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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 34; no. 4, Part 2; pp. 865 - 871
• Main Authors: Salas, Sofía P, Vuletin, José F, Giacaman, Andrea, Rosso, Pedro, Vío, Carlos P
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.1999; Hagerstown, MD Lippincott
• Subjects: Animals; Biological and medical sciences; Diseases of mother, fetus and pregnancy; Enzyme Inhibitors - pharmacology; Female; Gynecology. Andrology. Obstetrics; Kallikreins - metabolism; Kidney - metabolism; Kidney - physiopathology; Medical sciences; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - metabolism; Nitroarginine - pharmacology; Pregnancy; Pregnancy, Animal - metabolism; Pregnancy. Fetus. Placenta; Rats; Rats, Sprague-Dawley; Renin - metabolism; Immunohistochemistry; Pregnancy disorders; Rat; Enzyme; Pathogenesis; Rodentia; Sex; Pregnancy toxemia; Nitric-oxide synthase; Kidney; Pathology; Vertebrata; Mammalia; Animal; Preeclampsia; Female; Arterial pressure; Oxidoreductases
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.hyp.34.4.865

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 N-nitro-L-arginine (L-NNA, 50 mg · kg · d, 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(day 5), at days 11, 17, and 21 of pregnancy (during treatment), and at postpartum days 7 and 21 (after the drug was withdrawn at delivery).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 (n=5 to 8) had its corresponding control group (C) that received only vehicle. Additional rats were treated with N-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-NNA=1147±213 and C=2317±146 nmol/16 h, P<0.001). Plasma renin activity was reduced at day 21 (L-NNA=9.6±2.1 and C=25.9±5 ng · mL · h, 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 (ED1+) 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 excess of L-arginine. We postulate that the reduction in renal kallikrein may contribute to the hemodynamic alterations described in this model.