Mibefradil, a T-type calcium channel blocker, and abnormal rhythm in subacute myocardial infarction.
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Animals↗
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Diverse effects of calcium channel blockers in the collar model.
OBJECTIVE: Calcium channel blockers (CCBs) are among the most frequently prescribed cardiovascular drugs. It has been shown that these drugs have antiatherosclerotic effects in both experimental and clinical settings. However, calcium channel blockers have markedly different chemical structures and different effects on the cardiovascular system. We investigated the effect of CD-832, a Ca(+2) channel antagonist, on collar-induced intimal thickening, as well as accompanied reactivity changes in rabbit carotid artery. METHODS AND RESULTS: Rabbits received 5 mg/kg/day CD-832 or vehicle (polyethylene glycol, 0.5 ml/kg/day) intramuscularly for a week before and 2 weeks after the collar application. Histological and isometric force measurements were performed in segments from sham and collared carotid arteries. A three-week treatment with CD-832 did not inhibit the intimal thickening caused by perivascular application of a silicone collar. Potassium chloride (KCl), phenylephrine, 5-hydroxytryptamine (5-HT, serotonin) and histamine induced concentration-dependent contractions in both sham-operated (sham) and collared arteries. Collar-induced attenuations in maximum KCl, histamine, phenylephrine and 5-HT contractions were not affected by CD-832. Collaring caused an increase in pD2 values of 5-HT and a decrease in those of phenylephrine, histamine and acetylcholine. CD-832 did not affect the altered sensitivity to these agonists. CONCLUSIONS: These results demonstrate that, in rabbit carotid artery, CD-832 did not inhibit the collar-induced intimal thickening and did not affect the accompanying changes in vascular reactivity.
Acetylcholine↗
Calcium channel blockers: nursing care for hypertension.
Calcium channel blockers are gaining wider use in patients with cardiac disease, particularly hypertension and angina. The nurse must be aware of the actions, side effects, and interactions of these agents if they are to be administered safely.
Calcium Channel Blockers↗
No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.
Calcium channel antagonists are commonly used drugs that have recently been reported to be associated with an increased incidence of gastrointestinal hemorrhage. We performed a retrospective cohort study among 105,824 enrollees of the Tennessee Medicaid program 65 years of age or older between 1984 and 1986. Exposure to calcium channel blockers and other medications was determined from pharmacy files. Hospitalization for bleeding peptic ulcers was identified by hospital claims and verified by a review of the medical record. Univariate estimates of relative risk for current users of calcium channel blockers and beta-blocker users were 1.8 (95% confidence interval (CI) 1.2-2.7) and 1.1 (95% CI 0.7-1.6) (reference group was nonuse of either). After adjustment for potential confounders, the relative risks for bleeding peptic ulcer among current users of calcium channel blockers and beta blockers were 1.1 (95% CI 0.7-1.7) and 1.0 (95% CI 0.7-1.6), respectively, when compared with those who used neither drug. In this population, after controlling for important confounders, there was no increased risk for hospitalization with bleeding peptic ulcer among users of calcium channel blockers.
Adrenergic beta-Antagonists↗
[Calcium channel blockers and pulse wave velocity].
Calcium channel blockers (CCB) are widely used in the treatment of hypertension. Recent studies suggest that some CCB improve clinical outcome in patients with cardiovascular diseases. Pulse wave velocity (PWV) is noted as a marker of arterial stiffness. In addition, PWV is thought to be applicable as a marker related to the severity of atherosclerosis and/or predicting future atherosclerotic cardiovascular events. Recent studies suggest that CCB improve structural damage of vascular wall. Further study is proposal to evaluate whether the improvement of structural vascular damage by CCB contribute to the improvement of the prognosis.
Atherosclerosis↗
The influence of calcium channel blockers on superoxide anions.
Four calcium channel blockers were tested from the point of view of their influence on enzymic lipid oxidation and on generation of superoxide anions. All the compounds were found to be antioxidants as tested by the inhibition of NADPH-stimulated malonaldehyde formation from lipids. IC50 values were 60 microM for nifedipine; 1.1 microM for verapamil; 1.4 microM for fendiline and 20.6 microM for diltiazem. Only nifedipine scavenged superoxide anions both in an enzymic (xanthine:xanthine oxidase) and non-enzymic (phenazine methosulphate:NADH) generating system. IC50 values for this inhibition were about 2.5 times higher than for inhibition of formation of malonaldehyde. Nifedipine inhibited also xanthine oxidase-mediated formation of uric acid.
Animals↗
Catalepsy induced by manidipine, a calcium channel blocker, in mice.
Manidipine, a calcium channel blocker, is a piperazine derivative similar to flunarizine or cinnarizine, which are known to induce parkinsonism. Since it has been reported that manidipine can worsen parkinsonian symptoms in a patient with Parkinson's disease, we have evaluated catalepsy in manidipine-treated mice and compared this with flunarizine-and haloperidol-induced catalepsy. The minimum dose at which manidipine induced catalepsy was 200 times higher than that of haloperidol whereas for flunarizine, the minimum dose was 50 times higher than that for haloperidol. Manidipine, flunarizine and haloperidol occupied both dopamine D1 and D2 receptors and D2-receptor occupancy was higher than D1-receptor occupancy. These results suggest that the blockade of dopamine D1 and D2 receptors by drugs and the drug-induced catalepsy are related to the structure (piperazinyl substituent) of the drugs.
Animals↗
High-throughput screening for N-type calcium channel blockers using a scintillation proximity assay.
N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125I]-labeled omega-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper's Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 microM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125I]GVIA binding. This is the 1st demonstration of the use of [125I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery.
Animals↗
Calcium channel blockers and coronary heart disease.
Calcium channel blockers (CCBs) are drugs with several pharmacological properties, widely used in cardiovascular medicine for a variety of indications, including treatment of hypertension and angina pectoris. This review summarizes the most recent evidence on coronary outcomes of CCBs, used either to treat hypertension or in secondary prevention of overt coronary heart disease (CHD). The anti-atherosclerotic properties of these drugs will also be reviewed. Several randomized trials and meta-analyses published from the mid-1990s indicate that, as a class, CCBs are superior to placebos in preventing CHD events in patients with hypertension, although in head-to-head comparisons with other antihypertensive agents their effects are more controversial and largely dependent on the specific CCB considered. Conversely, older studies report that short-acting CCBs may increase the risk of CHD outcomes, a finding contradicted by recent trials on long-acting, lipophilic agents. In patients with prevalent CHD, CCBs do not improve survival and most major CHD outcomes, although they reduce symptoms of angina and the need for revascularization procedures also in active treatment comparisons. Besides their action on blood pressure and on coronary vessel smooth muscle, this protective effect is probably mediated by their plaque stabilization properties.
Aged↗
Calcium channel blockers in treatment of hypertension.
Calcium channel blockers (CCBs) are among the most often prescribed drugs for the treatment of hypertension, but there is still uncertainty regarding the risks and benefits of their use as first-line drugs in the treatment of hypertension. Compared with placebo, dihydropyridine CCBs (long-acting nifedipine and nitrendipine) reduce the risk for cardiovascular endpoints, and in a pooled analysis of available studies on treatment of hypertension, significantly decrease the risk for strokes and cardiovascular and total mortality. This also holds true for patients with diabetes who have a clearly reduced risk when treated with CCBs as compared with placebo. However, compared with other active treatments in mixed study populations, CCBs are associated with a small risk increase for myocardial infarction and heart failure, but for cardiovascular mortality, there is only a very small and nonsignificant trend to a risk increase, and total mortality is similar. Among patients with diabetes, compared with angiotensin-converting enzyme inhibitors in particular, available data suggest that CCB use is associated with a moderate increase in cardiac endpoints. Therefore, among patients with diabetes and those with heart failure, angiotensin-converting enzyme inhibitors are preferable as first-line drugs; among the large fraction of patients without these conditions, there is no convincing evidence that long-acting dihydropyridine or nondihydropyridine CCBs are inferior to other blood pressure-lowering drugs. In these patients, the choice of blood pressure-lowering medication can be based on the expected tolerability, costs, and personal preferences.
Age Factors↗
Clinical use of calcium channel blockers as ventricular unloading agents.
Calcium channel blockers relax the arterial smooth vasculature and lower blood pressure when it is elevated because of excessive vasoconstriction. They may be regarded as ventricular unloading agents. Nifedipine (11 cases, Group 1) and verapamil (12 cases, Group 2) were tested in hypertensive patients with cardiac enlargement (LV diastolic diameter greater than or equal to 60 mm), ECG signs of LV strain, lung congestion and dyspnea at rest, in an acute (nifedipine 20 mg; verapamil 160 mg) and 1-month (nifedipine 20 mg q.i.d.; verapamil 160 mg t.i.d.) therapeutic evaluation. In the acute study nifedipine reduced systemic vascular resistance (SVR), mean arterial pressure (MAP), mean pulmonary wedge pressure (PWP) and LV diastolic diameter (DD) and improved cardiac index (CI) and Vcf. In Group 2 verapamil reduced SVR and MAP, improved CI and was not effective on PWP, LV DD and Vcf. Verapamil was discontinued in 2 patients who developed severe dyspnea at rest after 3-4 days of continued oral treatment. At the end of the trial Vcf, PWP and LV DD were unchanged in the remaining subjects in Group 2 despite persistent pressure reduction. In Group 1 all of the patients had relief of dyspnea and lung congestion, reduction of heart size, persistent decrease of MAP and PWP, and improvement in Vcf. The only side effect was ankle edema in 4 cases. A less potent vasodilating action of verapamil and a predominant depression in cardiac contractility may account for the different results with the two drugs, in spite of a shared antihypertensive effect. These findings prove that functional changes in the failing hypertensive heart may differ after nifedipine compared to verapamil as a result of interaction and relative preponderance of influences on afterload and contractility.
Adult↗
Calcium channel blockers in organ transplantation: important new therapeutic modalities.
The calcium channel blockers have emerged as important therapeutic modalities in the treatment of hypertension, ischemic heart disease, and other cardiovascular diseases. More recently, their potential benefit in recipients of organ transplants has come under closer scrutiny. Calcium channel blockers depress in vitro cellular immunity in an additive fashion with cyclosporine and have been demonstrated to reduce the incidence of rejection posttransplantation in early clinical trials. This class of drugs may also diminish ischemic damage to transplanted organs and reduce the destructive aspects of reperfusion injury. Because of their ability to depress cellular immune responses to mitogens, calcium channel blockers may also prove useful in decreasing the incidence of first-dose side effects (related to lymphocyte stimulation) in response to treatment with the OKT3 monoclonal antibody, a commonly used antirejection medication. Recent investigative efforts also suggest that calcium channel blockers may minimize cyclosporine nephrotoxicity by antagonizing either the direct or indirect vasoconstrictive actions of the drug. Some of the calcium channel blockers also reduce cyclosporine metabolism and excretion, thus allowing adequate levels of cyclosporine in blood with reduced doses of this valuable immunosuppressive agent. Cyclosporine-treated renal transplant recipients are frequently hypertensive, which is likely related to a salt-sensitive physiology. Calcium channel blockers have demonstrated important efficacy in reducing blood pressure in low-renin, salt-sensitive patients and similarly have been efficacious in controlling blood pressure in cyclosporine-treated transplant recipients. The numerous potential applications of calcium channel blockers in the field of organ transplantation illustrates the need for expanded clinical trials evaluating their use in this area.
Animals↗
Better renoprotective effect of angiotensin II antagonist compared to dihydropyridine calcium channel blocker in childhood.
BACKGROUND: The dihydropyridine calcium channel blocker amlodipine and the angiotensin II antagonist irbesartan effectively reduce blood pressure in hypertensive children. METHODS: Eligible for the open-label, randomized study were nephropathic children between 6.0 and 18 years of age with plasma creatinine <177 micromol/L, overt proteinuria, untreated arterial hypertension (systolic, 5 to 30 mm Hg; and diastolic, 1 to 15 mm Hg;>95th centile) and stable immunosuppressive treatment. The initial dose of amlodipine was 5 mg (body weight, 20 to 40 kg) and 10 mg (body weight,>40 kg), respectively, that of irbesartan, which was 75 mg (body weight, 20 to 40 kg) and 150 mg (body weight,>40 kg), respectively. The dosage was doubled if necessary. RESULTS: A total of 26 children aged 6.1 to 17 years were allocated to receive either amlodipine (N = 13) or irbesartan (N = 13) for 16 weeks. Severe edema and headache occurred in two patients on amlodipine who withdrew from the study. No adverse experiences were noted in patients given irbesartan. Amlodipine [by 12 (10 to 14)/7 (5 to 10) mm Hg; median and interquartile range, respectively] and irbesartan [by 13 (9 to 16)/9 (7 to 11) mm Hg, respectively] reduced blood pressure (P < 0.01) in a similar fashion. Heart rate, plasma sodium, and creatinine did not change. Irbesartan slightly increased plasma potassium [by 0.1 (0.0 to 0.2) mmol/L; P < 0.05]. Plasma albumin and the urinary albumin/creatinine ratio were similar before and with amlodipine. On the contrary, irbesartan increased plasma albumin [by 4 (3 to 5) g/L; P < 0.03] and decreased the urinary albumin/creatinine ratio [by 242 (68 to 312) mg/mmol; P < 0.03]. CONCLUSION: The study demonstrates that in children the effect of angiotensin II antagonists on proteinuria is better than that of dihydropyridine calcium channel blockers.
Adolescent↗
Inhibitory effect on calcium channel blockers on alpha -adrenergic activation of glycogenolysis and calcium efflux in perfused rat liver.
In an attempt to verify the importance of calcium ions in mediating alpha -adrenergic stimulation, the effects of a calcium channel blocker, verapamil, on phenylephrine-induced glycogenolysis and calcium efflux in perfused livers prepared from fed rats were determined. The blocker inhibited phenylephrine-induced glycogenolysis in a noncompetitive and dose-dependent manner between 50 micro M and 500 micro M. However, it did not affect 2, 4-dinitrophenol-induced glycogenolysis. It had no significant effect on 45 Ca uptake by the perfused liver, but inhibited basal as well as phenylephrine-induced efflux of 45Ca from 45Ca-loaded liver. The inhibitory effects on basal 45Ca release and phenylephrine-induced glycogenolysis and 45Ca released correlated very well. All the the effects of verapamil were reproduced by another calcium channel blocker, diltiazem, suggesting that these effects are common to a variety of calcium channel blockers. These results indicate that the process of calcium influx and the function of phosphorylase per se are not directly involved in the inhibitory action of the blocker. Although it is possible that verapamil interferes with binding of the alpha -adrenergic agonist to the plasma membrane, the good correlation between the inhibitory effects of verapamil on basal 45Ca released and on phenylephrine-induced release of 45Ca suggests another mechanism, involving calcium ions. The blocker appears to inhibit the glycogen phosphorylase activity induced by phenylephrine via a cell-membrane mechanism in which calcium ion flux changes are intimately involved.
Animals↗
The use of calcium-channel blockers in pregnancy.
Over the past 10 yrs, calcium-channel blockers have been used in obstetrics and gynecology for the treatment of patients with both gestational hypertension and preterm labor. Several randomized trials have been performed which demonstrated that calcium-channel blockers are at least as efficacious as other, better-known antihypertensive agents. Despite animal studies which have shown unfavorable outcomes with the use of some of these agents, the use of calcium-channel blockers in pregnancy has been increasing. As we gain further information on the correlation between calcium homeostasis and several additional disease states, the role of calcium-channel blockers will become further elucidated.
Animals↗
Calcium channel blockers in cirrhotic patients with portal hypertension.
Four calcium channel blockers, i.e. nifedipine, verapamil, cinnarizine and tetrandrine are currently available and used widely in treating cardiovascular diseases. To confirm the effects, if any, of calcium channel blockers on cirrhotic patients with portal hypertension, a study was performed on esophageal variceal pressure and rebleeding rate of esophageal varices after 2 years by using calcium channel blocker in 321 patients from some 23 hospitals. The results demonstrated that the calcium channel blockers could significantly reduce the esophageal variceal pressure and the portal blood flow in cirrhotic patients with portal hypertension. The proportion of patients with no recurrent gastrointestinal bleeding after 2 years medication of tetrandrine was 87.9% in tetrandrine group, significantly higher than those in the other 4 groups (P < 0.05). It is suggested that tetrandrine should be more effective for cirrhotic patients with portal hypertension in preventing recurrent variceal bleeding.
Adolescent↗
Clinical and electrophysiologic effects of calcium channel blockers in patients receiving ibutilide.
BACKGROUND: Ibutilide is indicated for the acute termination of atrial fibrillation and atrial flutter. Recent work concludes that ibutilide activates a late inward sodium current that is blocked by nifedipine. Because calcium channel blockers are commonly used in patients with atrial fibrillation, it is important to exclude an antagonistic effect on ibutilide in the clinical setting. METHODS: We performed a retrospective electrocardiographic (ECG) review of patients enrolled in 3 clinical trials of ibutilide (2 atrial fibrillation conversion protocols and 1 ventricular tachycardia suppression protocol) to determine clinical efficacy and ECG effects of ibutilide in patients receiving and not receiving calcium channel blockers. Calcium channel blockers were administered as clinically indicated. A meta-analysis of the effects of calcium channel blockers on the conversion efficacy of atrial fibrillation and atrial flutter by ibutilide was also performed for studies in the literature. RESULTS: One hundred thirty patients were included in the ECG analysis (106 from atrial fibrillation protocols and 24 from the ventricular tachycardia protocol). Sixty-eight of the 130 patients were taking calcium channel blockers at the time of ibutilide administration. There were no differences in the QT or QTc intervals, conversion rate for atrial fibrillation or atrial flutter, or suppression of ventricular tachycardia between patients taking and not taking calcium channel blockers. In the meta-analysis of 4 studies, there was no difference in the conversion rates between patients taking (52%, n = 221) and not taking (45%, n = 402) calcium channel blockers (P =.09). CONCLUSIONS: In the clinical setting, the concomitant use of calcium channel blockers does not alter the ECG effects or efficacy of ibutilide for the treatment of atrial or ventricular arrhythmias.
Aged↗
Responses of osteoblastic cell line MC3T3-E1 cell to the calcium channel blocker diltiazem and verapamil.
The effects of the calcium channel blockers, diltiazem and verapamil, on osteoblastic functions were investigated in cultured osteoblastic cells MC3T3-E1. DNA synthesis was evaluated by the incorporation of [3H]thymidine, and collagen synthesis by measuring the incorporation of [3H]proline into collagenase-digestible protein (CDP) and noncollagen protein (NCP). Diltiazem inhibited the DNA synthesis of osteoblastic cells by up to 57.6 and 54.6% at concentrations of 25 and 50 microM. Verapamil also significantly inhibited DNA synthesis by up to 61.6 and 40.9% at concentrations of 25 and 50 microM. The percent control of CDP formation were decreased by up to 76.7% in 5 microM and 44.3% in 50 microM of diltiazem. Verapamil also decreased CDP synthesis to 49.7% at 10 microM and 32.6% at 50 microM. NCP synthesis was decreased by the calcium channel blocker but inhibition of the CDP formation was greater than that of NCP. The calculated percent collagen synthesis was decreased at a calcium channel blocker concentration of 10 microM. The inhibitory effects of diltiazem and verapamil on percent collagen synthesis were not reversed by increasing the calcium concentration of culture media by either 1 or 5 mM. From this study, we conclude that calcium channel blockers have a direct inhibitory effect on osteoblastic function. Long-term administration of diltiazem or verapamil produces adverse effects on normal bone metabolism.
Animals↗