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

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. and Muzzulini, U. and Essin, K. and Tsang, S.Y. and Kirsch, T. and Litteral, J. and Waldron, P. and Conrad, H. and Klugbauer, N. and Hofmann, F. and Haller, H. and Luft, F.C. and 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 (U.S.A.)
Volume:20
Number:5
Page Range:885-893
Date:May 2002
PubMed:View item in PubMed

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