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The relevance of T-type calcium antagonists: a profile of mibefradil
1Division of Clinical Pharmacology, University of South Florida, Tampa 33613, USA.
Insights
Voltage-dependent calcium channels, specifically T-type, are crucial for cardiovascular health and managing hypertension. Modulating these channels, like with mibefradil, shows promise in treating cardiovascular conditions.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
Background:
- L- and T-type calcium channels are vital for cardiovascular function.
- T-type channels are implicated in hypertension, ischemic damage, arrhythmias, and cardiac hypertrophy.
- Alterations in both L- and T-type channels contribute to hypertension development.
Purpose of the Study:
- To explore the role of T-type calcium channels in cardiovascular physiology and pathophysiology.
- To evaluate the therapeutic potential of pharmacologic modulation of T-type calcium channels.
- To assess the efficacy and safety of mibefradil, a novel calcium channel blocker.
Main Methods:
- Review of existing literature on L- and T-type calcium channels.
- Analysis of T-type channel function during ischemic damage.
- Clinical studies evaluating mibefradil's effects on blood pressure, angina, and ischemia.
Main Results:
- T-type channels remain functional during early ischemia, unlike inactivated L-type channels.
- Mibefradil effectively lowers blood pressure and acts as an antianginal and anti-ischemic agent.
- Mibefradil reduces heart rate without negative inotropic effects and has a favorable side effect profile.
Conclusions:
- Pharmacologic targeting of heterogeneous T-type calcium channels offers therapeutic potential.
- Mibefradil demonstrates clinical efficacy in treating hypertension and ischemic heart disease.
- Caution is advised when using mibefradil with other cytochrome P450 metabolized drugs.
Abstract:
L- and T-type voltage-dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T-type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to be involved in the control of blood pressure in patients with essential hypertension and in protection from ischemic damage. Alterations of both L- and T-type calcium channels are involved in the development of hypertension. Pharmacologic modulation of T-type calcium channels appears to reduce membrane calcium flux and ameliorate hypertension. During early ischemic damage, T-type calcium channels appear to remain functional whereas L-type channels are already inactivated. T-type calcium channels also appear to be involved in the development of supraventricular arrhythmias, some forms of arrhythmias in cardiomyopathy, and cardiac hypertrophy. The heterogeneity of T-type calcium channels should make it possible to target drugs to specific subgroups of T-type calcium channels. A new class of calcium antagonist, the benzimidazolyl-substituted tetraline derivatives, has been shown to block both L- and T-type calcium channels. The first member of this class approved for clinical use is mibefradil. Clinical studies have demonstrated the efficacy of mibefradil in lowering blood pressure and as an antianginal and antiischemic agent. At clinically recommended doses, mibefradil has a heart rate lowering effect without a negative inotropic effect, and a favorable side effect profile. Because it is metabolized by the cytochrome P450 pathway, it should be used cautiously with other agents similarly metabolized.