Izumi M, Mitsui-Saito M, Ozaki H, Karaki H
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
Jpn J Pharmacol. 1998 Jan;76(1):57-63. doi: 10.1254/jjp.76.57.
The mechanism by which cicletanine (3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyri dine) induces vasodilatation was examined in isolated vascular smooth muscle. Cicletanine inhibited the contraction induced by high K+, norepinephrine (NE) and prostaglandin F2alpha in a concentration-dependent manner in rat aorta. High K+ (15.8-72.7 mM) elicited elevation of cytosolic Ca2+ level ([Ca2+]i) and contraction in a concentration-dependent manner. Cicletanine (300 microM) inhibited the high K+-induced contractions without changing the [Ca2+]i/tension relationship. NE (3-300 nM) elicited greater contractions than high K+ at a given [Ca2+]i, suggesting that NE increased Ca2+ sensitivity of the contractile elements. Cicletanine inhibited the NE-induced contractions without changing the slope of the [Ca2+]i/tension relationship. Cicletanine inhibited the transient increases in both [Ca2+]i and muscle tension elicited by NE but not the transient increase in [Ca2+]i elicited by caffeine in Ca2+-free solution. Cicletanine did not inhibit contraction induced by Ca2+ in the permeabilized rabbit mesenteric artery with alpha-toxin. These results suggest that cicletanine inhibits vascular smooth muscle contraction by multiple mechanisms: 1) inhibition of Ca2+ influx via voltage-dependent Ca2+ channel and 2) inhibition of Ca2+ release mediated by the alpha-adrenoceptors, but not by caffeine.
在离体血管平滑肌中研究了西氯他宁（3-(4-氯苯基)-1,3-二氢-7-羟基-6-甲基呋喃并[3,4-c]吡啶）诱导血管舒张的机制。西氯他宁在大鼠主动脉中以浓度依赖性方式抑制高钾、去甲肾上腺素（NE）和前列腺素F2α诱导的收缩。高钾（15.8 - 72.7 mM）以浓度依赖性方式引起胞质钙水平（[Ca2+]i）升高和收缩。西氯他宁（300 μM）抑制高钾诱导的收缩，而不改变[Ca2+]i/张力关系。在给定的[Ca2+]i下，NE（3 - 300 nM）引起的收缩比高钾更大，表明NE增加了收缩元件对钙的敏感性。西氯他宁抑制NE诱导的收缩，而不改变[Ca2+]i/张力关系的斜率。西氯他宁抑制NE引起的[Ca2+]i和肌肉张力的瞬时增加，但不抑制无钙溶液中咖啡因引起的[Ca2+]i的瞬时增加。西氯他宁不抑制用α-毒素通透的兔肠系膜动脉中钙诱导的收缩。这些结果表明，西氯他宁通过多种机制抑制血管平滑肌收缩：1）通过电压依赖性钙通道抑制钙内流；2）抑制α-肾上腺素受体介导的钙释放，但不抑制咖啡因介导的钙释放。
