Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling.
Nitroxyl anion (HNONO(-)), 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 beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/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 beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-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 beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.
Paolocci
Nazareno
N
Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Katori
Tatsuo
T
Champion
Hunter C
HC
St  John
Marcus E
ME
Miranda
Katrina M
KM
Fukuto
Jon M
JM
Wink
David A
DA
Kass
David A
DA
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects*; D009589:Nitrogen Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D009589:Nitrogen Oxides; D011943:Receptors, Adrenergic, beta; C039900:nitroxyl; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide