ANGIOTENSIN-II INCREASES CGMP CONTENT VIA ENDOTHELIAL ANGIOTENSIN-II AT1 SUBTYPE RECEPTORS IN THE RAT CAROTID-ARTERY

Angiotensin II (Ang II) has been reported to modulate cGMP formation i n various types of cells. To acquire direct information on the intrace llular transduction involved in this mechanism, we tested the effects of Ang II on vascular tone and on cGMP content of in vitro isolated ca rotid arteries from 12-week-old Wistar-Kyoto rats. Segments of carotid artery 20 mm long (n=8 for each group) maintained at a transmural pre ssure of 100 mm Hg were immersed in a bath (38 degrees C) containing o xygenated Tyrode's solution. At the end of each experiment, the vessel diameter was measured, and the wall cGMP content was determined by en zyme immunoassay. Under basal conditions, mean diameter was 968+/-19 m u m, and mean cGMP carotid artery content was 38.9+/-3.5 fmol/mg tissu e. Incubation for 20 minutes with Aug II (10(-5) mol/L) significantly increased cGMP wall content, twofold above the basal content (P<.O1), and constricted the vessel (60+/-2.2% of the control diameter, P<.001) . After preincubation with a nonselective antagonist of Ang II recepto rs, saralasin ([Sar(1),Val(5),Ala(8)]Ang II, 5x10(-5) mol/L), or with a specific antagonist of Ang II AT1 receptor subtype, losartan (5x10(- 5) mol/L), carotid diameter and cGMP content were no longer affected b y Ang II. Exposure of carotid arteries to a specific antagonist of Ang II AT2 receptor, PD 123319 (10(-7) mom), modified neither Ang II-indu ced diameter decrease nor cGMP content increase. Constriction of the v essel with KCl (26+/-3%, P<.001) did not modify the basal cGMP wall co ntent. Endothelium removal or incubation with N-G-nitro-L-arginine met hyl ester (10(-3) mol/L) reduced the cGMP content (22+/-9%, P<.05 and 20+/-11%, P<.05, respectively); Ang II further decreased the diameter (P<.001) but no longer increased the cGMP content under these experime ntal conditions. The present study shows that Ang II constricts the ca rotid artery and increases cGMP level specifically via the Ang II AT1 receptor subtype in in vitro intact rat carotid artery. The mechanism underlying this increase in cGMP is thought to be mediated through end othelial NO synthase stimulation by Ang II.