Ca2+ antagonists have proven to be remarkably effective antihypertensive agents, but have so far been limited to block of only 1 of the 2 types of Ca2+ channels found in vascular muscle cells. We investigated the possibility that the novel Ca2+ antagonist, mibefradil, acted on T-type as well as L-type Ca2+ channel in single cell voltage clamp experiments. In single vascular muscle cells from azygos veins of neonatal rats, we recorded Ca2+ currents in response to a carefully defined voltage protocol that isolates low-threshold, transient (T) type current from high-threshold, long-lasting (L) type current, and studied the action of 0.1 to 10 fM mibefradil. At 1 fM (the effective therapeutic concentration in humans), mibefradil selectively (>75%) blocked T-type Ca2+ current while blocking 25% of the L-type current peak amplitude. After block of L-type Ca2+ current with a dihydropyridine Ca2+ antagonist, 1 fM mibefradil abolished the remaining T-type current. Mibefradil is the only substance which can block T-type Ca2+ current at a well-tolerated dose. From the ED50 point on dose-response curves, the concentration to block T-type Ca2+ channels was 30 to 100X. Correlations of T-type Ca2+ channel with vascular muscle proliferation suggest that both structural and functional mechanisms may contribute to the antihypertensive and protective actions of mibefradil.
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