The signal transduction of ischemic preconditioning involves activation of endogenous receptor-based systems, including alpha 1-adrenoceptors and adenosine receptors. Whereas preconditioning protects against ischemia-reperfusion injury, it is unknown whether this protective strategy might be useful clinically. Furthermore, human atrium has been successfully preconditioned, but it is unknown whether human ventricle can be functionally protected against hypoxia-reoxygenation. To study these questions, isolated rat ventricle and human ventricular trabeculae were suspended in an organ bath and subjected to 30 min of hypoxia and 60 min of reoxygenation. In the rat ventricle, preconditioning was induced by 5 min of rapid pacing at 3 Hz in hypoxic buffer without glucose (simulated ischemia), alpha 1-adrenoceptor stimulation (phenylephrine), or adenosine receptor stimulation (adenosine). In the human trabeculae the effects of preceding simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation were examined against hypoxia-reoxygenation. In the rat, pretreatment with simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation improved recovery of developed tension (56 +/- 3, 56 +/- 4, and 58 +/- 2%, respectively) compared with control trabeculae (25 +/- 2%) after hypoxia-reoxygenation (P < 0.05). In human trabeculae, simulated ischemic preconditioning and alpha 1-adrenoceptor and adenosine receptor stimulation augmented recovery of developed tension (65 +/- 5, 59 +/- 6, and 60 +/- 3%, respectively) compared with control (29 +/- 2%) after hypoxia-reoxygenation (P < 0.05). We conclude that functional cardioadaptation (preconditioning) against hypoxia-reoxygenation injury in rat and human myocardium exists and that alpha 1-adrenergic and adenosine receptor signaling participate in conferring this protection.