The overall goal of this research proposal is to investigate the cellular mechanisms of myocardial contractile depression by drugs used in clinical anesthesia. There is evidence that anesthetics depress myocardial contractility by directly decreasing the availability of calcium ions in the cytoplasm and (for some anesthetics) by altering myofibrillar calcium sensitivity (i.e., the amount of force developed at a given intracellular calcium). The specific goal is to elucidate mechanisms responsible for these direct effects which occur at clinically useful anesthetic concentrations. In experimental models of different physiological complexity, the applicant will test the following hypotheses: 1) Anesthetics delay the onset of myofibrillar activation by decreasing the rate of calcium release from the SR. 2) Peak unload velocity of shortening in cardiac muscle is dependent on intracellular calcium only in the initial 50 ms of contraction. The ability of anesthetic to slow the rate of rise of intracellular calcium results in a delayed and lower peak velocity of unloaded shortening. 3) Anesthetics do not influence the rate of relaxation, suggesting minimal effects on calcium uptake by the SR. 4) Anesthetics decrease myofibrillar calcium sensitivity in all contractile conditions. 5) Anesthetics do not alter the relation between bound calcium and force in skinned cardiac fibers, suggesting that changes in calcium sensitivity are due mostly to alterations in calcium affinity of troponin C. It is hoped that these results will allow one to quantify the effects of anesthetics on each step in cardiac excitation/contraction coupling addressed and to identify the underlying mechanisms. Moreover, these results might provide a rational basis of knowledge on which to formulate pharmacological action to reverse or prevent myocardial depression in surgical patients.
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