EFFECT OF PROPOFOL ON CA2-SUSCEPTIBLE MUSCLE MEMBRANES( REGULATION BYMALIGNANT HYPERTHERMIA)

Background: The effects of inhalation anesthetics on Ca2+ regulation i n malignant hyperthermia-susceptible skeletal muscle are considered to be responsible for triggering malignant hyperthermia. The intravenous anesthetic propofol does not trigger malignant hyperthermia in suscep tible patients or experimental animals, suggesting that there are impo rtant differences between the effects of propofol and the effects of i nhalation anesthetics on Ca2+ regulation in malignant hyperthermia-sus ceptible muscle. Understanding these differences may help to clarify t he mechanisms responsible for triggering malignant hyperthermia.Method s: To investigate the effects of propofol on Ca2+ regulation by malign ant hyperthermia-susceptible skeletal muscle, we determined its effect s on the membrane channels and pumps that control myoplasmic Ca2+ conc entrations: the sarcoplasmic reticulum ryanodine receptor, the transve rse tubule dihydropyridine receptor, and the sarcoplasmic reticulum Ca 2+-adenosine triphosphatase (Ca2+-ATPase). Terminal cisternae-derived sarcoplasmic reticulum vesicles enriched in the junctional proteins of the sarcoplasmic reticulum and the transverse tubule membranes were i solated from the muscle of malignant hyperthermia-susceptible and norm al pigs. Ca2+ flux, Ca2+-ATPase, and ligand binding measurements on th ese isolated vesicle preparations were performed in the presence of va rying propofol concentrations. Results: Propofol (10-500 mu M) had no effect on ryanodine receptor-mediated Ca2+ efflux from muscle membrane vesicles. Propofol(1-100 mu M) also had no effect on sarcoplasmic ret iculum vesicle [H-3]ryanodine binding, whereas higher concentrations ( 200-300 mu M) slightly inhibited [H-3]ryanodine binding. Binding of th e dihydropyridine receptor Ca2+ channel blocker [H-3]PN200-110 to thes e preparations was inhibited by propofol (10-300 mu M). Ca2+-ATPase ac tivity was stimulated by 10-100 mu M propofol but was inhibited by hig her concentrations, In all cases, the effects of propofol on malignant hyperthermia-susceptible and normal membrane preparations were simila r. Conclusions: In contrast to malignant hyperthermia-triggering inhal ation anesthetics, propofol does not stimulate malignant hyperthermia- susceptible or normal ryanodine receptor channel activity, even at >10 0 times clinical concentrations, Effects on dihydropyridine receptor a nd Ca2+-ATPase function, however, are similar to the effects of inhala tion anesthetics and require much lower concentrations of propofol. Th ese findings, demonstrating that propofol does not activate ryanodine receptor Ca2+ channels, suggest a plausible explanation for why propof ol does not trigger malignant hyperthermia in susceptible persons.