A comparison of nine calcium ion antagonists and propranolol: Exercise tolerance,heart rate and ST-segment changes in patients with chronic stable angina pectoris

Summary The effects of nine calcium ion antagonists on exercise tolerance, heart rate and ST-segment changes were compared with those of propranolol in two hundred and eighty patients with established chronic stable angina pectoris. These patients participated in clinical trials for anti-anginal efficacy against placebo, using identical methods and similar protocols, but the comprison reported here was retrospective. The trials were all fixed dose, and the dose was determined by previous upward titration to arrive at an average maximal tolerance level. All the drugs except prenylamine increased the exercise tolerance significantly when compared with placebo. Maximal ST-segment depression on exercise was reduced during treatment with propranolol while treatment with the calcium ion antagonists had no significant effect. The time to the development of 1 mm ST-segment depression was prolonged by all the drugs. Nifedipine, PY-108-068 and nicardipine increased the resting heart rate whereas verapamil, diltiazem, gallopamil, KB-944, prenylamine and tiapamil produced a slight reduction. Propranolol produced a highly significant reduction in the resting and maximal heart rates and the rate-pressure product, whereas gallopamil increased the rate-pressure product by +8% and prenylamine reduced it by-10%. At the doses used, diltiazem, gallopamil and verapamil produced a greater increase in exercise tolerance than did propranolol, while the other drugs were inferior. None of the calcium ion antagonists matched the increase in the time taken to develop 1 mm ST-segment depression with propranolol, although the results with verapamil and gallopamil were close. The calcium ion antagonists are effective antianginal agents which produce their effects by mechanisms which are very different to the beta-adrenoreceptor blocking agents.     

Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions.

The orally administered antianginal agent trimetazidine increases cell tolerance to ischaemia by maintaining cellular homeostasis. In theory, this cytoprotective activity should limit myocyte loss during ischaemia in patients with angina pectoris. Data from studies in patients with coronary artery disease indicate that, unlike the effects of other antianginals, the anti-ischaemic effects of trimetazidine 20 mg are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. Furthermore, limited evidence suggests trimetazidine may improve left ventricular function in patients with chronic coronary artery disease or ischaemic cardiomyopathy and in patients experiencing acute periods of ischaemia when undergoing percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20 mg 3 times daily reduces the frequency of anginal attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. Its clinical effects are broadly similar to those of nifedipine 40 mg/day and propranolol 120 to 160 mg/day but, unlike these agents, trimetazidine does not affect the rate-pressure product during peak exercise or at rest. Adjunctive trimetazidine 60 mg/day reduces the frequency of anginal attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antianginal agents. Furthermore, the drug appears to be more effective than isosorbide dinitrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranolol 120 mg/day. The tolerability profile of trimetazidine 60 mg/day was similar to that of placebo when used as add-on therapy in patients with angina pectoris insufficiently controlled by other antianginal agents and was superior to that of either nifedipine 40 mg/day or propranolol 120 to 160 mg/day when used as monotherapy. The most frequently reported adverse events in trimetazidine recipients were gastrointestinal disorders, although the incidence of these events was low. CONCLUSIONS: Trimetazidine is an effective and well tolerated anti-ischaemic agent which, in addition to providing symptom relief and functional improvement in patients with angina pectoris, has a cytoprotective action during ischaemia. The drug is suitable for initial use as monotherapy in patients with angina pectoris and, because of its different mechanism of action, as adjunctive therapy in those with symptoms not sufficiently controlled by nitrates, beta-blockers or calcium antagonists. The role of trimetazidine in other coronary conditions has yet to be clearly established.     

Bepridil. A review of its pharmacological properties and therapeutic use in stable angina pectoris.

Bepridil is a calcium antagonist with direct negative chronotropic, dromotropic, inotropic and vasodilatory actions which reduces myocardial oxygen consumption and increases coronary blood flow, leading to a significant anti-ischaemic and antianginal effect in the absence of reflex tachycardia. In contrast to other calcium channel blockers, bepridil produces only modest peripheral vasodilatation and displays weak antihypertensive activity. Its plasma elimination half-life of 1 to 2 days permits once daily administration. Results of short term clinical trials have shown bepridil to be of comparable efficacy to nifedipine, verapamil, diltiazem, propranolol and nadolol in decreasing the frequency of anginal attacks and consumption of nitroglycerin (glyceryl trinitrate) in patients with stable angina. Bepridil is more effective than nifedipine in improving exercise performance in patients with stable angina. Although bepridil proved superior to diltiazem in improving exercise performance in patients refractory to diltiazem, further studies are required to confirm the efficacy of bepridil in patients refractory to, or intolerant of, other antianginal agents. Bepridil in therapeutic doses is well tolerated, and appears to have a similar adverse effect profile to the established calcium antagonists. However, rate-dependent prolongation of the QTc interval and development of torsade de pointes have been associated with the use of bepridil. Therefore, bepridil is contraindicated in patients with hypokalaemia, those receiving other drugs that may prolong the QT interval, and those with congenital QT interval prolongation. Future clinical research will help to further define the position of bepridil as an antianginal treatment relative to the traditional calcium antagonists; in the interim, bepridil is indicated for the treatment of patients with angina refractory to or intolerant of other agents.     

Trimetazidine for stable angina pectoris

Stable angina pectoris, a symptom of coronary heart disease (CHD), manifests as stress-induced ischaemic episodes resulting in severe chest pain. Therapeutic aims are to improve quality of life by decreasing anginal attacks and to prevent myocardial infarction (MI) and death. Current anginal medications include β-blockers and calcium antagonists, which decrease ischaemic severity by reducing cardiac workload, and nitrates, which increase coronary blood flow. A new therapeutic approach is the use of metabolic agents, such as trimetazidine, which are cytoprotective during ischaemia. Results of several clinical trials demonstrated that trimetazidine, at the standard dose of 20 mg t.i.d., increased exercise capacity, decreased anginal incidence and decreased left-ventricular (LV) dysfunction compared to placebo. Trimetazidine was also as effective as propranolol (120 - 160 mg/day) and nifedipine (40 mg/day) in decreasing anginal episodes and improving exercise parameters. Trimetazidine improved anginal frequency and symptoms in patients in which treatment with diltiazem, nifedipine, propranolol, pindolol, oxprenolol or long-acting nitrates had failed. Trimetazidine was also more effective than isosorbide dinitrate (30 mg/day) as an adjunct to propranolol. Despite efficacy being equivalent to that of β-blockers and calcium antagonists, trimetazidine does not depress cardiac function and, correspondingly, is not contraindicated in any condition. Adverse effects of trimetazidine are mild and infrequent. In summary, clinical data indicate that trimetazidine is a safe, effective treatment for the symptoms of stable angina pectoris when used either as a monotherapy or an adjunctive therapy. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing rates of mortality and MI.     

Trimetazidine for stable angina pectoris

Stable angina pectoris, a symptom of coronary heart disease (CHD), manifests as stress-induced ischaemic episodes resulting in severe chest pain. Therapeutic aims are to improve quality of life by decreasing anginal attacks and to prevent myocardial infarction (MI) and death. Current anginal medications include beta-blockers and calcium antagonists, which decrease ischaemic severity by reducing cardiac workload, and nitrates, which increase coronary blood flow. A new therapeutic approach is the use of metabolic agents, such as trimetazidine, which are cytoprotective during ischaemia. Results of several clinical trials demonstrated that trimetazidine, at the standard dose of 20 mg t.i.d., increased exercise capacity, decreased anginal incidence and decreased left-ventricular (LV) dysfunction compared to placebo. Trimetazidine was also as effective as propranolol (120 - 160 mg/day) and nifedipine (40 mg/day) in decreasing anginal episodes and improving exercise parameters. Trimetazidine improved anginal frequency and symptoms in patients in which treatment with diltiazem, nifedipine, propranolol, pindolol, oxprenolol or long-acting nitrates had failed. Trimetazidine was also more effective than isosorbide dinitrate (30 mg/day) as an adjunct to propranolol. Despite efficacy being equivalent to that of beta-blockers and calcium antagonists, trimetazidine does not depress cardiac function and, correspondingly, is not contraindicated in any condition. Adverse effects of trimetazidine are mild and infrequent. In summary, clinical data indicate that trimetazidine is a safe, effective treatment for the symptoms of stable angina pectoris when used either as a monotherapy or an adjunctive therapy. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing rates of mortality and MI.     

Diltiazem and Propranolol,Alone and in Combination,on Exercise Performance and Left Ventricular Function in Patients with Stable Effort Angina: A Double-Blind,Randomized, and Placebo-Controlled Study

Abstract: Diltiazem and propranolol alone and in combination as antianginal agents were compared with placebo in 12 patients with stable exertional angina at Stanford University Medical Center. The patients performed symptom-limited, multi-stage upright bicycle ergometric exercise while undergoing radionuclide angiographic studies every two weeks while being treated with 90 mg of diltiazem four times daily, 60 mg of propranolol four times daily, a combination of 90 mg of diltiazem and 60 mg of propranolol four times daily, and placebo. Diltiazem, propranolol and a combination all significantly increased exercise duration compared to placebo (526 ± 149 , 525 ± 115 , and 549 ± 129 vs 430 ± 132 sec). Although rate pressure product and heart rate decreased with diltiazem therapy at submaximal workloads, these values were unchanged at peak exercise in contrast to propranolol or the combination of propranolol or diltiazem. Diltiazem decreased the sub-maximal and maximal degree of exercise-induced ST segment depression by over 50% compared to placebo (P < 0.01 vs placebo). Diltiazem resulted in a higher exercise left ventricular ejection fraction compared to placebo, propranolol or the combination of diltiazem or propranolol (all less than P < 0.05). Sinus bradycardia or orthostatic hypertension occurred in four patients on the high-dose combination therapy and required dose reduction. We concluded that high-dose diltiazem, appeared to be even more effective than moderate-dose propranolol or the combination of diltiazem and propranolol in improving exercise tolerance, electrocardiographic evidence of myocardial ischaemia and left ventricular function in patients with stable effort angina due to occlusive coronary artery disease.     

PREVENTIVE EFFECT OF A NEW CALCIUM ANTAGONIST, MONATEPIL, ON DRUG-INDUCED ISCHAEMIC ELECTROCARDIOGRAPHIC CHANGES IN RATS

1. The preventive effects of monatepil, a new calcium antagonist with α₁-adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine). 2. In order to assess the contribution of the α₁-adrenoceptor blocking action of monatepil to its anti-vasospastic action, the anti-ST depression effect of prazosin, an α₁-adrenoceptor blocker, was also examined. 3. Monatepil given orally (3–30 mg/kg) inhibited vasopressin (0.2 IU/kg, i.v.)-induced ST depression which is considered to indicate ischaemic electrocardiographic changes in a vasospastic angina. This effect of monatepil was more potent and long-lasting than that of diltiazem, and was similar to that of verapamil and nicardipine. At a dose of 30 mg/kg, monatepil produced a significant inhibition, even at 7 h after administration. 4. Monatepil given intravenously (0.3 mg/kg) exerted a significant inhibitory effect on methacholine (16 μg/kg, intracoronary arterial administration; i.c.a.)-induced ST elevation which seems to be caused by coronary vasospasm. This effect was more potent or equipotent to those of the existing calcium antagonists. 5. These results indicate that monatepil produces the preventive effect on the drug-induced ischaemic electrocardiographic changes in rats and suggest that monatepil may have potential for the treatment of vasospastic angina.     

Efficacy of nicardipine in angina pectoris

The dose-related efficacy and safety of nicardipine, a new calcium antagonist of the dihydropyridine class, was assessed by exercise tolerance testing in a randomized, double-blinded, placebo-controlled study in 19 patients with chronic, stable effort angina pectoris. Four patients were assigned to each of four treatment sequences receiving nicardipine three times daily in an extended Latin-Square study design. An increase in total exercise capacity, time to onset of angina and time to 1 mm ST segment depression was observed with nicardipine 90 mg/day compared to placebo (P less than .05). Gradual upward dose titration in 30 mg/day increments starting from 30 mg/day appeared to produce maximal increase in exercise capacity. Two patients developed adverse side effects attributable to the drug when administered nicardipine 90 mg/day directly from placebo.     

Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]-nitrendipine binding sites.

[3H]-nitrendipine binding data and isolated tissue response for five calcium antagonists were evaluated in rabbit myocardium and aorta. The [3H]-nitrendipine binding site was qualitatively identical in myocardium and aorta, as the [3H]-nitrendipine KD, KIS for nicardipine and nifedipine and interactions with verapamil, D600 and diltiazem were not different in aortic and cardiac membranes prepared by similar means. In contrast, the inhibition of the Ca2+-induced contractile response in right ventricular myocardium and aortic ring segments indicated a greater than 10,000 fold selectivity of nicardipine for antagonism of vascular responses. This resulted in a different order of potency for calcium antagonist interaction with the [3H]-nitrendipine binding site in cardiac membranes (nicardipine greater than nifedipine greater than D600 greater than verapamil greater than diltiazem) as compared to antagonism of myocardial tissue response (D600 greater than verapamil greater than or equal to nifedipine greater than nicardipine greater than or equal to diltiazem). In heart the difference between the potency of nicardipine in binding experiments and tissue response approached 4 orders of magnitude. We conclude that tissue response selectivity of calcium antagonists is not explained by heterogeneity of [3H]-nitrendipine binding sites.     

Calcium Channel blockers: Spectrum of Side Effects and Drug Interactions

Abstract: Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of β-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.     

Antianginal Response to Once-Daily Diltiazem CD in Patients Receiving Concomitant β-Blockers,Long-Acting Nitrates,or Both

Study Objective . To determine the safety and efficacy of diltiazem CD 180 mg administered once/day in patients with chronic stable angina inadequately controlled with β-blockers, long-acting nitrates, or both. Design . Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Setting . Medical clinics in the private and academic sectors. Patients . Of 172 patients, 170 completed the 2-week double-blind treatment period. Interventions . Patients received either diltiazem CD 180 mg or placebo once/day in combination with existing antianginal therapy. Measurements and Main Results . The time to termination of exercise tolerance testing, 24 hours after the dose increased significantly in the diltiazem CD group (37.2 sec) compared with the placebo group (21.3 sec, p=0.0438). Time to onset of angina during exercise testing also increased (57.6 vs 35.0 sec, respectively, p=0.0324), as did time to moderate angina (37.5 vs 20.6 sec, respectively, p=0.0354). The rates of total angina attacks and of angina attacks on exertion were significantly reduced in the diltiazem CD group versus placebo (p<0.05). Significant reductions in systolic and diastolic blood pressures and heart rate-blood pressure product measured at rest, submaximum exercise, and exercise termination were observed in diltiazem CD-treated patients compared with placebo (p<0.05). The frequency of treatment-related adverse events was identical in the two groups, 15.1%. Conclusion . Diltiazem CD 180 mg once/day is an effective, safe, and beneficial initial dosage when added to existing antianginal therapy.     

Diltiazem. A review of its pharmacological properties and therapeutic efficacy

Diltiazem is an orally and intravenously active calcium channel blocking agent shown to be an effective and well-tolerated treatment for stable angina and angina due to coronary artery spasm. Its efficacy in these diseases has generally been similar to that of nifedipine or verapamil - alternative calcium channel blockers with which diltiazem has many electrophysiological, haemodynamic, and antiarrhythmic similarities. The antianginal mechanism of diltiazem cannot be precisely described; however, it appears to increase myocardial oxygen supply and decrease myocardial oxygen demand, mainly by coronary artery dilatation and/or via both direct and indirect haemodynamic alterations. Diltiazem has also shown substantial efficacy in the treatment of unstable angina, hypertension, and supraventricular tachyarrhythmias, but further study is necessary before its place in the treatment of these diseases may be clearly established. Although headache due to peripheral vasodilatation and depression of atrioventricular nodal conduction may be troublesome, side effects occur in only 2 to 10% of patients receiving diltiazem and are generally minor in nature. Thus, diltiazem offers a worthwhile alternative to other agents currently available for the treatment of angina pectoris. Although the infrequency of serious side effects may offer an advantage, its relative place in therapy compared with that of other calcium channel blockers remains to be clarified.     

Assessment of Anti-Ischemic and Antianginal Effect at Trough Plasma Concentration and Safety of Trimetazidine MR 35mg in Patients with Stable Angina Pectoris

Objective

The study aimed to assess, at trough plasma concentration, the anti-ischemic and antianginal efficacy and tolerability of trimetazidine modified release (MR) 35mg taken twice daily by patients with stable angina pectoris.

Design

This multicenter, randomized, double-blind, placebo-controlled, international study started with a run-in period of 3 weeks with atenolol 50 mg/day and placebo, followed by a 6-month treatment period with once daily atenolol 50mg and twice daily trimetazidine MR 35mg or placebo.

Patients

The study involved 223 patients with stable angina pectoris (class II or III of the Canadian Cardiovascular Society [CCS] classification). 180 patients were analyzed in the full analysis set (FAS) following the intention to treat principle (ITT) and 167 patients were analyzed in the per protocol set (PPS). The PPS data are presented here.

Interventions

Two exercise tolerance tests (ETTs) were performed during the run-in period in order to assess the stability of exercise tolerance before angina pectoris and significant ST segment depression. Efficacy was assessed by a third ETT performed after 8 weeks of treatment, at trough, 12 hours after the intake of the drug. Safety was evaluated over the 6-month duration of the study.

Main outcomes measures

Time to 1mm ST segment depression.

Results

Time to 1mm ST segment depression was increased by 44 seconds more in the trimetazidine MR 35mg group than in the placebo group (p = 0.005). A significant difference was also evidenced for the time to onset of angina pectoris (p = 0.049) and for the reason for stopping the exercise (p = 0.02). No difference between groups was found for safety parameters.

Conclusion

This study demonstrates the anti-ischemic and antianginal efficacy of trimetazidine MR 35mg twice daily at trough plasma concentrations in patients with stable angina pectoris receiving atenolol 50 mg/day. Furthermore, the drug is well tolerated over 6 months.     

On the relation of calcium channel blockers to rat parotid and submandibular glands function in vivo

• 1.1. The effects of nifedipine, verapamil and diltiazem on rat parotid and submandibular glands function were studied.
• 2.2. Nifedipine (5 mg/kg), verapamil (5 mg/kg) and diltiazem (10 mg/kg) were injected intraperitoneally 15 min before saliva collection.
• 3.3. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and 8 mg/kg of pilocarpine was used as secretagogue.
• 4.4. Submandibular saliva was analyzed for flow rate, protein and calcium concentrations; and parotid saliva for calcium and amylase contents.
• 5.5. In treated groups, flow rate and calcium of submandibular saliva were significantly lower than controls. Parotid calcium in the nifedipine group was decreased and in verapamil and diltiazem groups was increased. Parotid amylase was significantly decreased in both the nifedipine and diltiazem groups.
• 6.6. It is concluded that a blockade of calcium channels in salivary glands acinar cells by CCBs causes some alterations in salivary secretions.

     

Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance

The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.     

Clinical utility of nifedipine and diltiazem plasma levels in patients with angina pectoris receiving monotherapy and combination treatment

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run-in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem-nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high-pressure liquid chromatography from specimens obtained 2-5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage.     

An 8-week double-blind study of amlodipine and diltiazem in patients with stable exertional angina pectoris

A multicenter, double-blind study was performed to compare the antianginal efficacy and safety of the new dihydropyridine calcium antagonist amlodipine with the benzothiazepine calcium antagonist diltiazem in patients with stable exertional angina pectoris. Following a 2-week placebo run-in period, 39 patients were randomized to receive amlodipine (2.5-10 mg once daily) and 41 patients to receive diltiazem (60-120 mg three times daily) in an 8-week double-blind treatment phase. The study used standardized bicycle exercise testing as a primary efficacy assessment. Patients also recorded angina frequency and nitroglycerin (NTG) tablet consumption/ week. Treatment with amlodipine and diltiazem resulted in an improvement in total exercise time, time to angina and total work, mean ST-segment deviation at maximum common load, median number of angina attacks/week, and NTG tablet consumption/week. The incidence and severity of possibly treatment-related side effects and laboratory test abnormalities were comparable for both drugs. The most frequently reported side effects were dizziness, headache, peripheral edema, and nausea. Two patients withdrew from diltiazem treatment due to pruritus in one case and severe headache and moderate dyspnea in the other. No amlodipine-treated patients withdrew due to side effects. In conclusion, this study demonstrated that the antianginal efficacy and tolerability of amlodipine is equivalent to diltiazem, but amlodipine has the advantage of once-daily dosing.     

Dihydropyridine calcium channel antagonists reduce immobility in the mouse behavioral despair test; antidepressants facilitate nifedipine action

The effect of the calcium channel antagonists nifedipine, nitrendipine, nimodipine, verapamil and diltiazem in the mouse behavioral despair test was investigated. The dihydropyridine calcium channel antagonists nifedipine, nitrendipine, nimodipine (0.1, 1, 10 mg/kg p.o.) but not the non-dihydropyridine compounds verapamil or diltiazem, dose dependently reduced immobility. Various antidepressant drugs (imipramine, mianserin, citalopram, (+)oxaprotiline) and (-)oxaprotiline in combination with nifedipine facilitated its effect.     

Oral verapamil does not affect glucose tolerance in non-diabetics.

Verapamil, a calcium antagonist used to treat angina pectoris, inhibits insulin release in vitro and, when administered intravenously to humans, decreases glucose tolerance. Oral verapamil, 120 mg/day for 1 week increasing thereafter to 240 mg/day in divided doses, was given to nine non-diabetic patients with angina pectoris for 4 weeks. The glucose and insulin responses to a standard glucose load showed no significant difference before and after verapamil. Oral verapamil in the doses used in this study had no significant effect on glucose tolerance in non-diabetics.     

Calcium channel blockers apparently decrease noradrenaline release from nerve-skin terminals in Caudiverbera caudiverbera

• 1.1. The effects of three calcium channel blockers, verapamil, diltiazem and nifedipine were examined on the response of the skin neuroepithelial synapse of the toad Caudiverbera caudiverbera to electrical stimulation.
• 2.2. The stimulus induced a significant rise in potential difference (PD) and short-circuit current (SCC). The three calcium antagonists reduced the responses in a dose-dependent manner. The greatest reduction was induced by verapamil followed by diltiazem and nifedipine.
• 3.3. Amiloride treatment did not affect the responses to electrical stimulation, indicating that the response to nerve stimulation is not due to current flowing through sodium channels.
• 4.4. When the preparation was blocked by either of the three antagonists, the skin response to noradrenaline was not affected.
• 5.5. It may be concluded that verapamil, diltiazem or nifedipine reduce the release of noradrenaline at the neuroepithelial synapse of C. caudiverbera.