The emergence of nitroxyl (HNO) as a pharmacological agent

Abstract

Once a virtually unknown nitrogen oxide, nitroxyl (HNO) has emerged as a potential pharmacological agent. Recent advances in the understanding of the chemistry of HNO has led to the an understanding of HNO biochemistry which is vastly different from the known chemistry and biochemistry of nitric oxide (NO), the one-electron oxidation product of HNO. The cardiovascular roles of NO have been extensively studied, as NO is a key modulator of vascular tone and is involved in a number of vascular related pathologies. HNO displays unique cardiovascular properties and has been shown to have positive lusitropic and ionotropic effects in failing hearts without a chronotropic effect. Additionally, HNO causes a release of CGRP and modulates calcium channels such as ryanodine receptors. HNO has shown beneficial effects in ischemia reperfusion injury, as HNO treatment before ischemia-reperfusion reduces infarct size. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. HNO has been demonstrated to inhibit GAPDH, a key glycolytic enzyme. Due to the Warburg effect, inhibiting glycolysis is an attractive target for inhibiting tumor proliferation. Indeed, HNO has recently been shown to inhibit tumor proliferation in mouse xenografts. Additionally, HNO inhibits tumor angiogenesis and induces cancer cell apoptosis. The effects seen with HNO donors are quite different from NO donors and in some cases are opposite. The chemical nature of HNO explains how HNO and NO, although closely chemically related, act so differently in biochemical systems. This also gives insight into the potential molecular motifs that may be reactive towards HNO and opens up a novel field of pharmacological development.

Figure 1. Comparison of HNO and Superoxide Chemistry

(A) Molecular oxygen (O₂) reduction to superoxide (O₂⁻) is thermodynamically unfavorable, as is the reduction of NO to HNO/NO⁻. Further reduction of O₂⁻ to hydrogen peroxide is thermodynamically favorable, as is the reduction of HNO. (B) Reduction of O2 or NO results in an anionic species that has an associated pK_a in aqueous conditions. Superoxide has a pK_a of 4.88 and in neutral conditions the anion is the predominant species. Nitroxyl has a pK_a of 11.4 and the dominant species in biology will be HNO. (C) Superoxide and HNO both auto-react resulting in the destruction of these species.

Figure 2. Potential Mechanisms of Endogenous HNO Formation

HNO has been postulated to be formed from the enzymatic activity of nitric oxide synthase (NOS) in which the substrate arginine is reduced by six electron to yield HNO instead of five electrons to yield NO. Another route is from the decomposition of nitrosothiol by thiols such as glutathione. HNO can also be generated by the oxidation of hydroxylamine from the peroxidase activity of heme proteins.