TRANSGENIC A(1) ADENOSINE RECEPTOR OVEREXPRESSION INCREASES MYOCARDIAL RESISTANCE TO ISCHEMIA

Activation of myocardial A(1) adenosine receptors (A(1)AR) protects th e heart from ischemic injury, In this study transgenic mice were creat ed using the cardiac-specific alpha-myosin heavy chain promoter and ra t A(1)AR cDNA. Heart membranes from two transgene positive lines displ ayed approximate to 1,000-fold overexpression of A(1)AR (6,574 +/- 965 and 10,691 +/- 1,002 fmol per mg of protein vs, 8 +/- 5 fmol per mg o f 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 devel oped tension (1.2 g vs, 1.6 g, P < 0.05), and similar coronary resista nce, The difference in developed tension was eliminated by pacing, Inj ury of control hearts during global ischemia, indexed by time-to-ische mic contracture, was accelerated by blocking adenosine receptors with 50 mu M 8-(p-sulfophenyl) theophylline but was unaffected by addition of 20 nM N-6-cyclopentyladenosine, an A(1)AR agonist, Thus A(1)ARs in ischemic myocardium are presumably saturated by endogenous adenosine, Overexpressing myocardial A(1)ARs increased time-to-ischemic contractu re and improved functional recovery during reperfusion, The data indic ate that A(1)AR activation by endogenous adenosine affords protection during ischemia, but that the response is limited by A(1)AR number in murine myocardium. Overexpression of A(1)AR affords additional protect ion, These data support the concept that genetic manipulation of A(1)A R expression may improve myocardial tolerance to ischemia.