Chronic NOS inhibition reverses systemic vasodilation and glomerular hyperfiltration in pregnancy

Abstract

The chronic role of nitric oxide (NO), independent of prostaglandin synthesis, in the primary peripheral vasodilation, increased glomerular filtration rate (GFR), and renal plasma flow (RPF) in normal pregnancy remains to be defined. The purpose of the present study was to chronically inhibit NOS to return systemic vascular resistance (SVR), cardiac output (CO), GFR, and RPF to nonpregnant values. Pregnant rats received the nitric oxide synthase (NOS) inhibitor, nitro-L-arginine methyl ester (L-NAME), orally from gestational days 7 through 14. Results were compared with nonpregnant and untreated pregnant rats. At 14 days gestation, CO significantly increased in pregnant vs. nonpregnant rats (187 +/- 17 vs. 125 +/- 10 ml/min, P < 0.05) as SVR decreased (0.64 +/- 0.08 vs. 1.08 +/- 0.08 mmHg. ml(-1). min, P < 0.05) and mean arterial pressure was unchanged (117 +/- 5 vs. 125 +/- 2 mmHg, not significant). Pregnant rats also demonstrated increased GFR (3,015 +/- 33 vs. 2,165 +/- 136 microl/min, P < 0.01) and RPF (7,869 +/- 967 vs. 5,507 +/- 290 microl/min, P < 0.05) vs. nonpregnant rats. L-NAME-treated pregnant rats had values for CO (118 +/- 7 ml/min), SVR (1.09 +/- 0.07 mmHg. ml(-1). min), GFR (2,264 +/- 150 microl/min), and RPF (5,777 +/- 498 microl/min), which were no different than nonpregnant animals. In summary, similar to human pregnancy, primary peripheral vasodilation occurs early in rat pregnancy. Furthermore, the hyperdynamic circulation and glomerular hyperfiltration of normal rat midterm pregnancy can be chronically reversed by NOS inhibition. These findings suggest a role for endothelial damage and decreased NO in the pathogenesis of preeclampsia.

Obstetric Nephrology

“…The proposed mechanism of relaxin involves an increase in vascular gelatinase activity, which upregulates NO-dependent vasodilation via the endothelin-B NO pathway (14). In pregnant rats, investigators have convincingly demonstrated increments in endogenous production of NO (15), and through acute or chronic inhibition of NO synthase, investigators have demonstrated abolishment of the glomerular hyperfiltration in pregnancy (16,17). Hence, NO is necessary for the hemodynamic adaptation in renal function during pregnancy, and relaxin may represent a pregnancy-specific mechanism for augmenting the effects of NO.…”

Systemic Arterial Vasodilation, Vasopressin, and Vasopressinase in Pregnancy

“…Estrogens are known to upregulate nitric oxide (NO) synthase, 2 and there is experimental evidence that NO contributes to this arterial vasodilation during pregnancy. 3,4 Moreover, an increase in circulating relaxin during early pregnancy is also known to increase NO-mediated arterial vasodilation. 5 Systemic arterial vasodilation in pregnancy is associated consequently with a secondary increase in cardiac output.…”

Decreased Effective Blood Volume in Edematous Disorders

“…Estrogen upregulates endothelial nitric oxide synthase in pregnancy, and inhibitors of nitric oxide synthesis normalize the systemic and renal hemodynamics in rat pregnancy. 21 On the background of this unifying mechanism of body fluid volume regulation by the kidney, the clinical use of the term "decreased effective blood volume" can be considered outdated and be replaced by "arterial underfilling." However, if the use of the term persists in clinical medicine, then it should be "decreased effective arterial blood volume.…”