PREGNANCY-INDUCED HYPERTENSION IN RATS WITH ADRIAMYCIN NEPHROPATHY ISASSOCIATED WITH AN INADEQUATE PRODUCTION OF NITRIC-OXIDE

Hypertensive complications are relatively common in pregnancy, particu larly in the presence of preexisting renal disease. Although the patho genesis 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 o f 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 co nfirm this hypothesis. Pregnant rats, both normal (PREG) and those wit h adriamycin nephropathy (AN-PREG), received 100 mg/L N-omega-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 eithe r L-arginine or D-arginine (2 g/L) from midpregnancy. At term, systoli c pressure, mean arterial pressure, urinary metabolites of NO, creatin ine clearance, and urinary protein were assessed. At term, compared wi th 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 ap proximately 1.7-fold (P<.01) versus PREG rats. With the exception of A N-PREG rats, inhibition of NO synthesis with N-omega-nitro-L-arginine methyl ester enhanced blood pressure and decreased creatinine clearanc e 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 physiol ogically required. Correction of this deficit by L-arginine treatment induced a significant clinical improvement.