Cyclic AMP selectively enhances bradykinin receptor synthesis and expression in cultured arterial smooth muscle. Inhibition of angiotensin II and vasopressin response.
Bradykinin receptors on vascular smooth muscle may play an important role in regulating the endogenous effects of the vascular kallikrein-kinin system. The present study examined the effect of cyclic nucleotides on bradykinin-stimulated responses in cultured arterial smooth muscle cells. Short term stimulation (1 min) with cyclic AMP produced a variable inhibition of bradykinin-stimulated calcium mobilization which was lost in later passaged cells. However, long-term stimulation (24 h) produced a consistent increase in bradykinin-stimulated calcium mobilization in both early and late passaged cells. Further analysis demonstrated that chronic exposure to cAMP produced a twofold increase in both the number of cell surface bradykinin receptors and in bradykinin-stimulated phosphoinositide hydrolysis. The increase in bradykinin receptors was time dependent (> 7 h) and blocked by protein synthesis inhibitors, suggesting that cAMP enhanced the synthesis of new bradykinin receptors. The increase in bradykinin receptor binding and calcium mobilization was also stimulated by cholera toxin, forskolin, and isobutylmethylxanthine, but not isoproterenol or prostaglandin E2. Of considerable interest, prolonged exposure to cAMP inhibited both angiotensin II and arginine vasopressin-stimulated phosphoinositide hydrolysis and intracellular calcium mobilization. In summary, prolonged treatment with cAMP selectively stimulates the synthesis and expression of bradykinin receptors on arterial smooth muscle while decreasing the responsiveness to vasoconstrictor agonists such as angiotensin II and vasopressin.
Dixon
B S
BS
Department of Medicine, University of Iowa College of Medicine, Iowa City 52242.
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000378:metabolism*
D010716:Phosphatidylinositols; D018002:Receptors, Bradykinin; D000804:Angiotensin II; D001127:Arginine Vasopressin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D001920:Bradykinin; D002118:Calcium