A SELECTIVE INHIBITOR OF INDUCIBLE NITRIC-OXIDE SYNTHASE PROLONGS SURVIVAL IN A RAT MODEL OF BACTERIAL PERITONITIS - COMPARISON WITH 2 NONSELECTIVE STRATEGIES

We evaluated the effects on survival of three different strategies for blocking the actions of nitric oxide (NO) during Gram-negative sepsis in rats. Male Sprague-Dawley rats underwent placement of a jugular ve in catheter and i.p. implantation of a gelatin capsule containing a pa ste (.11 +/- .01 g final weight) consisting of sterile rat feces mixed with a suspension (.2 mL) of viable Escherichia coil (strain sm18; 5. 7 x 10(5) colony-forming units) in saline. Beginning at T = 6 h, all a nimals received i.v. ampicillin (85 mg/kg every 12 h) until death or t he administration of five doses. At the same time points, pairs of ani mals received an i.v. dose of either an experimental treatment agent o r an appropriate control substance. The following experimental regimen s were tested: 5 mg/kg per dose of S-methylisothiourea sulfate (SMT), a selective inhibitor of the inducible isoform of nitric oxide synthas e (NOS); 10 mg/kg per dose or 25 mg/kg per dose of N-G-nitro-L-arginin e methyl ester (L-NAME), an inhibitor of the inducible and constitutiv e isoforms of NOS; 200 mg/kg per dose of cross-linked human hemoglobin (HGB), an NO scavenger. SMT significantly prolonged survival in septi c rats, although cumulative survival at T = 168 h was approximately eq uivalent in SMT- or saline-treated animals. In contrast, HGB and the h igher dose of L-NAME significantly shortened survival times. At T = 20 h, arterial Po-2 was significantly lower in rats treated with HGB as compared to time-matched controls. We conclude that SMT, a compound wi th reported activity as a selective inhibitor of the inducible isoform of NOS, prolongs survival in a rat model of antibiotic-treated Gram-n egative sepsis.