title: The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature.
abstract: OBJECTIVE
  The nitroxyl anion (HNO) is the one-electron reduction product of NO(). This redox variant has been shown to be endogenously produced and to have effects that are pharmacologically distinct from NO(). This study investigates the vasodilator and chronotropic effects of HNO in the rat isolated coronary vasculature.
  
  
  METHODS
  Sprague-Dawley rat hearts were retrogradely perfused with Krebs' solution (8 ml/min) using the Langendorff technique. Perfusion pressure was raised using a combination of infusion of phenylephrine and bolus additions of the thromboxane mimetic U46619 to attain a baseline perfusion pressure of 100-120 mm Hg. The vasodilator effects of a nitroxyl anion donor, Angeli's salt, were examined in the absence and presence of HNO and NO* scavengers, K+ channel inhibition, and soluble guanylate cyclase (sGC) inhibition. In addition, the inotropic and chronotropic effects of Angeli's salt were examined in hearts at resting perfusion pressure (50-60 mm Hg) and compared to responses evoked by acetylcholine and isoprenaline.
  
  
  RESULTS
  Angeli's salt causes a potent and reproducible vasodilatation in isolated perfused rat hearts. This response is unaffected by the NO* scavenger hydroxocobalamin (0.1 mM) but is significantly inhibited by the HNO scavenger N-acetyl-L-cysteine (4 mM), suggesting that HNO is the mediator of the observed responses. Vasodilatation responses to Angeli's salt were virtually abolished in the presence of the sGC inhibitor ODQ (10 microM). The magnitude of the vasodilatation response to Angeli's salt was significantly reduced in the presence of 30 mM K+, 10 microM glibenclamide and in the presence of the calcitonin gene-related peptide (CGRP) antagonist CGRP((8-37)) (0.1 microM). Angeli's salt had little effect on heart rate or force of contraction, whilst isoprenaline and acetylcholine elicited significant positive and negative cardiotropic effects, respectively.
  
  
  CONCLUSIONS
  The HNO donor Angeli's salt elicits a potent and reproducible vasodilatation response. The results suggest that the response is elicited by HNO through sGC-mediated CGRP release and K(ATP) channel activation.
authors.affiliation: Department of Pharmacology and Centre for Vascular Health Initiative, School of Biomedical Sciences, Monash University, Clayton Vic 3800, Australia. joanne.favaloro@med.monash.edu.au
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Favaloro
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
mesh_terms: D000109:Acetylcholine; D000818:Animals; D000838:Anions / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009573:Nitrites / Q000494:pharmacology*; D009589:Nitrogen Oxides; D010069:Oxadiazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012977:Sodium Nitrite / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000838:Anions; D000975:Antioxidants; D009573:Nitrites; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D010446:Peptide Fragments; D011810:Quinoxalines; C058636:calcitonin gene-related peptide (8-37); C021229:oxyhyponitrite; D006162:Guanylate Cyclase; C039900:nitroxyl; D009543:Nifedipine; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D012977:Sodium Nitrite; D000109:Acetylcholine; D011188:Potassium