Biosynthesis of constitutive nitric oxide synthase-derived nitric oxide attenuates coronary vasoconstriction and myocardial depression in a model of septic heart failure induced by Staphylococcus aureus alpha-toxin

Objective: Myocardial depression, which frequently occurs in the course of septic shock, has been attributed to the cardiodepressant properties of nit ric oxide (NO) generated by either the inducible NO synthase (iNOS) or the constitutive isoform (cNOS). We have previously demonstrated that alpha -to xin from Staphylococcus aureus induces thromboxane-mediated vasoconstrictio n accompanied by severe cardiodepression in isolated rat hearts. In the pre sent study, we investigated the role of NO in the alpha -toxin-induced vasc ular and contractile abnormalities. Design: Prospective, experimental study. Setting: Research laboratory at a university hospital. Subjects: Isolated hearts from male Wistar rats. Interventions: Isolated hearts were perfused with purified staphylococcal a lpha -toxin for 60 mins. Measurements and Main Results: At a concentration of 0.25 and 0.5 mug/mL, a lpha -toxin induced a rise in coronary perfusion pressure, depressed myocar dial contractility, and caused edema formation. Simultaneously, a time- and dose-dependent rapid release of NO into the perfusate was noted as quantif ied by a chemiluminescence technique. L-NMMA, a nonselective inhibitor of N OS, but not PBITU, an iNOS-selective inhibitor, blocked NO synthesis, marke dly increased the rise in coronary perfusion pressure and the loss in contr actility, and enhanced edema formation in response to alpha -toxin. In cont rast, zaprinast, a selective inhibitor of phosphodiesterase type V that is used for stabilization of cyclic guanosine monophosphate, attenuated the to xin-induced coronary vasoconstrictor response and the myocardial depression . L-arginine, the substrate of NOS, had similar, yet less potent, effects a s zaprinast and slightly increased the release of NO caused by alpha -toxin . Immunohistochemical analysis of the myocardium at the end of the perfusio n period demonstrated a positive staining for cNOS but not for iNOS. In add ition, no up-regulation of iNOS mRNA was detected in the tissue of toxin-ex posed hearts. Conclusions: Staphylococcal alpha -toxin provokes NO biosynthesis via activ ation of cNOS in rat hearts. MO partly antagonizes the deleterious effects of this pathogenicity factor on coronary vasoregulation and myocardial perf ormance.