Positive Inotropic and Lusitropic Effects of HNO/NO-in Failing Hearts: Independence from β-Adrenergic Signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (9), p.5537-5542
• Main Authors: Paolocci, Nazareno, Katori, Tatsuo, Champion, Hunter C., St. John, Marcus E., Miranda, Katrina M., Fukuto, Jon M., Wink, David A., Kass, David A.
• Format: Article
• Language: English
• Subjects: Adrenal glands; Animals; Biological Sciences; Blood plasma; Calcitonin Gene-Related Peptide - blood; Calcium; Cell division; Congestive heart failure; Coronary sinus; Cyclic GMP - blood; Dogs; Drug interactions; Electrons; Heart; Heart failure; Heart Failure - drug therapy; Heart Failure - physiopathology; Hemodynamics; Myocardial Contraction - drug effects; Nitrates; Nitric oxide; Nitrogen Oxides - pharmacology; Nitrogen Oxides - therapeutic use; Pharmacology; Receptors, Adrenergic, beta - metabolism; Signal Transduction; Vasodilation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0937302100

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 ($10\>\mu g/kg$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 calciumsignaling 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.