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PubMed1995

Protective effects of calcium channel blockers against free radical-impaired endothelial cell proliferation.

We have shown previously that the lipophilic calcium channel blockers exhibit membrane antioxidant activity. In the present study, when attached bovine aortic endothelial cells were exposed for 20 min to a low concentration of oxy-radicals generated from dihydroxyfumarate + Fe-ADP, no loss of glutathione or viability was detected; however, cell number, determined 48 hr later by the tetrazolium salt MTT assay, decreased to 45% of controls. Treatment of the cells for 1 hr with the calcium blockers (2-20 microM) prior to free radical exposure protected against the impaired cell growth in a concentration-dependent manner. The order of potency was nicardipine > or = nifedipine > or = verapamil > diltiazem, which appears to parallel their antioxidant potency. In addition, (+)-nicardipine, and its pharmacologically inactive isomer, (-)-nicardipine, were similarly effective. We conclude that it was the antioxidant activity of the calcium channel blockers that preserved the cell growth capacity against free-radical damage; such protective effects may contribute to their antiatherogenic effects.

Animals↗
PubMed1997

Pharmacokinetics of SNX-111, a selective N-type calcium channel blocker, in rats and cynomolgus monkeys.

SNX-111, a selective N-type voltage-sensitive calcium channel blocker, is in clinical trials for the treatment of ischemia-induced brain injury and chronic pain. Pharmacokinetic studies were conducted in rats and cynomologus monkeys to determine the disposition of this compound when it is administered for 24 hr by continuous, constant-rate intravenous infusion. Venous blood samples for determination of SNX-111 plasma levels were collected at regular intervals immediately before, during, and after dosing. Plasma concentrations of SNX-111 equivalents were measured by radioimmunoassay. Pharmacokinetic parameters were derived from plasma SNX-111 concentration-time data using a two-compartment pharmacokinetic model. Results showed close correspondences between pharmacokinetic parameters determined for both species. There were no consistent gender- or dose-related differences in calculated kinetic parameters. In all cases, apparent steady-state plasma SNX-111 concentrations were achieved within 2-4 hr of initiating SNX-111 infusion. Steady-state volume of distribution values were approximately 40% of body weight, indicating extravascular dissemination of SNX-111 to both extracellular and intracellular fluids. Elimination curves contained two exponential components. The fast component (rat t1/2, alpha = 0.375 hr; monkey t1/2, alpha = 0.730 hr) accounted for approximately 97% of the unit impulse disposition function. The apparent terminal half-life ranged from 4.61 hr (rat) to 6.48 hr (monkey). Current findings constitute the first description of the pharmacokinetics of a member of the omega-conopeptide family of neuronal calcium channel blockers.

Animals↗
PubMed2006

Potentiation of cyclic AMP-mediated proopiomelanocortin gene promoter activity by calcium channel blockers in a pituitary cell line.

Although it is known that the expression of proopiomelanocortin, a precursor protein of adrenocorticotropic hormone, can be affected by a variety of drugs, the effects of calcium channel blockers have not been studied. This study examined the effect of calcium channel blockers on proopiomelanocortin gene expression. Mouse pituitary tumor cells stably transfected with approximately 0.7 kb of the rat proopiomelanocortin 5' promoter-luciferase fusion gene were stimulated by potassium chloride, corticotropin-releasing hormone (CRH) or forskolin, in the presence or absence of calcium channel blockers (nifedipine, verapamil and diltiazem). Assessments were made of proopiomelanocortin gene promoter activity and cyclic adenosine 3',5'-monophosphate (cyclic AMP) efflux. A dose-dependent enhancement of CRH- or forskolin-stimulated proopiomelanocortin promoter activity was observed with nifedipine and verapamil, but not diltiazem. Cyclic AMP efflux induced by CRH or forskolin was also enhanced by nifedipine and verapamil. In the presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, enhancement of proopiomelanocortin promoter activity and cyclic AMP efflux by nifedipine and verapamil was not observed. It was concluded that the inhibition of phosphodiesterase is a probable mechanism for the effect of nifedipine and verapamil on CRH or forskolin induction of proopiomelanocortin gene expression.

Adrenocorticotropic Hormone↗
PubMed2001

Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis.

OBJECTIVE: Most patients with systemic sclerosis (SSc) have Raynaud's phenomenon (RP), which is often more severe than idiopathic RP. This study was a meta-analysis to determine the efficacy of calcium-channel blockers for the treatment of RP in SSc. The primary outcome measures were frequency and severity of ischemic attacks, digital skin temperature, patient and physician global assessments, and digital ulcers. METHODS: The Cochrane search strategy was used to ascertain all trials in all languages. Primary data sources included Medline, Current Contents, and the Cochrane Controlled Trials Register. Studies that met the inclusion criteria were randomized controlled trials of >2 days' duration with a dropout rate of <35%. Twenty-nine studies were found, of which 8 randomized controlled trials were eligible for inclusion. The total number of patients included was small (n = 109). Most trials included primary and secondary RP, and the main reasons for trial exclusion were inability to extract subset data on SSc patients (18 trials), data published previously (2 trials), and lack of a control group (1 trial). Data were abstracted independently by 2 reviewers, and either a weighted mean difference (WMD) or a standardized mean difference (SMD) was calculated for all continuous outcomes; however, information was not available for all outcomes within trials. RESULTS: The WMD of all calcium-channel blockers versus placebo (6 trials) and of nifedipine alone versus placebo (5 trials) for the reduction in the frequency of ischemic attacks over a 2-week period was -8.31 (95% confidence interval [95% CI] -15.71, -0.91) and -10.21 (95% CI -20.09, -0.34), respectively. The SMD of all calcium-channel blockers versus placebo (3 trials) and of nifedipine alone versus placebo (2 trials) for the reduction in the severity of ischemic attacks was -0.69 (95% CI -1.21, -0.17) and -0.99 (95% CI -1.74, -0.24), respectively. CONCLUSION: Calcium-channel blockers for RP in SSc have been tested in several small clinical trials and appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks. Most trials were crossover trials in which order effect was not studied. This could have introduced bias. The results of this study suggest that the efficacy of calcium-channel blockers in reducing the severity and frequency of ischemic attacks in RP secondary to SSc is moderate at best (mean reduction of 8.3 attacks in 2 weeks and 35% less severity), and a further large, randomized controlled trial needs to be conducted.

Calcium Channel Blockers↗
PubMed2004

Pre-electroconvulsive shock administration of calcium channel blockers reduces retrograde amnesia induced by ECS.

Effect of pre-electroconvulsive shock (ECS) administration of calcium channel blockers (CCBs) like verapamil, diltiazem, nifedipine, nimodipine, flunarizine and cinnarizine on retrograde amnesia induced by ECS was examined using passive avoidance paradigm in rats. The groups (Gr 1-7) of adult, male Wistar rats received true ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; ip) and other groups (Gr 8-14) received sham ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; i.p). The anti-amnestic activity of CCBs were evaluated using the passive avoidance paradigm in rats. Results showed that, the baseline latencies for all the groups did not differ significantly. Rats receiving true ECS produced significantly lower latencies. There was increase in the post ECS step through latencies of the rats administered CCBs before ECS. Therefore, pre-ECS administration of calcium channel blockers might reduce retrograde amnesia produced by ECS without altering seizure duration.

Amnesia↗
PubMed1997

In vitro evaluation of antiproliferative potential of calcium channel blockers in human Tenon's fibroblasts.

The calcium cation has been known to play a central and diverse role in the proliferation of numerous types of cells including fibroblasts. Therefore, ib1p4llows that calcium channel blockers (CCBs) may potentially inhibit fibroblast attachment and proliferation. The time and dose-related effects of five commonly used CCBs-verapamil, diltiazem, nicardipine, trifluoperazine, and dantrolene-on human Tenon's fibroblast attachment and proliferation were studied. Fibroblasts were incubated with different concentrations of each drug. To evaluate the effect of each drug on fibroblast attachment, cell density was quantified by Coulter counter and hexosaminidase assays after 24 hours of incubation. To evaluate the effect of each drug on fibroblast proliferation, cell density was quantified by Coulter counter, hexosaminidase, and 3H-thymidine uptake assays on days 1, 3, and 7. Dantrolene had minimal effect, failing to cause even 20% inhibition at 10(-5) M, the highest concentration tested. Verapamil, diltiazem, nicardipine, and trifluoperazine all inhibited fibroblast attachment and proliferation. Trifluoperazine was the most potent inhibitor of attachment and proliferation with ID50S in the 10(-5) M range. Verapamil, diltiazem, and nicardipine had similar potency in inhibiting attachment and proliferation with ID50S in the 10(-4) M range. Because CCBs seem to inhibit fibroblast attachment and proliferation, future clinical studies may show that these agents reduce collagen production, scar formation, and bleb failure following glaucoma filtration surgery.

Calcium Channel Blockers↗
PubMedDate not supplied

Effects of four calcium channel blockers on central cardiovascular control.

The cardiovascular effects of intravenous and intracisternal administration of low doses of calcium channel blockers (nicardipine: 0.3 to 10 micrograms/kg; nifedipine: 0.01 to 10 micrograms/kg; verapamil: 0.003 to 0.1 mg/kg and diltiazem: 1 to 300 micrograms/kg) were investigated in pentobarbital-anesthetized dogs. All studied calcium channel blockers induced a decrease in blood pressure and an increase in heart rate after intravenous injection. In contrast, the same doses injected by intracisternal route elicited an increase in both blood pressure and heart rate. These results show that blockade of central calcium channels in dogs increases blood pressure and heart rate and suggest that the pharmacological effects of these drugs are the addition of peripheral and central actions. However, the magnitude of these central properties seems to be higher for dihydropyridine than for phenylalkylamine or benzothiazepine derivatives.

Anesthesia↗
PubMed1993

The use of calcium channel blockers in general practice.

Over the past decade the calcium antagonist drugs, also known as calcium channel blockers, have become established for use in a variety of cardiovascular diseases. A bewildering (and ever-growing) number of drugs in this class now becoming available. This article summarises the important characteristics of the calcium antagonists and discusses their practical use in hypertension, angina and other conditions in general practice.

Calcium Channel Blockers↗
PubMed2006

Interaction of grapefruit juice and calcium channel blockers.

Drug-drug interactions are commonly recognized occurrences in the hypertensive population. Drug-nutrient interactions, however, are less well appreciated. The grapefruit juice-calcium channel blocker interaction is one that has been known since 1989. The basis for this interaction has been diligently explored and appears to relate to both flavanoid and nonflavanoid components of grapefruit juice interfering with enterocyte CYP3A4 activity. In the process, presystemic clearance of susceptible drugs decreases and bioavailability increases. A number of calcium channel blockers are prone to this interaction, with the most prominent interaction occurring with felodipine. The calcium channel blocker and grapefruit juice interaction should be incorporated into the knowledge base of rational therapeutics for the prescribing physician.

Beverages↗
PubMed2006

The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells.

OBJECTIVES: Amlodipine is a calcium channel blocker (CCB) known to stimulate nitric oxide production from endothelial cells. Whether this ancillary property can be related to the capacity of amlodipine to concentrate and alter the structure of cholesterol-containing membrane bilayers is a matter of investigation. Here, we reasoned that since the endothelial nitric oxide synthase is, in part, expressed in cholesterol-rich plasmalemmal microdomains (e.g., caveolae and rafts), amlodipine could interfere with this specific locale of the enzyme and thereby modulate NO production in endothelial cells. METHODS AND RESULTS: Using a method combining lubrol-based extraction and subcellular fractionation on sucrose gradient, we found that amlodipine, but not verapamil or nifedipine, induced the segregation of endothelial NO synthase (eNOS) from caveolin-enriched low-density membranes (8+/-2% vs. 42+/-3% in untreated condition; P<0.01). We then performed co-immunoprecipitation experiments and found that amlodipine dose-dependently disrupted the caveolin/eNOS interaction contrary to other calcium channel blockers, and potentiated the stimulation of NO production by agonists such as bradykinin and vascular endothelial growth factor (VEGF) (+138+/-28% and +183+/-27% over values obtained with the agonist alone, respectively; P<0.01). Interestingly, we also documented that the dissociation of the caveolin/eNOS heterocomplex induced by amlodipine was not mediated by the traditional calcium-dependent calmodulin binding to eNOS and that recombinant caveolin expression could compete with the stimulatory effects of amlodipine on eNOS activity. Finally, we showed that the amlodipine-triggered, caveolin-dependent mechanism of eNOS activation was independent of other pleiotropic effects of the CCB such as superoxide anion scavenging and angiotensin-converting enzyme (ACE) inhibition. CONCLUSIONS: This study unravels the modulatory effects of amlodipine on caveolar integrity and the capacity of caveolin to maintain eNOS in its vicinity in the absence of any detectable changes in intracellular calcium levels. The resulting increase in caveolin-free eNOS potentiates the NO production in response to agonists including VEGF and bradykinin. More generally, this work opens new avenues of treatment for drugs able to structurally alter signaling pathways concentrated in caveolae.

Amlodipine↗
PubMed2004

Calcium channel blockers for preventing acute tubular necrosis in kidney transplant recipients.

BACKGROUND: The incidence of delayed graft function in cadaveric grafts has increased over the last few years due in part to the large demand for cadaveric kidneys necessitating the use of kidneys from marginal donors. Calcium channel blockers have the potential to reduce the incidence of post-transplant acute tubular necrosis (ATN) if given in the peri-operative period. However, there is controversy surrounding their use in this situation with no consensus as to their efficacy. OBJECTIVES: To evaluate the benefits and harms of using calcium channel blockers in the peri-transplant period in patients at risk of ATN following cadaveric kidney transplantation. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library issue 2, 2003) MEDLINE (1966 to January 2003) and EMBASE (1980 - January 2003). The Trials Search Coordinator was contacted to develop the search strategy. SELECTION CRITERIA: Randomised controlled trials comparing calcium channel blockers given in the peri-transplant period with controls were included. Quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals (CI). MAIN RESULTS: Nine trials were suitable for inclusion. Treatment with calcium channel blockers in the peri-transplant period was associated with a significant decrease in the incidence of post transplant ATN (RR 0.57, 95%CI 0.40 to 0.82) and delayed graft function (RR 0.44, 95% CI 0.28 to 0.69). There was no difference between control and treatment groups in graft loss, mortality, requirement for haemodialysis. There was insufficient information to comment on adverse events. REVIEWER'S CONCLUSIONS: These results suggest that calcium channel blockers given in the peri-operative period may reduce the incidence of ATN post-transplantation. The result should be treated with caution due to the heterogeneity of the trials which made comparison of studies and pooling of data difficult.

Calcium Channel Blockers↗
PubMed2005

Calcium channel blockers for preventing acute tubular necrosis in kidney transplant recipients.

BACKGROUND: The incidence of delayed graft function in cadaveric grafts has increased over the last few years due in part to the large demand for cadaveric kidneys necessitating the use of kidneys from marginal donors. Calcium channel blockers have the potential to reduce the incidence of post-transplant acute tubular necrosis (ATN) if given in the peri-operative period. However, there is controversy surrounding their use in this situation with no consensus as to their efficacy. OBJECTIVES: To evaluate the benefits and harms of using calcium channel blockers in the peri-transplant period in patients at risk of ATN following cadaveric kidney transplantation. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library) MEDLINE (from 1966) and EMBASE (from 1980). The Trials Search Coordinator was contacted to develop the search strategy. Date of last database and register search: January 2005 SELECTION CRITERIA: Randomised controlled trials comparing calcium channel blockers given in the peri-transplant period with controls were included. Quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals (CI). MAIN RESULTS: Ten trials were suitable for inclusion. Treatment with calcium channel blockers in the peri-transplant period was associated with a significant decrease in the incidence of post transplant ATN (RR 0.57, 95%CI 0.40 to 0.82) and delayed graft function (RR 0.51, 95% CI 0.36 to 0.72). There was no difference between control and treatment groups in graft loss, mortality, requirement for haemodialysis. There was insufficient information to comment on adverse events. AUTHORS' CONCLUSIONS: These results suggest that calcium channel blockers given in the peri-operative period may reduce the incidence of ATN post-transplantation. The result should be treated with caution due to the heterogeneity of the trials which made comparison of studies and pooling of data difficult.

Calcium Channel Blockers↗
PubMed1997

A challenge to the concept that the use of calcium channel blockers causes reversible male infertility.

The objective of this study was retrospectively to evaluate both in-vitro fertilization (IVF) and non-IVF cycles in which the male partner had been taking calcium channel blockers, either to confirm or refute previous data from another centre, suggesting that these drugs cause a severe but reversible subfertility problem in the male. These drugs were found to inhibit expression of mannose-ligand binding receptors, thus preventing spermatozoa from attaching to the zona pellucida; they were postulated to cause failed fertilization based on one case having this defect, in whom a return to normal was achieved after stopping the drug. However, the couple did not undergo a cycle with IVF to see if fertilization now occurred. The data presented here demonstrated fertilization in all patients having IVF who were taking calcium channel blockers. The subsequent pregnancy rate per transfer was 17.4%. Also, five out of 11 (45.4%) non-IVF patients conceived after correction of various female factors. Failure of the other six patients to conceive could be explained by other confounding factors, especially oligoasthenozoospermia. Taking into consideration other data suggesting poor fertilization when this mannose-ligand binding receptor abnormality was demonstrated, we propose the possibility that this defect, when not associated with calcium channel blockers, may be associated with some other cryptic factor that causes poor fertilization. According to our hypothesis, calcium channel blockers might cause the problem in mannose expression but also adversely affect some other factor that is deficient when non-drug related abnormalities in mannose-ligand binding expression are found.

Calcium Channel Blockers↗
PubMed2000

Electrophysiological and cardiohemodynamic effects of AH-1058, a new type calcium channel blocker, assessed by the in vivo canine model.

AH-1058 (4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)- 1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride) is a novel calcium channel blocker whose chemical structure is quite different from those of typical calcium channel blockers. In this study, electrophysiological and hemodynamic effects of AH-1058 were assessed in the halothane-anesthetized, closed-chest canine model. Intravenous administration of a canine antiarrhythmic dose of 100 microg/kg of AH-1058 (n = 6) did not affect the cardiovascular variables, except that the cardiac output was decreased at 30 min after the drug administration. Additional administration of 200 microg/kg of AH-1058 (n = 6) suppressed the sinus nodal automaticity, AV nodal conduction and ventricular contraction and decreased the mean blood pressure, cardiac output and double product. The effects gradually appeared, while no change was detected in the intraventricular conduction, ventricular repolarization period, ventricular effective refractory period, preload to the left ventricle and total peripheral vascular resistance during the observation period of 30 min. The cardiosuppressive effects of AH-1058 can be explained by its calcium channel blocking action demonstrated in a previous in vitro experiment, while the lack of the effect on the vascular resistance would suggest that AH-1058 may become a slow-acting cardioselective calcium channel blocker.

Animals↗
PubMed1987

Effects of calcium channel blockers on the contractile response to dihydroergotamine in isolated human femoral veins.

Contractions induced in spirally cut human postmortem femoral veins by dihydroergotamine, noradrenaline, or 5-hydroxytryptamine (5-HT) were measured isometrically. The influence of calcium channel blockers (verapamil, diltiazem and nifedipine), lanthanum chloride and withdrawal of external calcium on the contractile response of veins to dihydroergotamine was investigated. The agonists noradrenaline and 5-HT were studied in comparison. Verapamil and nifedipine up to a concentration of 1 mumol/l caused a shift to the right of the cumulative concentration-response curves for noradrenaline and 5-HT with a reduction of the maximum contraction. Diltiazem affected the contractile response to 5-HT slightly. The venocontractions induced by dihydroergotamine at a concentration of 0.03 mumol/l were inhibited by the calcium channel blockers in a concentration-dependent manner. Verapamil was most effective, followed by nifedipine and diltiazem. In dihydroergotamine-precontracted veins nifedipine produced a more pronounced relaxation than verapamil. Lanthanum chloride (5 mmol/l) inhibited the dihydroergotamine-induced contraction by about 90%. Exposure of veins to a calcium-free medium for 30 min resulted in an inhibition of the dihydroergotamine-induced venocontraction by more than 90%. The addition of calcium ions to the medium caused an increase in the contraction with a maximum which closely resembled that of the control. The present studies demonstrate that the contractile response of human femoral veins to dihydroergotamine depends to a great extent on extracellular calcium. However, the calcium channel blockers verapamil, diltiazem and nifedipine, inhibit the agonist-induced venocontractions in part only.

Adult↗
PubMed1997

Calcium-channel blockers preserve coronary endothelial reactivity after ischemia-reperfusion.

BACKGROUND: Calcium-channel blockers have been reported to improve myocardial recovery after ischemia-reperfusion, but their effects on coronary blood flow regulation remain to be defined. Experiments were designed to evaluate the effects of calcium antagonists on coronary artery vasoregulation exposed to ischemia-reperfusion. METHODS: Three groups of hearts (n = 6) were pretreated with a 10-minute infusion of either diltiazem, verapamil, or nifedipine at concentrations of 10(-9) mol/L to 10(-6) mol/L and exposed to 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxations were tested by assessing coronary flow increase to 5-hydroxytryptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusion, respectively. Left ventricular pressure, its first derivative, and coronary basal flow were recorded before and after ischemia as well as during calcium antagonist infusion. RESULTS: Endothelium-dependent relaxation after ischemia was significantly improved with all three drugs in a dose-dependent fashion; nifedipine was found to be the more potent. Endothelium-independent relaxation was also significantly preserved with calcium antagonists regardless of the type, whereas left ventricular hemodynamics were not. During perfusion, nifedipine was found to have the most negative inotropic effect and to be the most potent vasodilator on the coronary circulation. Diltiazem was the less effective drug on both left ventricular hemodynamics and coronary circulation. CONCLUSIONS: This study indicates that preischemic infusion of calcium antagonists enhance endothelium-dependent and -independent coronary artery relaxation in the isolated rat heart model in a dose- and drug-dependent fashion. This can be achieved at low doses without affecting left ventricular hemodynamics and should contribute to preserve coronary artery autoregulation.

Animals↗