Induction of nitric oxide synthases early in pregnancy

Abstract

We have previously demonstrated that calcium-dependent nitric oxide synthase is induced by estrogen and that by the end of pregnancy nitric oxide synthase of both endothelial and neuronal origin is increased in various maternal tissues. This rise in activity may be crucial for the alterations in muscle activity necessary for a successful pregnancy. If so, the increase in nitric oxide synthase activity must occur early in gestation. We tested the hypothesis that pregnancy increases nitric oxide synthase activity early in gestation by measuring in heart, kidney, skeletal muscle, and esophagus of time-mated guinea pigs the conversion by nitric oxide synthase of carbon 14-labeled L-arginine to carbon 14-labeled citrulline and the concentration of cyclic guanosine monophosphate, the second messenger of nitric oxide. Calcium-dependent nitric oxide synthase activity was increased twofold to fourfold by pregnancy in each tissue examined. The rise began by 0.14 gestation (9 of 63 +/- 2 days) and reached a plateau by 0.30 gestation (19 days), which was then maintained until term. The treatment of pregnant animals with tamoxifen decreased nitric oxide synthase activity to nonpregnant values in the heart, where tamoxifen is an estrogen receptor antagonist, but not in kidney, skeletal muscle, and esophagus. Cyclic guanosine monophosphate also rose progressively in each tissue studied until about 0.70 gestation before declining in skeletal muscle, kidney, and heart. It remained elevated in the esophagus. These studies demonstrate that nitric oxide synthase activity in maternal tissues rises early in pregnancy and is associated with an increase in cyclic guanosine monophosphate, the second messenger of nitric oxide. These findings are consistent with the hypothesis that an increase in nitric oxide synthase plays a role in smooth muscle adaptations of pregnancy.