1,4-dihydropyridine (DHP) Ca(2+) antagonists have recently been shown to block T-type
Ca(2+) channels, which may render favorable actions on cardiovascular systems. However,
this evaluation remains to be done systematically for each T-type Ca(2+) channel subtype
except for the Ca(v)3.1 (alpha(1G)) subtype. To address this issue at the molecular
level, blocking effects of 14 kinds of DHPs (amlodipine, aranidipine, azelnidipine,
barnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine,
nifedipine, nilvadipine, nimodipine, nitrendipine), which are clinically used for
treatments of hypertension, on 3 subtypes of T-type Ca(2+) channels [Ca(v)3.2 (alpha(1H)),
Ca(v)3.3 (alpha(1I)), and Ca(v)3.1 (alpha(1G))] were investigated in the Xenopus oocyte
expression system using the two-microelectrode voltage-clamp technique. These 3 kinds
(alpha(1H), alpha(1I) and alpha(1G)) of T-type channels were blocked by amlodipine,
manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine
and efonidipine significantly blocked alpha(1H) and alpha(1G), but not alpha(1I) channels,
while nilvadipine and nimodipine apparently blocked alpha(1H) and alpha(1I), but not
alpha(1G) channels. Moreover, aranidipine blocked only alpha(1H) channels. By contrast,
cilnidipine, felodipine, nifedipine and nitrendipine had little effects on these subtypes
of T-type channels. The result indicates that the blockade of T-type Ca(2+) channels
by derivatives of DHP Ca(2+) antagonist was selective for the channel subtype. Therefore,
these selectivities of DHPs in blocking T-type Ca(2+) channel subtypes would provide
useful pharmacological and clinical information on the mode of action of the drugs
including side-effects and adverse effects.