PRECONDITIONING AGAINST MYOCARDIAL DYSFUNCTION AFTER ISCHEMIA AND REPERFUSION BY AN ALPHA-1-ADRENERGIC MECHANISM

Preconditioning may find ready applicability in humans facing schedule d global cardiac ischemia-reperfusion (IR) during bypass or transplant ation, 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. Pr econditioning by 2 minutes of TI followed by 10 minutes of normal perf usion protected isolated rat left ventricle function assessed after 20 minutes of global, 37-degrees-C ischemia and 40 minutes of reperfusio n. Final recovery of developed pressure (DP) was improved (91.5+/-1.9% of equilibration DP versus unconditioned IR control, 57.4+/-2.4%, P<. 01) and was accompanied by increased contractility (+/-dP/dt). Norepin ephrine release increased after TI, and reserpine pretreatment abolish ed TI preconditioning. This suggests that endogenous norepinephrine me diates functional preconditioning in rat. Brief pretreatment (2 minute s) with exogenous norepinephrine reproduced the protection (89.1+/-1.4 %) of postischemic function. Functional protection persisted after the hemodynamic effects had resolved. Norepinephrine-induced precondition ing was simulated by phenylephrine and blocked by alpha1-adrenergic re ceptor antagonist. TI preconditioning was similarly lost after selecti ve alpha1-adrenergic receptor blockade. We conclude that transient isc hemic preconditioning is mediated by the sympathetic neurotransmitter release and alpha1-adrenergic receptor stimulation. Although the postr eceptor mechanism remains unclear, functional protection after IR does not seem related to the magnitude of ATP depletion and elevation of r esting pressure during ischemia. Rather, the endogenous mechanisms fac ilitate both recovery of mechanical function and ATP repletion during reperfusion.