Decreased Endothelium-Dependent Vascular Relaxation During Reduction of Uterine Perfusion Pressure in Pregnant Rat

Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to 4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0. 7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/-0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0. 1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100 micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3) N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium-intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3) N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.