The proposed research is planned to investigate basic membrane mechanisms involved in the cardiodepressant effects of volatile anesthetic agents. Although the plasma membrane of excitable cells is considered to be the primary site of action of these agents, the mechanism(s) by which these agents decrease myocardial contractility is unknown. Recent evidence that these agents alter sarcolemma Ca2+ channel fluxes indicates that the specific membrane sites may be affected. The primary goal of this study is to determine effects of halothane and enflurane on the regulation of calcium binding and transmembrane fluxes by sarcolemma enriched membranes isolated from canine ventricular myocardium. These experiments will involve the use of sarcolemma vesicles which exhibit Ca2+ binding, ATP-dependent Ca2+ transport by way of a Mg2+ dependent, Ca2+ ATPase; Na+ CA2+ exchange via a cationic antiporter and Ca2+ flux mechanisms which are dependent on transmembrane voltage. The effects of anesthetics on sarcolemma enzyme activities and Ca+ binding and transport will be compared with the effects of calcium-channel blocking agents (e.g., verapamil and nitrendipine) in an attempt to distinguish between site specific effects and generalized disruption of membrane function. Data analysis will be based on binding curves and association-dissociation rate constants and experimental data will be statistically compared with that of control experiments performed in the absence of anesthetic agents. The study of cardiac sarcolemma effects of volatile anesthetics will contribute to a further understanding of the regulation and drug-induced alterations of trans-sarcolemma calcium involved in the myocardial excitation-contraction-relaxation cycle as well as to a more definitive concept of excitable membrane events involved in anesthesia.
