title: Differential effects of tyrosine kinase inhibitors on contraction and relaxation of the aortas of normotensive and hypertensive rats.
abstract: 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 microM) and genistein (30 microM). 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 microM) 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U337, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Zerrouk
authors.forename: M
authors.initials: M
authors.lastname: Auguet
authors.forename: H
authors.initials: H
authors.lastname: Dabiré
authors.forename: A M
authors.initials: AM
authors.lastname: Brisac
authors.forename: M
authors.initials: M
authors.lastname: Safar
authors.forename: P E
authors.initials: PE
authors.lastname: Chabrier
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D007211:Indoles; D002217:Carbachol; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D002118:Calcium; C000543:cyclopiazonic acid