Positive inotropic and lusitropic effects of HNO/NO ⁻ in failing hearts: Independence from β-adrenergic signaling

Abstract

Nitroxyl anion (HNO͞NO ؊ ), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO͞NO ؊ augments systolic and diastolic function of failing hearts, and whether contrary to NO͞nitrates such modulation enhances rather than blunts ␤-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO͞NO ؊ generated by Angelis' salt (AS) was infused (10 g͞kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine-(DEA)͞NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed ␤-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA͞NO blunted ␤-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA͞NO or NTG, supporting a proposed role of this peptide to HNO͞NO ؊ cardiotropic action. Thus, HNO͞NO ؊ has positive inotropic and lusitropic action, which unlike NO͞nitrates is independent and additive to ␤-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO͞NO ؊ donors for the treatment of heart failure.nitroxyl ͉ contractility ͉ heart failure ͉ nitric oxide ͉ CGRP O rganic nitrates such as nitroglycerin (NTG) are widely used for the treatment of congestive heart failure (CHF) because of their capacity to unload the heart by balanced venous and arterial vasodilation (1). However, these agents as well as direct nitric oxide (NO) donors also influence cardiac inotropy (2), particularly in the setting of enhanced ␤-sympathetic stimulation (3-6). NO-stimulated guanylyl cyclase increases cGMP thereby blunting adrenergic activation (7,8). This modulation seems more pronounced in failing hearts where inhibition of NO synthase enhances ␤-stimulation more than in normal ventricles (5, 9). The interaction of NO͞cGMP and adrenergic signaling is clinically important, because they are often concomitantly administered to treat cardiovascular decompensation.The nitroxyl anion (HNO͞NO Ϫ ) is the one-electron reduced form of NO, and recent data suggest that this species may provide a very different hemodynamic profile and interaction with ␤-agonists. When administered i.v. to healthy conscious dogs, HNO͞NO Ϫ [generated by Angelis' salt (AS)] has load-and reflex-independent, redox-sensitive positive inotropic and selective venodilator effects that are not mimicked by pure NO donors (10). Part of its mechanism involves release of calcitonin generelated peptide (CGRP), a member of the nonad...

Formation of Nitroxyl and Hydroxyl Radical in Solutions of Sodium Trioxodinitrate

“…Similar to NO ⅐ and NO ϩ , HNO is a potent inducer of the antioxidant protein heme oxygenase 1 (8), exhibits vasorelaxant properties (9), and modulates the activity of thiol-containing proteins, such as aldehyde dehydrogenase (10,11) and the N-methyl-D-aspartate receptor (12,13). In in vivo experiments, Paolocci et al (14) observed that HNO exerts positive inotropic and lusitropic action, which unlike NO ⅐ and nitrates is independent and additive to ␤-adrenergic stimulation and increases the release of plasma calcitonin gene-related peptide; these results suggest that donors of HNO are potential prodrugs for the treatment of heart failure (14). At high doses, HNO has been shown to induce DNA singlestrand breakage (15,16) and a concentration-dependent cytotoxicity in murine thymocytes (16).…”

Visualization of nitroxyl (HNO) in vivo via a lysosome-targetable near-infrared fluorescent probe

“…4 More importantly, HNO can increase systolic force and decrease diastolic pressure in both normal and failing canine hearts through upregulating calcitonin gene-related peptide. 5 Thus, more and more examinations suggest that HNO may provide a powerful therapeutic agent for heart failure cure. Despite biochemical studies have proposed some biosynthetic pathways, for instance, HNO can be formed directly from NO and H2S via a redox reaction.…”

New nitric oxide donors based on ruthenium complexes

“…Increased vascular tone, a typical feature of most forms of hypertension, has been associated with impaired NO signaling. Although the main mechanism of vasodilatation induced by the ruthenium-derived NO donors is due to K + channel activation and membrane hyperpolarization in normotensive rat aorta, we have reported that none of the K + channel subtypes are activated by the NO donor trans-[RuCl( [15] aneN 4 )NO] 2+ in the aorta from renal hypertensive rats (35). These results demonstrate that in this model of hypertension, impaired K + channels can contribute to decreased vasodilatation in response to NO.…”

“…Lunardi et al www.bjournal.com.br nitrovasodilators, which are clinically used to control hypertensive crisis, protect patients from attacks of angina pectoris, and unload the heart during acute heart failure. Numerous other compounds, including NONOates, are available for the experimental generation of NO (3,4). Several NO donors have been used in clinical settings for decades (e.g., nitroglycerin and sodium nitroprusside).…”