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 BP was lower than in WT mice (∼95 mm Hg vs. ∼105 mm Hg). When the Tg mice were fed chow containing IC3, plasma prolactin concentrations increased threefold, BP increased to ∼130 mm Hg, and cardiac function became markedly impaired. IC3 chow did not affect the WT mice. Urinary excretion 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 production became significantly less in the Tg mice 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 suggest that pregnant women with abnormally high prolactin levels may need special attention.Prolactin, a 23-kDa polypeptide hormone, is a potent multifunctional cytokine with a broad range of biological effects, including water and salt balance, lactogenesis, cell proliferation and differentiation, testicular Leydig cell function, T-cell immunity, pancreatic β-cell function, hematopoiesis, and adipogenesis (1). Prolactin is physiologically secreted mainly from the anterior lobe of pituitary gland. The secretion is negatively regulated by dopamine and positively regulated by prolactin-releasing peptide (2) synthesized in the hypothalamus. The levels of prolactin in the serum, urine, and amniotic fluids are significantly higher in patients with preeclampsia than in subjects with normal pregnancy (3–5), suggesting that prolactin is involved in the pathogenesis of pregnancy-associated hypertension. However, animal experiments have shown inconsistent effects of prolactin on blood pressure (BP). Thus, acute i.v. infusion of prolactin increased BP in rabbits (6), but, when ovine prolactin was chronically given i.p. via an osmotic minipump in rats, BP was decreased (7). It has also been reported that chronic prolactin infusion caused an increase in urinary sodium, potassium, and water excretion, but no significant changes in arterial pressure, in rats (8).To study the chronic effects of different plasma concentrations of prolactin on BP and general well-being, we have generated male mice with a single-copy transgene [Tg; inserted into the hypoxanthine-guanine phosphoribosyltransferase (Hprt) locus] that enables hepatic production of prolactin and its cleavage product when the mice are fed indole-3-carbinol (I3C), a xenobiotic agent naturally present at high levels in broccoli and similar vegetables. The Tg is leaky, and, when the mice are fed normal chow (NC), it leads to basal prolactin levels comparable to those in the plasma of WT female mice in the last third of a normal pregnancy, accompanied by a decrease in BP and an increase in nitric oxide (NO) production, likewise similar to those occurring in females during pregnancy. When the Tg mice are fed a diet containing IC3, plasma levels become threefold basal, BP increases, and cardiac insufficiency develops. In the absence of endothelial NO synthase (eNOS), these changes did not occur.