The goal of this proposal is to determine the mechanism of the myocardial depressant effects of the widely used volatile anesthetics halothane, enflurane and isofluane. Isolated, intact rat heart cells, either singly or in suspension, will be utilized for the experiments. Continuous measurement of the length of single cells will reveal the properties of spontaneous contractile waves and stimulated twitches and their interaction. Anesthetic- induced alterations in these variables will provide information on changes in the Ca metabolism of the sarcoplasmic reticulum (SR) in intact cells. Determination of the free intracellular Ca concentration with the fluorescent dye quin2 will show whether anesthetics alter this concentraton and, through the use of caffeine, will reveal to what extent the agents change the amount of Ca stored in the SR. Patch clamp electrodes will be applied to single cells, and normal action potentials and the slow inward current will be measured. Simultaneous with these electrophysiologic determinations, contractile activity will be monitored. Thus, correlation between anesthetic changes in electrical variables and contractility will be made. Reversal of the anesthetic-induced myocardial depression by increasing extracellular Ca and by adding the beta agonist isoproterenol will be evaluated by analysis of spontaneous waves and twitch properties and by electrophysiologic measurements. In addition to revealing the completeness of reversal of the depression and the reason if reversal is not complete, a possible mechanism for the production of arrhythmias by the anesthetic/beta agonists interaction may be elucitated. Taken together, the experiments proposed will define anesthetic action on the slow inward current and or SR Ca metabolism and correlate these findings with actual changes in contractility.
|Wheeler, D M; Rice, R T; duBell, W H et al. (1997) Initial contractile response of isolated rat heart cells to halothane, enflurane, and isoflurane. Anesthesiology 86:137-46|
|Wheeler, D M; Katz, A; Rice, R T et al. (1994) Volatile anesthetic effects on sarcoplasmic reticulum Ca content and sarcolemmal Ca flux in isolated rat cardiac cell suspensions. Anesthesiology 80:372-82|
|Wheeler, D M; Katz, A; Rice, R T (1991) Effects of volatile anesthetics on cardiac sarcoplasmic reticulum as determined in intact cells. Adv Exp Med Biol 301:143-54|
|Zuckerman, R L; Wheeler, D M (1991) Effect of halothane on arrhythmogenic responses induced by sympathomimetic agents in single rat heart cells. Anesth Analg 72:596-603|
|Wheeler, D M; Rice, R T; Lakatta, E G (1990) The action of halothane on spontaneous contractile waves and stimulated contractions in isolated rat and dog heart cells. Anesthesiology 72:911-20|