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Etomidate exerts a mild, positive inotropic effect in rat ventricular myocardium, yet has a negative inotropic effect in isolated rabbit ventricular myocardium. The aim of this study was to investigate the mechanisms of etomidate's inotropic effect and its underlying mechanism in Isolated ferret ventricular myocardium (which shows similar physiologic characteristics as human ventricular myocardium) and in frog ventricular myocardium, in which Ca++ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx.The authors analyzed the effects of etomidate after β-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca++-regulated photoprotein aequorin. Etomidate's effects were also evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular strips with little or no SR function.At concentrations ≥ 3 μg/ml, which by far exceed the clinically useful concentration range, etomidate decreased contractility and the amplitude of the intracellular Ca++ transient. At equal peak force, control peak aequorin luminescence in [Ca++]o = 2.25 mM and peak aequorin luminescence in etomidate 10 μg/ml and [Ca++]o > 2.25 mM did not differ, which indicates that etomidate does not alter myofibrillar Ca++ sensitivity. After inactivation of sarcoplasmic reticulum Ca++ release with ryanodine 10–6 M, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, etomidate caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and etomidate's relative negative Inotropic effect was not different from that in control muscles not exposed to ryanodine. Etomidate 10 μg/ml decreased contractility in frog ventricular myocardium.These findings indicate that the direct negative Inotropic effect of etomidate results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of etomidate's action is caused by inhibition of transsarcolemmal Ca++ influx. Yet, these effects become apparent only at concentrations that are at least one order of magnitude larger than those encountered in clinical practice.