Abnormality in calcium release from skeletal sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia.

Two fractions of sarcoplasmic reticulum, one light (LSR) and one heavy (HSR), were isolated from gracilis muscle of control and malignant hyperthermia (MH)-susceptible pigs. Part of the gracilis muscle biopsy was used to compare the contracture sensitivity of the muscle to the calcium-releasing effects of caffeine on isolated SR membranes. Gracilis muscle of MH pigs was more sensitive to the contracture-producing effects of caffeine than control pig muscle. The caffeine dose-cumulative contracture response curve for MH muscle was shifted left of that for controls. The amount of caffeine-induced calcium released from SR is a function of the amount of calcium preload and this did not differ between LSR of MH and control muscle. When LSR fractions were optimally loaded with calcium for caffeine-induced calcium release, no difference in calcium-releasing effects of varying caffeine doses was observed between MH and control LSR. At calcium preloads below optimal, the MH-LSR appeared to be more sensitive to caffeine-induced calcium release. The HSR fractions could not be loaded with calcium in a manner similar to the LSR fractions because of an apparent calcium-induced calcium release phenomenon. Therefore, calcium threshold for calcium-induced calcium release was compared between MH and control HSR fraction. The effect of caffeine on the calcium-induced calcium release was also studied. The average calcium concentration threshold for calcium-induced calcium release was markedly lower for MH vs. control HSR; 20 vs. 63 nmol Ca2+/mg, respectively. Caffeine decreased the threshold for calcium-induced calcium release more in the MH than in control HSR. Under all conditions studied, the amount of calcium released did not differ between the two groups. Ruthenium red increased the threshold calcium concentration for calcium-induced calcium release while it reduced the amount of calcium released. Increasing concentrations of Mg2+ increased the Ca2+ threshold for release and the amount of Ca2+ released but did not significantly affect rate of Ca2+ release. Results of the study suggest a defect in the mechanisms causing calcium release from SR in MH-affected muscle.