Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: Independence from β-adrenergic signaling

Nazareno Paolocci, Tatsuo Katori, Hunter C. Champion, Marcus E. St. John, Katrina M. Miranda, Jon M. Fukuto, David A. Wink, David A. Kass

Research output: Contribution to journalArticle

Abstract

Nitroxyl anion (HNO/NO-), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO- augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts β-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO- generated by Angelis' salt (AS) was infused (10 μg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)/NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed β-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted β-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO- cardiotropic action. Thus, HNO/NO- has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to β-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO- donors for the treatment of heart failure.

Original languageEnglish (US)
Pages (from-to)5537-5542
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

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Keywords

  • CGRP
  • Contractility
  • Heart failure
  • Nitric oxide
  • Nitroxyl

ASJC Scopus subject areas

  • General

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