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PubMed2006

CACNA1C polymorphisms are associated with the efficacy of calcium channel blockers in the treatment of hypertension.

Retrospective pharmacogenetic analysis was performed on 120 Caucasian subjects. Subjects were obtained in collaboration with the Estonian Genome Project and Egeen Inc. (CA, USA), who provided blinded medical record and genetic data to the researchers, respectively. Subjects selected from the Estonian Genome Project had a diagnosis of hypertension confirmed by at least two blood pressure measurements and multiple follow-up measurements for assessing calcium channel blocker antihypertensive treatment outcome. Treatment outcome was scored positive if at least three follow-up blood pressure measurements were nonhypertensive and no more than one follow-up measurement was hypertensive (>140/90). The genotypes of 62 single nucleotide polymorphisms (SNPs) in the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) gene were obtained for each subject from a blood sample. Univariate analyses with multiple test correction were conducted using family-wise error rate and false discovery rate methods. Three SNPs in CANCA1C had significant associations with antihypertensive outcome, combining to yield a positive treatment outcome of less than 15 to 80%.

Adolescent↗
PubMed1992

Clinical potency of calcium channel blockers in asthma may be related to their inhibition of receptor-mediated phasic responses in vitro.

The calcium channel blockers (CCB) have been clinically effective in exercise-induced asthma. The completeness of protection with the CCB might be related specifically to inhibition of Ca2+ influx or release. To examine this hypothesis, the rank order of potency of inhibition of the CCB, nicardipine, diltiazem and verapamil on the steady-state and kinetic parameters of the phasic and tonic responses to the muscarinic receptor agonist carbachol (10 microM) and KCl (40 mM) in the intact isolated guinea-pig trachea was determined. The Ca2+ channel agonist Bay K 8644 was also examined for its effects on intracellular Ca2+. Nicardipine abolished the KCl response at both 0.1 microM and 1 microM concentrations. The amplitude of the KCl response was inhibited equally by 1 microM diltiazem (61% inhibition) and 1 microM verapamil (68% inhibition). The rate constant of onset of the KCl response was similarly inhibited 60% by diltiazem and 66% by verapamil. Nicardipine abolished the carbachol phasic response at the 1 microM concentration. The amplitude of the phasic response was inhibited equally by 0.1 microM nicardipine (61.3% inhibition), 1 microM diltiazem (64.5% inhibition) and 1 microM verapamil (71% inhibition). The rate constant of decay of the phasic response was inhibited equally by 0.1 microM nicardipine (43% inhibition) and 1 microM diltiazem (29% inhibition). The rate constant of onset of the phasic response was unaffected by nicardipine, diltiazem and verapamil. Only 1 microM nicardipine inhibited the amplitude and rate constant of onset of the tonic response. The only effect of Bay K 8644 (1 microM) was to increase the phasic response amplitude. The CCB demonstrate a similar order of potency for inhibition of the phasic responses and clinical efficacy of the CCB in exercise-induced asthma (nicardipine > verapamil > diltiazem).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

Effects of calcium channel blockers on pial vascular responses to receptor mediated constrictors.

Published studies have seldom examined the in vivo effect of calcium channel blockers on the contractile response of cerebral vessels to receptor mediated constrictors, and have had little success in demonstrating any effect of a single systemic dose of the channel blockers in contrast to the effects of continuous infusions. The present study examines the effect of topical norepinephrine, prostaglandin F2 alpha and serotonin on pial arterioles of the mouse, in the presence of locally applied channel blockers and also 15 and 30 minutes after a single i.p. injection of the blockers. Verapamil, nisoldipine and nimodipine were all effective inhibitors of constriction by either route of administration, and in doses having little or no dilating action. The data not only indicate that single systemic doses can effectively alter contractile behavior of cerebral arterioles, but also demonstrate the importance of testing these drugs against receptor mediated constrictors whose effects, alone or in combination, may be important during initiation or maintenance of cerebral vasospasm.

Administration, Topical↗
PubMed2001

Effect of calcium antagonists, calcium channel blockers and calmodulin inhibitors on the growth and encystation of Entamoeba histolytica and E. invadens.

The effects of calcium antagonists, calcium channel blockers, and calmodulin inhibitors on the growth of Entamoeba histolytica and the growth and encystation of Entamoeba invadens were examined. Calcium chelators ethyleneglycol bis (beta-aminoethyl ether)-N,N'-tetraacetate (EGTA) and ethylene-diaminetetraacetate (EDTA) inhibited the growth of both Entamoeba and also the encystation of E. invadens in a dose-dependent manner, with EDTA being more effective than EGTA. A putative antagonist of intracellular calcium flux, 8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate (TMB-8) also inhibited both growth and encystation, with the E. histolytica being more sensitive than E. invadens, and with the growth of E. invadens being more sensitive than encystation. The slow Na+-Ca2+ channel blockers bepridil and verapamil inhibited both growth and encystation. Bepridil was more effective than verapamil. The calmodulin (CaM) inhibitors, W-7 (N-(6-aminohexyl)-chloro-1-naphtalene sulphonamide) and trifluoperazine (TFP), were also inhibitory for both the growth and encystation; TFP was more effective than W-7, and encystation was more sensitive than growth in E. invadens. These results indicate that extracellular calcium ions, amebic intracellular calcium flux, calcium channels, and a CaM-dependent process contribute to the growth and encystation of Entamoeba.

Animals↗
PubMed1991

Sex difference in the stereoselective metabolism of a new dihydropyridine calcium channel blocker, in rat studies in vivo and in vitro.

1. After oral dosing with a new racemic dihydropyridine calcium channel blocker (I), plasma levels of (+/-)-I, the 3-desisopropyl metabolite (M-2), the pyridine metabolite (M-3) and the 5-desmethyl metabolite (M-10) in female rats were higher than in males, and plasma levels of (+)-I were higher than those of the (-)-enantiomer in both sexes. 2. Plasma levels of M-2 after oral dosing with (-)-I were much higher than those after dosing with (+)-I, in both male and female rats. 3. Stereoselective metabolism of I by rat liver microsomes was shown in the formation of the 3-(2'-hydroxy-1'-methylethyl) ester metabolite (M-1), and metabolites M-2 and M-10. 4. Marked sex differences were seen in the formation of M-1 and M-3 in adult rats (7 weeks of age), but not in immature rats (3 weeks of age). 5. In liver microsomes of rats pretreated with phenobarbital, the formation of M-1 was decreased in adult male rats, and formation of M-2 and M-3 was increased in adult rats of both sexes.

Animals↗
PubMed1996

Lack of effect of calcium channel blockers on open-angle glaucoma.

PURPOSE: The objective of this study is to evaluate the effect of calcium channel blockers (CCB) on the clinical course of glaucoma. METHODS: Open-angle glaucoma patients receiving oral CCB for nonophthalmic diseases were sequentially selected from the private practice of the Glaucoma Service of Wills Eye Hospital. The course of visual fields and optic discs and serial intraocular pressures were analyzed in subsequent follow-ups. The findings in these 83 cases were compared with a control group of patients with the same ocular diagnosis, but who were not on CCB. A subset of 43 cases of the study group was compared with an age-matched subset of the control group. RESULTS: There was no apparent difference in the absolute intraocular pressure, stability/change of visual fields or optic discs when we compared patients using CCB with the control group. Among patients with the diagnosis of "low-tension glaucoma," we also could not demonstrate any statistically significant difference between the two groups. CONCLUSIONS: In this study, neither a beneficial nor a detrimental effect of CCB on the course of the patients glaucomatous disease was apparent.

Aged↗
PubMed2001

Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

Aged↗
PubMed2000

New insights into the therapeutic mechanism of action of calcium channel blockers in salt-dependent hypertension: their interaction with endothelin gene expression.

It appears that the beneficial action of calcium channel blockers (CCBs) in hypertension may be related to short-term and long-term effects. This paper summarises pharmacological studies aiming to characterise those effects. The primary consequence of the short-term effects is the decrease of blood pressure related to a selective interaction of CCBs with calcium channels in hypertensive vessels. The long-term effects may additionally control the disease through prevention of end organ damage, accompanying the interaction of CCBs with the pathways, leading to the re-expression of embryonic genes and to the overactivation of type I collagen gene, which are amplified by a high-salt diet. ET-1 and tumour growth factor beta-1 could be among the main factors activating those pathways. The processes leading to overexpression of those factors and to tissue remodelling may be controlled by lacidipine, independent of the reduction of blood pressure.

Animals↗
PubMedDate not supplied

[The influence of calcium channel blockers on the effects of haloperidol and phenamine in mice and rats].

Effects of verapamil (5 and 25 mg/kg), nifedipine (5 and 10 mg/kg), diltiazem (5, 10 and 20 mg/kg), cinnarizine (25 and 50 mg/kg), and fendilin (20 mg/kg) on the haloperidol (3 mg/kg)-induced catalepsy have been studied in rats. In higher doses these drugs attenuate and in lower doses potentiate the action of haloperidol. The bilateral intrastriatal injection of verapamil (5 mcg), diltiazem (5 mcg), and nimodipine (0.4 mcg) also alleviates the haloperidol catalepsy. Intraperitoneal administration of calcium channel blockers potentiated the amphetamine group toxicity in mice. No mediation of the effects of calcium channel blockers via dopaminergic processes is assumed.

Amphetamine↗
PubMed1994

Effect of calcium-channel blockers on cell proliferation, DNA synthesis and collagen synthesis of cultured gingival fibroblasts derived from human nifedipine responders and non-responders.

Human gingival fibroblasts from six patients who developed gingival hyperplasia as a result of nifedipine medication and five who did not were studied for the effects of calcium-channel blockers (nifedipine, diltiazem, verapamil and nicardipine) on cell proliferation, DNA synthesis and collagen synthesis. Phenytoin was used as a positive control. The fibroblasts from reactive patients gave trends toward better cell proliferation rates, DNA synthesis ([3H]-thymidine incorporation), and collagen synthesis ([3H]-proline incorporation) than those from non-reactive patients in the presence of 1 microM of calcium-channel blockers or phenytoin.

Adult↗
PubMed1987

Sensitivity of pancreatic beta cell to calcium channel blockers. An electrophysiologic study of verapamil and nifedipine.

Microelectrodes were used to study the comparative effects of 2 calcium channel blockers on glucose-induced electrical activity in mouse beta cells. In 2.8 mM glucose, verapamil (10(-5) M), but not nifedipine (10(-7) M), induces a silent depolarization. In 11.1 mM glucose, verapamil (10(-7) to 5.10(-5) M) induces continuous spike activity by a decrease in the maximum repolarization potential. Nifedipine (10(-10) to 10(-6) M) induces the same activity, but subsequent to a hyperpolarization of the cell at the maximal repolarization potential followed by a silent phase to the plateau potential. The 2 drugs induce a dose-dependent decrease in spike frequency without any change in spike amplitude. In 22 mM glucose exposure to nifedipine, but not to verapamil, induces a transient period of slow-wave activity. The 2 drugs induce a dose-dependent decrease in spike frequency. At higher concentrations (nifedipine greater than 10(-7) M; verapamil greater than 10(-6) M) they induce the disappearance of spikes through a decrease in amplitude. These results show that the beta cell is more sensitive to nifedipine (ED50 = 3 X 10(-8) M) than to verapamil, and that glucose stimulation increases the cell's sensitivity to verapamil (11.1 mM glucose: ED50 = 10(-5) M versus 5 X 10(-7) M in 22 mM glucose) but not to nifedipine.

Animals↗
PubMed2006

Comparison of the antiatherosclerotic effects of dihydropyridine calcium channel blocker and HMG-CoA reductase inhibitor on hypercholesterolemic rabbits.

The antiatherosclerotic effects of the dihydropyridine-type calcium channel blocker, benidipine hydrochloride (benidipine), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin sodium (pravastatin), were compared in hypercholesterolemic rabbits. Male, New Zealand white rabbits were fed a 0.5% cholesterol diet. Pravastatin (10 mg/kg) or benidipine (10 mg/kg) was orally administered once daily after start of feeding. After 8 weeks of cholesterol feeding, serum cholesterol was increased and endothelial function of thoracic aorta was impaired. Pravastatin prevented elevation of serum cholesterol and aortic tunica intima hyperplasia. Although benidipine had little effect on serum cholesterol, it significantly inhibited aortic tunica intima hyperplasia and impairment of endothelial function. Expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mRNA in aorta of hypercholesterolemic rabbit were higher than those of normal rabbit. Benidipine significantly prevented upregulation of VCAM-1 mRNA expression and showed a tendency to inhibit elevation of LOX-1 mRNA expression. Pravastatin significantly prevented upregulation of both VCAM-1 and LOX-1 mRNA expression. The results demonstrate that pravastatin inhibits increase of serum cholesterol and vascular dysfunction in hypercholesterolemic rabbit. Benidipine is effective in preventing vascular hyperplasia without altering serum cholesterol levels and this may be due to inhibition of expression of VCAM-1.

Animals↗
PubMed1996

Role of angiotensin II in reflex tachycardia during hypotension caused by a calcium channel blocker.

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.

Angiotensin II↗
PubMed1997

Effects of isradipine, an L-type calcium channel blocker on permanent and transient focal cerebral ischemia in spontaneously hypertensive rats.

Permanent or transient focal cerebral ischemia was induced in spontaneously hypertensive rats (SHR) using the intraluminal filament method. Successful occlusion of the middle cerebral artery (MCA) was achieved using 4/O filaments (terminal diameter 0.20-0.25 mm) coated with poly-L-lysine. The L-type calcium channel blocker isradipine (2.5 mg/kg) administered subcutaneously 30 min following permanent MCA occlusion significantly reduced the volume of ischemic brain damage in the cerebral hemisphere (25%; P = 0.0001), cerebral cortex (18%; P = 0.0034), and caudate nucleus (33%; P = 0.0002) when assessed at 24 h post-MCA occlusion. Isradipine did not affect the functional deficit (measured using a subjective neurological scoring system) induced by MCA occlusion. In SHR undergoing transient (2 h) MCA occlusion isradipine administered 30 min post-MCA occlusion produced a significant reduction (47%; P = 0.001) in hemispheric infarct volume, whereas isradipine administered at the onset of reperfusion did not confer any significant neuroprotection. No change in functional deficit was seen with isradipine with either dosing paradigm at 24 h post-MCA occlusion. These results demonstrate that the intraluminal filament method of MCA occlusion can be used in the SHR strain and also substantiates the neuroprotective efficacy of isradipine in SHR models of permanent and transient focal cerebral ischemia.

Animals↗
PubMed1996

Calcium-channel blockers in ischemic heart disease.

Recent reports add to a growing body of evidence that short-acting calcium-channel blockers, whether used for hypertension, unstable angina, or acute myocardial infarction, may have unfavorable effects. Short-acting nifedipine has no role in acute myocardial infarction, and the United States Food and Drug Administration has recently issued a warning discouraging its use in hypertension and unstable angina. Other short-acting calcium antagonists such as diltiazem and verapamil may have associated adverse effects as well, although the evidence is not as definitive. What effect sustained-release preparations and newer calcium antagonists have on the clinical endpoints of myocardial infarction and death is not known, and large prospective randomized clinical trials with these medications, some of which are underway, are needed to address these issues. Until that time, only medications with clearly documented efficacy and safety should be used for first-line therapy for hypertension, unstable angina, and acute myocardial infarction.

Angina Pectoris↗
PubMed1997

Bilateral reduction mammoplasty in a patient treated with calcium channel blocker and cyclosporine after renal transplant: a case report.

A 28-year-old woman with end-stage renal disease secondary to diabetes mellitus and hypertension underwent cadaver renal transplant in April 1992. After surgery, she developed bilateral breast enlargement while she was taking cyclosporine for immunosuppression therapy and felodipine, a calcium channel blocker, for blood pressure control. She underwent bilateral reduction mammoplasty in June 1995 to treat progressive breast enlargement which interfered with her normal life activities. Through mechanisms only partially understood, calcium channel blockers and cyclosporine are reported to increase the serum prolactin level, producing gynecomastia in men. There is no report in current literature to support a similar phenomenon in women.

Adult↗
PubMed1999

Class differences in the effects of calcium channel blockers in the rat remnant kidney model.

BACKGROUND: Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved. METHODS: Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three weeks after renal ablation. RESULTS: Although an excellent linear correlation was observed between the average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), significant protection was not achieved with any of the CCBs, but for different reasons. The antihypertensive effects of diltiazem were not sustained beyond the second week. Verapamil significantly reduced the average BP (144 +/- 4 mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5 vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on the relationship between BP and GS, the rank order of GS for any given BP elevation was as follows: felodipine > verapamil > diltiazem = untreated. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil on GS were attributable to the greater amplitude of BP fluctuations that was observed in the verapamil-treated rats such that for any given average BP, these rats were exposed to greater peak pressures as compared with the other groups. None of the CCBs had a significant effect on glomerular hypertrophy. CONCLUSIONS: These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.

Animals↗
PubMed2006

Calcium channel blockers and beta-blockers in relation to Parkinson's disease.

We investigated the risk of Parkinson's disease (PD) associated with calcium channel blockers (CCBs) and beta-blockers in a population-based case-control study of 206 men and women between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 controls without PD or other neurodegenerative disorders who were frequency matched on age, sex, duration of GHC enrollment and clinic. The adjusted odds ratio associated with ever use was 0.85 (95% confidence interval [CI]: 0.43, 1.66) for CCBs, and 1.20 (95% CI: 0.71, 2.03) for beta-blockers. We observed no association with PD risk for either class of medication in terms of duration, dose, number of prescriptions or pattern of use. The weakness of these associations and the absence of additional influence of dose or duration of use argue against any causal interpretation.

Adrenergic beta-Antagonists↗