Sodium channel in human malignant hyperthermia.

BACKGROUND: The abundance of a specific sodium channel subunit (SkM2) appeared to be altered in vitro in cell cultures from persons susceptible to malignant hyperthermia. This study sought to determine whether these findings are artifacts of cell culture or whether they may be relevant to malignant hyperthermia. METHODS: Regulation of transcript levels of SkM2, a specific sodium channel alpha-subunit, was determined by mRNA analysis. Functional SkM2 protein was estimated in biopsy sections of vastus lateralis muscle by inhibiting the directly elicited muscle twitch by tetrodotoxin, which can differentiate at least three sodium currents in skeletal muscle. RESULTS: The transcript levels of SkM2 were depressed by 115-fold in six of seven persons susceptible to malignant hyperthermia; and the functional expression of the SkM2 protein, based on the tetrodotoxin sensitivity of the directly elicited twitch, was decreased by at least fourfold in muscle from persons susceptible to malignant hyperthermia compared with persons who were not susceptible. CONCLUSIONS: As in previous studies in cell culture, altered mRNA and/or the functional expression of a specific subunit of the sodium channel (SkM2) was found in biopsy sections of muscle from all 12 persons examined who were susceptible to malignant hyperthermia but in none of the 16 nonsusceptible participants. Human malignant hyperthermia is a heterogeneous disorder, and the down-regulation of SkM2 may be involved in the final common pathway through which mutations in any one of several proteins, including the ryanodine receptor, could render a person susceptible.

Prolonging viability of swine muscle biopsy specimens in malignant hyperthermia testing.

In North America, the caffeine halothane contracture test (CHCT) is the standard test for the diagnosis of malignant hyperthermia (MH). Current CHCT protocol recommends that the test be completed within 5 h of muscle excision. The purpose of this study was to investigate whether the period of skeletal muscle viability could be extended to 24 h. We tested the gracilis muscle from normal (n = 8) and MH-susceptible swine (n = 8). After baseline (1-2 h after excision) CHCT, the remaining muscles were placed into one of the following four treatment groups. In Groups 1 and 2, the muscles remained under tension and were stored in Krebs buffer (pH 7.4) at 23 degrees C-25 degrees C (clamped-warm) and 4 degrees C (clamped-cold), respectively. In Groups 3 and 4, the muscle strips were dissected, and the ends were tied with silk sutures, cut from the clamp, and placed in Krebs buffer at 23 degrees C-25 degrees C (free-warm) and 4 degrees C (free-cold), respectively. The responses of the treatment groups to halothane (3%) and caffeine (0.5-32 mM) were tested 22-26 h after excision. The clamped-warm storage was the only storage method to correctly diagnose MH susceptibility in all muscle strips tested. This finding was also confirmed in muscle stored under clamped-warm conditions and shipped overnight to another testing center for a parallel CHCT.

Intravenous lecithin-coated microcrystals of dantrolene are effective in the treatment of malignant hyperthermia: an investigation in rats, dogs, and swine.

Dantrolene effectively treats malignant hyperthermia (MH) hut the current form, Dantrium, must be dissolved to a 0.33 mg/mL, pH 9.5 solution. This study describes lecithin-coated microcrystal formulations of sodium dantrolene (MC-NaD) and neutral dantrolene (MC-D) which reconstitute to 200 mg/mL within 1 min. In rats, the pharmacokinetics and pharmacodynamics of MC-NaD and Dantrium were similar: half-lives of 3.1 h, volume distributions of 0.54 and 0.59 L/kg, and 95% effective dose (ED95) values for depression of skeletal muscle twitch height (ED95T) of 2.6 +/- 0.7 and 2.8 +/- 0.5 mg/kg. In swine, the ED95T values for MC-NaD and Dantrium were also similar (2.8 +/- 0.4 vs 2.7 +/- 0.6 mg/kg), but MC-D and Dantrium were only similar at doses more than 2.5 mg/kg (ED95T: 3.5 +/- 0.4 vs 2.7 +/- 0.5 mg/kg). In susceptible swine, MC-NaD successfully treated five of six MH episodes and prevented MH in three of four swine. However, MC-NaD caused marked pulmonary hypertension in swine, while MC-D caused only a mild response that was eliminated by filtration. Likewise, MC-D caused no pulmonary response in dogs. These observations suggest that MC-D has potential to improve the treatment of MH.