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

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) α_1C-b and (T-type) α_1G 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 α_1Cb currents were blocked by cilnidipine at much higher doses (steady-state IC₅₀, 20 μmol/l) whereas α_1G currents were not inhibited by cilnidipine (30 μmol/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 α_1C-b subunit, the data further suggest that this unique slow-acting mechanism of cilnidipine is mediated by a complex interaction of cilnidipine with α_1C-b and accessory channel subunits. © 2002 Lippincott Williams & Wilkins.