The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum

To clarify the mechanism by which volatile anesthetics initiate malignant hyperthermia (MH), we examined the effect of halothane, isoflurane, and enflurane on Ca²⁺ uptake and release by sarcoplasmic reticulum vesicles isolated from MH-susceptible (MHS) and normal pig muscle. Clinical concentrations of these anesthetics (0.1-0.5 mM) stimulated sarcoplasmic reticulum ATP-dependent Ca²⁺ uptake (maximal at approximately 4 mM), whereas 10-20 times the clinical anesthetic concentration inhibited Ca²⁺ uptake. There was no significant difference between MHS and normal sarcoplasmic reticulum in any aspect of Ca²⁺ uptake. Ca²⁺ release from ⁴⁵Ca²⁺-filled sarcoplasmic reticulum vesicles in a 10^-8 M Ca²⁺- containing medium (pH 7.0) was significantly stimulated at clinical concentrations of all three volatile anesthetics (anesthetic concentration for the 50% stimulation of Ca²⁺ release = 0.096-0.22 mM); however, the rate constant for Ca²⁺ release from MHS sarcoplasmic reticulum was in all cases significantly greater than that from normal sarcoplasmic reticulum. Furthermore, 0.5 mM halothane had no effect on Ca²⁺ release from normal sarcoplasmic reticulum at pH values less than 6.8, although it could still significantly stimulate Ca²⁺ release from MHS sarcoplasmic reticulum even at pH 6.4; similar results were obtained for isoflurane and enflurane. These studies thus demonstrate that the interaction of volatile anesthetics with the sarcoplasmic reticulum Ca²⁺-release channel is altered in MHS porcine muscle such that the channel may be activated even at a Ca²⁺ concentration or pH that would be expected to maintain the channel in the closed state.