Effect of cilnidipine, a novel dihydropyridine Ca++-channel antagonist, on N-type Ca++ channel in rat dorsal root ganglion neurons.
We investigated the effects of cilnidipine, a dihydropyridine derivative, on neuronal Ca++ channels in rat dorsal root ganglion neurons. Voltage-dependent Ca++-channel currents were recorded, using 5 mM Ba++ as the charge carrier, by means of the whole-cell patch-clamp technique. The Ba++ current was subdivided pharmacologically into calciseptine-sensitive (L-type), omega-conotoxin GVIA- (omegaCgTx) sensitive (N-type), omega-agatoxin IVA- (omegaAgTx) sensitive (P/Q-type) and toxin-resistant currents. Cilnidipine inhibited the L-type current with an IC50 of 100 nM in neurons pretreated with omegaCgTx plus omegaAgTx. In neurons pretreated with Cal plus omegaAgTx, cilnidipine induced a potent inhibition of the N-type current, but was unable to block the residual Ba++ current. The IC50 for cilnidipine in respect of the N-type current was 200 nM. Cilnidipine (300-500 nM) modified neither the voltage-dependent inactivation curve nor the decay of the N-type current. Furthermore, elevation of the holding potential did not enhance the inhibitory action of cilnidipine (300 nM) on the N-type current. No effect was induced by 100 nM cilnidipine on the P/Q-type current. However, nicardipine (1 microM) barely inhibited the N-type current at a concentration that almost completely blocked the L-type current. In conclusion, cilnidipine has potent inhibitory actions on N-type as well as L-type voltage-dependent Ca++-channel in rat dorsal root ganglion neurons. The former action may bestow an additional clinical advantage for the treatment of hypertension, such as suppression of reflex tachycardia.
Fujii
S
S
Pharmaceuticals Research Laboratories, Fujirebio Inc., Hachioji, Tokyo, Japan.
Kameyama
K
K
Hosono
M
M
Hayashi
Y
Y
Kitamura
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C065927:cilnidipine