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 microM and IC50 values of 15, 35 and 40 microM respectively. By contrast, phenylephrine-induced dose-response curves in rabbit aorta were largely unaffected by tyrosine kinase inhibitors at 50 microM. In a separate analysis of intracellular Ca(2+)-dependent and extracellular Ca(2+)-dependent alpha 1-adrenoceptor responses of rabbit aorta, genistein (50 microM) did partially reduce the initial intracellular Ca(2+)-dependent response, but did not reduce maximal response. Methyl 2,5-dihydroxycinnamate (25 microM) 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 microM 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.
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Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
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D000818:Animals; D001011:Aorta / Q000378:metabolism; D000068438:Brimonidine Tartrate; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019833:Genistein; D006873:Hydroquinones / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D002934:Cinnamates; D006873:Hydroquinones; D007529:Isoflavones; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D010656:Phenylephrine; D000068438:Brimonidine Tartrate; C067472:methyl 2,5-dihydroxycinnamate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C048212:erbstatin