Reduced Mg2+ inhibition of Ca2+ release in muscle fibers of pigs susceptible to malignant hyperthermia.
The inhibitory effect of myoplasmic Mg2+ on Ca2+ release from the sarcoplasmic reticulum (SR) was examined in mechanically skinned skeletal muscle fibers from pigs of different ryanodine-receptor (RyR) genotypes. In fibers from pigs homozygous for the normal RyR allele, the free Mg2+ concentration ([Mg2+]) had to be lowered from the normal resting level of 1 to approximately 0.1 mM to induce Ca2+ release and a force response. Fibers from pigs heterozygous or homozygous for the RyR allele associated with malignant hyperthermia (MH) needed only a smaller reduction in free [Mg2+] to induce Ca2+ release (reduction to 0.1-0.2 and > or = 0.2 mM, respectively). Dantrolene (20 microM) counteracted the effect of this reduced Mg2+ inhibition in MH muscle. The response of muscle fiber bundles to the caffeine-halothane contracture test in the three genotypes correlated well with the responsiveness of single fibers to reduced [Mg2+]. Thus the abnormal responsiveness of MH muscle to various stimuli may largely result from the reduced ability of myoplasmic Mg2+ to inhibit Ca2+ release from the SR.
Owen
V J
VJ
School of Zoology, La Trobe University, Bundoora, Victoria, Australia.
Taske
N L
NL
Lamb
G D
GD
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003620:Dantrolene / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006221:Halothane / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology*; D008305:Malignant Hyperthermia / Q000235:genetics*; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D013552:Swine / Q000235:genetics
D002121:Calcium Channel Blockers; D002110:Caffeine; D003620:Dantrolene; D008274:Magnesium; D002118:Calcium; D006221:Halothane