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.