To determine whether the renal nitric oxide (NO) system has a role in the pathogenesis of polycystic kidney disease (PKD) in Han:Sprague-Dawley (SPRD) rats, the NO synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), 70 mg/L, or L-arginine, 0.5 g/L, was administered to heterozygous diseased (cy/+) and homozygous normal animals. Urine nitrate and nitrite excretion was reduced by L-NAME treatment and, in the male cy/+ rats, increased by L-arginine administration. The administration of L-NAME significantly increased blood pressure in all groups, whereas L-arginine had no effect. L-NAME and L-arginine had a modest but significant overall effect on the severity of cystic disease in male rats, reflected by relative kidney weights and cyst volume densities. This effect was gender dependent because it was not observed in female animals. The administration of L-NAME resulted in a significant increase in plasma creatinine concentration of the cy/+ rats, which was more marked in male than female animals. These observations support the recently reported gender differences in the renal NO system and a small role for NO synthesis that can be inhibited by L-NAME in the pathogenesis of PKD in Han:SPRD rats. These observations do not exclude a more important role for the endogenous renal NO production in the pathogenesis of PKD in view of a recent report of a major NOS resistant to conventional inhibitors in the rat kidney.