(Hypertension. 1997;29:986-991.)
© 1997 American Heart Association, Inc.
Articles |
Pregnancy-Induced Hypertension in Rats With Adriamycin Nephropathy Is Associated With an Inadequate Production of Nitric Oxide
From the Department of Nephrology and Hypertension, Meir Hospital, Sackler School of Medicine, University of Tel-Aviv (Israel).
Correspondence to Prof J. Bernheim, Meir Hospital, 44281 Kfar Saba, Israel.
Abstract Hypertensive complications are relatively common in
pregnancy, particularly in the presence of preexisting renal disease.
Although the pathogenesis of such complications is still unknown,
recent animal studies have suggested that it may be related to impaired
synthesis of nitric oxide (NO). Rats with adriamycin
nephropathy develop a "preeclamptic-type" pregnant
state characterized by elevated blood pressure, lack of
hyperfiltration, and enhanced proteinuria. Preliminary studies with
this model have implicated inadequate NO synthesis in the development
of preeclamptic-like pregnancy. The aim of the present study was to
confirm this hypothesis. Pregnant rats, both normal (PREG) and those
with adriamycin nephropathy (AN-PREG), received 100
mg/L N
-nitro-L-arginine methyl
ester PO from the middle of gestation to term (day 11, term
approximately 22 days). One group of AN-PREG rats received either
L-arginine or D-arginine (2 g/L) from
midpregnancy. At term, systolic pressure, mean
arterial pressure, urinary metabolites of NO,
creatinine clearance, and urinary protein were assessed. At
term, compared with virgin rats with adriamycin
nephropathy, untreated AN-PREG rats had increased
systolic pressure, mean arterial pressure, and
proteinuria (mean arterial pressure, 124±2.5 versus
99.7±1.6 mm Hg [P<.05]; proteinuria, 434±58
versus 216±63 mg/d [P<.05]). Creatinine
clearance did not change (1.68±0.23 versus 1.35±0.09 mL/min,
P=NS). In PREG rats, urinary metabolites of NO increased
approximately threefold at term pregnancy compared with control. By
contrast, in AN-PREG rats, excretion of urinary metabolites of NO
increased only by approximately 1.7-fold (P<.01) versus
PREG rats. With the exception of AN-PREG rats, inhibition of NO
synthesis with N-nitro-L-arginine
methyl ester enhanced blood pressure and decreased
creatinine clearance but did not influence proteinuria.
Excretion of urinary metabolites of NO was similarly inhibited in all
rats. In AN-PREG rats, L-arginine normalized blood pressure
(91±2.15 mm Hg) and lowered proteinuria partially but
significantly. D-Arginine had no effect. In summary,
AN-PREG rats are unable to adequately increase NO synthesis when
physiologically required. Correction of this
deficit by L-arginine treatment induced a significant
clinical improvement.
Key Words: doxorubicin • pregnancy • rats • nitric oxide
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