat smooth muscle cells: involvement of two different types of channel.

    PubMed Central

    Iwasawa, K; Nakajima, T; Hazama, H; Goto, A; Shin, W S; Toyo-oka, T; Omata, M

    1997-01-01

    1. The effects of extracellular pH (pHo) on receptor (vasopressin or endothelin-1)-mediated Ca2- entry and Ca(2+)-permeable channels were investigated in aortic smooth muscle cells (A7r5) from rat embryonic thoracic aorta. Intracellular Ca2+ ([Ca2+]i) was measured using fura-2 AM and whole-cell voltage clamp techniques were employed. 2. Vasopressin and endothelin-1 (100 nM) in the presence of nicardipine (10 microM) evoked a sustained rise in [Ca2+]i due to calcium entry. Extracellular acidosis decreased receptor (vasopressin or endothelin-1)-mediated Ca2+ entry, while extracellular alkalosis potentiated it. 3. Depletion of intracellular Ca2+ stores with thapsigargin (1 microM) also evoked Ca2+ entry activated by emptying of intracellular Ca2+ stores (capacitative Ca2+ entry). Extracellular acidosis decreased this capacitative Ca2+ entry, while extracellular alkalosis potentiated it. 4. Under voltage-clamp conditions with Ca+ internal solution, vasopressin and endothelin-1 activated non-selective cation currents (ICAT). Ba2+ or Ca2+ were also charge carriers of ICAT. Reducing the pHo inhibited ICAT, while increasing pHo potentiated it in a reversible manner. 5. Intracellular pH (pHi) changes did not cause the same marked effects as pHo changes, and a high concentration of Hepes (50 mM) in the patch pipette did not inhibit the effects of pHo on ICAT. 6. Similar results were obtained when ICAT was activated by GTP gamma S (1 mM) applied through the patch pipette, even in the absence of agonists, probably because of direct activation of GTP-binding proteins coupled to the receptors. 7. In cells treated with thapsigargin, addition of Ca2+ to the bath solution induced Ca(2+)-dependent K+ currents activated by capacitative Ca2+ entry. However, no measurable ionic currents activated by capacitative Ca2+ entry (ICRAC) were observed under conditions with Cs+ internal solution and EGTA (5 mM), although vasopressin still activated ICAT. 8. These results suggest that the

  14. Hypertensive emergencies.

    PubMed

    Murphy, C

    1995-11-01

    Hypertensive emergencies are uncommon and physiologically diverse. Consequently, it is difficult for most physicians to develop a familiarity with all the different hypertensive crises and with all drugs available for treating them (Table 4). Clinicians should not agonize over which is the perfect therapeutic agent for a particular emergency, but instead, they should focus on scrupulous monitoring and familiarize themselves with a few agents that will serve in most situations. Generally, these agents will be sodium nitroprusside and nitroglycerin. Vigilant neurologic monitoring is mandatory in all hypertensive emergencies. The early symptoms and signs of cerebral hypoperfusion can be vague and subtle, but if recognized, serious complications of therapy can be avoided. Remember, the patient may still be hypertensive. Avoid acute (during the first hour) reductions in MAP of more than 20% whenever possible; subsequent reductions should be gradual. In patients known to have markedly elevated ICP and who need acute reductions in their BP, serious consideration should be given to direct monitoring of the ICP so that CPP can be maintained within safe limits. In general, oral agents should not be used for the treatment of hypertensive emergencies. Intravenous Labetalol and intravenous nicardipine are not suitable for general use in hypertensive emergencies. In special situations (e.g., perioperative hypertension and subarachnoid hemorrhage), however, they may be employed. Their role may expand with further study. Trimethaphan may be superior to nitroprusside for hypertension complicated by elevated ICP or cerebral dysfunction. Realistically, most physicians will continue to use nitroprusside. Intense neurologic monitoring is more important than the specific agent used. Nitroglycerin is the agent of choice for acute ischemic heart disease complicated by severe hypertension; if it fails, use nitroprusside. For aortic dissection, the combination of nitroprusside and IV

  15. Uncoupling of Cav1.2 From Ca2+-Induced Ca2+ Release and SK Channel Regulation in Pancreatic β-Cells

    PubMed Central

    Wang, Yuchen; Jarrard, Rachel E.; Pratt, Evan P.S.; Guerra, Marcy L.; Salyer, Amy E.; Lange, Allison M.; Soderling, Ian M.

    2014-01-01

    We investigated the role of Cav1.2 in pancreatic β-cell function by expressing a Cav1.2 II-III loop/green fluorescent protein fusion in INS-1 cells (Cav1.2/II-III cells) to disrupt channel-protein interactions. Neither block of KATP channels nor stimulation of membrane depolarization by tolbutamide was different in INS-1 cells compared with Cav1.2/II-III cells, but whole-cell Cav current density was significantly increased in Cav1.2/II-III cells. Tolbutamide (200 μM) stimulated insulin secretion and Ca2+ transients in INS-1 cells, and Cav1.2/II-III cells were completely blocked by nicardipine (2 μM), but thapsigargin (1 μM) blocked tolbutamide-stimulated secretion and Ca2+ transients only in INS-1 cells. Tolbutamide-stimulated endoplasmic reticulum [Ca2+] decrease was reduced in Cav1.2/II-III cells compared with INS-1 cells. However, Ca2+ transients in both INS-1 cells and Cav1.2/II-III cells were significantly potentiated by 8-pCPT-2′-O-Me-cAMP (5 μM), FPL-64176 (0.5 μM), or replacement of extracellular Ca2+ with Sr2+. Glucose (10 mM) + glucagon-like peptide-1 (10 nM) stimulated discrete spikes in [Ca2+]i in the presence of verapamil at a higher frequency in INS-1 cells than in Cav1.2/II-II cells. Glucose (18 mM) stimulated more frequent action potentials in Cav1.2/II-III cells and primary rat β-cells expressing the Cav1.2/II-II loop than in control cells. Further, apamin (1 μM) increased glucose-stimulated action potential frequency in INS-1 cells, but not Cav1.2/II-III cells, suggesting that SK channels were not activated under these conditions in Cav1.2/II-III loop-expressing cells. We propose the II-III loop of Cav1.2 as a key molecular determinant that couples the channel to Ca2+-induced Ca2+ release and activation of SK channels in pancreatic β-cells. PMID:24506535

  16. 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

  17. 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

  18. 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

  19. [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. PMID:11613536

  20. Mechanisms of bradykinin-induced contraction of the guinea-pig gallbladder in vitro.

    PubMed

    Cabrini, D A; Silva, A M; Calixto, J B

    1995-04-01

    1. The mechanisms underlying bradykinin (BK)-mediated contractions in strips of guinea-pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists. 2. Addition of BK and related kinins (0.1 pM-10 microM) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM-1 nM) and low affinity (3 nM-10 microM). The rank order of potency for the first phase (mean EC50, pM) was: BK (1.36) = Hyp3-BK (1.44) = Lys-BK (1.54) > Tyr8-BK (2.72) > Met-Lys-BK (4.30). The rank order of potency for the second phase (mean EC50, nM, at concentration producing 50% of the contraction caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK (60.92) > BK (77.35). The contractile responses (g of tension) to 3 microM of BK (the highest concentration tested) were: Hyp3-BK, 1.76 +/- 0.09; BK, 1.65 +/- 0.12; Lys-BK, 1.45 +/- 0.13; Tyr8-BK, 1.36 +/- 0.15 and Met-Lys-BK, 1.36 +/- 0.15. The selective B1 agonist, des-Arg9-BK, caused only a weak contraction with maximal response (0.21 +/- 0.05 g), which corresponded to approximately 10% of that induced by BK. 3. BK-induced contraction in GPG was inhibited by indomethacin (3 microM) or ibuprofen (30 microM), and was partially reduced by phenidone (30 microM), but was not affected by atropine (1 JM), nicardipine (1 gM),Ca2+-free medium plus EGTA, dazoxiben (30 nM), L-655,240 (10 nM, a selective receptor antagonist ofthromboxane A2), MK-571 (0.1 microM, a selective leukotriene D4 receptor antagonist), tetrodotoxin(0.3microM), CP 96,345 (0.3 microM, a NK1 receptor antagonist), mepyramine (1 microM), glibenclamide (1 microM), H-7(3 microM), staurosporine (100 nM), or phorbol 12-myristate 13-acetate (1 microM). However, BK-induced contractions in GPG maintained in Ca2+-free medium were markedly attenuated by ryanodine (10