Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo bycalcitonin gene-related peptide signaling

Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO.) and is enzymatically generated by NO synthase in vitro. The physiolog ic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chroni cally instrumented dogs, and pressure-dimension analysis was used to discri minate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload vo lume and diastolic pressure (venodilation) without a change in arterial res istance. There were no associated changes in arterial or venous plasma cGMP . The inotropic response was similar despite reflex blockade with hexametho nium or volume reexpansion, indicating its independence from baroreflex sti mulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with t he pure NO donor diethylamine/NO, which induced a negligible inotropic resp onse and a more balanced veno/arterial dilation. AS-induced positive inotro py, but not systemic vasodilatation, was highly redox-sensitive, being virt ually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic sig naling by NO- was mediated by calcitonin gene-related peptide (CGRP), as tr eatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented t his effect but not systemic vasodilation. Thus, NO- is a redox-sensitive po sitive inotrope with selective venodilator action, whose cardiac effects ar e mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholi nergic peptide signaling. Given its cardiac and vascular properties, NO- ma y prove useful for the treatment of cardiovascular diseases characterized b y cardiac depression and elevated venous filling pressures.