Differential effects of tyrosine kinase inhibitors on contraction and relaxation of the aortas of normotensive and hypertensive rats

The contribution of tyrosine kinase activity to vasoreactivity in normotens ive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats was invest igated on isolated aortic preparations by the use of two tyrosine kinase in hibitors: methyl-2,5-dihydroxycinnamate (30 mu M) and genistein (30 mu M). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinn amate reduced the sensitivity of the rings to noradrenaline to a larger ext ent in SHR than in WKY. The relaxing effects evoked by methyl-2,5-dihydroxy cinnamate 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 r esponses to equipotent doses of cyclopiazonic acid were more depressed in S HR than in WKY. In WKY and SHR endothelium-intact aortas contracted with ei ther phenylephrine or endothelin-1, carbachol and cyclopiazonic acid evoked endothelium derived relaxing factor (EDRF)/nitric oxide (NO)-dependent rel axations which were reduced by pretreatment of the rings with methyl-2,5-di hydroxycinnamate or genistein. These inhibitory effects were larger in WKY rings and more important on the cyclopiazonic acid response. In addition, s odium orthovanadate (30 mu M) potentiated the noradrenaline-mediated contra ctions of endothelium-denuded SHR rings and reduced the cyclopiazonic acid- induced relaxation of endothelium-intact WKY rings. The present study sugge sts a regulatory role for tyrosine kinase in the smooth muscle contraction and the endothelium-dependent relaxation in WKY and SHR aortas and demonstr ates the existence of a different relationship in the effect of tyrosine ki nase inhibitors on vasoreactivity between SHR and WKY. We propose that an i ncrease in the tyrosine kinase activity in SHR could lead to an enhanced re activity of Ca2+-linked contractile mechanisms. In addition, our results su ggest a link between the loss of tyrosine kinase activity and the altered e ndothelium-dependent relaxation associated with hypertension. (C) 1999 Else vier Science B.V. All rights reserved.