Jr. Lopez et al., Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+], ANESTHESIOL, 92(6), 2000, pp. 1799-1806
Citations number
36
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syn
drome that is triggered by halogenated anesthetics and/or depolarizing musc
le relaxants. MH-susceptible (MBS) skeletal muscle has been shown to be mor
e sensitive to caffeine-induced contracture than muscle from nonsusceptible
(MHN) subjects and is the basis for the most commonly used clinical diagno
stic test to determine MH susceptibility.
Methods: We studied the effects of caffeine on myoplasmic free calcium conc
entration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-s
elective microelectrodes before and after K+-induced partial depolarization
.
Results: [Ca2+](i) in untreated MHN fibers was 123 +/- 8 nM versus 342 +/-
33 nM in MHS fibers. Caffeine (2 mM) caused an increase in [Ca2+](i) in bot
h groups (296 +/- 41 nM MHN us. 1,159 +/- 235 nM MHS) with no change in res
ting membrane potential. When either MHN or MBS, muscle fibers were incubat
ed in 10 mM K+ [Ca2+](i) transiently increased to 272 +/- 22 nar in MHN and
967 +/- 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine
while resting [Ca2+], was elevated induced an increment in [Ca2+](i) to 340
+/- 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to co
ntrol levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2
+](i) returned to control, despite continued partial membrane depolarizatio
n.
Conclusions: These results suggest that the increased "sensitivity" to caff
eine of MHS swine muscle fibers is a nonspecific response related, at least
in part, to the high resting [Ca2+](i) and not an increased caffeine sensi
tivity of the sarcoplasmic reticulum Ca2+ release channel per se.