Mechanisms of Flunarizine‐Induced Vasodilation in the Rabbit Mesenteric Artery
作者:
Takeo Itoh,
Shinji Satoh,
Toyohiro Ishimatsu,
Takashi Fujiwara,
Yuichi Kanmura,
期刊:
Circulation Research
(OVID Available online 1987)
卷期:
Volume 61,
issue 3
页码: 446-454
ISSN:0009-7330
年代: 1987
出版商: OVID
关键词: flunarizine-induced vasodilation;voltage-dependent Ca2+influx;receptor-operated Ca2+influx;inositol trisphosphate-induced Ca2+release;rabbit mesenteric artery
数据来源: OVID
摘要:
The vasodilating effects of flunarizine on smooth muscle strips of rabbit mesenteric artery have been investigated and compared with those of nifedipine. Flunarizine (30-300 nM) dose-dependently inhibited Ca2+-induced contractions in Ca2+-free solution containing 100 mM K+. Double reciprocal analysis showed that this inhibition was either competitive at low concentrations (30-100 nM; nifedipine-like) or noncompetitive at high concentrations (0.3-1 μM). The latter seemed to be partly related to an inhibition of contractile proteins as estimated from Ca2+-induced contractions in saponin-treated chemically skinned muscle strips. In contrast to the actions of nifedipine, flunarizine inhibited norepinephrine (NE)-induced contractions more than those induced by high K+, and at 0.3 μM, this agent totally blocked NE-induced contraction. Flunarizine also inhibited NE-induced contraction in Ca2+-free solution containing 2 mM EGTA. In Ca2+-free solution, NE rapidly hydrolyzed phosphatidylinositol 4,5-bisphosphate (PI-P2) and produced phosphatidic acid (PA). Flunarizine (30 and 300 nM), but not nifedipine (100 nM), inhibited NE-induced hydrolysis of PI-P2and production of PA. However, flunarizine (100 nM) did not modify the contraction induced by 10 μM inositol 1,4,5-trisphosphate in chemically skinned muscle strips. It is concluded that flunarizine inhibits both voltage-dependent (nifedipine-like) and receptor-operated Ca2+influx induced by NE and also inhibits NE-induced Ca2+release from intracellular stores due to inhibition of the hydrolysis of PI-P2.
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