title: Transgenic A1 adenosine receptor overexpression increases myocardial resistance to ischemia.
abstract: Activation of myocardial A1 adenosine receptors (A1AR) protects the heart from ischemic injury. In this study transgenic mice were created using the cardiac-specific alpha-myosin heavy chain promoter and rat A1AR cDNA. Heart membranes from two transgene positive lines displayed approximately 1,000-fold overexpression of A1AR (6,574 +/- 965 and 10,691 +/- 1,002 fmol per mg of protein vs. 8 +/- 5 fmol per mg of protein in control hearts). Compared with control hearts, transgenic Langendorff-perfused hearts had a significantly lower intrinsic heart rate (248 beats per min vs. 318 beats per min, P < 0. 05), lower developed tension (1.2 g vs. 1.6 g, P < 0.05), and similar coronary resistance. The difference in developed tension was eliminated by pacing. Injury of control hearts during global ischemia, indexed by time-to-ischemic contracture, was accelerated by blocking adenosine receptors with 50 microM 8-(p-sulfophenyl) theophylline but was unaffected by addition of 20 nM N6-cyclopentyladenosine, an A1AR agonist. Thus A1ARs in ischemic myocardium are presumably saturated by endogenous adenosine. Overexpressing myocardial A1ARs increased time-to-ischemic contracture and improved functional recovery during reperfusion. The data indicate that A1AR activation by endogenous adenosine affords protection during ischemia, but that the response is limited by A1AR number in murine myocardium. Overexpression of A1AR affords additional protection. These data support the concept that genetic manipulation of A1AR expression may improve myocardial tolerance to ischemia.
authors.affiliation: Department of Pediatrics, Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Matherne
authors.forename: J
authors.initials: J
authors.lastname: Linden
authors.forename: A M
authors.initials: AM
authors.lastname: Byford
authors.forename: N S
authors.initials: NS
authors.lastname: Gauthier
authors.forename: J P
authors.initials: JP
authors.lastname: Headrick
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003331:Coronary Vessels / Q000502:physiology / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006339:Heart Rate; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014655:Vascular Resistance
chemical_list: D018047:Receptors, Purinergic P1; D011993:Recombinant Fusion Proteins; C048599:N(6)-cyclopentyladenosine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D018995:Myosin Heavy Chains; D000241:Adenosine