Masahiro Hosono (1), Shigeo Fujii (1), Tohru Hiruma (1), Kiyoshi Watanabe (1), Yutaka Hayashi (1), Haruo Ohnishi (1), Yoshinobu Takata (2) and Hitoshi Kato (2)
(1) Pharmaceutical Research Laboratories, Fujirebio Inc., 51 Komiya-cho, Hachioji, Tokyo 192, Japan
(2) Department of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-01, Japan
Abstract: We reported previously that cilnidipine inhibited increases in blood pressure and plasma norepinephrine (NE) level in response to cold stress in spontaneously hypertensive rats (SHRs). In the present study, we investigated the effect of cilnidipine on sympathetic neurotransmission and subsequent vasoconstriction in SHRs. In pithed SHRs, electrical sympathetic nerve stimulation (ESNS) elevated blood pressure, and this pressor response was abolished by guanethidine. Cilnidipine at 10 microg/kg, i.v. and phentolamine at 1 mg/kg, i.v. suppressed the pressor response to ESNS by 28+-6% and 67+-3%, respectively. Neither nifedipine nor nicardipine inhibited it. The pressor response to exogenous NE was not influenced by cilnidipine. alpha,beta-Methylene ATP inhibited the pressor response to ESNS in the presence or absence of phentolamine. Cilnidipine also attenuated the phentolamine-resistant pressor response to ESNS. In SHR mesenteric vasculatures preloaded with [3H]-NE, cilnidipine (10-7 M) as well as omega-conotoxin significantly inhibited the 3H overflow evoked by periarterial nerve stimulation. In radioligand binding experiments, cilnidipine inhibited [125I]-omega-conotoxin binding to rat synaptosomes, but it did not inhibit [3H]-prazosin binding to rat cortex membranes. These results suggest that cilnidipine may reduce electrically stimulated NE release from the sympathetic nerve endings of SHR vasculatures probably through its N-type Ca channel blocking action and that cilnidipine may also inhibit the vasoconstriction induced by ATP released concomitantly during nerve stimulation.
Keywords: Cilnidipine, Pithed spontaneously hypertensive rat, Norepinephrine release, alpha,beta-Methylene ATP, omega-Conotoxin