Selective in vivo inhibition of inducible nitric oxide synthase in a rat model of sepsis

Elevated production of nitric oxide (NO) by the inducible NO synthase (type II, iNOS) may contribute to the vascular hyporesponsiveness and hemodynami c alterations associated with sepsis. Selective inhibition of this isoenzym e is a possible therapeutic intervention to correct these pathophysiologica l alterations. Aminoguanidine has been shown to be a selective iNOS inhibit or and to correct the endotoxin-mediated vascular hypocontractility in vitr o. However, to date aminoguanidine has not been shown to selectively block iNOS activity in vivo. The in vivo effects of aminoguanidine were assessed in the cecal ligation and perforation model of sepsis in rats. Aminoguanidi ne (1.75-175 mg/kg) was administered to septic and sham-operated rats for 3 h before euthanasia and harvest of tissues. NOS activities were determined in the thoracic aorta and lung from these animals. Aminoguanidine (17.5 mg /kg) did not alter the mean arterial pressure; however, it did inhibit indu ced iNOS (but not constitutive NOS) activity in the lung and thoracic aorta from septic animals. Only the higher dose of aminoguanidine (1.75-175 mg/k g) was able to increase the mean arterial pressure in septic and sham-opera ted animals. Thus selective inhibition of iNOS in vivo with aminoguanidine is possible, but our data suggest that other mechanisms, in addition to iNO S induction, are responsible for the loss of vascular tone characteristic o f sepsis.