The calcium channel antagonists verapamil (100 microM) and nifedipine (100 microM) inhibited twitch response and KCl induced hypercontractility in malignant hyperpyrexia (MH)-susceptible porcine skeletal muscle. These calcium channel antagonists did not effect hypercontractility induced by 3% halothane or 2 mM caffeine. 2. The calcium channel agonist BAY K 8644 (50 microM) induced contracture in MH-susceptible muscle but did not potentiate contracture response induced by 2 mM caffeine or 3% halothane. BAY K 8644 did not increase the resting tension of control muscle or increase the sensitivity of control muscle to 4 mM caffeine, 3% halothane or 80 mM KCl. 3. The sarcoplasmic reticulum (SR) from MH-susceptible and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 4. Verapamil and diltiazem [which has been previously shown to inhibit the hypercontractility of MH-susceptible porcine muscle to caffeine, halothane and KCl (Foster and Denborough, 1989 Br. J. Anaesth. 62, 566-572)] did not effect Ca2+ uptake or Ca(2+)-dependent ATPase activities of SR longitudinal tubule membranes, from MH-susceptible or control muscle. These calcium channel antagonists did not effect Ca2+ release from terminal cisternae preparations. 5. The skeletal muscle relaxant dantrolene inhibited Ca2+ efflux and equilibrium-Ca2+ exchange associated with the terminal cisternae membrane of MH-susceptible and control skeletal muscle. 6. Calcium channel antagonists modify Ca2+ fluxes in MH-susceptible and control muscle by acting at a site distal to the SR. Calcium channel antagonists may inhibit contractile response by modifying events of excitation-contraction coupling associated with the voltage sensor molecule (dihydropyridine-receptor) of the transverse-tubule membrane, whereas dantrolene directly acts on the terminal cisternae membrane to inhibit Ca2+ efflux and equilibrium Ca2+ exchange. Different calcium channel antagonists seem to modify the voltage-sensor mechanism in different ways in MH-susceptible muscle. 7. An abnormality in the coupling mechanism of the voltage sensor-SR calcium release channel may exist in MH-susceptible muscle. This dysfunction may be an adaptation to the elevated levels of myoplasmic Ca2+ and/or the molecular defect described in the Ca2+ release channel of the SR of MH-susceptible porcine muscle. In view of these results it is unlikely that nifedipine or verapamil would be of therapeutic value for the treatment of MH.
摘要
钙通道拮抗剂维拉帕米（100微摩尔）和硝苯地平（100微摩尔）可抑制恶性高热（MH）易感猪骨骼肌的抽搐反应以及氯化钾诱导的高收缩性。这些钙通道拮抗剂对3%氟烷或2毫摩尔咖啡因诱导的高收缩性无影响。2. 钙通道激动剂BAY K 8644（50微摩尔）可在MH易感肌肉中诱导挛缩，但不能增强2毫摩尔咖啡因或3%氟烷诱导的挛缩反应。BAY K 8644不会增加对照肌肉的静息张力，也不会增加对照肌肉对4毫摩尔咖啡因、3%氟烷或80毫摩尔氯化钾的敏感性。3. 将MH易感和对照猪骨骼肌的肌浆网（SR）分离成富含终末池和纵管膜成分的囊泡部分。4. 维拉帕米和地尔硫䓬[先前已证明可抑制MH易感猪肌肉对咖啡因、氟烷和氯化钾的高收缩性（福斯特和登博罗，1989年，《英国麻醉学杂志》62卷，566 - 572页）]对MH易感或对照肌肉的SR纵管膜的钙离子摄取或钙离子依赖性ATP酶活性无影响。这些钙通道拮抗剂对终末池制剂的钙离子释放无影响。5. 骨骼肌松弛剂丹曲林可抑制MH易感和对照骨骼肌终末池膜相关的钙离子外流和平衡钙离子交换。6. 钙通道拮抗剂通过作用于SR远端的位点来改变MH易感和对照肌肉中的钙离子通量。钙通道拮抗剂可能通过改变与横管膜电压传感器分子（二氢吡啶受体）相关的兴奋 - 收缩偶联事件来抑制收缩反应，而丹曲林直接作用于终末池膜以抑制钙离子外流和平衡钙离子交换。在MH易感肌肉中，不同的钙通道拮抗剂似乎以不同方式改变电压传感器机制。7. MH易感肌肉中可能存在电压传感器 - SR钙离子释放通道偶联机制的异常。这种功能障碍可能是对肌浆钙离子水平升高和/或MH易感猪肌肉SR钙离子释放通道中所述分子缺陷的一种适应。鉴于这些结果，硝苯地平或维拉帕米不太可能对MH治疗具有治疗价值。
