TYROSINE KINASE INHIBITORS AND THE CONTRACTILE ACTION OF G-PROTEIN-LINKED VASCULAR AGONISTS

In a porcine coronary artery helical strip preparation, the tyrosine kinase inhibitors genistein and tyrphostin (AG82) attenuated the contractile actions of angiotensin II, arginine vasopressin, epidermal growth factor - urogastrone, noradrenaline, and prostaglandin F-2 alpha, under conditions where contractions due to acetylcholine and KCI were not affected. Both genistein and tyrphostin also caused a selective inhibition of angiotensin II action in rat aorta helical strips, without affecting KCI-mediated contractions. The IC50 values for the inhibition of contraction in the porcine coronary artery were in the range of 2-5 mu M for genistein and 8-15 mu M for tyrphostin. Comparable IC50 values were observed for the inhibitory effects of genistein on angiotensin II and prostaglandin F-2 alpha action in the rat aorta, whereas much higher tyrphostin concentrations (IC50 greater than or equal to 40 mu M) were required to block angiotensin II action in this preparation. Angiotensin II caused an elevation of phosphotyrosyl protein (antiphosphotyrosine Western blot) in the porcine coronary artery, which was reversed by genistein. In addition, porcine coronary artery derived membrane and cytosolic fractions exhibited sarcoma virus related tyrosine kinase activity, which was inhibited by both genistein and tyrphostin. Our data (i) document the selective inhibition by genistein and tyrphostin of the contractile action of some, but by no means all, G-protein-linked vascular agonists in porcine and rat arterial preparations, (ii) establish the presence of sarcoma virus related tyrosine kinase activity in the porcine coronary artery, and (iii) demonstrate angiotensin II mediated increases in phosphotyrosyl protein content in porcine coronary artery tissue. These data support the hypothesis that selected G-protein-linked contractile vascular agonists may act in part via the stimulation of nonreceptor tyrosine kinases. The data also indicate the complex actions of the tyrosine kinase inhibitors, even for the same agonist acting in vascular preparations obtained from different species.