Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI₂ and NO in pregnancy

Uterine vasculature is less responsive than systemic vasculature to angiotensin II (ANG II)-induced vasoconstriction. We hypothesized that pregnancy augments basal and ANG II-stimulated endothelial prostacyclin (PGI₂) and/or nitric oxide (NO) production, which locally increase vascular smooth muscle (VSM) adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), respectively. Uterine (UA) and systemic arteries (SA) from pregnant (P) and nonpregnant (NP) sheep were incubated with isobutylmethylxanthine. Basal PGI₂, cAMP, and cGMP production was 2.4- , 1.6-, and 5.9-fold greater (P < 0.01) in UA from P vs. NP sheep; endothelium removal lowered (P < 0.05) values 69, 44, and 88%. Basal SA PGI₂ and cAMP, but not cGMP, also were elevated by pregnancy. Indomethacin (Indo; 100 μM) decreased PGI₂ and cAMP, but not cGMP production; N(ω)-nitro-L- arginine methyl ester (L-NAME; 10 μM) and methylene blue (MB, 10 μM) only decreased cGMP. Basal UA, but not SA, NO synthase activity (conversion of [³H]arginine to [³H]citrulline), was 1.8-fold higher in pregnancy and decreased (P < 0.01) after endothelium removal and with L-NAME. ANG II (50 nM) increased PGI₂ (86%) and cAMP (56%) production only in UA from P sheep (P < 0.05); this was abolished by endothelium removal or Indo. ANG II also increased (P < 0.01) cGMP production by UA from both groups but only by SA from P ewes; this was absent in denuded, L-NAME-, or MB-treated vessels. Stimulation of VSM cGMP production with sodium nitroprusside (50 μM) was inhibited by MB, but not L-NAME or endothelium removal. In pregnancy, endothelial PGI₂ and NO production are enhanced and may contribute to attenuated ANG II vasoconstriction via VSM cAMP and cGMP.