The effects of dantrolene in the presence or absence of ryanodine receptor type 1 variants in individuals predisposed to malignant hyperthermia

Abstract

Dantrolene is currently the only drug known to specifically treat malignant hyperthermia (MH) crises. Although dantrolene attenuates Ca2+ disorders by acting mainly on the ryanodine receptor type 1 (RYR1), some patients who manifest MH without RYR1 variants have also been successfully treated with dantrolene. Thus, dantrolene appears to have an inhibitory effect on patients with and without RYR1 variants. This study aimed to investigate whether the effects of dantrolene differed depending on the presence or absence of RYR1 variants using muscle cells from MH-predisposed individuals. The study participants were individuals diagnosed with MH predisposition by the Ca2+-induced Ca2+ release rate test. They were genetically tested and divided into two groups: with and without RYR1 variants. We investigated whether these two groups showed differences in the changes in the half-maximal effective concentration (EC50) for caffeine and the resting intracellular Ca2+ concentration ([Ca2+]i) before and after dantrolene administration. Dantrolene administration significantly increased the EC50 ( P < 0.0001) and decreased the resting [Ca2+]i ( P < 0.0001). The inhibitory effects of dantrolene and the presence of RYR1 variants showed no statistically significant interactions related to the EC50 ( P = 0.59) and resting [Ca2+]i ( P = 0.21). In conclusion, the presence or absence of RYR1 variants does not appear to influence the effect of dantrolene.

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

“…The isometric tension was measured using a force transducer to determine the CICR rate. MH predisposition was achieved if CICR was increased and defined as a CICR rate > two standard deviations (SD) above the mean of the control (IVCT and CHCT negative) [16] CICR values [17,18].…”

“…Previously, we isolated myoblasts as described in [18]. In brief, myoblasts were obtained from skeletal muscle for CICR examination and cultured.…”

Epidemiological and clinical features of malignant hyperthermia: A scoping review

“…It relieves skeletal muscle contraction by inhibiting the release of calcium from the sarcoplasmic reticulum. 11,12 The mortality of MH has been reduced from more than 80% to less than 5% after dantrolene treatment of MH since 1979. 13,14 The availability of dantrolene varies greatly from country to country, and some countries do not even have dantrolene in stock at all.…”

“…Dantrolene, a specific RyR1 antagonist, is currently the only FDA‐approved drug available for MH. It relieves skeletal muscle contraction by inhibiting the release of calcium from the sarcoplasmic reticulum 11,12 . The mortality of MH has been reduced from more than 80% to less than 5% after dantrolene treatment of MH since 1979 13,14 .…”