Mattheussen M, Housmans P R
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905.
Anesthesiology. 1993 Dec;79(6):1284-95. doi: 10.1097/00000542-199312000-00020.
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 beta-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 > or = 3 micrograms/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 micrograms/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 micrograms/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.
依托咪酯对大鼠心室肌有轻度正性肌力作用，但对离体兔心室肌有负性肌力作用。本研究旨在探讨依托咪酯在离体雪貂心室肌（其生理特性与人类心室肌相似）和蛙心室肌中产生肌力作用的机制及其潜在机制，在蛙心室肌中，肌原纤维激活所需的钙离子几乎完全来自跨肌膜内流。
作者分析了β肾上腺素能受体阻断后依托咪酯对收缩性和舒张变量以及用钙离子调节光蛋白水母发光蛋白检测的细胞内游离钙离子瞬变的影响。还在雪貂右心室乳头肌中评估了依托咪酯的作用，其中用ryanodine损害了肌浆网（SR）功能，以及在SR功能很少或没有SR功能的蛙心室肌条中评估了依托咪酯的作用。
在浓度≥3微克/毫升时，该浓度远远超过临床常用浓度范围，依托咪酯降低了收缩性和细胞内钙离子瞬变的幅度。在同等峰值力下，[Ca++]o = 2.25毫摩尔时对照峰值水母发光蛋白发光以及依托咪酯10微克/毫升且[Ca++]o＞2.25毫摩尔时的峰值水母发光蛋白发光无差异，这表明依托咪酯不改变肌原纤维对钙离子的敏感性。在用10(-6)M ryanodine使肌浆网钙离子释放失活后，即肌原纤维激活几乎完全依赖跨肌膜钙离子内流的情况下，依托咪酯导致收缩性降低和细胞内钙离子瞬变幅度降低，且依托咪酯的相对负性肌力作用与未暴露于ryanodine的对照肌肉中的作用无差异。10微克/毫升的依托咪酯降低了蛙心室肌的收缩性。
这些发现表明，依托咪酯的直接负性肌力作用是由于细胞内钙离子可用性降低，而肌原纤维对钙离子的敏感性无变化。依托咪酯的作用至少部分是由跨肌膜钙离子内流的抑制引起的。然而，这些作用仅在浓度至少比临床实践中遇到的浓度大一个数量级时才明显。
