TITLE:
Malignant hyperthermia: A runaway thermogenic futile cycle at the sodium channel level
AUTHORS:
Charles H. Williams
KEYWORDS:
Malignant Hyperthermia; Thermogenic
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.5 No.3,
January
29,
2014
ABSTRACT: Malignant Hyperthermia (“MH”)—the rapid onset of
extremely high fever with muscle rigidity—is caused by a runaway heat
production futile cycle mediated via the sodium channels at the myoneural
receptor 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 is
triggered and develops. We believe that the acetylcholine receptor/sodium
channels in the muscles of MH susceptible pigs initiate MH by allowing an
increased flux of sodium ions when it is depolarized by acetylcholine or other
depolarizing agents, such as succinylcholine and Halothane. Our theory is
consistent with our observations of the effects of general anesthetics over twenty
years. Succinylcholine is a depolarizing agent that is a potent MH trigger.
Acetylcholine, the natural depolarizing muscle activator, may trigger MH if the
susceptible patient or animal is exposed to sufficient stress, i.e., during strenuous activity, such as
transport, fighting, breeding, etc. Halothane apparently destabilizes the
myoneural sodium channels, which rapidly induces MH. The increased sodium
channel activity releases heat with cascades that further releases of heat
which results in the rapid onset of MH. MH susceptible pigs have increased
action potential amplitudes at their myoneural junctions that are abnormally
long in duration. This increased activity is thought to induce hypertrophy of
muscle mass, increase metabolic rate, and
cause other physical manifestations. When slaughtered, this increased
metabolic activity causes the rapid post mortem release of heat in the
muscles of MH susceptible pigs and, at the same time, the accumulation of low
acidity, 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. The
inhalation anesthetic Halothane is a strong trigger of MH, causing MH within
minutes of exposure. In contrast, the anesthetic Sevoflurane is a very weak
trigger of MH, requiring several hours of inhalation exposure to trigger MH. Because
of this, changing from Halothane to Sevoflurane as the general anesthetic of choice
for surgeries in hospitals in the Greater Kansas City area during 1994 to 2006
led 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”) temporarily
prevents MH in MH susceptible pigs when they are given sufficient dosages of it
before being challenged with either Halothane or succinylcholine. Binding
Rocuronium to the myoneural receptor sites apparently stabilizes them, thereby
preventing increased sodium channel activity, and resulting MH. However, other
non-depolarizing muscle relaxants do not have this protective effect— for
examples Vecuronium, Arduan, and Organon 9616 do not. Uncoupling of
mitochondria is not the source of accelerated heat production in MH susceptible
pigs, as heart, liver, and skeletal muscle mitochondria isolated from MH
susceptible pigs are all competent.