Blockade of N-type Ca²⁺ current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurones

1. The inhibitory effects of cilnidipine (FRC-8653) and various organic Ca²⁺ channel blockers on high voltage-activated Ba²⁺ currents (HVA I(Ba)) in rat sympathetic neurones were examined by means of the conventional whole-cell patch-clamp recording mode under voltage-clamped conditions. 2. HVA I(Ba) was classified into three different current components with subtype selective peptide Ca²⁺ channel blockers. No ω-Agatoxin IVA-sensitive (P-type) or ω-conotoxin MVIIC-sensitive (Q-type) current components were observed. Most ( > 85%) I(Ba) was found to consist of ω-conotoxin GVIA-sensitive N-type components. 3. The application of cilnidipine inhibited HVA I(Ba) in a concentration-dependent manner. The K(d) value for cilnidipine was 0.8 μM. Cilnidipine did not shift the current-voltage (I-V) relationship for HVA I(Ba), as regards the threshold potential and peak potential where the amplitude reached a maximum. 4. High concentrations of three hypotensive Ca²⁺ channel blockers, nifedipine, diltiazem and verapamil, all inhibited HVA I(Ba) in a concentration-dependent manner. The K(d) values for nifedipine, diltiazem and verapamil were 131, 151 and 47 μM, respectively. A piperazine-type Ca²⁺ channel blocker, flunarizine, showed a relatively potent blocking action on I(Ba). The K(d) value was about 3 μM. 5. These results thus show that cilnidipine potently inhibits the sympathetic Ca²⁺ channels which predominantly consist of an ω-Cg-GVIA-sensitive component. This blockade of the N-type Ca²⁺ channel, as well as the L-type Ca²⁺ channel by cilnidipine suggests that it could be used therapeutically for treatment of hypersensitive sympathetic disorders associated with hypertension.