Effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible muscle membranes.

BACKGROUND

The effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible skeletal muscle are considered to be responsible for triggering malignant hyperthermia. The intravenous anesthetic propofol does not trigger malignant hyperthermia in susceptible patients or experimental animals, suggesting that there are important differences between the effects of propofol and the effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible muscle. Understanding these differences may help to clarify the mechanisms responsible for triggering malignant hyperthermia.

METHODS

To investigate the effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible skeletal muscle, we determined its effects on the membrane channels and pumps that control myoplasmic Ca2+ concentrations: the sarcoplasmic reticulum ryanodine receptor, the transverse tubule dihydropyridine receptor, and the sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase). Terminal cisternae-derived sarcoplasmic reticulum vesicles enriched in the junctional proteins of the sarcoplasmic reticulum and the transverse tubule membranes were isolated from the muscle of malignant hyperthermia-susceptible and normal pigs. Ca2+ flux, Ca(2+)-ATPase, and ligand binding measurements on these isolated vesicle preparations were performed in the presence of varying propofol concentrations.

RESULTS

Propofol (10-500 microM) had no effect on ryanodine receptor-mediated Ca2+ efflux from muscle membrane vesicles. Propofol (1-100 microM) also had no effect on sarcoplasmic reticulum vesicle [3H]ryanodine binding, whereas higher concentrations (200-300 microM) slightly inhibited [3H]ryanodine binding. Binding of the dihydropyridine receptor Ca2+ channel blocker [3H]PN200-110 to these preparations was inhibited by propofol (10-300 microM). Ca(2+)-ATPase activity was stimulated by 10-100 microM propofol but was inhibited by higher concentrations. In all cases, the effects of propofol on malignant hyperthermia-susceptible and normal membrane preparations were similar.

CONCLUSIONS

In contrast to malignant hyperthermia-triggering inhalation anesthetics, propofol does not stimulate malignant hyperthermia-susceptible or normal ryanodine receptor channel activity, even at > 100 times clinical concentrations. Effects on dihydropyridine receptor and Ca(2+)-ATPase function, however, are similar to the effects of inhalation anesthestics and require much lower concentrations of propofol. These findings, demonstrating that propofol does not activate ryanodine receptor Ca2+ channels, suggest a plausible explanation for why propofol does not trigger malignant hyperthermia in susceptible persons.