Effects of inducible nitric oxide synthase and neuronal nitric oxide synthase inhibition on methicillin-resistant Staphylococcus aureus sepsis

Background

Methicillin-resistant Staphylococcus aureus (MRSA)-induced sepsis/septic shock is a major cause of death in the ICU. We have previously reported that excessive nitric oxide (NO) plays a key role in impaired cardiovascular function during MRSA sepsis. In the present study, we demonstrate a role of inducible (iNOS) and neuronal (nNOS) nitric oxide synthase-derived excessive NO in MRSA-induced cardiovascular morbidity using potent and selective iNOS dimerization inhibitor BBS-2 and selective nNOS inhibitor 7-nitroindazole (7-NI).

Methods

Ewes were operatively prepared and randomized after a 5-day to 7-day recovery period to the groups: sham (noninjured, nontreated, n = 6); control (injured, nontreated, n = 6); BBS-2 (injured, treated with BBS-2, n = 5); and 7-NI (injured, treated with 7-NI, n = 3). Injury consisted of insufflation of 48 breaths of cotton smoke followed by instillation of 2 to 5 × 10¹¹ colony-forming units of live MRSA into the airways of the sheep. BBS-2 (100 μg/kg/hour) and 7-NI (1 mg/kg/hour) was given starting from 1 hour to the end of the study (24 hours).

Results

Hemodynamic variables were stable in sham animals. Control sheep developed a hyperdynamic circulatory state as evidenced by a significant increase in cardiac output and a severe fall in mean arterial pressure (Table 1). BBS-2 significantly attenuated hypotension 12 and 18 hours (P < 0.05) post injury. In contrary, 7-NI reversed the fall in blood pressure at a later time point. Severe fluid retention seen in control animals was reduced by 7-NI, but not by BBS-2. 7-NI also improved oxygenation. Elevated levels of heart tissue 3-nitrotyrosine (marker of peroxy-nitrite formation) and poly (ADP)ribose (footprint of DNA damage) were attenuated by both iNOS and nNOS inhibition.

Table 1 Hemodynamic variables

Conclusion

iNOS inhibition had a partial effect in MRSA sepsis-related cardiovascular morbidity. However, nNOS inhibition had a stronger effect on both severe hypotension and fluid retention following MRSA sepsis. Since nonspecific NOS inhibition is associated with unwanted side effects, more targeted inhibition of NO using specific NOS inhibitors may be a useful tool against the MRSA sepsis-related menace.