Preconditioning may find ready applicability in humans facing scheduled global cardiac ischemiareperfusion (IR) during bypass or transplantation, where such a maneuver is feasible before arrest. Our objective was to delineate and exploit the endogenous preconditioning mechanism triggered by transient ischemia (TI) and thereby attenuate myocardial postischemic mechanical dysfunction by clinically acceptable means. Preconditioning by 2 minutes of TI followed by 10 minutes of normal perfusion protected isolated rat left ventricle function assessed after 20 minutes of global, 37°C ischemia and 40 minutes of reperfusion. Final recovery of developed pressure (DP) was improved (91.5±l.9%o of equilibration DP versus unconditioned IR control, 57.4+2.4%, P<.01) and was accompanied by increased contractility (±dP/dt). Norepinephrine release increased after TI, and reserpine pretreatment abolished TI preconditioning. This suggests that endogenous norepinephrine mediates functional preconditioning in rat. Brief pretreatment (2 minutes) with exogenous norepinephrine reproduced the protection (89.1+1.4%) of postischemic function. Functional protection persisted after the hemodynamic effects had resolved. Norepinephrine-induced preconditioning was simulated by phenylephrine and blocked by al-adrenergic receptor antagonist. TI preconditioning was similarly lost after selective ovl-adrenergic receptor blockade. We conclude that transient ischemic preconditioning is mediated by the sympathetic neurotransmitter release and at,-adrenergic receptor stimulation. Although the postreceptor mechanism remains unclear, functional protection after IR does not seem related to the magnitude of ATP depletion and elevation of resting pressure during ischemia. Rather, the endogenous mechanisms facilitate both recovery of mechanical function and ATP repletion during reperfusion. (Circ Res. 1993;73:656-670.) KEY WoRDs * adaptation * preconditioning mechanism * myocardial function * norepinephrine * cl-adrenergic receptors * ATP * rat heart T he high rate of energy turnover in myocardial tissue renders the heart very susceptible to ischemia.' Although perfusion must be restored to preserve myocardial function and viability, reperfusion can itself be deleterious.12 Yet, the 150 000 cardiopulmonary bypass and 1000 heart transplantation operations performed annually necessitate extended periods of myocardial ischemia with subsequent reperfusion. Although myocardial dysfunction becomes progressively irreversible with extended ischemia, brief periods of myocardial ischemia trigger an adaptive response that protects the heart against sustained ischemia and reperfusion.2-4 This "preconditioning" phenomenon suggests that transient ischemia (TI) induces intrinsic changes within the myocardium, thereby enhancing its resistance to subsequent ischemia-reperfusion (IR) injury. These protective changes appear effective against a range of post-IR pathophysiology, including stunning, arrhythmias, and infarction. If this preconditioning effect

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