Cilnidipine, a slow‐acting Ca2+ channel blocker, induces relaxation in porcine coronary artery: role of endothelial nitric oxide and [Ca2+]i

Abstract

Cilnidipine is a dual blocker of L-type voltage-gated Ca(2+) channels in vascular smooth muscle and N-type Ca(2+) channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood. This study was designed to compare the time course of relaxant responses to cilnidipine and nifedipine, and to examine the role of endothelial NO and [Ca(2+)](i) in the vasorelaxation. Porcine left circumflex coronary arteries were isolated and isometric tension was measured with Grass force transducers. Endothelial [Ca(2+)](i) in intact arteries was determined by a calcium fluorescence imaging technique. The free radical scavenging capacity was also assayed. Cilnidipine and nifedipine induced concentration-dependent relaxations in high KCl-precontracted artery rings, while the former-induced relaxation was slower as compared to the latter. Treatment with L-NAME or ODQ reduced relaxations to cilnidipine or nifedipine to the same extent as in rings without endothelium. Indomethacin or omega-conotoxin had no effects. L-Arginine antagonized the effect of L-NAME on cilnidipine-induced relaxations. Cilnidipine did not affect sodium nitroprusside-induced relaxation in rings with and without endothelium. Cilnidipine and nifedipine caused extracellular Ca(2+)-dependent increases in endothelial [Ca(2+)](i) in intact arteries and cilnidipine's action had a slower onset, similar to that of cilnidipine-induced relaxation. Neither cilnidipine nor nifedipine exhibited a free radical scavenging property. The present results demonstrate that cilnidipine can produce endothelium-dependent relaxation in porcine coronary arteries in vitro in addition to blocking Ca(2+) channels. Like short-acting nifedipine, cilnidipine-dependent relaxation, albeit to a slower onset, is partly mediated by endothelial NO but not by prostacyclin. The increased release or bioavailability of NO may causally result from elevated endothelial [Ca(2+)](i) in arteries. The Ca(2+) channel-independent effect suggests the usefulness of cilnidipine in the treatment of cardiovascular diseases associated with diminished NO release, such as atherosclerosis.