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

Abstract

Nitroxyl anion (NO ؊ ) is the one-electron reduction product of nitric oxide (NO ⅐ ) and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO ؊ in vivo remains unknown. The NO ؊ generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine͞NO, which induced a negligible inotropic response and a more balanced veno͞arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO ؊ was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8 -37) prevented this effect but not systemic vasodilation. Thus, NO ؊ is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO ؊ to redox-sensitive cardiac contractile modulation by nonadrenergic͞noncholinergic peptide signaling. Given its cardiac and vascular properties, NO ؊ may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.N itric oxide (NO ⅐ )-related species play a crucial role in diverse physiological processes, including blood pressure regulation, neurotransmission, and cytostatic͞cytotoxic signaling (1). Whereas some NO ⅐ -mediated cardiovascular effects are firmly established, its control over myocardial contractility remains controversial in that positive, negative, or neutral effects can be observed. The net result varies with the tissue preparation, NO ⅐ concentration and donor, and myocardial redox state (2, 3). These factors can critically influence the particular NO ⅐ species generated and, thereby, the net contractile response.Among the NO ⅐ -related species is nitroxyl anion (NO Ϫ ), the one-electron reduction product of NO ⅐ that is formed by NO ⅐ synthase in vitro by direct enzyme action or metabolism of the decoupled NO ⅐ synthase product N G -hydroxy-L-arginine (4-8). At high concentrations of 0.1-5 mM, NO Ϫ seems more cytotoxic than NO ⅐ in vitro, causing DNA strand breaks and base oxidation (9, 10). Like NO ⅐ , NO Ϫ induces vasodilation in vivo and in vitro in association with the formation of iron-nitro...

Induction of Heme Oxygenase 1 by Nitrosative Stress

“…Recent reports using donors of nitroxyl revealed opposite effects by showing either NO Ϫ -mediated exacerbation of post-ischemic myocardial injury (43) or cytoprotection against neuronal damage (57). In another study, the positive inotropic effects of NO Ϫ and its beneficial cardiovascular activities have been reported (58). Although the mechanism by which nitroxyl anion manifests these divergent effects is currently under intense investigation, the possible involvement of this reduced form of NO in the expression of stress inducible genes has not been previously examined.…”

Xerogel Optical Sensor Films for Quantitative Detection of Nitroxyl

“…4 -6 yields: (7) where k 1 [AS] is the rate of Angeli's salt decomposition, and k 2 is the kinetic coefficient of the HNO dimerization reaction (8 × 10 6 M −1 s −1 ). 13 Angeli's salt decomposition rates were determined in PBS by monitoring the decrease in 250 nm absorbance over 60 min and fitting to an exponential decay model (absorbance = Ae −kt + c).…”

“…3 Nitroxyl's high reactivity with thiols and metalloproteins has led to potential pharmaceutical application in protective preconditioning of ischemic injury, 4 treatment for alcohol abuse through targeted inhibition of aldehyde dehydrogenase, 5,6 and as an efficient means of enhancing left ventricular contractility in victims of congestive heart failure. 7 These discoveries have led to efforts focusing on the design and development of new HNO-donor molecules and prodrugs. Research in this area has been hindered by an inability to easily monitor HNO.…”

Metal-Based Optical Probes for Live Cell Imaging of Nitroxyl (HNO)

“…22 Activation of TRPA1 by HNO leads to release of calcitonin gene-related peptide (CGRP), which is an established biomarker of HNO signaling. 23 …”