Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep

The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uteri ne and systemic vasculatures. Seven nonpregnant estrogenized ewes with indw elling uterine artery catheters and flow probes received bolus injections ( 0.1, 0.3 and 1 mu g) of ANG LI locally into the uterine artery followed by a systemic infusion of ANG II at 100 ng.kg(-1).min(-1) for 10 min to determ ine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor: (AT(2 )) antagonist PD-123319 and then repeated again in the:presence of an ANG I I type 1 receptor (AT(1)) antagonist L-158809. In a second experiment, desi gned to investigate the mechanism of ANG II potentiation that occurred in t he presence of AT(2) blockade, nonestrogenized sheep received a uterine art ery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 mu g/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow (P < 0.03), which were potentiated in the presence of t he AT(2) antagonist (P < 0.02). Addition of the AT(1) antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in syst emic arterial pressure (P < 0.01). Significant uterine vasodilation (P < 0. 01) was noted with AT(1) blockade in the second experiment, which was rever sed by administration of the AT(2) antagonist or by the nitric oxide synthe tase inhibitor N-omega-nitro-L-arginine methyl ester. We conclude that the AT(1)- receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. AT(2)-receptor blockade resulted in a po tentiation of the uterine vasoconstrictor response to ANG II, suggesting th at the AT(2)-receptor subtype may modulate uterine vascular responses to AN G II potentially by release of nitric oxide.