Transgenic A1 Adenosine Receptor Overexpression Increases Myocardial Resistance to Ischemia

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 12; pp. 6541 - 6546
• Main Authors: Matherne, G. Paul, Linden, Joel, Byford, Anne M., Gauthier, Naomi S., Headrick, John P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 10.06.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Agonists; Analysis of Variance; Animals; Biological Sciences; Biology; Cell Membrane - metabolism; Circulatory system; Coronary Vessels - physiology; Coronary Vessels - physiopathology; Female; Heart; Heart - drug effects; Heart - physiology; Heart - physiopathology; Heart Rate; In Vitro Techniques; Ischemia; Ligands; Male; Mice; Mice, Transgenic; Myocardial Contraction - drug effects; Myocardial Ischemia - genetics; Myocardial Ischemia - physiopathology; Myocardial Ischemia - prevention & control; Myocardial Reperfusion; Myocardium - metabolism; Myosin Heavy Chains - biosynthesis; Myosin Heavy Chains - genetics; Promoter Regions, Genetic; Purinergic P1 receptors; Radioligand Assay; Rats; Receptors; Receptors, Purinergic P1 - biosynthesis; Receptors, Purinergic P1 - genetics; Receptors, Purinergic P1 - physiology; Recombinant Fusion Proteins - biosynthesis; Theophylline - analogs & derivatives; Theophylline - pharmacology; Transgenes; Transgenic animals; Vascular Resistance
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.12.6541

Activation of myocardial A1 adenosine receptors (A1AR) protects the heart from ischemic injury. In this study transgenic mice were created using the cardiac-specific α -myosin heavy chain promoter and rat A1AR cDNA. Heart membranes from two transgene positive lines displayed ≈ 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 μ M 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.