Effect of Simulated Preconditioning on Neural Response During Ischemia.Introduction:Preconditioning the myocardium with brief episodes of ischemia preserves efferent autonomic responsiveness of noninfarcted myocardium apical to a site of acute transmural ischemia by mechanism(s) still unknown. We hypothesized that repeated brief exposure of the myocardium to a simulated ischemic milieu including hypoxia, high K. low pH, and adenosine would be as effective as brief coronary occlusions in creating this protection.Methods and Results:Open chest anesthetized dogs received an extra corporeal bypass between the left carotid artery and a diagonal branch of the left anterior descending coronary artery. We analyzed the effects of simulated ischemia on the time course and extent of efferent sympathetic denervation during a subsequent 3‐hour sustained ischemia in three groups of dogs: two groups of dogs underwent four cycles of 5‐minute intracoronary perfusion with either hypoxic altered Tyrode's solution (12 mM K+, 6.8 pH, and 10 μ adenosine; n = 11) or normal Tyrode's solution mil. Each Tyrode's perfusion was separated by 5 minutes of blood perfusion prior to permanent coronary occlusion by latex remobilization of the annulated coronary artery. A third group received a continuous 3‐hour blood perfusion before the final ischemic episode (n = 5). Shortening of effective refractory periods (ERPs) induced by bilateral ansae subelaviae stimulation (2 to 4 Hz) basal and apical to the intervention site was determined before and after perfusions and 20, 60, 120, and 180 minutes after sustained occlusion. In all groups, sympathetically‐induced ERP shortening was unchanged at basal sites throughout the experiment. ERP shortening at apical sites was unchanged after perfusions with either the altered or normal Tyrode's solution or after a continuous 3‐hour blood perfusion. However, EKP shortening became significantly attenuated at apical sites after coronary occlusion in all groups. Neither the size in reduction of sympathetically‐induced ERP shortening at apical test sites nor the cumulative percentage of denervated apical test sites (≤ 2‐msec shortening) during a 3‐hour period of permanent ischemia differed significantly among groups (P = 0.052 and P = 0.752, respectively). The degree of subepicardial involvement in the myocardial infarction was comparable among groups.Conclusion:Thus, brief exposure of the left ventricular myocardium to ischemic metabolites prior to a subsequent permanent coronary occlusion does not trigger mechanism(s) that are responsible for protection against efferent sympathetic denervation apical to an area of trans‐mural myocardial