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 r ole in regulating the endogenous effects of the vascular kallikrein-ki nin system. The present study examined the effect of cyclic nucleotide s on bradykinin-stimulated responses in cultured arterial smooth muscl e cells. Short term stimulation (1 min) with cyclic AR IP produced a v ariable 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 mob ilization in both early and late passaged cells. Further analysis demo nstrated 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 re ceptors was time dependent (> 7 h) and blocked by protein synthesis in hibitors, suggesting that cAMP enhanced the synthesis of new bradykini n receptors. The increase in bradykinin receptor binding and calcium m obilization was also stimulated by cholera toxin, forskolin, and isobu tylmethylxanthine, but not isoproterenol or prostaglandin E(2). Of con siderable interest, prolonged exposure to cAMP inhibited both angioten sin II and arginine vasopressin-stimulated phosphoinositide hydrolysis and intracellular calcium mobilization. In summary, prolonged treatme nt with cAMP selectively stimulates the synthesis and expression of br adykinin receptors on arterial smooth muscle while decreasing the resp onsiveness to vasoconstrictor agonists such as angiotensin II and vaso pressin.