A selective inhibitor of inducible in nitric oxide synthase prolongs survival in a rat model of bacterial peritonitis: comparison with two 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 vein catheter and i.p. implantation of a gelatin capsule containing a paste (.11 +/- 0.1 g final weight) consisting of sterile rat feces mixed with a suspension (.2 mL) of viable Escherichia coli (strain sm 18; 5.7 x 10(5) colony-forming units) in saline. Beginning at T = 6h, all animals received i.v. ampicillin (85 mg/kg every 12 h) until death or the administration of five doses. At the same time points, pairs of animals received an i.v. dose of either an experimental treatment agent or an appropriate control substance. The following experimental regimens were tested: 5 mg/kg per dose of S-methylisothiourea sulfate (SMT), a selective inhibitor of the inducible isoform of nitric oxide synthase (NOS); 10 mg/kg per dose or 25 mg/kg per dose of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the inducible and constitutive isoforms of NOS; 200 mg/kg per dose of cross-linked human hemoglobin (HGB), an NO scavenger. SMT significantly prolonged survival in septic rats, although cumulative survival at T = 168 h was approximately equivalent in SMT- or saline-treated animals. In contrast, HGB and the higher dose of L-NAME significantly shortened survival times. At T = 20 h, arterial PO2 was significantly lower in rats treated with HGB as compared to time-matched controls. We conclude that SMT, a compound with reported activity as a selective inhibitor of the inducible isoform of NOS, prolongs survival in a rat model of antibiotic-treated Gram-negative sepsis.
Aranow
J S
JS
Department of Surgery, Beth Israel Hospital, Boston, MA 02215, USA.
Zhuang
J
J
Wang
H
H
Larkin
V
V
Smith
M
M
Fink
M P
MP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004927:Escherichia coli Infections / Q000188:drug therapy; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D006454:Hemoglobins / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester