(Hypertension. 1999;34:865-871.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Long-Term Nitric Oxide Synthase Inhibition in Rat Pregnancy Reduces Renal Kallikrein
From the Center for Medical Research (S.P.S., J.F.V., A.G., P.R.) and the Departments of Obstetrics and Gynecology (S.P.S.) and Pediatrics (P.R.), School of Medicine, and the Department of Physiology (C.P.V.), Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
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
N
-nitro-L-arginine (L-NNA, 50
mg · kg-1 · d-1, 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withdrawn at delivery).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 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-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-1 ·
h-1, 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.
Key Words: pregnancy • nitric oxide • plasma renin activity • renal kallikrein • renal lesions • macrophages
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