INHIBITION OF CONSTITUTIVE NITRIC-OXIDE SYNTHASE (NOS) BY NITRIC-OXIDE GENERATED BY INDUCIBLE NOS AFTER LIPOPOLYSACCHARIDE ADMINISTRATION PROVOKES RENAL DYSFUNCTION IN RATS

Excess NO generation plays a major role in the hypotension and systemi c vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunc tion. We have examined the roles of inducible nitric oxide synthase (i NOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccha ride administration by comparing the effects of specific iNOS inhibiti on, L-N-6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino-6-hydroxy-pyri midine vs. nonspecific NOS inhibitors (nitro-L-arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively, LPS significantly decre ased blood pressure and GFR (112+/-4 vs, 83+/-4 mmHg; 2.66+/-0.29 vs, 0.96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh, GC activity was reciprocally increased, L-NIL and 2,4-diamino-6-hydrox y-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 mi/min, respectively), restored the normal response t o CCh, and GC activity was normalized. In vitro application of L-NIL a lso restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors v erified that CCh responses reflected eNOS activity, L-NAME, a nonspeci fic inhibitor, worsened GFR (0.41+/-0.15 mi/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated t he CCh response. No differences were observed in eNOS mRNA expression among the experimental groups, Selective iNOS inhibition prevents redu ctions in GFR, whereas nonselective inhibition of NOS further decrease s GFR. These findings suggest that the decrease in GFR after LPS is du e to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.