Endothelium-derived relaxing factor and indomethacin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy

Abstract

Pregnancy reduces uterine artery contractile responses to norepinephrine and angiotensin II in many species, including the human and the guinea pig, by release of endothelium-derived relaxing substances. We hypothesized that vascular reactivity to thromboxane during pregnancy would also be reduced by a similar mechanism. Isolated ring segments of uterine and carotid arteries from nonpregnant and near-term pregnant guinea pigs were suspended in a myograph for the measurement of isometric tension. Uterine but not carotid artery sensitivity to cumulative addition of the thromboxane analog U46619 was decreased during pregnancy. The maximal contractile responses of both vessels were unaltered by pregnancy. N omega-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide endothelium-derived relaxing factor synthesis, increased the sensitivity of uterine and carotid arteries to U46619 in both pregnant and nonpregnant animals. The maximal contractile response of uterine arteries from pregnant guinea pigs was also increased, but that of nonpregnant ones was not. The maximal U46619 contractile response of the carotid artery was not significantly altered by N omega-nitro-L-arginine. Indomethacin (10(-5) mol/L), a cyclooxygenase inhibitor, reduced both the sensitivity and the maximal response of U46619 in each vessel group. Removal of the endothelium from uterine artery of pregnant animals enhanced both sensitivity and maximal response to U46619. Pretreatment of the denuded segments with indomethacin reduced the sensitivity to U46619. However, indomethacin-treated denuded segments were still more sensitive to U46619 than controls. The sensitivity of guinea pig uterine artery but not carotid artery to thromboxane is reduced during pregnancy. Although the precise mechanism remains unclear, both endothelium-derived relaxing factor and an indomethacin-sensitive contracting factor are involved. If indomethacin-sensitive contracting factor is released by humans and disease alters that release, it is possible that any enhanced contractile response to thromboxane resulting from the loss of endothelium-derived relaxing agents such as prostacyclin and endothelium-derived relaxing factor would be offset by the loss of indomethacin-sensitive contracting factor.