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PubMed2002

Antioxidant effect of T-type calcium channel blockers in gastric injury.

It is known that calcium ion has an important role in the cellular function. For this reason, calcium channel blockers may have a protective action against gastric injury which is induced by various stimuli. In this study, the influence of mibefradil on ethanol-induced gastric injury was investigated in rats. Mibefradil was given at a dose 50 mg/kg intraperitoneally 30 min before administration of 1 ml absolute ethanol given by gavage. We compared this effect of mibefradil with that of omeprazol. Ethanol-induced mucosal damage was evaluated using three different approaches: analysis of biochemical parameters and pathologic and macroscopic investigation. It was found that pretreatment with mibefradil significantly reduced ethanol-induced macroscopic, pathologic, and biochemical changes in the gastric mucosa. In conclusion, it is speculated that this findings may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.

Animals↗
PubMed2001

Effects of short- and long-acting calcium channel blockers on the relationship between blood pressure and physical activity.

Calcium channel blockers are widely used as antihypertensive drugs. However, there is some controversy as to how they should be used. Our first aim was to clarify how the dihydropyridine calcium channel blocker, benidipine, affects the quantitative relationship between blood pressure (BP) and physical activity. The second aim was to determine whether there is a relationship between systolic blood pressure (SBP) and physical activity in patients with hypertension when treating with a short-acting (nifedipine) or long-acting (benidipine) calcium channel blocker. In Study 1, ambulatory BP and physical activity were measured simultaneously in 27 patients with hypertension before and after 6 months with benidipine. In Study 2, ambulatory BP and physical activity were measured simultaneously in 16 patients with hypertension before (placebo) and after 6 weeks of crossover treatment with nifedipine and benidipine. In Study 1, there was no difference in the SBP change caused by physical activity between the pre- and posttreatment periods. In Study 2, SBP was significantly related to physical activity in the placebo (16/16) and benidipine (16/16) groups but not in the nifedipine (12/16) group. The lowest BP during day-time and nighttime in the nifedipine group were significantly lower than those in the benidipine group. Plasma renin activity (ng/mL/h) was significantly higher in the nifedipine group (1.20+/-1.05) than in the placebo (0.57+/-0.59) and benidipine (0.75+/-0.78) groups. These findings indicate that nifedipine might interfere with the adaptation mechanism of BP changed by physical activity and that the activated renin-angiotensin system might cause cardiac events.

Adult↗
PubMed2005

Comparative analysis of mouse skeletal muscle fibre type composition and contractile responses to calcium channel blocker.

BACKGROUND: In this study, we examined the correlation between excitation-contraction coupling characteristics and skeletal muscle fibre type by (1) localizing the distribution of dihydropyridine receptor (DHPR) protein and (2) comparing the effect of DHPR blocker on muscles with different fibre type composition, in order to better understand the differences between contractile phenotypes of fibres and to explain the contradictory reports to date on the interaction of dihydropyridines with skeletal muscle isoform of DHPR. RESULTS: Histochemical experiments revealed that fluorophore conjugated dihydropyridines stain selectively the membranes of muscle fibres. The staining was most evident in type IIA fibres. The major fibre type in gluteus and femoris, revealed by mATPase staining, was IIA (45.0 and 38.1 %, respectively). In gastrocnemius the content of IIA fibres was 22.7 %. Contraction forces before and after the addition of blocker for the three muscles investigated were: gluteus 0.075 +/- 0.017 N vs. 0.052 +/- 0.011 N, femoris 0.045 +/- 0.005 N vs. 0.033 +/- 0.005 N and gastrocnemius 0.089 +/- 0.016 N vs. 0.075 +/- 0.014 N, respectively. The attenuation of contraction force proportional to the cross-sectional area of the muscle was significantly (P = 0.023) higher in gluteus (28.3 +/- 3.5 %) and femoris (27.6 +/- 3.2 %) as compared to gastrocnemius (16.1 +/- 2.5 %). However, no significant change in the control measurements was observed ruling out the possibility of fatigue. CONCLUSION: The results indicate that the attenuation of the contraction force was largest in muscles with a high percentage of type IIA fibres. This supports our finding that the abundance of dihydropyridine receptors of IIA fibres outnumbers that in the other fibre types. The present data show that the correlation of density of dihydropyridine receptors can be one of the important factors influencing the overall contractile properties of the muscle and for its part explain the contradictory results of previous studies on coupling process.

Animals↗
PubMed1984

Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites.

The ability of calcium channel blockers to displace the binding of benzodiazepine ligands was investigated in rat heart, kidney, and brain. The dihydropyridine calcium channel blockers nifedipine and nitrendipine displaced the binding of the non-neuronal-site ligand [3H]Ro5-4864, but not that of the neuronal-site ligands [3H]flurazepam or [3H]clonazepam. The inhibition was competitive, with Ki values in the micromolar range. Other calcium channel blockers--i.e., verapamil and diltiazem--were inactive at both sites. Thus, non-neuronal benzodiazepines bind to a class of sites that also binds dihydropyridines. This implies a role for benzodiazepines in the mediation of calcium-dependent phenomena.

Animals↗
PubMed1991

Binding of the dihydropyridine calcium channel blocker (+)-[3H] isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2, 6-dimethyl-3-pyridinecarboxylate (PN200-110) to RINm5F membranes and cells: characterization and functional significance.

This report provides direct evidence for a dihydropyridine receptor/calcium channel in the insulin-secreting beta-cell line RINm5F. The receptor/channel can modulate the intracellular Ca++ concentration and the resultant insulin secretion by regulating the influx of extracellular Ca++ through dihydropyridine-sensitive voltage-dependent L-type Ca++ channels. Elevated extracellular K+ or the dihydropyridine Ca++ channel agonist, BAY k 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl- phenyl)pyridine-5-carboxylate], stimulated the uptake of 45Ca++, raised [Ca++]i, and increased insulin secretion in a concentration-dependent manner. These actions were inhibited by L-type Ca++ channel blockers including nitrendipine, verapamil and diltiazem. (+)-[3H]PN200-110 bound specifically with high affinity to RINm5F cell membranes (Kd approximately 200 pM). Specific binding was inhibited competitively by dihydropyridines whereas phenylalkylamines inhibited incompletely (+)-[3H]PN200-110 binding, consistent with an allosteric interaction. The benzothiazepine diltiazem had no effect on (+)-[3H]PN200-110 binding in the presence of Ca++, but increased binding allosterically in the absence of Ca++ (in the presence of EGTA). Maximal (+)-[3H]PN200-110 binding required divalent cations, with Mg++, Mn++ and Ba++ essentially as effective as Ca++ in reversing the effects of EGTA, whereas binding was not supported by Cd++ or La . Specific high affinity (+)-[3H]PN200-110 binding was also demonstrated in intact RINm5F cells and shown to be modulated by membrane potential. Depolarization of the cells by raising extracellular K+ from 5 to 80 mM increased the affinity of (+)-[3H]PN200-110 4- to 5-fold (decreased Kd) with no significant effect on the maximum number of binding sites.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Calcium-channel blockers in prophylaxis and treatment of asthma.

Calcium-channel blocking drugs do not induce bronchoconstriction in susceptible persons with cardiac disease and concomitant hyperreactive airways (such as asthma or chronic bronchitis). The ways in which calcium blockers might in fact play a beneficial role in preventing bronchoconstriction or inducing bronchodilation in asthma are explored. Nifedipine and verapamil have been shown to inhibit the bronchoconstriction provoked by exercise, histamine, methacholine and antigen. The potential mechanisms by which this protective effect is mediated--whether by direct action on tracheobronchial smooth muscle, inhibition of release of mediators from activated mast cells or both--are examined by reviewing in vitro studies of both cell systems. Calcium blockers also exhibit some bronchodilating activity in vitro. Early clinical trials of these drugs in ambulatory asthmatic patients have shown little, if any, therapeutic benefit, but results must be considered preliminary in view of the nature of the short-term, small-scale trials performed to date. Regardless of their therapeutic potential in obstructive lung diseases, the calcium-channel blockers offer a powerful probe into the role of calcium in the physiologic make-up of airways and, in particular, the pathophysiologic features of airway hyperreactivity.

Animals↗
PubMed2000

Pharmacodynamic interaction between mibefradil and other calcium channel blockers.

Briefly after withdrawal of the (T-type) calcium channel blocker mibefradil from the market, four cases of life-threatening interaction of mibefradil with dihydropyridines were reported. We investigated in vitro whether mibefradil interacts with a dihydropyridine, as described for other non-dihydropyridine compounds. Rat working hearts were used to examine functional interactions between amlodipine and mibefradil. Gallopamil and another T-type-channel blocker, ethosuximide, were included for comparison. Effects of mibefradil, (+)- and (-)-gallopamil on [3H](+)-isradipine binding were studied in membranes from tsA201-cells transfected with alpha(1c)-, alpha(2)delta-, and beta(1a)- or beta(2a)-calcium channel subunits. Mibefradil increased negative inotropic effect of amlodipine, but not of gallopamil. Gallopamil and ethosuximide showed no influence on contractile effects of amlodipine. Furthermore, mibefradil concentration-dependently caused bradycardic rhythm disturbance. The same type of arrhythmia was observed combining low concentrations of mibefradil with amlodipine, or with gallopamil, respectively. Amlodipine alone, or the combination of gallopamil or ethosuximide with amlodipine did not cause any arrhythmia. Binding studies showed a concentration-dependent positive allosteric interaction between [3H](+)-isradipine and mibefradil, but not with [3H](+)-isradipine and gallopamil enantiomers. Molecular and functional evidence points to an interaction between a dihydropyridine and mibefradil. Mibefradil caused rhythm disturbances and potentiation of negative inotropy when combined with amlodipine.

Amlodipine↗
PubMed1999

T-channel-selective calcium channel blockade: a promising therapeutic possibility, only preliminarily tested so far: a review of published data. T-Channel Calcium Channel Blocker Study Group.

Basic studies as well as short-term clinical trials of the T-channel-selective calcium channel blocker, mibefradil, are reviewed. The compound reduced afterload and was effective for the symptomatic treatment of hypertension and stable angina pectoris. It did not display any relevant negative inotropic or positive chronotropic effect. Mibefradil has been withdrawn by the manufacturer because of drug interaction at the cytochrome P-450 3A4 enzyme. It is hoped that new T-channel-selective calcium channel blockers will be developed to explore further this promising but so far only preliminarily tested therapeutic possibility.

Angina Pectoris↗
PubMed1990

Calcium channel blockers and atherosclerosis.

Several chemical classes of calcium channel blockers (CCBs) inhibit atherosclerotic lesion formation in rabbit models by reduction of calcium, lipid, and matrix accumulation in the arterial wall. The mechanisms of these antiatherogenic effects are under investigation. Smooth muscle cells and macrophages, which synthesize matrix products and accumulate intracellular lipids, play a central role in lesion formation. Smooth muscle cell hyperplasia, with intracellular and functional changes, is common to both atherosclerosis and hypertension. The antiatherogenic properties of CCBs may be related in part to the protection of arterial cells from calcium overload through inhibition of calcium flux across voltage-regulated ion channels. CCBs may also inhibit cell migration, influence the uptake and catabolism of lipoproteins, alter smooth muscle matrix synthesis, and promote the depletion of intracellular cholesteryl ester stores. It appears that CCBs may inhibit the development of atherosclerotic lesions by two sets of mechanisms: alteration of lipid metabolism in smooth muscle cells and regulation of calcium-initiated or -accelerated intracellular processes.

Animals↗
PubMed1987

The effect of calcium channel blockers on blood platelet function, especially calcium uptake.

The effects of organic and inorganic calcium antagonists on washed platelets from rat and human have been studied. Platelet aggregation was assessed by turbidimetry. Endogenous serotonin release was measured on the same sample by means of electrochemically treated carbon fiber electrodes. The organic calcium antagonist, nitrendipine, and the inorganic calcium channel blockers (Co2+, Mn2+, Cd2+, La3+) drastically inhibited rat and human platelet aggregation induced by thrombin, ADP or adrenaline in the presence of 0.32 mM Ca2+. In our conditions, the thrombin-induced release of endogenous serotonin was found to be external Ca2+-dependent and completely inhibited by 20 microM nitrendipine or 1 mM Cd2+. In addition, Ba2+ or Sr2+ ions can be substituted for Ca2+ to bring about platelet aggregation as well as endogenous serotonin secretion. In Ba2+ or Sr2+-containing media, rat platelet aggregation and/or serotonin secretion can be inhibited by either nitrendipine or Cd2+. Finally, we have also studied the thrombin- and external Ca2+-dependence of radiolabeled calcium uptake by rat platelets. We found that the thrombin-induced 45Ca uptake was inhibited by either 18 microM nitrendipine or 1 mM Cd2+. These results provide strong evidence for the existence of an influx of divalent cations (Ca2+, Sr2+, Ba2+) triggering platelet function. They also suggest, although they do not prove, that the translocation of these cations occurs through an agonist-operated channel as proposed by Hallam and Rink (FEBS Lett. 186 (1986) 175-179).

Animals↗
PubMed1997

[Calcium channel blocker for therapy of patients with hypertension].

Calcium channel blocker (CCB) is one of the most frequently prescribed cardiovascular drugs. Two main classes of CCBs, dihydropyridines and benzothiazepines, are now clinically available for the treatment of hypertension in Japan. Both drugs inhibit the inward current of calcium ions through the L-type calcium channels. However CCBs have markedly different chemical structures and different effects on cardiovascular system. Therefore, in the present paper, their pharmacokinetic properties and interactions with other drugs are reviewed, and newly developed CCB are also described.

Benzimidazoles↗
PubMed1985

Potentiation of antitumor agents by calcium channel blockers with special reference to cross-resistance patterns.

The calcium channel blockers verapamil, diltiazem, nicardipine, and niludipine potentiated the antitumor activities of mitotic poison antitumor agents, such as vincristine, vinblastine, vindesine, VP16-213, and taxol in P388 leukemia cells resistant to vincristine. The potentiating effect was generally dependent on the extent of cross-resistance seen in the cell line for these drugs. Calcium channel blockers also potentiate the antitumor activities of several DNA-interacting drugs, such as adriamycin, THP-adriamycin, daunomycin, aclacinomycin A, mitomycin C, actinomycin D, mitoxantrone, and nogalamycin derivatives in P388 leukemia resistant to adriamycin. Greater potentiation was observed for those antitumor agents to which the ADM-resistant cell line had become markedly cross-resistant, with the exception of the nogalamycin derivatives. Only a two-fold enhancement was observed for mitomycin C and aclacinomycin, as the cell line was only weakly cross-resistant to these agents. These results suggest the potential for therapeutic gain through the use of calcium channel blockers in combination with classic chemotherapeutic agents.

Animals↗
PubMedDate not supplied

Calcium channel blockers do not enhance increases in plasma potassium after succinylcholine in humans.

STUDY OBJECTIVE: To determine whether chronic calcium channel blocker therapy exaggerates the rise in plasma potassium concentration ([K+]) after succinylcholine administration. DESIGN: Prospective clinical study. SETTING: University and Veterans Affairs hospitals. PATIENTS: 36 ASA physical status III and IV male patients: 21 patients taking chronic calcium channel blockers and 15 patients not receiving calcium channel blockers, all of whom were scheduled for inpatient surgical procedures with general anesthesia. INTERVENTIONS: In all patients, anesthesia was induced with high-dose opioids plus a sedative-hypnotic, and intubation was facilitated with 1 to 1.5 mg/kg succinylcholine without nondepolarizing neuromuscular blocker pretreatment. MEASUREMENTS AND MAIN RESULTS: Plasma [K+] was measured prior to induction and 1, 3, 5, 8, 11, and 15 minutes after succinylcholine was administered. A modest average peak rise of 0.5 mEq/L in plasma [K+] was observed, but there were no differences between patients who were or were not receiving calcium channel blockers. CONCLUSIONS: Patients receiving chronic calcium channel blocker therapy are at no greater risk of hyperkalemia after succinylcholine than those not taking such medications.

Anesthesia, Intravenous↗
PubMed1998

Calcium channel blockers and the risk of cancer.

CONTEXT: Recent epidemiologic studies have raised the concern that calcium channel blocker use may increase the risk of cancer overall and of several specific cancers. OBJECTIVE: To assess whether calcium channel blocker use increases the risk of cancer overall and of specific cancers. DESIGN: Case-control drug surveillance study based on data collected from 1983 to 1996. SETTING: Hospitals in Baltimore, Md, New York, NY, and Philadelphia, Pa. PATIENTS: A total of 9513 patients aged 40 to 69 years with incident cancer of various sites and 6492 controls aged 40 to 69 years admitted for nonmalignant conditions. MAIN OUTCOME MEASURES: Incident cancer overall and 23 specific cancers. RESULTS: Calcium channel blocker use was unrelated to the risk of cancer overall (relative risk [RR], 1.1; 95% confidence interval [CI], 0.9-1.3). Use was not significantly associated with increased risks of individual cancers, including those previously implicated, except cancer of the kidney (RR, 1.8; 95% CI, 1.1 -2.7). Recent use, use for 5 or more years, and use of individual calcium channel blocker drugs were also not associated with cancer incidence. Use of beta-blockers and angiotensin-converting enzyme inhibitors was generally unrelated to cancer overall or individual cancers, but both were associated with kidney cancer (RR, 1.8; 95% CI, 1.3-2.5; and RR, 1.9; 95% CI, 1.2-3.0, respectively). CONCLUSIONS: The present study suggests that the use of calcium channel blockers is unrelated to an increase in the overall risk of cancer or of individual cancers, except kidney cancer, which has been associated with hypertension or drugs to treat hypertension in previous studies.

Adult↗
PubMed1996

Temporal variation in the interaction between calcium channel blockers and morphine-induced analgesia.

Circadian variations in the interaction between calcium channel blockers and morphine-induced analgesia were determined by the mouse hot-plate test. Calcium channel blockers diltiazem, verapamil, or nicardipine alone did not display any significant analgesic effect, but all of them potentiated morphine-induced analgesia when injected 30 min prior to morphine at most of the injection times. In terms of percent absolute potentiation, they produced more potentiation during the light period than darkness. Their potentiating effects decreased abruptly during darkness, and around the midtime of the dark period no significant potentiation of morphine-induced analgesia was observed. It is concluded that these fluctuations in the magnitude of interaction between calcium channel blockers and morphine must be taken into consideration particularly in studies dealing with the role of calcium in analgesia.

Analgesia↗
PubMed2006

Growth inhibition of human cancer cells in vitro by T-type calcium channel blockers.

This paper describes the preliminary biological results that novel T-type calcium channel blockers inhibit the growth of human cancer cells by blocking calcium influx into the cell, based on unknown mechanism on the cell cycle responsible for cellular proliferation. Among the selected compounds from compound library, compound 9c (KYS05041) was identified to be nearly equipotent with Cisplatin against some human cancers in the micromolar range.

Antineoplastic Agents↗
PubMed1993

The use of glucagon in a case of calcium channel blocker overdose.

The hypotension and myocardial depression that result from calcium channel blocker ingestion often are refractory to standard therapeutic modalities. Anecdotal reports on the use of glucagon have failed to show significant hemodynamic improvement. We report the first case of calcium channel blocker overdose that responded to glucagon. We conclude that glucagon is safe and effective in the management of hemodynamic instability associated with calcium channel blocker poisonings.

Acute Disease↗
PubMed1994

Calcium channel blockers and coronary atherosclerosis: from the rabbit to the real world.

Many calcium channel blockers have been shown to retard the development of atherosclerosis in cholesterol-fed rabbits. The mechanisms that may contribute to this effect include stimulation of cholesteryl ester hydrolase activity in smooth muscle cells, amelioration of hypercholesterolemic-induced endothelial dysfunction, or inhibition of smooth muscle cell proliferation and migration. The effect of calcium channel blockers on the evolution of coronary atherosclerosis in humans has been assessed in three clinical trials. In the Montreal Heart Institute trial, nicardipine did not influence the overall rate of progression and regression; however, patients treated with nicardipine experienced significantly less progression of minimal lesions, defined as stenoses of less than or equal to 20% severity. In the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT), nifedipine had no effect on overall progression and regression but, by one method of analysis, reduced the rate of appearance of new coronary lesions. In a preliminary report, diltiazem prevented the development of coronary atherosclerosis in heart transplant recipients. These studies indicate that calcium channel blockers retard the development of early atherosclerosis not only in animal models but also in human coronary arteries. Other studies recently completed or now under way will help to clarify the clinical role of calcium channel blockers in antiatherosclerotic therapy.

Animals↗