The negative inotropic effect of volatile anesthetics is well documented clinically and experimentally and the long-term goal of this study is to clarify the molecular basis of this action. The negative inotropic effect of these anesthetics has been linked to calcium-related mechanisms. It has been shown in this laboratory that volatile anesthetics, e.g., halothane increase cyclic 3', 5'- guanosine monophosphate (cGMP) content in mouse myocardium by an act that involves cellular processes which appear to be associated with the alpha adrenergic system. Cyclic GMP has been implicated in the negative inotropic effect of alpha adrenergic agonists and other transmitters, and it has been demonstrated that cGMP decreases the slow calcium current, an effect associated with a decrease in contractile force. Furthermore, various phospholipid metabolites are potent activators of guanylate cyclase and there is evidence that the phospholipid bilayer of the cell membrane where the hormone receptors are embedded. Experiments are designed to determine the effect of halothane on the cGMP content of the rat papillary muscle and to correlate this effect with the negative inotropic effect of halothane. The relative potency of selective alpha-1 and alpha-2 adrenergic antagonists to inhibit the biochemical and functional responses to halothane and to an alpha adrenergic agonist will be compared. Other experiments are planned to determine whether phospholipids and their metabolites modulate the cGMP and the negative inotropic responses to halothane. Compounds which affect the release of fatty acids from phospholipids and the formation of oxidized metabolites of fatty acids will be tested on the cGMP and the negative inotropic responses to halothane in rat papillary muscle. The effect of halothane on phosphoinositides turnover rate and hydrolysis will be investigated in rat ventricular slices. Cyclic GMP content will be measured by radioimmunoassay. The negative inotropic effect will be evaluated by measuring the halothane-induced decrease in the tension of the electrically- driven rat papillary muscle. Phosphoinositides turnover rate will be determined by measuring the incorporation of 32P- orthophosphoric acid or myo(2-3H)inositol into phosphatidylinositol, the hydrolysis of phosphoinositides by measuring the accumulation of inositol phosphates from prelabeled 3H-inositol-phosphoinositides. The results of this study will add to the understanding of how volatile anesthetics depress myocardial contractility and thereby provide a basis for a more rational selection and safer use.
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