Large numbers of patients with advanced heart disease undergo anesthesia and surgery each year. Methods of safely anesthetizing these patients are available, but they are frequently associated with delayed emergence and a prolonged period of respiratory depression requiring mechanically assisted ventilation, often in an intensive care setting. The use of the potent inhalation agents in these patients would be ideal from the standpoint of affording a more rapid recovery. However, cardiac contractile depression with these anesthetics can be appreciable and can result in dangerous depression of circulatory function. Antagonism of the depression of cardiac function caused by the potent agents is not readily accomplished with the presently available cardiotonic drugs because of side effects, such as dysrhythmias, associated with their use. It is proposed that a better understanding of the mechanisms which underlie anesthetic-induced negative inotropy will facilitate the development of rational methods for its reversal. The general scientific goals of the presently proposed research are to perform, in isolated, intact, cardiac contractile tissue, a systematic investigation of the effects of general anesthetics on the steps in electromechanical coupling which result in contraction, and to investigate methods for reversing such depression. Specific aims are to study the effects of anesthetics on the sources of calcium which activate contraction, i.e. on the calcium which is derived via transsarcolemmal influx and via intracellular release from the sarcoplasmic reticulum. Determination of the effect of an anesthetic on a particular source of activator calcium will be accomplished by measuring the anesthetic's effect on contractile performance under conditions which inhibit, or enhance the influence of the particular source of calcium on the activation of contraction. Calcium selective microelectrodes will be used to evaluate the effect of anesthetics on calcium movement (calcium influx) during contraction under these conditions. It is expected that knowledge concerning the differential effects of anesthetics on the calcium will suggest which of the several newly developed positive inotropic agents will be effective in reversing their specific negative inotrophic effects. Studies employing these agents will be performed.