The goal of the proposed research is to investigate the intracellular mechanisms of anesthetic action on cardiac, skeletal and vascular smooth muscle. Functionally skinned muscle fiber preparations from rabbits will be used. The effects of the drugs will be studied on: (1) Ca2+ activation of the contractile proteins by measuring Ca2+ - activated tension development; and (2) Ca2+ uptake and release from the sarcoplasmic reticulum (SR) using chemically induced Ca2+ release by measuring changes in tension transient or 45Ca. Depending on the findings obtained from the functionally skinned fiber preparation, I will then further study the effects of the drugs on (1) Ca2+ binding to the isolated regulatory protein (troponin C) in striated muscles and phosphorylation of myosin light chain in the vascular smooth muscle, and (2) Ca2+ kinetics in isolated SR vesicles. I will also investigate the effects of drug interaction between anesthetics and antiarrhythmic agents on isolated papillary muscle by measuring changes in isometric twitch tension, and on the above intracellular mechanisms for muscle contraction with functionally skinned muscle fibers. The elucidation of the mechanism of anesthetic-induced myocardial depression will provide an understanding how the drugs act to depress myocardial function in man, and suggest possible approaches to therapy to reverse unwanted myocardial depression.
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