Adenosine A1 receptor activation reduces reactive oxygen species and attenuates stunning in ventricular myocytes.
Reactive oxygen species (ROS) formation following brief periods of ischemia or hypoxia is thought to be the underlying cause of myocardial stunning. Adenosine A1 receptor activation prior to ischemia/hypoxia attenuates stunning, although the mechanism for this effect remains unknown. Isolated rat ventricular myocytes loaded with the ROS-sensitive indicator dichlorofluorescin were subjected to 30 min glucose-free hypoxia followed by reoxygenation. Intracellular ROS increased approximately 175% (from pre-hypoxic levels) during reoxygenation while cell shortening decreased approximately 50%. In myocytes pretreated with the adenosine A1 agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA), reoxygenation-induced ROS formation was attenuated by 40% and stunning was attenuated by 50% (compared to untreated myocytes). The mitochondrial K(ATP) channel opener diazoxide mimicked the effects of CCPA. Pretreatment with the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate, or the non-selective K(ATP) channel blocker glibenclamide, blocked the effects of CCPA. These results suggest that adenosine A1 receptor activation attenuates stunning by reducing ROS formation. These effects of A1 receptor activation appear to be dependent on the opening of K(ATP) channels.
Narayan
P
P
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA. pnaraya@pop.uky.edu
Mentzer
R M
RM
Lasley
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RD
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000814:Aniline Compounds / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D004357:Drug Synergism; D005452:Fluoresceins / Q000032:analysis; D005456:Fluorescent Dyes / Q000032:analysis; D005905:Glyburide / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008856:Microscopy, Fluorescence; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000032:analysis; D014970:Xanthines / Q000494:pharmacology
D000814:Aniline Compounds; D003652:Decanoic Acids; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006880:Hydroxy Acids; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D018047:Receptors, Purinergic P1; D014966:Xanthenes; D014970:Xanthines; C029569:diacetyldichlorofluorescein; C059715:Fluo-3; C058394:2-chloro-N(6)cyclopentyladenosine; C052853:5-hydroxydecanoic acid; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D011188:Potassium; D005905:Glyburide; D002118:Calcium