Hydrolysis of Acyloxy Nitroso Compounds Yields Nitroxyl (HNO)

Abstract

Nitroxyl (HNO/NO(-)), the reduced form of nitric oxide, has gained attention based on its separate chemistry and biology from nitric oxide. The inherent reactivity of HNO requires new and mechanistically unique donors for the detailed study of HNO chemistry and biology. Oxidation of cyclohexanone oxime with lead tetraacetate yields 1-nitrosocyclohexyl acetate, whereas oxidation of oximes in the presence of excess carboxylic acid gives various acyloxy nitroso compounds. These bright blue compounds exist as monomers as indicated by their infrared, proton, and carbon NMR spectra, and X-ray crystallographic analysis reveals the nitroso groups possess a "nitroxyl-like" bent configuration. Hydrolysis of these compounds produces nitrous oxide, the dimerization and dehydration product of HNO, and provides evidence for the intermediacy of HNO. Both thiols and oxidative metal complexes inhibit nitrous oxide formation. Hydrolysis of these compounds in the presence of ferric heme complexes forms ferrous nitrosyl complexes providing further evidence for the intermediacy of HNO. Kinetic analysis shows that the rate of hydrolysis depends on pH and the structure of the acyl group of the acyloxy nitroso compound. These compounds relax pre-constricted rat aortic rings similar to known HNO donors. Together, these results identify acyloxy nitroso compounds as a new class of HNO donors.

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

“…An alternative putative HNO donor, 1-NCA, has been described, reportedly releasing HNO at physiological pH. Vasodilation and cardiomyocyte contractility are enhanced by 1-NCA in vitro [24][25][26] ; both HNO and NO• may, however, contribute to its actions. Although the half-life of 1-NCA has only been reported in cell-free settings, this has been reported as ≈13 hours in a methanol:neutral buffer mixture 24 (considerably longer than that offered by CXL-1020 or conventional HNO donors).…”

“…24 There is, however, previous evidence implicating both HNO and NO• in its actions in vitro. [24][25][26] We selected this donor here, however, on the basis of both its reportedly longer half-life than that offered by CXL-1020 or conventional HNO donors, as well as its stability as an HNO donor at physiological pH. 24 In the present study, we sought to determine the relative contribution of the 2 redox siblings to the vasodilator properties of 1-NCA, by examining its acute sensitivity to selective scavengers of HNO (L-cysteine) and NO• (hydroxocobalamin) in the normal isolated rat heart ex vivo.…”

Reversal of Isoflurane-Induced Depression of Myocardial Contraction by Nitroxyl via Myofilament Sensitization to Ca2+

“…If ISO inhibits force generation by directly decreasing myofilament Ca 2ϩ responsiveness, agents that increase myofilament Ca 2ϩ responsiveness (so-called Ca 2ϩ sensitizers) should be able to restore force in the presence of this anesthetic agent. We tested this hypothesis by exposing the muscles to the new HNO donor, NCA (Sha et al, 2006; DuMond and King, 2011; Shoman et al, 2011). As we learned earlier, Fig.…”

“…To do so, we determined the steady-state force-Ca 2ϩ relations of individual muscles, before and after skinning. Our second aim was to test whether the HNO donor, 1-nitrosocyclohexyl acetate (NCA) (Sha et al, 2006;Shoman et al, 2011), can restore cardiac force development in the presence of ISO by virtue of its Ca 2ϩ -sensitizing effect (Dai et al, 2007). We hope to demonstrate that HNO, donated by NCA, can restore myocardial contractility during ISO-induced anesthesia and that HNO donors are probably able to provide an inotropic counterbalancing effect in patients displaying compromised cardiac function due to inhalation of volatile anesthetics such as ISO, thus justifying the use of HNO donors for patients with heart failure undergoing inhalational anesthesia.…”

Photoinduced Upregulation of Calcitonin Gene-Related Peptide in A549 Cells through HNO Release from a Hydrophilic Photocontrollable HNO Donor

“…Piloty's acid 26) (PhSO 2 NHOH) and cyanamide 27) (NH 2 CN) also offer only uncontrolled HNO release. King and colleagues reported a useful type of HNO donor, acyloxy nitroso compounds, 28) which have the property of slow release of HNO; they have been useful to elucidate HNO actions, 29) but the HNO release is still uncontrollable.…”