Abstract
Background We investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells. Methods We compared the enhanced responsiveness of HEK-293 cells expressing wild-type RYR1 with that of mutant RYR1 to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC50; i.e., the concentration required to reach half-maximal activation) using an unpaired two-tailed t-test while a P < 0.05 was considered significant. Results Remimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca2+ levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. In wild-type RYR1, EC50 values of remimazolam following refusion vs. nonperfusion were 2.86 mM vs. 2.75 mM (P = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76 mM vs. 2.75 mM, respectively (P = 0.83). In mutant RYR1, EC50 values of remimazolam refusion vs. nonperfusion were 1.58 mM vs. 1.71 mM, respectively (P = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65 mM vs. 1.71 mM, respectively (P = 0.73). Remimazolam and propofol increased intracellular Ca2+ levels in a concentration-dependent manner, but the effect was not enhanced by RYR1. EC50 values of remimazolam with non-RYR1 vs. wild-type RYR1 were 1.00 mM vs. 0.92 mM, respectively (P = 0.91) while those of propofol were 1.09 mM vs. 1.05 mM, respectively (P = 0.84). Conclusions The increase in intracellular Ca2+ concentration caused by remimazolam or propofol was not considered an RYR1-mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with RYR1-mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs.
Highlights
Malignant hyperthermia (MH; OMIM #145600) is an autosomal dominant pharmacogenetic disorder and one of the serious complications caused by exposure of MHsusceptible patients to volatile anesthetics [1, 2]
To elucidate the regulatory effects of remimazolam and propofol on intracellular Ca2+, we investigated whether exposure to these agents promotes the responsiveness of various ryanodine receptor 1- (RYR1-)expressing human embryonic kidney 293 (HEK-293) cells to caffeine, which is an agonist of ryanodine receptor 1 (RYR1)
Since the values of the Fura-2 ratio at resting represent the leakage of Ca2+ from the sarcoplasmic reticulum (SR) by RYR1, the results we present in Table 1 show that there is no significant difference in the expression levels of wild-type RYR1 and mutated RYR1
Summary
Malignant hyperthermia (MH; OMIM #145600) is an autosomal dominant pharmacogenetic disorder and one of the serious complications caused by exposure of MHsusceptible patients to volatile anesthetics [1, 2] The pathogenesis of this disease is dysregulation of intracellular Ca2+ in skeletal muscle cells while dysfunction of the ryanodine receptor 1 (RYR1), a Ca2+ release channel in the sarcoplasmic reticulum of skeletal muscle cells, is a known etiological factor [3]. We compared the enhanced responsiveness of HEK-293 cells expressing wild-type RYR1 with that of mutant RYR1 to caffeine following perfusion with remimazolam or propofol. Remimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca2+ levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with RYR1-mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs
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