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Malignant Hyperthermia -MH-—the rapid onset ofextremely high fever with muscle rigidity—is caused by a runaway heatproduction futile cycle mediated via the sodium channels at the myoneuralreceptor sites. MH is not triggered by non-depolarizing muscle relaxants; however,depolarizing muscle relaxants may trigger it 1. Here we present a de novo hypothesis of how MH istriggered and develops. We believe that the acetylcholine receptor-sodiumchannels in the muscles of MH susceptible pigs initiate MH by allowing anincreased flux of sodium ions when it is depolarized by acetylcholine or otherdepolarizing agents, such as succinylcholine and Halothane. Our theory isconsistent with our observations of the effects of general anesthetics over twentyyears. Succinylcholine is a depolarizing agent that is a potent MH trigger.Acetylcholine, the natural depolarizing muscle activator, may trigger MH if thesusceptible patient or animal is exposed to sufficient stress, i.e., during strenuous activity, such astransport, fighting, breeding, etc. Halothane apparently destabilizes themyoneural sodium channels, which rapidly induces MH. The increased sodiumchannel activity releases heat with cascades that further releases of heatwhich results in the rapid onset of MH. MH susceptible pigs have increasedaction potential amplitudes at their myoneural junctions that are abnormallylong in duration. This increased activity is thought to induce hypertrophy ofmuscle mass, increase metabolic rate, andcause other physical manifestations. When slaughtered, this increasedmetabolic activity causes the rapid post mortem release of heat in themuscles of MH susceptible pigs and, at the same time, the accumulation of lowacidity, all of which denatures the muscle proteins to result in a pale, soft,exudative, pork meat considered to be of lesser quality for human consumption.The potency of inhalation anesthetics as a MH triggers varies widely. Theinhalation anesthetic Halothane is a strong trigger of MH, causing MH withinminutes of exposure. In contrast, the anesthetic Sevoflurane is a very weaktrigger of MH, requiring several hours of inhalation exposure to trigger MH. Becauseof this, changing from Halothane to Sevoflurane as the general anesthetic of choicefor surgeries in hospitals in the Greater Kansas City area during 1994 to 2006led to an 11-fold decrease in the incidence of MH, from 1:50,000 to 1:550,000 11.One non-depolarizing muscle relaxant, Organon 9426 -Rocuronium- temporarilyprevents MH in MH susceptible pigs when they are given sufficient dosages of itbefore being challenged with either Halothane or succinylcholine. BindingRocuronium to the myoneural receptor sites apparently stabilizes them, therebypreventing increased sodium channel activity, and resulting MH. However, othernon-depolarizing muscle relaxants do not have this protective effect— forexamples Vecuronium, Arduan, and Organon 9616 do not. Uncoupling ofmitochondria is not the source of accelerated heat production in MH susceptiblepigs, as heart, liver, and skeletal muscle mitochondria isolated from MHsusceptible pigs are all competent.


Malignant Hyperthermia; Thermogenic

Cite this paper

Williams, C. 2014 Malignant hyperthermia: A runaway thermogenic futile cycle at the sodium channel level. Advances in Bioscience and Biotechnology, 5, 197-200. doi: 10.4236-abb.2014.53025.

Autor: Charles H. Williams



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