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An attempt to determine the consequences of prolonged ischemia on simultaneous regional changes in norepinephrine (NE) and neuropeptide Y (NPY) interstitial myocardial concentrations in a pig modelin vivowas made. The aim of the authors was to investigate further the mechanism of the major NE release previously observed in perfused hearts preserved using a Langendorff technique. Regional myocardial ischemia was induced by ligation of the left anterior descending coronary artery (LAD) in ten anesthetized pigs. NE and NPY release was studied using interstitial microdialyis, a technique initially used to monitor neurotransmitter kinetics in brain dialysate samples. Four dialysis probes were implanted into the left ventricular wall of the beating heart. Two were implanted into the ischemic region (LAD) (for NE and NPY determinations, respectively) and the remaining two into the non-ischemic left circumflex coronary artery region (LCX). Dialysate NE and NPY concentrations, as indices of interstitial myocardial NE and NPY concentrations, were measured by HPLC and RIA, respectively. A slight but significant increase in NPY levels was observed in both territories (LAD: from 190±27 to 349±62 pmol/l, LCX: 146±30 to 257±52 pmol/l) suggesting moderate stimulation of cardiac sympathetic nerve activity following LAD occlusion. On the contrary, a marked but progressive increase in NE release was observed in the ischemic region (from 8.8±1.0 to 251.4±44.8 nmol/l), when NE levels in the non-ischemic region remained stable (from 10.3±2.1 to 11.0±1.9 nmol/l). These results demonstrate the utility of regionalin-vivomyocardial NE and NPY monitoring using microdialysis. The strong and sustained NE accumulation occurring in the ischemic region is consistent with the hypothesis of a local non-exocytotic metabolic NE release in case of prolonged myocardial ischemia, when exocytotic release remain only minimal as attested by the slight increase in NPY observed.