Do calcium channel blockers increase heart attack risk?
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Calcium Channel Blockers↗
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[Solubilization and isolation of dihydropyridine calcium channel blocker receptor from the rabbit skeletal muscle].
A microsomal fraction of rabbit skeletal muscle was sed for the isolation of a dihydropyridine (DHP) receptor, a putative potential-dependent calcium channel. The receptor purification was followed by the binding of 3H-labeled riodipine derivative which possesses a high affinity for digitonin-solubilized DHP receptor. The DHP-Sepharose affinity chromatography of an enriched receptor fraction allowed to isolate a receptor, 60-70% homogeneous on the basis of DHP-binding activity. SDS gel electrophoresis showed that the purified receptor is composed of two subunits with molecular masses of 160 and 53 kD. The large subunit changes its electrophoretic mobility after the reduction of disulfide bonds.
Animals↗
Reversal of experimental neuropathic pain by T-type calcium channel blockers.
Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.
Administration, Topical↗
Left ventricular hypertrophy: impact of calcium channel blocker therapy.
Left ventricular hypertrophy (LVH) of the concentric type is the classic cardiac adaptation to sustained arterial hypertension. Data from the Framingham cohort have shown that patients with LVH have a severalfold higher risk of sudden death, acute myocardial infarction, and other cardiovascular morbidity than those with normal hearts. Common sequelae of LVH are ventricular ectopy, impaired ventricular contractility, myocardial ischemia, and decreased left ventricular filling. The benefits of antihypertensive therapy should not be limited to lowering arterial pressure, but should extend to preventing or reducing target organ damage. A variety of antihypertensive agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, antiadrenergic drugs, and, to a lesser extent, beta blockers, have been shown to reduce LVH and to improve left ventricular filling. We have shown that calcium channel blockers diminish ventricular ectopy in parallel with the reduction of LVH, whereas antihypertensive therapy with diuretics neither reduced LVH nor suppressed ventricular ectopy, although it lowered arterial pressure to a similar extent. Whether or not these cardiac changes with antihypertensive therapies will improve cardiovascular morbidity and mortality in patients with LVH remains to be documented.
Arrhythmias, Cardiac↗
Comparison of the effects of nitric oxide donors and calcium channel blockers on the intrinsic myogenic tone of sheep isolated internal anal sphincter.
BACKGROUND: Chronic anal fissure is associated with considerable pain and anal hypertonia. Numerous clinical studies attest to the effectiveness of individual nitro-containing drugs and organic calcium channel blockers in this condition but there are few comparative studies. METHODS: Isolated segments of sheep internal anal sphincter were prepared for isometric tension recording. The effect of various drugs on myogenic tone was examined in the absence or presence of sodium orthovanadate (SOV), an agent used to mimic anal hypertonia by increasing myogenic tone. RESULTS: All the drugs tested produced concentration-dependent inhibition of myogenic tone, with the maximum effect ranging from 66.4 per cent (verapamil) to 100 per cent (sodium nitroprusside). Sodium nitroprusside and diltiazem were the most potent, followed by glyceryl trinitrate (GTN), nifedipine and verapamil, which had similar potency, and finally nicorandil. The potency of GTN and diltiazem was reduced threefold in the presence of 1 mmol/l SOV. The combined effect of GTN and diltiazem was greater than the effect of either agent alone, even in the presence of 3 mmol/l SOV. CONCLUSION: Nitro-containing drugs and organic calcium channel blockers are potent inhibitors of anal sphincter myogenic tone that may be used in combination to treat chronic anal fissure.
Anal Canal↗
Anticonvulsant properties of calcium channel blockers in mice: N-methyl-D-,L-aspartate- and Bay K 8644-induced convulsions are potently blocked by the dihydropyridines.
Ten calcium channel blockers were evaluated in mice after intraperitoneal (i.p.) administration for prevention of seizures induced by various convulsants. The dihydropyridines (class II calcium antagonists, i.e., nisoldipine, nitrendipine, nicardipine, nifedipine, and nimodipine) selectively prevented seizures elicited by administration of pentylenetetrazol (PTZ), N-methyl-D,L-aspartate (NMDLA) and the dihydropyridine calcium channel agonist BAY K 8644. With regard to prevention of NMDLA-induced seizures and the subsequent mortality, these compounds were similar in potency to the noncompetitive NMDA receptor antagonist MK801. Unlike MK801 (IC50 = 0.014 microM), the dihydropyridines did not inhibit in vitro binding of MK801 to synaptic membrane fractions prepared from rat cerebrohippocampal tissue. The dihydropyridines did not influence seizures elicited by maximal electroshock (MES). Flunarizine (diphenyl-alkylamine, class IV) was selectively active in the MES test, considerably less potent against NMDLA-induced convulsions/mortality, exhibited weak noncompetitive NMDA antagonism in vitro (IC50 = 28 microM), and was inactive in the PTZ and BAY K 8644 testing paradigms. Diltiazem, a class III benzothiazepine, possessed relatively weak broad spectra of activity against MES, PTZ, NMDLA, and BAY K 8644 test situations. It was inactive in vitro as a noncompetitive NMDA antagonist. The class I compound verapamil (phenylalkylamine) displayed only moderate inhibition of NMDLA-evoked seizures/mortality. Prenylamine (class V) was moderately active against convulsions produced by MES and NMDLA while retaining a degree (IC50 = 16 microM) of noncompetitive NMDA antagonism. Lidoflazine (class VI) was inactive in all tests. The Ca2+ channel blockers and MK801 were inconsistent in their ability to prevent bicuculline (BIC)-elicited convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Efficacy of calcium channel blockers as maintenance therapy for asthma.
AIMS: Previous bronchoprovocation studies indicate that nifedipine attenuates airway responsiveness to several stimuli whereas diltiazem has no effect. The aim of this study was to determine whether such studies predict the efficacy of calcium channel blockers as maintenance therapy for persistent asthma. METHODS: Twenty-one otherwise healthy adults with persistent asthma, mean age 25 years, completed treatment with maximum tolerated doses of placebo (P), nifedipine (N), and diltiazem (D) in a double-blind, randomized, three-treatment, three-period, crossover manner, each for 4 weeks. Frequency and severity of asthmatic symptoms were recorded twice daily, as well as peak expiratory flow and frequency of 'prn' use of inhaled terbutaline. Blood pressure, heart rate, P-R interval of the ECG and spirometry were measured biweekly. At the end of each treatment, airway responsiveness to exercise was measured. RESULTS: The mean (s.e. mean)% of days with wheeze was 69plus minus7% during P, 75plus minus6% during N and 72plus minus6% during D (P=0.7). FEV1 was 79plus minus2% of predicted during P, 81plus minus2% during N and 79plus minus2% during D (P=0.6). The decrease in FEV1 after exercise was 32plus minus4% during P, 32plus minus5% during N and 27plus minus4% during D (P=0.5). Heart rate was elevated during N (P=0.0002) whereas P-R interval was prolonged during D (P=0.0001). CONCLUSIONS: Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.
Adolescent↗
Calcium channel blockers and cardiac mortality in the treatment of hypertension: a report from the Department of Health Hypertension Care Computing Project (DHCCP).
OBJECTIVE: A case control study has reported a 60% higher risk of myocardial infarction in hypertensives treated with a calcium channel blocker (CCB). We examined the Department of Health Hypertension Care Computing Project (DHCCP) data to see if we could confirm or refute this suggestion. DESIGN: Two case control studies, matched and unmatched, plus two longitudinal studies from 1 year of presentation, one for all subjects given a CCB for more than 1 year compared with those not given this drug, and the second comparing survival on the different drugs initially given between 3 and 12 months of follow-up. SUBJECTS: A total of 9328 subjects were included in the analyses and 2154 died. Of these, 6406 received one or more of the following index drugs: 26% a calcium channel blocker (CCB); 84% a diuretic; 29% alpha methyldopa; 12% a beta-blocker (BB); and 11% an angiotensin-converting enzyme (ACE) inhibitor. The CCBs were nifedipine, diltiazem or verapamil. RESULTS: In the case control studies a group given diuretics +/- other treatments (but not including one of the index drugs) provided a reference group with a relative risk (RR) of 1.0. In the matched case control study the adjusted RR for a CCB without a diuretic was 1.32 (95% CI 0.64-2.70) for IHD mortality and 1.05 (95% CI 0.60-1.84) for cardiovascular mortality. Similar results were observed for methyldopa, BBs and ACE inhibitors. The results in the unmatched case control analysis were also similar. The longitudinal study comparing all those treated for over 1 year with a CCB with all other treatments showed a RR for total mortality of 1.03 (95% CI 0.85-1.25). The longitudinal study of total mortality according to treatment initiated at 3-12 months found results of a similar magnitude for CCBs, methyldopa and BBs. CONCLUSIONS: The reference diuretic group had less severe cardiovascular disease than other groups. Treatment with a CCB, BB or methyldopa was associated with an excess mortality in comparison with this reference group. The excess was similar in the different drug groups.
Adolescent↗
Interaction between calcium channel blockers and volatile anaesthetics in the rat heart-lung preparation.
We have studied the effects of the calcium channel blockers verapamil, diltiazem and nifedipine and the volatile anaesthetics halothane, enflurane and isoflurane on myocardial metabolism after postischaemic reperfusion in the rat isolated heart-lung preparation. In the presence of the volatile anaesthetics, the preparations were perfused for 10 min, made globally ischaemic for 8 min, and then reperfused for 10 min. Each of the calcium blockers was administered 5 min before ischaemia. Three hearts in the halothane-verapamil group (n = 10) failed to recover from the ischaemia and the recovery time in the same group was significantly longer than in the enflurane-verapamil or isoflurane-verapamil groups. Although there was no significant difference in myocardial lactate concentrations among the groups, ATP and glycogen contents in the halothane-verapamil group were significantly less than those in the other groups. The results suggest that the combination of halothane and verapamil causes significant myocardial depression during recovery from ischaemia and subsequent metabolic deterioration.
Anesthetics↗
[The elements of commonality in calcium channel blockers and M-cholinolytics].
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Animals↗
Enhancement of vasoconstrictor and attenuation of vasodilator effects of 5-hydroxytryptamine by the calcium channel blockers nimodipine and nifedipine in the pig.
As calcium (Ca2+) channel blockers are effective against the vasoconstrictor responses to 5-hydroxytryptamine (5-HT) in vitro, and a favourable response is claimed for these drugs in migraine prophylaxis, we studied the interaction between nimodipine or nifedipine, and 5-HT for effects on carotid haemodynamics in the anaesthetized pig. Intracarotid infusions of nimodipine (0.25 microgram X kg-1 X min-1), nifedipine (0.75 microgram X kg-1 X min-1) or 5-HT (2.0 micrograms X kg-1 X min-1) caused a redistribution of carotid blood flow in favour of the nutrient (capillary) fraction at the expense of the non-nutrient (arteriovenous anastomoses; AVA) fraction. Compared to those of 5-HT, the effects of the Ca2+ channel blockers on cranial AVAs were much weaker and the increase in the capillary fraction was observed mainly in the skeletal muscles, rather than in the skin and ears as with 5-HT. When 5-HT was infused in the presence of nimodipine or nifedipine, the amine-induced vasoconstrictor responses in the total carotid vascular bed and its AVA fraction were either not attenuated or were increased while the vasodilator responses were reduced. We conclude that: in contrast to what was found in vitro, the 5-HT-induced vasoconstriction in vivo, involving either '5-HT1-like' (AVAs) or 5-HT2 (arterioles) receptors, was not antagonized by nimodipine or nifedipine; the attenuation of the 5-HT-induced dermal vasodilatation by the two Ca2+ channel blockers is most likely to be the result of a 'steal' due to the profound vasodilatation in the skeletal muscle region; and the comparatively mild reduction in AVA conductance caused by the Ca2+ channel blockers may be one of the reasons for their inability to abort acute attacks of migraine. The increase in nutrient blood flow is of potential benefit, but whether this property of the Ca2+ channel blockers is linked to their usefulness in migraine prophylaxis remains to be ascertained.
Animals↗
The enhancement of myocardial protection through an acalcemic storage solution containing nicardipine, a potent calcium channel blocker. A basic study using rat ventricular myocytes.
Adult rat ventricular myocytes were used as a model system for investigating the direct effects of nicardipine, a potent calcium-channel blocker, on preservation of the heart during periods of simple cold storage. Cells were stored at 4 degrees C for 24 hr with an acalcemic storage solution. The superfusate then was exchanged with hypoxic Tyrode solution (1.8 mmol/L CaCl2). After 2 hr of hypoxia at 20 degrees C, cells were reoxygenated and simultaneously warmed to 37 degrees C. The addition of nicardipine to both the storage solution and Tyrode solution resulted in the highest percentage of viable cells (70.5%). Using either the storage solution or Tyrode solution containing the compound, the percentages of viable myocytes were 51.9% and 52.2%, respectively. In the absence of the drug in either solution, the percentage was 38.0%. The effect of diltiazem, another potent calcium-channel blocker, was examined using the same experimental procedure. The addition of diltiazem to Tyrode solution elevated the viability of ventricular myocytes, but addition to the storage solution showed no cardioprotective effect. Moreover, the addition of 8-bromo cyclic GMP to the storage solution resulted in a cardioprotective effect. These results suggested that nicardipine exerts a direct effect on myocardial protection in hypothermic and acalcemic storage solution and that the pharmacological effect of nicardipine depends on a mechanism other than its calcium-channel blocking action.
Animals↗
Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging.
OBJECTIVE: To investigate the association between use of calcium channel blockers (CCB), dihydropyridine (DHP) or nondihydropyridine (nonDHP) type CCB and risk of developing Alzheimer's Disease (AD) or mortality. There is evidence suggesting that calcium plays a key role in changes in the brain leading to AD. Previous reports suggest a possible role for CCB in the treatment of AD. However, there are some indications that CCB increase mortality in patients with cardiac disease. METHODS: Subjects were 1092 participants in the Baltimore Longitudinal Study of Aging (BLSA) older than 60 years of age. Data on CCB use was collected prospectively for up to 19 years. Cox proportional hazards regression was used to estimate relative risks (RR) and confidence intervals (CI) of AD and mortality associated with use of CCB or use of only DHP or nonDHP-CCB. Analyses were adjusted for gender, education, smoking, blood pressure and history of heart problems. RESULTS: Use of DHP-CCB was not associated with a significantly reduced risk of AD compared to non-users, although the estimate of the RR was low with DHP-CCB (RR = 0.30, 95% CI = 0.07-1.25, P = 0.10). Use of nonDHP-CCB was not associated with reduced risk of AD and the estimate of the RR risk was close to one (RR = 0.82, 95% CI = 0.37-1.83, P = 0.63). In addition, there was no increase in mortality among users of DHP-CCB (RR = 0.64, 95% CI = 0.32-1.29, P = 0.21) or nonDHP-CCB (RR = 1.10, 95% CI = 0.65-1.87, P = 0.72). CONCLUSION: Users of DHP-CCB and nonDHP-CCB in this study did not have a significantly reduced risk of AD.
Aged↗
Management of coronary heart disease risk factors and progression with calcium channel blockers.
The death rate from coronary heart disease (CHD) declined by 25% in the United States during 1987-1997, but the actual number of deaths fell by only 9%. Modifiable risk factors for CHD include hypertension, elevated low-density lipoprotein cholesterol, reduced high-density lipoprotein cholesterol, cigarette smoking, and diabetes. Several randomized clinical trials demonstrated that calcium channel blockers reduce the frequency of strokes in patients with hypertension, with particular benefit observed in patients with both hypertension and diabetes. Results of a meta-analysis suggest that calcium channel blockers are similar to beta-blockers in preventing death or myocardial infarction and in improving exercise tolerance among patients with established CHD. In addition, amlodipine, a long-acting dihydropyridine, was reported to reduce nonfatal vascular events and major vascular procedures in patients with angina. Ongoing clinical trials are comparing amlodipine with an angiotensin-converting enzyme inhibitor for slowing the onset and progression of coronary artery plaque and cardiovascular events.
Amlodipine↗
[The effect of calcium channel blockers on anxiety evoked by amputation of the vibrissae in rats].
The effect of diazepam (0.5 mg/kg) and calcium channel blockers on the behavior of rats in an "open field" was studied on a model of incomplete amputation of vibrissae. Diazepam, diltiazem (1 mg/kg), fendiline (1 mg/kg), and cinnarizine (1 mg/kg) stimulated motor activity of animals with amputated vibrissae. Nifedipine (0.5-5 mg/kg) and verapamil (0.5-5 mg/kg) were practically inactive in these tests. It is concluded that diltiazem, fendiline, and cinnarizine possess anxiolytic activity in this model. On the basis of the results obtained, the methods for studying the anxiolytic activity on animals are discussed.
Animals↗
[Effect of calcium-channel blockers on human thrombocyte aggregation induced by alpha-adrenoreceptor agonists].
A comparative study of the effects of calcium channel blockers nifedipine and verapamil on platelet aggregation in healthy donors induced by adrenaline. A partial agonist of alpha 2-adrenoreceptors clofelin and also clofelin in combination with the threshold concentrations of ADP inducing aggregation was performed. It was found that verapamil is a more potent inhibitor of platelet aggregation induced by adrenaline as compared with nifedipine inhibiting this process only at high concentrations. The aggregation-inducing effect of a partial agonist of alpha 2-adrenoreceptors clofelin is eliminated at low concentrations in the aggregating mixture of nifedipine than verapamil.
Adrenergic alpha-Agonists↗
Calcium channel blockers and cancer: is there preclinical evidence for an association?
The preclinical evidence for a potential influence of calcium channel blockers (CCB) on carcinogenesis is discussed in the light of rodent carcinogenicity studies as well as mechanistic data. In the bioassays performed in rats and mice on the dihydropyridine CCB nifedipine, nimodipine, nisoldipine and nitrendipine, no evidence was found for a carcinogenic potential of these compounds. Moreover, the mechanistic knowledge on the influence of CCB on the fundamental processes of cell proliferation and apoptosis is not in favor of a tumor-promoting activity of these compounds. It is, therefore, concluded that there is no preclinical evidence that the therapeutic use of CCB of the dihydropyridine class is associated with an increased risk of cancer.
Animals↗
Choosing calcium channel blockers for pregnant women with paroxysmal supraventriclar tachycardia and preterm labor: a case report.
Preterm labor is a major clinical hazard causing both maternal and neonatal morbidity and mortality. Paroxysmal supraventricular tachycardia (PSVT) complicated by preterm labor is rare. Of the many drugs used to treat PSVT, only calcium channel blockers are tocolytics. Here, we present the case of a 29-year-old female admitted to our ward with previously diagnosed PSVT and preterm labor at 31 weeks' gestation of her fourth pregnancy. Calcium channel blockers were administered and her uterine contractions subsided. Afterwards, no side effects were noted and she suffered no further tachycardic attacks during her pregnancy. She successfully delivered a full-term baby and received subsequent regular follow-up at the outpatient clinic.
Adult↗