ENDOTHELIAL AT(1)-MEDIATED RELEASE OF NITRIC-OXIDE DECREASES ANGIOTENSIN-II CONTRACTIONS IN RAT CAROTID-ARTERY

The purpose of this study was to examine whether angiotensin II (Ang I I) stimulates the release of endothelium-derived nitric oxide, which t hen impairs the contractions of vascular smooth muscle caused by the p eptide, and to determine the receptor subtypes mediating these respons es. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for t he measurement of intracellular levels of cGMP or suspended in organ c hambers for recording of changes in isometric force. Ang II (10(-7) mo l/L) caused a twofold increase in intracellular cGMP level in preparat ions with but not in those without endothelium. The presence of endoth elium impaired the contractions evoked by the peptide and caused appro ximately 50% inhibition of the maximal response to Ang II (3x10(-8) mo l/L); pD(2) values for Ang II were 8.9+/-0.1 and 9.6+/-0.2 in rings wi th and without endothelium, respectively. Tn rings with endothelium th e contractions to Ang II were augmented by nitro-L-arginine (an inhibi tor of nitric oxide synthase) but not indomethacin (an inhibitor of cy clooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferen tial angiotensin type 1 receptor antagonist) displayed competitive ant agonism toward Ang II (pA(2)=9.5); PD 123319 (a preferential angiotens in type 2 receptor antagonist; up to 10(-7) mol/L) did not affect the response to the peptide. Losartan (3x10(-9) mol/L) but not PD 123319 ( 10(-7) mol/L) impaired the endothelium-dependent component of the resp onse to the peptide. These results suggest that in the rat carotid art ery stimulation of an Ang II type 1 receptor causes the release of nit ric oxide, which in turn inhibits the contractions to Ang II also medi ated by type 1 receptors.