Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation

Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) media tes hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) f or 6 h and the selective iNNOS-inhibitor L-N6-(1-iminoethyl)lysine (L-NIL), the nonselective NOS-inhibitor N-G-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-indep endent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-f ormation were also determined. In control rats, L-NAME increased MAP, decre ased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased v asodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine s taining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasod ilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhale d NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or p revent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affe cting endothelium-dependent vasodilation whereas L-NAME does not.