Fruen B R, Mickelson J R, Roghair T J, Litterer L A, Louis C F
Department of Veterinary PathoBiology, University of Minnesota, St. Paul 55108, USA.
Anesthesiology. 1995 May;82(5):1274-82. doi: 10.1097/00000542-199505000-00023.
The effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible skeletal muscle are considered to be responsible for triggering malignant hyperthermia. The intravenous anesthetic propofol does not trigger malignant hyperthermia in susceptible patients or experimental animals, suggesting that there are important differences between the effects of propofol and the effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible muscle. Understanding these differences may help to clarify the mechanisms responsible for triggering malignant hyperthermia.
To investigate the effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible skeletal muscle, we determined its effects on the membrane channels and pumps that control myoplasmic Ca2+ concentrations: the sarcoplasmic reticulum ryanodine receptor, the transverse tubule dihydropyridine receptor, and the sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase). Terminal cisternae-derived sarcoplasmic reticulum vesicles enriched in the junctional proteins of the sarcoplasmic reticulum and the transverse tubule membranes were isolated from the muscle of malignant hyperthermia-susceptible and normal pigs. Ca2+ flux, Ca(2+)-ATPase, and ligand binding measurements on these isolated vesicle preparations were performed in the presence of varying propofol concentrations.
Propofol (10-500 microM) had no effect on ryanodine receptor-mediated Ca2+ efflux from muscle membrane vesicles. Propofol (1-100 microM) also had no effect on sarcoplasmic reticulum vesicle [3H]ryanodine binding, whereas higher concentrations (200-300 microM) slightly inhibited [3H]ryanodine binding. Binding of the dihydropyridine receptor Ca2+ channel blocker [3H]PN200-110 to these preparations was inhibited by propofol (10-300 microM). Ca(2+)-ATPase activity was stimulated by 10-100 microM propofol but was inhibited by higher concentrations. In all cases, the effects of propofol on malignant hyperthermia-susceptible and normal membrane preparations were similar.
In contrast to malignant hyperthermia-triggering inhalation anesthetics, propofol does not stimulate malignant hyperthermia-susceptible or normal ryanodine receptor channel activity, even at > 100 times clinical concentrations. Effects on dihydropyridine receptor and Ca(2+)-ATPase function, however, are similar to the effects of inhalation anesthestics and require much lower concentrations of propofol. These findings, demonstrating that propofol does not activate ryanodine receptor Ca2+ channels, suggest a plausible explanation for why propofol does not trigger malignant hyperthermia in susceptible persons.
吸入性麻醉剂对恶性高热易感骨骼肌中钙离子调节的影响被认为是引发恶性高热的原因。静脉麻醉剂丙泊酚不会在易感患者或实验动物中引发恶性高热，这表明丙泊酚的作用与吸入性麻醉剂对恶性高热易感肌肉中钙离子调节的作用存在重要差异。了解这些差异可能有助于阐明引发恶性高热的机制。
为了研究丙泊酚对恶性高热易感骨骼肌钙离子调节的影响，我们测定了其对控制肌浆钙离子浓度的膜通道和泵的影响：肌浆网兰尼碱受体（ryanodine receptor）、横管二氢吡啶受体（dihydropyridine receptor）和肌浆网钙-腺苷三磷酸酶（Ca(2+)-ATPase）。从恶性高热易感猪和正常猪的肌肉中分离出富含肌浆网和横管膜连接蛋白的终池来源的肌浆网囊泡。在不同丙泊酚浓度存在的情况下，对这些分离的囊泡制剂进行钙离子通量、Ca(2+)-ATPase和配体结合测量。
丙泊酚（10 - 500微摩尔）对兰尼碱受体介导的钙离子从肌膜囊泡外流没有影响。丙泊酚（1 - 100微摩尔）对肌浆网囊泡[3H]兰尼碱结合也没有影响，而较高浓度（200 - 300微摩尔）则轻微抑制[3H]兰尼碱结合。二氢吡啶受体钙离子通道阻滞剂[3H]PN200 - 110与这些制剂的结合受到丙泊酚（10 - 300微摩尔）的抑制。10 - 100微摩尔的丙泊酚刺激Ca(2+)-ATPase活性，但较高浓度则抑制该活性。在所有情况下，丙泊酚对恶性高热易感和正常膜制剂的作用相似。
与引发恶性高热的吸入性麻醉剂不同，即使在临床浓度的100倍以上，丙泊酚也不会刺激恶性高热易感或正常的兰尼碱受体通道活性。然而，对二氢吡啶受体和Ca(2+)-ATPase功能的影响与吸入性麻醉剂的影响相似，且所需丙泊酚浓度要低得多。这些发现表明丙泊酚不会激活兰尼碱受体钙离子通道，这为丙泊酚为何不会在易感人群中引发恶性高热提供了一个合理的解释。
