Migita T, Mukaida K, Kawamoto M, Kobayashi M, Nishino I, Yuget O
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima, Japan.
Anaesth Intensive Care. 2007 Dec;35(6):894-8. doi: 10.1177/0310057X0703500606.
Malignant hyperthermia is a pharmacogenetic disorder caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Propofol has been reported as a safe anaesthetic for malignant hyperthermia susceptible patients but has not been tested on cultured cells from patients with the ryanodine receptor type 1 mutation. The aim of this study was to determine whether propofol could trigger abnormal calcium fluxes in human myotubes isolated from malignant hyperthermia susceptible patients harbouring the native ryanodine receptor type 1 mutation. Muscle specimens were obtained from the patients to diagnose malignant hyperthermia disposition and the calcium-induced calcium release test and molecular genetic analyses were performed. Using the calcium sensitive probe Fura 2, we determined the 340/380 nm wave-length ratios by measuring alterations in calcium homeostasis in isolated myotubes from cultured skeletal muscle specimens. Two patients, one with ryanodine receptor type 1 R2508C and one with the L4838V mutation had accelerated calcium-induced calcium release rates. The 340/380 nm ratios increased when the propofol concentration exceeded 100 microM. The half-maximal activation concentrations (EC50) for propofol from patients 1 and 2 were 181.1 and 420.5 microM, respectively. Increases in calcium concentrations in response to propofol dosage were limited to doses at least 100-fold greater than those used in clinical settings. These observations correlate well with clinical observations that propofol does not trigger malignant hyperthermia in susceptible humans.
恶性高热是一种由1型兰尼碱受体基因常染色体显性突变引起的药物遗传学疾病。丙泊酚已被报道对恶性高热易感患者是一种安全的麻醉剂，但尚未在携带1型兰尼碱受体突变患者的培养细胞上进行测试。本研究的目的是确定丙泊酚是否能在从携带天然1型兰尼碱受体突变的恶性高热易感患者分离出的人肌管中引发异常的钙通量。从患者获取肌肉标本以诊断恶性高热易感性，并进行钙诱导的钙释放试验和分子遗传学分析。使用钙敏感探针Fura 2，我们通过测量培养的骨骼肌标本分离出的肌管中钙稳态的变化来确定340/380 nm波长比率。两名患者，一名携带1型兰尼碱受体R2508C突变，另一名携带L4838V突变，其钙诱导的钙释放速率加快。当丙泊酚浓度超过100 microM时，340/380 nm比率增加。患者1和患者2丙泊酚的半数最大激活浓度（EC50）分别为181.1和420.5 microM。丙泊酚剂量引起的钙浓度增加仅限于比临床使用剂量至少大100倍的剂量。这些观察结果与丙泊酚不会在易感人群中引发恶性高热的临床观察结果密切相关。
