title: Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling.
abstract: Nitroxyl anion (NO(-)) is the one-electron reduction product of nitric oxide (NO( small middle dot)) and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO(-) in vivo remains unknown. The NO(-) generator Angeli's salt (AS, Na(2)N(2)O(3)) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-l-cysteine. Cardiac inotropic signaling by NO(-) was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP(8-37) prevented this effect but not systemic vasodilation. Thus, NO(-) is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO(-) to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO(-) may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.
authors.affiliation: Division of Cardiology, Department of Medicine, and Department of Biomedical Engineering, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: N
authors.initials: N
authors.lastname: Paolocci
authors.forename: W F
authors.initials: WF
authors.lastname: Saavedra
authors.forename: K M
authors.initials: KM
authors.lastname: Miranda
authors.forename: C
authors.initials: C
authors.lastname: Martignani
authors.forename: T
authors.initials: T
authors.lastname: Isoda
authors.forename: J M
authors.initials: JM
authors.lastname: Hare
authors.forename: M G
authors.initials: MG
authors.lastname: Espey
authors.forename: J M
authors.initials: JM
authors.lastname: Fukuto
authors.forename: M
authors.initials: M
authors.lastname: Feelisch
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
authors.forename: D A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D000838:Anions; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000502:physiology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006152:Cyclic GMP / Q000502:physiology; D004285:Dogs; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000494:pharmacology; D009573:Nitrites / Q000097:blood / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000838:Anions; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D009566:Nitrates; D009573:Nitrites; D009589:Nitrogen Oxides; D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); C021229:oxyhyponitrite; D009569:Nitric Oxide; C039900:nitroxyl; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide