Chronic cardiac denervation makes the heart less vulnerable to myocardial ischemia. Chronically denervated hearts subjected to coronary occlusion develop less arrhythmia, small infarcts, greater levels of collateral blood flow, less S-T segment elevation, and maintain a higher level of contractile force than either acutely denervated or innervated hearts. Adequate explanation of mechanisms responsible remians unclear. Recent evidence suggests that these effects are secondary to a 35% reduction in LV oxygen consumption and 37% decrease in LV flow, although considerable controversy still surrounds these findings. Controversy has stemmed from use of different models of denervation and a variety of experimental protocols. The overal goal will be to determine the precise effects of chronic cardiac denervation in conscious animals and correlate these effects with tissue levels of catecholamines. Specifically, we will determine myocardial blood flow (MBF) and LV oxygen extraction in conscious innervated and chronically denervated dogs. Analysis of MBF and MVO2 at different heart rates and afterloads will allow comparisons at several different levels of activity. Another set of experiments will evaluate the responses of innervated and denervated hearts to circumflex occlusion in conscious, sedated dogs. These experiments will analyze changes in performance and regional myocardial blood flow. A separate set of experiments will compare effects of chronic (total) cardiac denervation with two different models of chronic selective sympathectomy on MBF and MFO2 in conscious dogs. Alterations in wall thickness, segment lengths, LVEDP, LV dP/dt and infacrt size (as a function of area at risk) following acute coronary occlusion will be determined in each group. A fourth set of experiments will determine whether a local area of denervation will ameliorate the response to myocardial ischemia to the same extent as total cardiac denervation. Modifications of our surgical denervation procedure is under study in he clinical setting for potential application to coronary bypass candidates. Therefore, we feel strongly that this research has important clinical implications.