Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C

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Item Type:	Article
Title:	Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C
Creators Name:	Loehn, M., Muzzulini, U., Essin, K., Tsang, S.Y., Kirsch, T., Litteral, J., Waldron, P., Conrad, H., Klugbauer, N., Hofmann, F., Haller, H., Luft, F.C., Huang, Y. and Gollasch, M.
Abstract:	Cilnidipine is a novel dihydropyridine (DHP) antagonist. However, its pharmacological effects on vascular DHP-sensitive L-type channels and protein kinase C (PKC)-mediated arterial contraction is incompletely understood. To address this issue, we studied the effects of cilnidipine on multi-subunit, C-class L-type Ca2+ channels in rat aortic A7r5 cells, as well as on Ca2+ channel (L-type) {alpha}1C-b and (T-type) alpha1G subunits in the Xenopus oocyte expression system. Cilnidipine dose- and time-dependently inhibited Ba2+ currents in A7r5 cells, with half-maximal inhibitions (IC50) at 10 nmol/l after 10 min. Unlike classical pharmacological Ca2+ channel blockers, cilnidipine's block of Ca2+ currents did not reach steady-state levels within 10 min, indicating steady-state half-maximal inhibition of native, multi-subunit L-type channels at < 10 nmol/l. In contrast, smooth muscle {alpha}1Cb currents were blocked by cilnidipine at much higher doses (steady-state IC50, 20 micromol/l) whereas alpha1G currents were not inhibited by cilnidipine (30 micromol/l). Cilnidipine dose-dependently inhibited depolarization- and Ca2+-induced contractions of rat aortic rings, with an IC50 of 10 nmol/l at 10 min. However, the onset of the effects was very slow, with approximately 71% inhibition by 3 nmol/l cilnidipine after 90 min exposure to cilnidipine. In contrast, cilnidipine did not inhibit phorbol 12-myristate-13-acetate (100 nmol/l)-mediated contractions. We conclude that cilnidipine represents an extremely slow-acting DHP that targets multi-subunit L-type channels, but not PKC in arterial smooth muscle. Because cilnidipine is less potent in cells expressing the pore-forming {alpha}1C-b subunit, the data further suggest that this unique slow-acting mechanism of cilnidipine is mediated by a complex interaction of cilnidipine with {alpha}1C-b and accessory channel subunits.
Keywords:	{alpha}1C-Subunit, Calcium Channel Blockers, C Class Channels, Patch Clamp, Smooth Muscle Cells, Animals, Rats
Source:	Journal of Hypertension
ISSN:	0263-6352
Publisher:	Lippincott Williams & Wilkins
Volume:	20
Number:	5
Page Range:	885-893
Date:	May 2002
PubMed:	View item in PubMed

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