Long-Term Nitric Oxide Synthase Inhibition in Rat Pregnancy Reduces Renal Kallikrein

Abstract—This study was performed to test the hypothesis that long-term nitric oxide synthase (NOS) inhibition during pregnancy may alter the predominance of the vasodilator kallikrein system. Sprague-Dawley rats were treated with the competitive inhibitor of NOS Nv-nitro-L-arginine (L-NNA, 50 mg z kg21 z d21, dissolved in water) from days 7 to 21 of pregnancy. Rats were studied before treatment (day 5), at days 11, 17, and 21 of pregnancy (during treatment), and at postpartum days 7 and 21 (after the drug was withdrawn at delivery). Each group (n55 to 8) had its corresponding control group (C) that received only vehicle. Additional rats were treated with NG-nitro-L-arginine methyl ester (L-NAME) alone or with an excess of L-arginine. At each study day, we measured blood pressure, collected urine overnight, obtained blood samples, and processed the kidneys for conventional histology and immunohistochemistry. In L-NNA rats, fetal and placental weights were reduced at days 17 and 21. Blood pressure was higher at days 17 and 21, returning to normal after L-NNA was removed. Urinary kallikrein activity was lower at days 11 and 17 (L-NNA511476213 and C523176146 nmol/16 h, P,0.001). Plasma renin activity was reduced at day 21 (L-NNA59.662.1 and C525.965 ng z mL21 z h21, P,0.05) and remained lower at postpartum day 7. L-NNA rats exhibited glomerular lesions and tubular atrophy, particularly of connecting tubules that displayed reduced kallikrein staining. Tubulointerstitial infiltrating macrophages (ED11) were also observed. Renal lesions were present as early as day 11 and persisted at day 7 postpartum. L-NAME rats exhibited similar alterations that were attenuated with an exces