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

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Abstract

1,4-dihydropyridine (DHP) Ca2+ antagonists have recently been shown to block T-type Ca2+ channels, which may render favorable actions on cardiovascular systems. However, this evaluation remains to be done systematically for each T-type Ca2+ channel subtype except for the Cav3.1 (α1G) 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 Ca2+ channels [Cav3.2 (α1H), Cav3.3 (α1I), and Cav3.1 (α1G)] were investigated in the Xenopus oocyte expression system using the two-microelectrode voltage-clamp technique. These 3 kinds (α1H, α1I and α1G) of T-type channels were blocked by amlodipine, manidipine and nicardipine. On the other hand, azelnidipine, barnidipine, benidipine and efonidipine significantly blocked α1H and α1G, but not α1I channels, while nilvadipine and nimodipine apparently blocked α1H and α1I, but not α1G channels. Moreover, aranidipine blocked only α1H 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 Ca2+ channels by derivatives of DHP Ca2+ antagonist was selective for the channel subtype. Therefore, these selectivities of DHPs in blocking T-type Ca2+ channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side-effects and adverse effects.

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