Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Increased levels of a cleaved form of prolactin (molecular weight 16 kDa) have been associated with preeclampsia. To study the effects of prolactin on blood pressure (BP),we generated male mice with a single-copy transgene (Tg; inserted into the hypoxanthine- guanine phosphoribosyltransferase locus) that enables inducible hepatic production of prolactin and its cleavage product. The Tg is driven by the indole-3-carbinol (I3C)-inducible rat cytochrome P450 1A1 promoter. When the Tg mice were fed normal chow (NC), plasma prolactin concentrations were comparable to those in female WT mice in the last third of pregnancy, and BPwas lower than inWT mice (∼95 mm Hg vs. ∼105 mm Hg). When the Tg mice were fed chowcontaining IC3, plasma prolactin concentrations increased three- fold, BP increased to ∼130 mm Hg, and cardiac function became markedly impaired. IC3 chow did not affect theWT mice. Urinary ex- cretion of nitrite/nitrate and the amount of Ser1177-phosphorylated endothelial nitric oxide (NO) synthase (eNOS) were significantly greater in the Tg mice fed NC than in WT mice, as they are during pregnancy. However, when I3C was fed, these indicators of NO pro- duction became significantly less in the Tgmice than in WT mice. The effects of increased plasma prolactin were abolished by a genetic absence of eNOS. Thus, a threefold increase in plasma prolactin is sufficient to increase BP significantly and to markedly impair cardiac function, with effects mediated by NO produced by eNOS. We sug- gest that pregnantwomenwith abnormally high prolactin levels may need special attention.