ALPHA(2)-ADRENOCEPTOR-MEDIATED VASOCONSTRICTION REQUIRES A TYROSINE KINASE

alpha(2)-adrenoceptor-mediated contractions of the rabbit saphenous vein were previously found to be inhibited by wortmannin, a protein kinase inhibitor which blocks receptor-dependent phospholipase D activation. Since other studies have indicated that receptor-dependent phospholipase D activation required activity of a tyrosine kinase, we examined the influence of several tyrosine kinase inhibitors on both alpha(2)-adrenoceptor-mediated contractions of rabbit saphenous vein and alpha(1)-adrenoceptor-mediated contractions of rabbit aorta. Methyl 2,5-dihydroxycinnamate, genistein and erbstatin each caused non-competitive inhibition of rabbit saphenous vein contractions elicited by the alpha(2)-adrenoceptor-selective agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline (UK14304), yielding complete inhibition at 100 mu M and IC50 values of 15, 35 and 40 mu M respectively. By contrast, phenylephrine-induced dose-response curves in rabbit aorta were largely unaffected by tyrosine kinase inhibitors at 50 mu M. In a separate analysis of intracellular Ca2+-dependent and extracellular Ca2+-dependent alpha(1)-adrenoceptor responses of rabbit aorta, genistein (50 mu M) did partially reduce the initial intracellular Ca2+-dependent response, but did not reduce maximal response. Methyl 2,5-dihydroxycinnamate (25 mu M) had no effect on intracellular or extracellular Ca2+ responses in rabbit aorta. High K+-induced contractions of both rabbit saphenous vein and aorta were unaffected by up to 100 mu M of the tyrosine kinase inhibitors. These results indicate an obligatory requirement for tyrosine kinase activity in alpha(2)-adrenoceptor-mediated but not alpha(1)-adrenoceptor-mediated vasoconstriction.