title: Endogenous adenosine reduces depression of cardiac function induced by beta-adrenergic stimulation during low flow perfusion.
abstract: High levels of norepinephrine in the heart are cardiotoxic resulting in contractile dysfunction and arrhythmic activity via beta-adrenoceptor mediated mechanisms. A low flow heart model perfused with physiological saline containing glucose and bubbled with an O2 gas mixture was used to determine whether adenosine, a nucleoside with antiadrenergic properties, could reduce the functional manifestations of catecholamine cardiotoxicity. Isolated rat hearts were treated with dipropylcyclopentylxanthine (DPCPX; 0.1 microM; A1 receptor antagonist) to block endogenous adenosine. In DPCPX-treated hearts stimulated with isoproterenol (ISO; 1 microM) during 45 min of low flow (0.5 ml/min) perfusion, the recovery of contractile function (ConF) at 15 min after the restoration of normal flow was 64% of control (before low flow) values as compared to 110% recovery of ConF in the absence of ISO. The incidence of arrhythmias observed upon restoration of control flow was increased by ISO when the action of endogenous adenosine was blocked with DPCPX. In the absence of DPCPX both the functional depression and arrhythmias induced by ISO were prevented in the presence of phenylisopropyladenosine (PIA; 1 microM; A1 receptor agonist). At 15 min after normal flow was restored. ConF in ISO-treated hearts with PIA was 53% greater than in the absence of PIA and presence of DPCPX. This enhancement of ConF by PIA was significantly reduced by DPCPX. By 30 min after flow restoration, these significant differences were absent. DPCPX reversed the PIA-induced reduction in arrhythmias observed upon restoration of normal flow. PIA and DPCPX alone in the absence of ISO, and ISO in the absence of PIA and DPCPX, did not result in altered ConF upon restoration of normal flow. These findings indicate that intense beta-adrenergic stimulation of the heart during low-flow perfusion in the absence of adenosine A1 receptor activity induces contractile depression and arrhythmicity subsequent to restoration of control perfusion. It is concluded that endogenous adenosine protects the heart against catecholamine toxicity via stimulation of adenosine A1 receptors.
authors.affiliation: Department of Physiology, University of Massachusetts Medical School, Worcester 01655, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Fenton
authors.forename: K J
authors.initials: KJ
authors.lastname: Galeckas
authors.forename: J G
authors.initials: JG
authors.lastname: Dobson
mesh_terms: D000241:Adenosine / Q000502:physiology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D003326:Coronary Circulation; D004837:Epinephrine / Q000378:metabolism; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D010477:Perfusion; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D058915:Purinergic P1 Receptor Antagonists; D011943:Receptors, Adrenergic, beta; D018047:Receptors, Purinergic P1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D007545:Isoproterenol; D004837:Epinephrine