EFFECTS OF A NOVEL ANTIHYPERTENSIVE DRUG, CILNIDIPINE, ON CATECHOLAMINE SECRETION FROM DIFFERENTIATED PC12 CELLS

Effects of a novel dihydropyridine type of antihypertensive drug, ciln idipine, on the regulation of the catecholamine secretion closely link ed to the intracellular Ca2+ were examined using nerve growth factor ( NGF)-differentiated rat phoechromocytoma PC12 cells. By measuring cate cholamine secretion with high performance liquid chromatography couple d with an electrochemical detector, we showed that high K+ stimulation evoked dopamine release from PC12 cells both before and NGF treatment s. Cilnidipine depressed dopamine release both from NGF-treated and un treated PC12 cells in a concentration-dependent manner. In contrast, i nhibition by nifedipine was markedly decreased in the differentiated P C12 cells. With intracellular Ca2+ concentration ([Ca2+] (i)) measurem ents using fura 2, the elevation of high K+-evoked [Ca2+](i) was separ ated into nifedipine-sensitive and -resistant components. The nifedipi ne-resistant [Ca2+](i) increase was also blocked by cilnidipine, as we ll as omega-conotoxin-GVIA. By the use of the conventional whole-cell patch-clamp technique, the compositions of the high-voltage-activated Ca(2+)channel currents in the NGF-treated PC12 cells were divided into types: L-type, N-type, and residual current components. It was also e stimated that cilnidipine at 1 and 3 mumol/L strongly blocked the N-ty pe current differentiated PC12 cells by blocking Ca2+ influx through t he N-type Ca2+ channel, in addition to its-well-known action on the L- type Ca2+ channel.