Fujii S, Kameyama K, Hosono M, Hayashi Y, Kitamura K
Pharmaceuticals Research Laboratories, Fujirebio Inc., Hachioji, Tokyo, Japan.
J Pharmacol Exp Ther. 1997 Mar;280(3):1184-91.
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.
我们研究了二氢吡啶衍生物西尼地平对大鼠背根神经节神经元中神经元钙通道的影响。使用全细胞膜片钳技术，以5 mM钡离子作为载流子记录电压依赖性钙通道电流。钡离子电流在药理学上可细分为对钙阻胺敏感的（L型）、对ω-芋螺毒素GVIA（ωCgTx）敏感的（N型）、对ω-蛛毒素IVA（ωAgTx）敏感的（P/Q型）以及对毒素有抗性的电流。在用ωCgTx加ωAgTx预处理的神经元中，西尼地平以100 nM的半数抑制浓度（IC50）抑制L型电流。在用钙阻胺加ωAgTx预处理的神经元中，西尼地平对N型电流有强效抑制作用，但无法阻断残余的钡离子电流。西尼地平对N型电流的IC50为200 nM。西尼地平（300 - 500 nM）既不改变电压依赖性失活曲线，也不改变N型电流的衰减。此外，升高钳制电位并不会增强西尼地平（300 nM）对N型电流的抑制作用。100 nM西尼地平对P/Q型电流无影响。然而，硝苯地平（1 μM）在几乎完全阻断L型电流的浓度下对N型电流几乎没有抑制作用。总之，西尼地平对大鼠背根神经节神经元中的N型以及L型电压依赖性钙通道有强效抑制作用。前一种作用可能为高血压治疗带来额外的临床优势，比如抑制反射性心动过速。
