title: Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C.
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) alpha1C-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 alpha1Cb 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 alpha1C-b subunit, the data further suggest that this unique slow-acting mechanism of cilnidipine is mediated by a complex interaction of cilnidipine with alpha1C-b and accessory channel subunits.
authors: Franz Volhard Clinic, Humboldt University of Berlin, Germany.
authors: Matthias
authors: M
authors: Löhn
authors: Ulf
authors: U
authors: Muzzulini
authors: Kirill
authors: K
authors: Essin
authors: Suk-Ying
authors: SY
authors: Tsang
authors: Torsten
authors: T
authors: Kirsch
authors: Jennifer
authors: J
authors: Litteral
authors: Patricia
authors: P
authors: Waldron
authors: Heinke
authors: H
authors: Conrad
authors: Norbert
authors: N
authors: Klugbauer
authors: Franz
authors: F
authors: Hofmann
authors: Hermann
authors: H
authors: Haller
authors: Friedrich C
authors: FC
authors: Luft
authors: Yu
authors: Y
authors: Huang
authors: Maik
authors: M
authors: Gollasch
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004095:Dihydropyridines / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology; D020033:Protein Isoforms / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D020033:Protein Isoforms; C065927:cilnidipine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium