ROLE OF ENDOTHELIAL NITRIC-OXIDE IN THE RESPONSE TO ANGIOTENSIN-II OFSMALL MESENTERIC-ARTERIES OF THE RAT

The role of endothelium-derived nitric oxide (NO) in the vascular cont ractile response to angiotensin II (Ang II) has been investigated in i solated small mesenteric resistance arteries of the rat. Both contract ion and intracellular Ca2+ ion concentration ([Ca2+](i)) were monitore d in vessels, with and without functional endothelium, which were expo sed to physiological salt solution containing 25 mM KCl. Ang II induce d concentration-dependent contractile responses and increases in [Ca2](i) which, at the concentration giving the maximal response (10 nM), were not sustained in arteries with functional endothelium; however, t he presence of a functional endothelium did not modify the peak respon ses. Ang II did not increase the cyclic guanosine 3',5'-monophosphate content of the tissue nor did it induce relaxation in arteries precont racted with 3 mu M noradrenaline. The decline of the Ang II responses was suppressed by removal of the endothelium or by exposure of arterie s with endothelium to either the NO synthase inhibitor, N-omega-nitro- L-arginine methyl ester (300 mu M), or the cyclic CMP-dependent protei n kinase inhibitor, Rp-8-bromoguanosine 3',5'-cyclic monophosphorothio ate (30 mu M). On the other hand, the NO donor SIN-1 (3-morpholino-syd nonimine, 10 mu M) accelerated the decline in [Ca2+](i) and contractio n. These results show that endothelium-derived NO does not affect the magnitude of the phasic element of the response to Ang II, but is invo lved in the rapid attenuation of the tonic component. Activation of cy clic GMP-dependent protein kinase accounts for this effect of endothel ium-derived NO.