title: Role of reactive oxygen species in the regulation of cardiac contractility.
abstract: Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K(ATP) channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K(ATP) channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondrial K(ATP) channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of β(1)-adrenergic receptor agonist dobutamine (250nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase-derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, β-adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Kubin
authors.forename: Réka
authors.initials: R
authors.lastname: Skoumal
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
authors.forename: Attila
authors.initials: A
authors.lastname: Kónyi
authors.forename: Abel
authors.initials: A
authors.lastname: Perjés
authors.forename: Hanna
authors.initials: H
authors.lastname: Leskinen
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: István
authors.initials: I
authors.lastname: Szokodi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004996:Ethidium / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D019332:Endothelin-1; D004996:Ethidium; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017382:Reactive Oxygen Species; D000099211:Phospholamban; C067883:dihydroethidium