Effects of dantrolene on myoplasmic free [Ca2+] measured in vivo in patients susceptible to malignant hyperthermia

Abstract

Malignant hyperthermia (MH) is a genetic disease characterized by hypermetabolism in skeletal muscle following a triggering stimulus and can be reversed or pretreated with dantrolene sodium. The myoplasmic free [Ca2+] was measured, using Ca2+ selective microelectrodes in vivo in the superficial fibers of the sartorius muscle of eight MH-susceptible and eight control subjects. Both groups received continuous epidural anesthesia with chloroprocaine 3%. In both the control and MH muscle fibers, the myoplasmic free [Ca2+] was measured before and after the intravenous administration of a cumulative dantrolene dose of 0.5, 1.5, and 2.5 mg/kg. The mean resting myoplasmic free [Ca2+] was 0.112 ± 0.004 μM (mean ± SEM n = 32) in the control and 0.485 ± 0.022 μM (n = 33) in the MH subjects. In the MH subjects, dantrolene induced a dose-dependent reduction in myoplasmic free [Ca2+]. The 0.5-mg/kg dose reduced it to 0.326 ± 0.017 μM (n = 22), the 1.5-mg/kg dose to 0.233 ± 0.015 μM (n = 25), and the 2.5-mg/kg dose to 0.092 ± 0.008 μM (n = 26). In controls, dantrolene also reduced resting myoplasmic free [Ca2+] but to a lesser extent. The 0.5-mg/kg dose reduced it to 0.096 ± 0.004 μM (n = 22), the 1.5-mg/kg dose to 0.077 ± 0.003 μM (n = 23), and the 2.5-mg/kg dose to 0.068 ± 0.002 μM (n = 27). The results of the study extend our previous findings in humans and swine and demonstrate that it is possible to measure myoplasmic free [Ca2+] in vivo in humans. They also demonstrate that the effect of administration dantrolene on human skeletal muscle in vivo is associated with a dose-dependent reduction in the myoplasmic free [Ca2+].