Blockade of N-type Ca super(2+) current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurones

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