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

Nitric oxide (NO), generated by inducible nitric oxide synthase (NOS) follo wing lipopolysaccharide (LPS) administration, produces renal failure throug h autoinhibition of glomerular endothelial NOS activity Preadministration o f selective iNOS inhibitors abolishes this effect. Although nonselective NO S 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 r enal failure and to define the outcome of LPS treated rats following nonsel ective NOS inhibition. Four hours following the administration of LPS (4mg/ kg), we measured creatinine clearance (CrCl) before and after the administr ation of either L-NIL (selective iNOS inhibitor, 3mg every 20 minutes) or s aline. Selective iNOS inhibition attenuated the decrease in blood pressure [Controls: 105 +/-6 to 98 +/-5, LPS: 92 +/-5* to 88 +/-4*, LPS + LNIL: 88 /-6* to 94 +/-6 mm Hg; *p <0.05, vs controls {n=6}]. and reversed the decre ase 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. Ah (6/6) animals treated w ith both LPS and L-NAME died within 2 hours following LPS, while rats treat ed with either LPS, L-NAME, or LPS + LNIL survived. Histologic studies perf ormed in all experimental groups were unremarkable. Overnight mortality was studied using smaller doses of L-NAME. Ah LPS + L-NAME (10/10) and 1/10 LP S treated rats died. L-NAME, control, and LPS + LNIL animals survived. The characteristic histologic findings in LPS + L-NAME rats were diffuse ischem ic changes, most importantly acute myocardial infarction. In conclusion: Se lective iNOS inhibition might prove to have clinical application as it prev ents the decrease in GFR following LPS, even after renal failure is establi shed. Treatment with a non selective NOS inhibitor in septic patients shoul d be reconsidered.