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PubMed1991

[The effect of calcium channel blockers on experimental hypercholesteremia in rabbits. Biochemical and histochemical study].

Calcium ions act as intracellular messengers in numerous cellular functions and participate also in the development of the atherosclerotic process. Calcium homeostasis could be an important factor in the development of atherosclerosis. One of the drugs which interferes with calcium homeostasis are calcium channel blockers. A number of studies have investigated the possibility whether these drugs may be also useful for prevention of atherosclerosis. However, other investigators have reported that calcium channel blockers did not suppress the atherosclerotic process. In our work we assumed the direct influence of calcium channel blockers on transendothelial transport mechanisms. Therefore we decided to investigate the influence of verapamil, diltiazem and isradipine on the development of experimental atherosclerosis in rabbits. Verapamil administered twice daily, 0.125 mg per kg s. c., reduced the size of atheromatous plaques in the thoracic aorta and the level of total cholesterol and triglycerides in serum. This above effect was not present after administration of diltiazem in doses of 1.0 mg per kg and isradipine 1.25 mg per kg twice daily subcutaneously. Our conclusion is that the anti-atherosclerotic effect of calcium channel blockers is dose-dependent. It is not clear whether this effect takes place in the plasma compartment and/or in the intracellular compartment.

Animals↗
PubMed2001

Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model.

We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is approximately 10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141+/-3 mm Hg) and amlodipine (143+/-5 mm Hg) compared with untreated rats (188+/-5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (r=0.74 to 0.85, P<0.02). However, the slope of the relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7+/-0.2; P<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.

Animals↗
PubMed1995

Modification of the behavioral effects of (+/-)BAY k 8644, cocaine and d-amphetamine by L-type calcium channel blockers in squirrel monkeys.

Behavioral effects of the 1,4-dihydropyridine L-type calcium channel activator (+/-)BAY k 8644 [(+/-)methyl-1,4-dihydro-2,6-dimethyl-3- nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] the monoamine reuptake inhibitor cocaine and the monoamine releaser d-amphetamine were determined alone and after pretreatment with the structurally distinct L-type calcium channel blockers nimodipine (1,4-dihydropyridine), verapamil (phenylakylamine), diltiazem (benzothiazepine) and flunarizine (diphenylalkylamine) in squirrel monkeys responding under a 10-response fixed-ratio schedule of stimulus-shock termination. When administered alone, (+/-)BAY k 8644 (0.1-0.56 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with nimodipine (3.0-10 mg/kg) or verapamil (1.0-3.0 mg/kg) produced dose-dependent rightward shifts of the (+/-)BAY k 8644 dose-response curve. In contrast, pretreatment with flunarizine (3.0 mg/kg) produced a leftward and downward shift of the (+/-)BAY k 8644 dose-response curve. Pretreatment with diltiazem (10-17.8 mg/kg) did not modify the (+/-)BAY k 8644 dose-effect curve. In addition, stereoselectivity was evident in the behavioral effects of (+/-)BAY k 8644 with the S(-)-enantiomer being approximately 3-fold more potent than the racemate. When administered alone, cocaine (0.1-5.6 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with flunarizine (3.0 mg/kg) produced rightward shifts of the cocaine and d-amphetamine dose-response curves. Pretreatment with nimodipine (10 mg/kg), verapamil (3 mg/kg) or diltiazem (17.8 mg/kg) did not modify the effects of cocaine or d-amphetamine. The results of the present study suggest that the behavioral effects of (+/-)BAY k 8644 are differentially modified by L-type calcium channel blockers interacting with different sites on the channel and also suggest that the calcium channel blockers can be distinguished based on their differing interactions with (+/-)BAY k 8644, cocaine and d-amphetamine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Calcium-channel blockers inhibit human low-density lipoprotein oxidation by oxygen radicals.

Previous studies have shown that calcium channel blockers may reduce the development of experimental atherosclerosis, and that nifedipine may slow the progression of coronary atherosclerosis in humans. The mechanisms responsible for this antiatherogenic effect are still unclear. It has been recently proposed that oxygen free radicals can induce the oxidation of human low-density lipoproteins (LDL) and that oxidized LDL may be an atherogenic stimulus. Previous studies in other systems have shown that calcium channel blockers may effectively inhibit oxygen radical-induced lipid peroxidation in vitro. Thus, the aim of the present study was to investigate whether calcium channel blockers may also reduce LDL modifications induced by oxygen radicals. Isolated human LDL were exposed to oxygen radicals generated by CuSO4 (10 microM for 18 hours) after a 30 minute pre-incubation with different concentrations (1-100 microM) of nifedipine, diltiazem, and verapamil. Lipid peroxidation was measured from malonyldihaldehyde (MDA) production. Oxygen radical-induced damage on apolipoprotein-B100 was evaluated by acrylamide and agarose gel electrophoresis. Calcium channel blockers dose-dependently prevented oxidation of both the lipid and protein components of LDL. MDA formation was reduced in LDL pre-incubated with calcium antagonists before exposure to oxygen radicals (% MDA inhibition was 89.8 +/- 6.9 with 30 microM nifedipine, 68.6 +/- 4.9 with 30 microM verapamil, and 65.6 +/- 7.1 with 30 microM diltiazem; p < 0.01 vs. controls). Similarly, apolipoprotein-B100 integrity was preserved against oxygen radical attack in the presence of calcium antagonists. Thus, calcium channel blockers reduce the oxidation of human LDL in vitro. These data suggest that reduced formation of atherogenic oxidized LDL may be an additional mechanism for the antiatherosclerotic effects of calcium channel blockers in vivo.

Analysis of Variance↗
PubMed2006

Calcium channel blockers in the spectrum of antihypertensive agents.

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Calcium channel blockers: an update.

This paper reviews the current literature pertaining to calcium channel blockers, including their classification, properties, and therapeutic indications, in light of several recent trials that have addressed their safety. Calcium channel blockers are a structurally and functionally heterogeneous group of medications that are used widely to control blood pressure and manage symptoms of angina. They are classified as dihydropyridines or nondihydropyridines. As a class, they are well tolerated and are associated with few side effects. The question of whether they may precipitate cardiovascular events has been largely settled by recent trials, such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the International Verapamil Slow-Release/Trandolapril Study (INVEST), and the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) study, in which no such association was found. Even so, the use of these agents has been linked with an increased risk of heart failure. Thus, long-acting calcium channel blockers may be safely used in the management of hypertension and angina. However, as a class, they are not as protective as other antihypertensive agents against heart failure.

Angina Pectoris↗
PubMed1989

Differential susceptibility of cholinergic and noncholinergic neurogenic responses to calcium channel blockers and low Ca2+ medium in rat urinary bladder.

1. The influence of calcium channel blockers and low Ca2+ medium on the neurogenic responses to single pulse electric field stimulation in rat urinary bladder has been examined. 2. Single pulse stimulation evoked a biphasic contractile response consisting of a fast component with a time to peak of 0.72 +/- 0.05 s and a slow component that reached a maximal tension at 2.8 +/- 0.21 s, possibly mediated by two different neurotransmitters. 3. Atropine (3 x 10(-6) M) selectively inhibited the slow component without altering the fast component, suggesting the involvement of cholinergic and non-cholinergic neurotransmitters, respectively. 4. Reducing Ca2+ in the medium to 1/4 of the normal, abolished the slow component of the neurogenic response while the fast contractile response was not altered which may indicate a relatively greater dependence of the cholinergic component on extracellular Ca2+ than the noncholinergic one. 5. The IC50 values for the fast component with respect to verapamil and diltiazem were 1.08 microM and 1.76 microM, respectively. The greater susceptibility of the slow component to calcium channel blockers (IC50 values of verapamil: 0.07 microM and of diltiazem: 0.25 microM) indicates the differential activation of slow calcium channels by the endogenously released substances. 6. Calcium channel blockers inhibited the ATP-induced contraction which was comparable to that of the non-cholinergic component of the neurogenic response suggesting the involvement of ATP as a possible neurotransmitter. 7. Ach-induced contractions were relatively less susceptible to calcium channel blockers and low Ca2+ medium than was the atropine-sensitive cholinergic component of the neurogenic response.

Acetylcholine↗
PubMed1993

Nisoldipine: a new dihydropyridine calcium-channel blocker.

Nisoldipine is a new calcium-channel blocker of the dihydropyridine subclass, with a chemical structure similar to nifedipine. It has been used in clinical trials to assess its efficacy and safety in patients with hypertension, angina pectoris, and congestive heart failure. Similar to other dihydropyridines, nisoldipine is a potent peripheral and coronary dilator. The most optimal dosage regimen has not been established in clinical trials. The drug appears to have a favorable side-effect profile.

Angina Pectoris↗
PubMed1989

The influence of the calcium channel blocker nimodipine on flap survival.

The calcium channel blocker nimodipine has been used successfully in neurological patients for the treatment of vasospasm after subarachnoid hemorrhage and stroke. In this study of experimental random pattern skin flaps in rats, an increase of nearly 50% in the survival rate to 94.33% (+/- 7.3% standard deviation) under nimodipine treatment versus 66.00% (+/- 16.5% standard deviation) in the controls could be demonstrated (p less than 0.001). Vital dye injections in a separate experiment indicated that the increased flap survival is mainly due to improved microcirculation. The distance traveled by the dye was 8.01 +/- 1.21 cm in the experimental versus 6.61 +/- 1.25 cm in the control group (p less than 0.05).

Animals↗
PubMed1988

Prolonged calcium channel blocker therapy of hypertension.

The dihydropyridine calcium channel blocker nitrendipine was studied in 329 hypertensive patients at 12 separate centers for periods of 1 year or more. Patients with untreated supine diastolic blood pressures greater than 90 mm Hg were given nitrendipine 5 mg twice daily for 1 week; if the goal blood pressure was not achieved (supine diastolic blood pressure less than 90 mm Hg with a fall of at least 10 mm Hg), the dose was doubled, and if necessary it was doubled again after an additional week. By the end of titration, the goal blood pressure had been achieved in 138 patients (44%). During the subsequent 11 months of study, 155 patients continued to take nitrendipine alone; their posttitration supine diastolic blood pressure was 85 +/- 7 mm Hg, and at the end of the 1 year study it was 84 +/- 6 mm Hg. There were no significant changes in body weight or in heart rate. At their discretion, investigators could add other antihypertensive agents in patients not responding adequately to nitrendipine alone. In 41 patients with a supine diastolic blood pressure of 95 +/- 9 mm Hg after initial titration, propranolol was added to the nitrendipine and decreased the supine diastolic blood pressure to 88 +/- 8 mm Hg by the end of the study; and in another 76 patients with a posttitration supine diastolic blood pressure of 92 +/- 7 mm Hg, the addition of hydrochlorothiazide decreased the supine diastolic blood pressure to 86 +/- 7 mm Hg by the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression.

AIMS: Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies. METHODS: Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription-event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed. RESULTS: The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0. 82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine, respectively. CONCLUSIONS: This study does not support the hypothesis that calcium channel blockers are associated with depression, when considering patients treated in general practice in the UK.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Cancer risk and mortality in users of calcium channel blockers. A cohort study.

BACKGROUND: Data regarding the association between the use of calcium channel blockers and cancer risk have been conflicting. In the current study, the authors examined the cancer risk and mortality in users of calcium channel blockers in North Jutland County, Denmark. METHODS: The authors conducted a cohort study using record linkage between a population-based prescription database, the Danish Cancer Registry, and the Danish Death Registry including 23, 167 users of calcium channel blockers who received >/=2 prescriptions between January 1, 1989 and December 31, 1995. The authors calculated the standardized incidence ratios and standard mortality ratios for cancer, along with corresponding 95% confidence intervals (95% CI). RESULTS: Overall, 967 incident cases of cancer occurred, resulting in a standardized incidence ratio of 1.04 (95% CI, 0.98-1.11). There was a slightly elevated nonsignificant risk of tobacco-related cancer. No increased risk of breast or colon carcinoma was observed. The cancer mortality was close to that expected in the background population (standardized mortality ratio of 0.97; 95% CI, 0.89-1.04). CONCLUSIONS: This large-scale, population-based cohort study adds to the increasing evidence indicating no substantial association between the use of calcium channel blockers and the incidence rate of cancer or cancer mortality.

Adolescent↗
PubMed1990

Effect of calcium channel blockers on experimentally induced seizures in rats.

Chemically different classes of calcium channel blockers were examined in rats for their effects on behavior, tolerability and protection against maximal electroshock seizures (MES) and pentylenetetrazol (PTZ) induced seizures. In MES test at doses (mg/kg, ip) that were devoid of side effects, felodipine, 50, afforded 100% protection, while nimodipine, 5; pimozide, 10; and thioridazine, 25, showed 50 to 66% protection. Nifedipine, 10, and diltiazem, 50, showed 30 and 66% protection respectively, but were associated with side effects. Verapamil and loperamide were ineffective against MES and PTZ induced seizures. Nimodipine, 1 mg/kg, ip, was the most potent agent and produced 100% protection against PTZ. Equieffective doses were pimozide, 25, felodipine, 50, and thioridazine, 50. The rest of the calcium channel blockers showed marginal to moderate activity against chemoshock. The data obtained suggest that some calcium channel blockers possess anticonvulsant activity and may be considered as adjuvant therapeutic agents in epileptics refractory to conventional antiepileptic medication.

Animals↗
PubMed2001

Calcium channel blockers: third-line antihypertensives.

(1) Two new trials have assessed calcium channel blockers in hypertensive patients in terms of cardiovascular morbidity and mortality. (2) In a large unblinded trial, diltiazem had no advantage over diuretic or betablocker therapy in terms of overall cardiovascular prevention or the total incidence of adverse effects. (3) In another trial, sustained-release nifedipine had more adverse effects than a diuretic combination, but the precise difference between the two treatments in terms of preventive effects could not be determined. (4) Some diuretics and betablockers, which have been thoroughly assessed in terms of morbidity and mortality, remain the first choice for antihypertensive drug therapy. Some well-assessed angiotensin-converting-enzyme inhibitors are second-line alternatives. Calcium channel blockers remain a third-line alternative. The risk-benefit ratio of diltiazem, a calcium channel blocker, seems to be closer to that of diuretics and betablockers and better than that of dihydropyridines.

Adrenergic beta-Antagonists↗
PubMed2000

Correlation between predicted theoretical mechanistic biochemistry (TMB) data and therapeutic effects in the management of vascular disorders with calcium channel blockers.

Theoretical mechanistic biochemistry (TMB) analysis was used to predict the therapeutic effects of calcium channel blockers in the drug management of hypertension, cerebrovascular disorders (CVD) and coronary artery disease (CAD). This analysis was extended to acetylsalicylic acid (aspirin) a non-calcium channel blocker which is nevertheless commonly used in the management of the same disorders. TMB data have suggested nisoldipine, nicardipine and nimodipine as agents of choice in the management of cerebrovascular disease, e.g. in transient ischemic attacks (TIAs). The same agents were found preferable in the management of coronary artery disease. It is noteworthy that atherosclerosis and vascular spasm are common pathogenic events in both conditions. For lowering blood pressure, without compromising cerebral and coronary blood flows TMB data suggested nisoldipine, nicardipine, nimodipine and nifedipine in that preferential order. For tissue selectivity, TMB data have identified nisoldipine, nicardipine, nifedipine, nimodipine and nitrendipine for vascular tissue and that verapamil, diltiazem and aspirin have little or no tissue selectivity. TMB data have gone further to suggest a combination of nicardipine, nisoldipine or nimodipine with beta-blockers in order to reduce the frequently uncomfortable reflex tachycardia often induced by some calcium channel blockers. By and large, TMB predicted data have been found to correlate reasonably well with clinically observed and reported therapeutic effects of calcium channel blockers. Their consistency in the management of hypertension, cerebrovascular disease and coronary artery disease is apparent in this study.

Calcium Channel Blockers↗
PubMed1993

Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord.

BACKGROUND: Opioids inhibit voltage-dependent calcium-channel conductance, which is essential for the nervous system to be able to signal a painful event. Accordingly, interference with calcium-channel conductance may enhance opioid analgesia. The current study was designed to investigate the effects of calcium-channel blocking drugs on the antinociception of morphine at the level of the spinal cord. METHODS: Rats were chronically implanted with catheters in the lumbar intrathecal space. Tail-flick test was used to assess thermal nociception. Intrathecally administered drugs were morphine, calcium-channel blockers (verapamil, diltiazem, and nicardipine), or a combination of morphine and calcium-channel blocker. RESULTS: Intrathecal administration of morphine produced a significant dose-dependent antinociception in the tail-flick test. In contrast, intrathecal administration of calcium-channel blockers, verapamil, diltiazem, and nicardipine, did not show any antinociception at the employed doses. However, when intrathecally administered calcium-channel blockers, verapamil (50 micrograms), diltiazem (100 micrograms), or nicardipine (20 micrograms), were combined with ineffective (0.25, 0.5, 1, or 2 micrograms) or moderately effective (5 micrograms) doses of intrathecally administered morphine, significant antinociception was produced. These interactions were synergistic. There were no significant changes in MAP or HR after the intrathecal administration of 200 micrograms verapamil or 2 micrograms morphine combined with 50 micrograms verapamil. CONCLUSIONS: The authors interpreted these results to indicate that calcium-channel blocking drugs synergistically potentiate the analgesic effects of morphine at the level of the spinal cord. Before these results can be translated into clinical use, however, adequate toxicity studies must be conducted to examine the effect of the perispinal administration of calcium-channel blocking drugs on spinal cord function.

Animals↗
PubMed1996

Calcium channel blockers and hypertension: 2. Safety issues.

As the safety of calcium channel blockers continues to be debated, it is important to realize that not all calcium channel blockers are alike. Safety, and efficacy, depend on the kinetic as well as the pharmacologic properties of the drug.

Antihypertensive Agents↗