Introduction: Septic shock is a serious circulatory disorder with an unacceptable mortality. The detrimental effects of endotoxin such as hypotension and unresponsiveness to both vasodilators and vasoconstrictors were explained by the production of nitric oxide (NO) in copious amounts. Thus it appears feasible to inhibit excessive NO production by using inducible nitric oxide synthase (iNOS) inhibitors in the treatment of septic shock. Therefore, we assessed our hypothesis in a caecal ligation and puncture (CLP) mice model of septic shock in which the overall survival was monitored.
Methods: Male Swiss albino mice (27-41 g, n=15 per group) were randomly allocated into five groups. The first group consisted of sham-operated animals treated with solvent (saline) while the second group (control) underwent CLP procedure. All animals in the third, fourth and fifth groups underwent CLP, but were also given one of the following iNOS inhibitors: AET (S-(2-aminoethyl)-isothiourea bromide hydrobromide; 240 mg/kg/day), SMT (S-methylisothiourea hemisulfate, 10 mg/kg/day) or aminoguanidine (15 mg/kg/day) twice daily for the following seven days commencing just after the surgery. The survival rates were then recorded and analyzed accordingly by using the log-rank test. Histopathological examinations of liver and spleen were also performed at the end of the experimental protocols.
Results: At 168 h (7 days) after the surgery the survival rate was 93.3% in sham-operated animals but decreased to 33.3% (P<0.01 vs. sham-operated) in controls which underwent CLP. However, the survival rates were 66.6% for the third and 60.0% for the fourth and the fifth groups (i. e. iNOS inhibitor treated) which were not significantly different than that of controls.
Conclusion: In our study, although an apparent improvement has been observed with new iNOS inhibitor usage, the magnitude of the beneficial effects has failed to reach statistical significance. Although SMT, AET and aminoguanidine had beneficial effects in many studies; we showed that selective iNOS inhibitors have no beneficial effects in a murine CLP model of septic shock.