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(Hypertension. 1998;31:1195-1199.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells

Hisayuki Uneyama; Hirohisa Uchida; Ryota Yoshimoto; Shinya Ueno; Kazuhide Inoue; ; Norio Akaike

From the Life Science Laboratories, Central Research Laboratories, Ajinomoto Co, Inc, Yokohama (H. Uneyama, H. Uchida, R.Y.); the Division of Pharmacology, National Institute of Health Sciences, Tokyo (S.U., K.I.); and the Department of Physiology, Faculty of Medicine, Kyushu University, Fukuoka (N.A.), Japan.

Correspondence to Hisayuki Uneyama, PhD, Life Science Laboratories, Central Research Laboratories, Ajinomoto Co, Ltd, Maeda-Cho 214, Totsuka, Yokohama 244, Japan. E-mail LL-UNEYAMA{at}te3.ajinomoto co.jp

Abstract—Effects of a novel dihydropyridine type of antihypertensive drug, cilnidipine, on the regulation of the catecholamine secretion closely linked to the intracellular Ca²⁺ were examined using nerve growth factor (NGF)–differentiated rat pheochromocytoma PC12 cells. By measuring catecholamine secretion with high-performance liquid chromatography coupled with an electrochemical detector, we showed that high K⁺ stimulation evoked dopamine release from PC12 cells both before and after NGF treatments. Cilnidipine depressed dopamine release both from NGF-treated and untreated PC12 cells in a concentration-dependent manner. In contrast, inhibition by nifedipine was markedly decreased in the differentiated PC12 cells. With intracellular Ca²⁺ concentration ([Ca²⁺]_i) measurements using fura 2, the elevation of high K⁺–evoked [Ca²⁺]_i was separated into nifedipine-sensitive and -resistant components. The nifedipine-resistant [Ca²⁺]_i increase was also blocked by cilnidipine, as well as -conotoxin-GVIA. By the use of the conventional whole-cell patch-clamp technique, the compositions of the high-voltage–activated Ca²⁺ channel currents in the NGF-treated PC12 cells were divided into types: L-type, N-type, and residual current components. It was also estimated that cilnidipine at 1 and 3 µmol/L strongly blocked the N-type current without affecting the residual current. These results suggest that cilnidipine inhibits catecholamine secretion from differentiated PC12 cells by blocking Ca²⁺ influx through the N-type Ca²⁺ channel, in addition to its well-known action on the L-type Ca²⁺ channel.

Key Words: cilnidipine • calcium channels • calcium, cytoplasmic • dopamine

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