Aminoguanidine inhibits inducible NOS and reverses cardiac dysfunction late after ischemia and reperfusion - Implications for iNOS-mediated myocardial stunning

Background: The functional significance of inducible nitric oxide synthase (iNOS) activation in response to myocardial ischemia and reperfusion (I/R) was investigated. Methods: New Zealand rabbits were randomly treated with e ither placebo, aminoguanidine (AMG; selective iNOS inhibitor), or L-arginin e. Left-ventricular hemodynamics and myocardial blood flow were measured be fore coronary occlusion and 30 minutes and 48 h after initiation of reperfu sion. Results: I/R resulted in left-ventricular dysfunction and increased m yocardial iNOS activity. Placebo treatment had no effects on myocardial fun ction. However, AMG significantly inhibited iNOS activity, significantly im proved left-ventricular maximum + dP/dt and decreased LVEDP, whereas admini stration of L-arginine reduced +dP/dt and slightly increased LVEDP, compare d to AMG-treated animals. Myocardial blood flow in the affected myocardium significantly increased after both AMG and L-arginine. Conclusion: The pres ent data indicate that induction of myocardial iNOS after 48 h I/R contribu tes to the development of reversible left-ventricular dysfunction, suggesti ng the involvement of iNOS in myocardial stunning. Whereas L-arginine is as sociated with further reduction of left-ventricular contractility, continuo us inhibition of iNOS activation by AMG improves left-ventricular performan ce; this may be a novel and clinically important therapeutic modality in ce rtain disease states associated with I/R, including cardiac operations usin g extracorporeal circulation and coronary angioplastic procedures.