Enhanced response to caffeine and 4-chloro-m-cresol in malignant hyperthermia-susceptible muscle is related in part to chronically elevated resting [Ca2+]i.

Abstract

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic syndrome caused by exposure to halogenated volatile anesthetics and/or depolarizing muscle relaxants. We have measured intracellular Ca(2+) concentration ([Ca(2+)](i)) using double-barreled, Ca(2+)-selective microelectrodes in myoballs prepared from skeletal muscle of MH-susceptible (MHS) and MH-nonsusceptible (MHN) swine. Resting [Ca(2+)](i) was approximately twofold in MHS compared with MHN quiescent myoballs (232 +/- 35 vs. 112 +/- 11 nM). Treatment of myoballs with caffeine or 4-chloro-m-cresol (4-CmC) produced an elevation in [Ca(2+)](i) in both groups; however, the concentration required to cause a rise in [Ca(2+)](i) elevation was four times lower in MHS than in MHN skeletal muscle cells. Incubation of MHS cells with the fast-complexing Ca(2+) buffer BAPTA reduced [Ca(2+)](i), raised the concentration of caffeine and 4-CmC required to cause an elevation of [Ca(2+)](i), and reduced the amount of Ca(2+) release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC may be mediated at least in part by the chronic high resting [Ca(2+)](i) levels in these cells.

• Authors: José R López, Nancy Linares, Isaac N Pessah, Paul D Allen
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 288 Issue 3 Pg. C606-12 (Mar 2005) ISSN: 0363-6143 [Print] United States
• PMID: 15537710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Central Nervous System Stimulants
• Chelating Agents
• Cresols
• Fungicides, Industrial
• chlorocresol
• Caffeine
• Egtazic Acid
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Calcium

Topics

• Animals
• Animals, Newborn
• Caffeine (pharmacology)
• Calcium (metabolism)
• Central Nervous System Stimulants (pharmacology)
• Chelating Agents (metabolism)
• Cresols (pharmacology)
• Egtazic Acid (analogs & derivatives, metabolism)
• Electrophysiology
• Fungicides, Industrial (pharmacology)
• Malignant Hyperthermia (metabolism)
• Membrane Potentials (physiology)
• Microelectrodes
• Muscle, Skeletal (drug effects, metabolism)
• Swine