Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]

Jose R. López, Jaime Contreras, Nancy Linares, Paul D. Allen

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods: We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-selective 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 both groups (296 ± 41 nM MHN vs. 1,159 ± 235 nM MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 ± 22 nM in MHN and 967 ± 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+](i) was elevated induced an increment in [Ca2+](i) to 940 ± 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to control levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2+](i) returned to control, despite continued partial membrane depolarization. Conclusions: These results suggest that the increased 'sensitivity' to caffeine 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 sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.

Original languageEnglish (US)
Pages (from-to)1799-1806
Number of pages8
JournalAnesthesiology
Volume92
Issue number6
StatePublished - Jun 2000
Externally publishedYes

Fingerprint

Malignant Hyperthermia
Caffeine
Hypersensitivity
Skeletal Muscle
Swine
Muscles
Neuromuscular Depolarizing Agents
Pharmacogenetics
Sarcoplasmic Reticulum
Microelectrodes
Contracture
Routine Diagnostic Tests
Membrane Potentials
Anesthetics
Calcium
Membranes

Keywords

  • Hyperpyrexia
  • Potassium
  • Xanthine

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]. / López, Jose R.; Contreras, Jaime; Linares, Nancy; Allen, Paul D.

In: Anesthesiology, Vol. 92, No. 6, 06.2000, p. 1799-1806.

Research output: Contribution to journalArticle

López, Jose R. ; Contreras, Jaime ; Linares, Nancy ; Allen, Paul D. / Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]. In: Anesthesiology. 2000 ; Vol. 92, No. 6. pp. 1799-1806.
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abstract = "Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods: We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-selective 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 both groups (296 ± 41 nM MHN vs. 1,159 ± 235 nM MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 ± 22 nM in MHN and 967 ± 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+](i) was elevated induced an increment in [Ca2+](i) to 940 ± 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to control levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2+](i) returned to control, despite continued partial membrane depolarization. Conclusions: These results suggest that the increased 'sensitivity' to caffeine 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 sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.",
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T1 - Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]

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AU - Contreras, Jaime

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AU - Allen, Paul D.

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N2 - Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods: We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-selective 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 both groups (296 ± 41 nM MHN vs. 1,159 ± 235 nM MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 ± 22 nM in MHN and 967 ± 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+](i) was elevated induced an increment in [Ca2+](i) to 940 ± 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to control levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2+](i) returned to control, despite continued partial membrane depolarization. Conclusions: These results suggest that the increased 'sensitivity' to caffeine 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 sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.

AB - Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic syndrome that is triggered by halogenated anesthetics and/or depolarizing muscle relaxants. MH-susceptible (MHS) skeletal muscle has been shown to be more sensitive to caffeine-induced contracture than muscle from nonsusceptible (MHN) subjects and is the basis for the most commonly used clinical diagnostic test to determine MH susceptibility. Methods: We studied the effects of caffeine on myoplasmic free calcium concentration ([Ca2+](i)) in MHN and MHS swine muscle fibers by means of Ca2+-selective 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 both groups (296 ± 41 nM MHN vs. 1,159 ± 235 nM MHS) with no change in resting membrane potential. When either MHN or MHS, muscle fibers were incubated in 10 mM K+ [Ca2+](i) transiently increased to 272 ± 22 nM in MHN and 967 ± 38 nM in MHS for 6-8 min. Exposure of MHN fibers to 2 mM caffeine while resting [Ca2+](i) was elevated induced an increment in [Ca2+](i) to 940 ± 37 nM. After 6-8 min of exposure to 10 mM K+, [Ca2+](i) returned to control levels in all fibers, and the effect of 2 mM caffeine on resting [Ca2+](i) returned to control, despite continued partial membrane depolarization. Conclusions: These results suggest that the increased 'sensitivity' to caffeine 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 sensitivity of the sarcoplasmic reticulum Ca2+ release channel per se.

KW - Hyperpyrexia

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KW - Xanthine

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