Received for publication September 4, 2008.
Revised October 28, 2008.
Accepted for publication October 29, 2008.

Molecular pharmacology of human Ca_v3.2 T-type Ca²⁺ channels: Block by antihypertensives, antiarrhythmics, and their analogs

Abstract

Antihypertensive drugs of the "calcium channel blocker" or "calcium antagonist" class have been used to establish the physiological role of L-type Ca²⁺ channels in vascular smooth muscle. In contrast, there has been limited progress on the pharmacology T-type Ca²⁺ channels. T-type channels play a role in cardiac pacemaking, aldosterone secretion, and renal hemodynamics, leading to the hypothesis that mixed T- and L-type blockers may have a therapeutic advantages over selective L-type blockers. The goal of this study was to identify compounds that block the Ca_v3.2 T-type channel with high affinity, focusing on two classes of compounds: phenylalkylamines (e.g. mibefradil) and dihydropyridines (e.g. efonidipine). Compounds were tested using a validated Ca²⁺ influx assay into a cell line expressing recombinant Ca_v3.2 channels. This study identified four clinically approved antihypertensive drugs (efonidipine, felodipine, isradipine, and nitrendipine) as potent T-channel blockers (IC₅₀ < 3 µM). In contrast, other widely prescribed dihydropyridines such as amlodipine and nifedipine were 10-fold less potent, making them a more appropriate choice in research studies on the role of L-type currents. In summary, the present results support the notion that many available antihypertensive drugs block a substantial fraction of T-current at therapeutically relevant concentrations, contributing to their mechanism of action.

Key words: T-type calcium channels, anihypertensives, antiarrhythmics, dihydropyridines, phenylalkylamines, voltage-gated calcium channels