Iaizzo P A, Johnson B A, Nagao K, Gallagher W J
Department of Anesthesiology, University of Minnesota, Minneapolis 55455, USA.
Anesthesiology. 1999 Jun;90(6):1723-32. doi: 10.1097/00000542-199906000-00030.
Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves.
Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed.
Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10).
4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.
氯甲酚在许多已被证明可诱导肌浆网Ca2+释放的商业药物中用作防腐剂；最有效的异构体是4-氯间甲酚。本研究的目的是：（1）研究4-氯间甲酚对易患恶性高热的猪的体内作用；（2）对比体内和体外剂量反应曲线。
对易患恶性高热的猪（体重：38.5 kg±3.55 kg）进行麻醉，并监测其生理反应的变化，包括呼气末二氧化碳、心率、血压、血液化学指标和体温。在首批研究的动物中，给予4-氯间甲酚，等效累积剂量分别为0.14、0.28、0.57、1.14、2.27、4.54和9.08 mg/kg（n = 3；12.5、25、50、100、200、400和800 μmol），在第二组中，使用了更大的剂量：1.14、3.41、7.95、17.04（n = 4）和/或35.22（n = 1）mg/kg（100、300、700、1500和/或3100 μmol）。为作比较，从正常和易患恶性高热的猪身上获取的体外腹直肌标本暴露于4-氯间甲酚，累积浓度分别为6.25、12.5、25、50、100、200、400、800和1600 μmol；还进行了标准咖啡因和氟烷挛缩试验。
低剂量4-氯间甲酚给药未引发恶性高热发作，但观察到短暂的心血管反应（如心动过速、心律失常和低血压）。随后，当给予氟烷（0.87；1 MAC）和琥珀酰胆碱（2 mg/kg）时，这些动物引发了发作。给予较高剂量4-氯间甲酚的动物，当等效累积浓度大于1500 μmol时，均发生了致命的恶性高热暴发性发作。血浆中4-氯间甲酚水平迅速下降：例如，给予1500 μmol剂量后5分钟，平均血浆水平仅为52±18 μmol（n = 4）。在浓度>200 μmol的4-氯间甲酚给药后检测到溶血。在体外，当4-氯间甲酚浴槽浓度为50 μmol时，来自易患恶性高热动物的肌肉引发的挛缩>200 mg（n = 29），而正常肌肉直到浴槽浓度>800 μmol时才引发此类挛缩（n = 10）。
4-氯间甲酚是易患恶性高热猪发生恶性高热的触发因素，但仅当血清浓度远高于人类可能遇到的浓度时才会如此。相对较低浓度的4-氯间甲酚，50 μmol，足以在体外激活肌浆网[Ca+2]释放（如挛缩）；在体内给予相同的推注剂量（0.57 mg/kg）由于其血浆水平迅速下降而影响最小。
