Differential effects of tyrosine kinase inhibitors on contraction and relaxation of the aortas of normotensive and hypertensive rats.
Differential effects of tyrosine kinase inhibitors on contraction and relaxation of the aortas of normotensive and hypertensive rats.
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DOI：
10.1016/s0014-2999(99)00304-0
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发表时间：
1999-06
影响因子：
5
通讯作者：
A. Zerrouk;M. Auguet;H. Dabire;A. Brisac;M. Safar;P. Chabrier
中科院分区：
文献类型：
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作者：
A. Zerrouk;M. Auguet;H. Dabire;A. Brisac;M. Safar;P. Chabrier
用2，5-二羟基肉桂酸甲酯(30μM)和金雀异黄素(30μM)两种酪氨酸激酶抑制剂，在自发性高血压(SHR)和正常血压(WKY)大鼠的离体主动脉标本上观察酪氨酸激酶活性对血管反应性的影响。用2，5-二羟基肉桂酸甲酯对去甲肾上腺素的敏感性降低，SHR的血管环对去甲肾上腺素的敏感性明显低于WKY。2，5-二羟基肉桂酸甲酯和金雀异黄素对内皮素-1引起的持续收缩的松弛作用在自发性高血压大鼠裸环上也更为明显。此外，在2，5-二羟基肉桂酸甲酯存在的情况下，SHR对等剂量环匹阿松酸的非内皮依赖性收缩反应比WKY更受抑制。在WKY和SHR，用苯肾上腺素或内皮素-1收缩的内皮完整的主动脉，卡巴胆碱和环匹阿佐酸可引起内皮衍生的松弛因子(EDRF)/一氧化氮(NO)依赖的松弛，这种松弛可被2，5-二羟基肉桂酸甲酯或染料木素所减弱。这些抑制作用在WKY环中较大，对环匹亚硝酸的反应更为重要。此外，原钒酸钠(30μM)可增强去甲肾上腺素引起的去内皮自发性高血压大鼠血管环的收缩，降低环匹阿奇酸所致的内皮完整的自发性高血压大鼠血管环的松弛。本研究提示酪氨酸激酶在WKY和SHR的血管收缩和内皮依赖性松弛中起调节作用，并证明了酪氨酸激酶抑制剂对SHR和WKY的血管反应性的影响存在不同的关系。我们认为，SHR酪氨酸激酶活性的增加可能导致钙离子连接的收缩机制的反应性增强。此外，我们的结果表明，酪氨酸激酶活性的丧失与高血压相关的内皮依赖性松弛改变之间存在联系。
The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats was investigated on isolated aortic preparations by the use of two tyrosine kinase inhibitors: methyl-2,5-dihydroxycinnamate (30 μM) and genistein (30 μM). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinnamate reduced the sensitivity of the rings to noradrenaline to a larger extent in SHR than in WKY. The relaxing effects evoked by methyl-2,5-dihydroxycinnamate and genistein on the sustained contraction induced by endothelin-1 were also more pronounced in SHR denuded rings. Furthermore, in presence of methyl-2,5-dihydroxycinnamate, the endothelium-independent contractile responses to equipotent doses of cyclopiazonic acid were more depressed in SHR than in WKY. In WKY and SHR endothelium-intact aortas contracted with either phenylephrine or endothelin-1, carbachol and cyclopiazonic acid evoked endothelium derived relaxing factor (EDRF)/nitric oxide (NO)-dependent relaxations which were reduced by pretreatment of the rings with methyl-2,5-dihydroxycinnamate or genistein. These inhibitory effects were larger in WKY rings and more important on the cyclopiazonic acid response. In addition, sodium orthovanadate (30 μM) potentiated the noradrenaline-mediated contractions of endothelium-denuded SHR rings and reduced the cyclopiazonic acid-induced relaxation of endothelium-intact WKY rings. The present study suggests a regulatory role for tyrosine kinase in the smooth muscle contraction and the endothelium-dependent relaxation in WKY and SHR aortas and demonstrates the existence of a different relationship in the effect of tyrosine kinase inhibitors on vasoreactivity between SHR and WKY. We propose that an increase in the tyrosine kinase activity in SHR could lead to an enhanced reactivity of Ca2+-linked contractile mechanisms. In addition, our results suggest a link between the loss of tyrosine kinase activity and the altered endothelium-dependent relaxation associated with hypertension.