1  Department of Pediatrics and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and 2  The Rotary Center for Cardiovascular Research, Griffith University Gold Coast Campus, Southport, Q 4217 Australia The role of A 1 adenosine receptors (A 1 AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A 1 AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A 1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691   ± 1,256 U · l 1 · g 1 · min 1 ) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A 1 AR. Compared with wild-type hearts, A 1 AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l 1 · g 1 · min 1 ) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A 1 AR. The beneficial effects of preconditioning and A 1 AR overexpression are not additive. Taken with the observation that A 1 AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A 1 AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways. mouse; heart; lactose dehydrogenase; infarct size