Nitroxyl (HNO): the Cinderella of the nitric oxide story

Until recently, most of the biological effects of nitric oxide (NO) have been attributed to its uncharged state (NO), yet NO can also exist in the reduced state as nitroxyl (HNO or NO⁻). Putatively generated from both NO synthase (NOS)-dependent and -independent sources, HNO is rapidly emerging as a novel entity with distinct pharmacology and therapeutic advantages over its redox sibling, NO. Thus, unlike NO, HNO can target cardiac sarcoplasmic ryanodine receptors to increase myocardial contractility, can interact directly with thiols and is resistant to both scavenging by superoxide (O₂⁻) and tolerance development. HNO donors are protective in the setting of heart failure in which NO donors have minimal impact. Here, we discuss the unique pharmacology of HNO versus NO and highlight the therapeutic potential of HNO donors in the treatment of cardiovascular disease.

Introduction

The gaseous signalling molecule nitric oxide (NO) has an integral role in several physiological processes including vascular homeostasis, platelet aggregation, inflammation, angiogenesis and fibrinolysis [1]. NO and its oxidised nitrogen oxides peroxynitrite (ONOO⁻), nitrite (NO₂⁻), nitrate (NO₃⁻), nitrogen dioxide (NO₂) and dinitrogen trioxide (N₂O₃) have, thus, attracted considerable attention across physiological and pathophysiological settings. By contrast, reduced congeners of NO such as nitroxyl (HNO), the one-electron reduced and protonated sibling of NO, have been relatively overlooked. Interest in this chemically distinct redox sibling of NO has recently been renewed with evidence that HNO might be produced endogenously [2] and displays unique biological effects compared with NO 3, 4, 5 (Table 1). Such effects include an ability of HNO to directly target thiols, elevate plasma levels of calcitonin gene-related peptide (CGRP, see Glossary) and serve as a positive cardiac inotrope [5], properties that facilitate the use of HNO as a pharmacological agent.

The therapeutic utility of the NO signalling pathway has long been recognized with nitrovasodilators employed in the treatment of cardiovascular disorders such as angina and heart failure for >100 years. The clinical efficacy of traditional NO donors, however, has been limited owing to susceptibility to tolerance development, decreased effectiveness under oxidative-stress conditions and potential cytotoxic effects. Excitingly, HNO donors offer new strategies in the treatment of cardiovascular disease. Upon initial consideration, the cardiovascular actions of HNO and NO seem to be similar with both nitrogen oxides serving as potent vasorelaxants 5, 6, 7. However, HNO, unlike NO, displays distinct interactions with many biomolecules (Table 1), interacting directly with thiols [8] and activating vascular voltage-dependent K⁺ channels (K_v) [6], in addition to increasing plasma CGRP 9, 10, 11 and serving as a cardiac inotrope 9, 10. Indeed, the cardiotropic effects of HNO seem to be related to its unique ability to activate cardiac sarcoplasmic ryanodine receptors [12] and augment myofilament Ca²⁺ sensitivity via thiol interaction [13] in order to increase myocardial contractility, in contrast to NO. Thus, HNO donors, with a concomitant ability to increase myocardial function and unload the heart (induce vasodilation) (Figure 1), have important therapeutic potential in the treatment of heart failure 5, 10. Moreover, HNO is resistant to scavenging by superoxide (O₂⁻) [14], does not develop vascular tolerance [7] and preferentially targets ferric rather than ferrous haem proteins [15]; these properties could preserve its actions under pathophysiological conditions in which NO function is compromised.

With a resurgent interest in HNO and clear clinical applications, here we discuss the pharmacology of HNO within the context of cardiovascular health and disease, exploring potential endogenous pathways via which HNO is formed, its biological targets, regulation of vascular and cardiac function by HNO and new therapeutic avenues.