During the fall in the ratio of O2 supply to O2 demand following myocardial ischemia, there are still areas of high flow, venous O2 saturation and/or O2 consumption within the ischemic zone. We have evidence that by reducing areas of high O2 consumption within the ischemic zone, propranolol can improve the overall ratio of O2 supply to O2 consumption. Thus, by affecting the spatial heterogeneity of O2 supply and/or O2 consumption it is possible to cause beneficial changes in the ischemic zone. In this grant proposal we would like to study the relationship between O2 supply and O2 consumption and its variability in normal and ischemic myocardium with the ultimate intention of improving this relationship. Both anesthetized open chest dogs and rabbits will be used in five studies. 1. In this series of experiments we intend to study the relationship between myocardial """"""""work"""""""" and heterogeneity, with the underlying hypothesis that work controls heterogeneity. In dog, we will study the effect of increasing work by various means; e.g., pacing, pressure, contractility and volume, on heterogeneity of venous O2 saturation and coronary flow in normal and ischemic myocardium. It is possible that by adjusting the type of work that the heart does, that ischemic damage can be reduced. This also applies to series 2. It is known that by increasing work in different ways, one can have very different O2 costs. We intend to measure local myocardial function through measurements of length and tension and compare it to local O2 consumption obtained from microsphere and microspectrophotometric data. Through increases in myocardial work efficiency it might be possible to reduce ischemic damage. 3. We would like to prove our observation that beta1 adrenoceptors are involved in the control of spatial heterogeneity. We will do this through measurements of beta adrenoceptor number and activity and comparison of these factors to spatial heterogeneity of flow and venous O2 saturation. The effects of short and long term up- and downregulation will be explored. 4. We intend to study various agents that have been proposed to reduce ischemic damage in our dog ischemia model to study how they alter the relationship between O2 supply and O2 consumption. 5. We have developed a method to determine both the total and perfused microvasculature in the heart. This technique will be used to study the changes in diffusion distance brought on by ischemia and treatment and whether it can be manipulated in a beneficial manner. These studies of local O2 supply, O2 consumption, """"""""work"""""""", and diffusion distance allow a complete picture of how ischemia affects a region and what a treatment does at the local level.
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