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...

Abstract-Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism.We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N G -monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the ϩ26.2Ϯ3.5% and ϩ66.5Ϯ17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MV O 2 ) while lowering left ventricular external work, reducing efficiency by 31.1Ϯ3.8% (PϽ0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure. Key Words: xanthine oxidase Ⅲ oxidative stress Ⅲ nitric oxide Ⅲ heart failure Ⅲ ascorbate T he failing heart displays substantial energetic inefficiency in both isolated muscle 1,2 and intact chambers. [3][4][5] This phenomenon can be best described as "mechanoenergetic uncoupling," given that the depression of contractile force is not matched by a concomitant depression of energy consumption. Among the proposed mechanisms is enhanced oxidative stress stemming from mitochondrial 6 and cytosolic free radical generating systems. 7 Xanthine oxidase (XO) is prominent among these enzymes, because it produces superoxide as a byproduct of the terminal two steps of purine metabolism. 3 XO is upregulated in failing myocardium of experimental animals 3,8 and humans, 9 and its inhibition by allopurinol improves the mechanical efficiency (the ratio between ventricular work performed and oxygen consumed) of intact failing hearts 3,9 ; such an effect was predicted by the initial observations that allopurinol and oxypurinol augment calcium-activated force without increasing activator Ca 2ϩ in isolated cardiac muscle. 2 To date, however, the signal transduction mechanisms of the salutary effects o...

Reverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.

1 Inhibition of cardiomyocyte-speci®c ATP-sensitive potassium (K ATP ) channels prolongs the action potential during intense ischaemia with attendant antiarrhythmic eects. However, this is accompanied by contractile depression in some models. These changes may be particularly troublesome in dilated cardiomyopathic hearts that display basal systolic dysfunction, limited energy reserve, and prolonged repolarization favouring arrhythmia. Mechanical eects of selective myocyte K ATP channel blockade on basal, b-adrenergic stimulated, and ischemic responses were therefore tested in dogs with cardiac failure induced by tachypacing. 2 Cardiovascular function was assessed by pressure ± dimension relationships in 10 conscious, chronically instrumented dogs (sonomicrometry/micromanometry), with or without cardiac failure. Cardiomyocyte K ATP channels were inhibited by HMR 1098, and data obtained under basal conditions, during epinephrine infusion to raise metabolic demand, during regional ischaemia, and with combined ischaemia+epinephrine. 3 HMR 1098 had no eect on baseline cardiac function nor did it induce arrhythmia in normal or failing hearts. Epinephrine raised cardiac work 65% and oxygen consumption 55%, yet HMR 1098 had no functional eect in either heart condition. Regional ischaemia with or without epinephrine co-stimulation depressed regional and global function, yet both were also unaected by HMR 1098. There was minimal arrhythmia without HMR 1098, and drug infusion did not alter this. 4 Thus, myocyte-K ATP channels play a negligible role modulating intact in vivo cardiac contraction or arrhythmia in normal and failing heart with and without increased metabolic demand and/or regional ischaemia. This supports the feasibility of administering such agents to depressed hearts, despite underlying contractile and electrophysiologic abnormalities.

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