HALOTHANE, ENFLURANE, AND ISOFLURANE STIMULATE CALCIUM LEAKAGE FROM RABBIT SARCOPLASMIC-RETICULUM

The sarcoplasmic reticulum (SR) controls uptake and release of Ca2+ in muscle. Little information is available regarding the effect of volatile anesthetics on Ca2+ release from SR isolated from normal skeletal muscle, even though an abnormality of Ca2+ handling is implicated in malignant hyperthermia. In this study we used a Ca2+ electrode to monitor continuously the release of Ca2+ from SR and the effect of volatile anesthetics on this process. We found that halothane, enflurane, and isoflurane at 0.6, 0.7, and 0.8 vol%, respectively, each increased the velocity of Ca2+ leakage by at least 150% when compared to control. Ruthenium red, a blocker of the SR Ca2+-release channel, was shown to have no effect on the velocity of Ca2+ leakage. Halothane and isoflurane both shortened the time at which Ca2+ leakage began (T) in a dose-dependent fashion. Halothane at 4.8 vol% decreased T from 293 +/- 21 s to 149 +/- 20 s. Isoflurane (4.8 vol%) decreased T to 203 +/- 16 s, and enflurane at 5 vol% had little effect, decreasing T to 259 +/- 19 s. We noted a marked stimulation in the ATPase activity of the SR by all three volatile anesthetics. Halothane at 0.63 vol%, isoflurane at 0.42 vol%, and enflurane at 0.62 vol% each increased ATPase activity by at least 300%. We conclude that the stimulation of the velocity of Ca2+ leakage by the volatile anesthetics is related to the more rapid depletion of ATP, but that the shortening of the onset of Ca2+ leakage is a independent phenomenon with a markedly different dose dependence. We also noted an enflurane-induced decrease in the Michaelis-Menten constant (K(m)) of the Ca2+ pump for ATP from 3.27 +/- 0.78 mM to 0.200 +/- 0.079 mM. Our data show that the volatile anesthetics increased the permeability of isolated SR to Ca2+. Although the permeability of the SR in vivo is uncertain, it is possible in vivo, in the presence of volatile anesthetics, that SR might be leaking Ca2+ into the cytoplasm. In malignant hyperthermic muscle, increased permeability of the SR caused by volatile anesthetics might contribute to the triggering of malignant hyperthermia.