The outcome of non-selective vs selective nitric oxide synthase inhibition in lipopolysaccharide treated rats

Nitric oxide (NO), generated by inducible nitric oxide synthase (NOS) following lipopolysaccharide (LPS) administration, produces renal failure through autoinhibition of glomerular endothelial NOS activity. Preadministration of selective iNOS inhibitors abolishes this effect. Although nonselective NOS inhibitors further decrease GFR, current clinical trials investigate the effect of nonselective NOS inhibition in septic patients. The goals of our study were to determine whether treatment with selective NOS inhibitors can reverse the decrease in GFR in LPS treated rats with already established renal failure and to define the outcome of LPS treated rats following nonselective NOS inhibition. Four hours following the administration of LPS (4mg/kg), we measured creatinine clearance (CrCl) before and after the administration of either L-NIL (selective iNOS inhibitor, 3mg every 20 minutes) or saline. Selective iNOS inhibition attenuated the decrease in blood pressure [Controls: 105±6 to 98±5, LPS: 92±5* to 83±4*, LPS + L-NIL: 88±6* to 94±6 mm Hg; *p<0.05, vs controls {n=6}]. and reversed the decrease in GFR after LPS [Controls: 2.21±0.13 to 2.07±0.11, LPS: 0.82±0.18* to 0.66±0.22*, LPS + L-NIL: 0.76±0.15* to 1.86±0.15 ml/min; *p<0.05 vs controls {n=6}]. We next studied the effect of complete non-selective NOS inhibition (L-NAME 200 mg, 2 hours after LPS) on LPS treated rats. All (6/6) animals treated with both LPS and L-NAME died within 2 hours following LPS, while rats treated with either LPS, L-NAME, or LPS + L-NIL survived. Histologic studies performed in all experimental groups were unremarkable. Overnight mortality was studied using smaller doses of L-NAME. All LPS + L-NAME (10/10) and 1/10 LPS treated rats died. L-NAME, control, and LPS + L-NIL animals survived. The characteristic histologic findings in LPS + L-NAME rats were diffuse ischemic changes, most importantly acute myocardial infarction. In conclusion: Selective iNOS inhibition might prove to have clinical application as it prevents the decrease in GFR following LPS, even after renal failure is established. Treatment with a non selective NOS inhibitor in septic patients should be reconsidered.