Modification of Ryanodine Toxicity by Dantrolene and Halothane in a Model of Malignant Hyperthermia

Open Access
Publisher Website
Google Scholar
Abstract
Ryanodine toxicity in animals may be a model of malignant hyperthermia [MH] . Dantrolene blocks the development of MH triggered by halothane in susceptible swine. The influences of dantrolene and halothane on the effects of ryanodine were studied in vitro in isolated rat diaphragm muscle segments and in vivo in mice, to explore the validity of this model. In the diaphragm experiments, dantrolene blocked or delayed the development of contractures produced by ryanodine and to delay the potentiation of ryanodine-induced contractures due to halothane. In mice, ryanodine at various dosages was injected and animals surviving after 1 h were examined. Such survivors appeared grossly to be normal, and may constitute a model for the MH patient. They were susceptible to halothane and to succinylcholine, being killed by treatment with these 2 agents at dosages that were not lethal to control mice. Pretreatment of mice for 48 h with orally administered dantrolene, followed by injection of ryanodine and then halothane anesthesia, decreased the lethality of ryanodine but did not reduce the number of deaths due to the subsequent exposure to halothane. The effects of ryanodine in vitro and in vivo are diminished and potentiated by dantrolene and halothane, respectively; the ryanodine toxicity model of MH may have validity and is worthy of further study. A prediction from this model is that the terminal cisternae of skeletal muscle sarcoplasmic reticulum may be altered in MH.