Five different profiles of dihydropyridines in blocking T-type Ca2+ channel subtypes (Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I)) expressed in Xenopus oocytes☆

Abstract 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 (α 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 (α 1H ), Ca v 3.3 (α 1I ), and Ca v 3.1 (α 1G )] were investigated in the Xenopus oocyte expression system using the two-microelectrode voltage-clamp technique. These 3 kinds (α 1H , α 1I and α 1G ) of T-type channels were blocked by amlodipine, manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine and efonidipine significantly blocked α 1H and α 1G , but not α 1I channels, while nilvadipine and nimodipine apparently blocked α 1H and α 1I , but not α 1G channels. Moreover, aranidipine blocked only α 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.