A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system

doi:10.1073/pnas.1430507100

A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system

^*Radiation Biology Branch, Building 10, Room B3-B69, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; ^§Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; ^¶Department of Molecular and Medical Pharmacology, Center for the Health Sciences, University of California, Los Angeles, CA 90095; ^∥Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; and ^**Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved May 20, 2003 (received for review February 20, 2003)

Abstract

The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual redox reactions in biological systems. However, several recent studies have demonstrated distinct pharmacological effects for donors of these two species. Here, infusion of the HNO donor Angeli's salt into normal dogs resulted in elevated plasma levels of calcitonin gene-related peptide, whereas neither the NO donor diethylamine/NONOate nor the nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely, plasma cGMP was increased by infusion of diethylamine/NONOate or nitroglycerin but was unaffected by Angeli's salt. These results suggest the existence of two mutually exclusive response pathways that involve stimulated release of discrete signaling agents from HNO and NO. In light of both the observed dichotomy of HNO and NO and the recent determination that, in contrast to the O₂/ $\text{[math]}$ couple, HNO is a weak reductant, the relative reactivity of HNO with common biomolecules was determined. This analysis suggests that under biological conditions, the lifetime of HNO with respect to oxidation to NO, dimerization, or reaction with O₂ is much longer than previously assumed. Rather, HNO is predicted to principally undergo addition reactions with thiols and ferric proteins. Calcitonin gene-related peptide release is suggested to occur via altered calcium channel function through binding of HNO to a ferric or thiol site. The orthogonality of HNO and NO may be due to differential reactivity toward metals and thiols and in the cardiovascular system, may ultimately be driven by respective alteration of cAMP and cGMP levels.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: wink{at}box-w.nih.gov or kmiranda{at}email.arizona.edu.
↵ ‡ Present address: Department of Chemistry, University of Arizona, 1306 East University Boulevard, Tucson, AZ 85721.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AS, Angeli's salt (Na₂N₂O₃); CGRP, calcitonin gene-related peptide; ferricyt c, ferricytochrome c; DEA/NO, diethylamine/NO adduct ([Et₂NN(O)NO]Na); DHR, dihydrorhodamine 123; GSH, reduced glutathione; HRP, horseradish peroxidase; metMb, ferric myoglobin; NAC, N-acetylcysteine; NOS, NO synthase; NTG, nitroglycerin; oxyMb, oxymyoglobin; RH, rhodamine 123; RNOS, reactive nitrogen oxide species; SOD, superoxide dismutase; HNO, nitrosyl hydride.