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

247 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Adrenergic Agents
Nitric Oxide
Calcitonin Gene-Related Peptide
Nitroglycerin
Nitric Oxide Donors
Nitrates
Heart Failure
Dobutamine
Calcium Signaling
Treatment Failure
Isoproterenol
Tachycardia
Propranolol
Anions
oxyhyponitrite
Dogs
Electrons
Peptides

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Positive inotropic and lusitropic effects of HNO/NO- in failing hearts : Independence from β-adrenergic signaling. / Paolocci, Nazareno; Katori, Tatsuo; Champion, Hunter C.; St. John, Marcus E.; Miranda, Katrina M; Fukuto, Jon M.; Wink, David A.; Kass, David A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 9, 29.04.2003, p. 5537-5542.

Research output: Contribution to journalArticle

Paolocci, Nazareno ; Katori, Tatsuo ; Champion, Hunter C. ; St. John, Marcus E. ; Miranda, Katrina M ; Fukuto, Jon M. ; Wink, David A. ; Kass, David A. / Positive inotropic and lusitropic effects of HNO/NO- in failing hearts : Independence from β-adrenergic signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 9. pp. 5537-5542.
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AU - Paolocci, Nazareno

AU - Katori, Tatsuo

AU - Champion, Hunter C.

AU - St. John, Marcus E.

AU - Miranda, Katrina M

AU - Fukuto, Jon M.

AU - Wink, David A.

AU - Kass, David A.

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N2 - 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.

AB - 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.

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