A tyrosine kinase regulates alpha-adrenoceptor-stimulated contraction and phospholipase D activation in the rat aorta.
Since previous studies had indicated a role for tyrosine kinases in alpha 2-adrenoceptor-induced contractile responses in other blood vessels, as well as in the activation of phospholipase D, we examined the sensitivity of these responses in rat aorta to the tyrosine kinase inhibitor genistein. Contractions induced by both noradrenaline and the alpha 2-adrenoceptor-selective agonist UK14304 (5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline) were fully inhibited by genistein, with the latter responses being more sensitive. Contractions induced by high K+ buffer were also inhibited, but to a lesser extent. Both agonists caused a stimulation of phospholipase D activity, which could be blocked by pretreatment with pertussis toxin, indicating involvement of either Gi or Go. Genistein completely inhibited the agonist-induced phospholipase D activity and also substantially reduced the basal level of phospholipase D activity. Pretreatment with either the alpha 1-adrenoceptor antagonist prazosin or the alpha 2-adrenoceptor antagonist rauwolscine was also effective in eliminating the agonist-induced increase of phospholipase D. These results indicate that a tyrosine kinase-regulated phospholipase D plays a critical role in alpha-adrenoceptor-induced contractions of the rat aorta and that stimulation of both alpha 1- and alpha 2-adrenoceptors is essential to allow phospholipase activation.
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Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D000068438:Brimonidine Tartrate; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D037342:Pertussis Toxin; D010739:Phospholipase D / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D011810:Quinoxalines / Q000037:antagonists & inhibitors; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D002120:Calcium Channel Agonists; D007529:Isoflavones; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D010566:Virulence Factors, Bordetella; D000068438:Brimonidine Tartrate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019833:Genistein; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D010739:Phospholipase D; D011188:Potassium; D009638:Norepinephrine