MODULATION OF CAMP-MEDIATED VASORELAXATION BY ENDOTHELIAL NITRIC-OXIDE AND BASAL CGMP IN VASCULAR SMOOTH-MUSCLE

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucida te roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilalors we examined the effects of removal of en dothelium and a NO synthase (NOS) inhibitor on relaxant responses in v itro of rat aortic strips to beta-adrenoceptor stimulants and colforsi n dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat ao rta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatme nt with NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME). Rela xant response of endothelium-intact segments to isoproterenol was asso ciated with increases in tissue cAMP and cGMP contents. Removal of end othelium or treatment with L-NAME markedly reduced basal cGMP and abol ished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprussi de (SNP) restored the diminished relaxant response to isoproterenol an d increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg pr otein), whereas it did not affect the isoproterenol-induced increase i n cAMP. The diminished relaxant response of endothelium-removed segmen ts to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-medialed vasodilators is mediated, in part, by NO production in endothelium and subsequent incr ease in cGMP in vascular smooth-muscle cells.