Modification of Ryanodine Toxicity by Dantrolene and Halothane in a Model of Malignant Hyperthermia
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Ryanodine toxicity in animals has been suggested to constitute a model of malignant hyperthermia. Dantrolene is known to block the development of malignant hyperthermia triggered by halothane in susceptible swine. The authors studied the influences of dantrolene and halothane on the effects of ryanodine 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 was found to block or delay the development of contractures produced by ryanodine and to delay the potentiation of ryanodine-induced contractures caused by halothane. In mice, ryanodine at various dosages was injected and animals surviving after one hour were examined. Such survivors appeared grossly to be normal, and may constitute a model for the malignant hyperthermia patient. They were found to be susceptible to halothane and to succinylcholine, being killed by treatment with these two agents at dosages that were not lethal to control mice. Pretreatment of mice for 48 hours 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 caused by the subsequent exposure to halothane. That the effects of ryanodine in vitro and in vivo are diminished and potentiated by dantrolene and halothane, respectively, would suggest that the ryanodine toxicity model of malignant hyperthermia 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.Keywords:
Malignant hyperthermia
Muscle contracture
Dantrolene Sodium
Anesthesiologists from 65 institutions participated in a multicenter study to assess the efficacy of lyophilized intravenous dantrolene sodium in treating anesthetically related malignant hyperthermia (MH). Of 21 patients treated with the drug, eight were judged to have unequivocal MH and were treated according to study protocol. Three were judged to have probable MH and were also treated according to study protocol. All 11 recovered without sequelae from MH and without adverse drug effects. A mean dantrolene dose of 2.5 mg/kg in these patients produced significant changes in clinical and biochemical parameters suggestive of decreased cellular metabolism. Four patients with unequivocal MH were treated with intravenous dantrolene more than 24 h after the diagnosis of MH; this delay in treatment of clinical signs in these patients, the mortality rate was 75 per cent, which is comparable to that reported without dantrolene. The six remaining patients had episodes of questionable MH during or subsequent to anesthesia and were treated with dantrolene. There was insufficient evidence to justify an unequivocal or probable diagnosis of MH, and they, therefore, were not included in the study. All survived and had no adverse drug reactions. Dantrolene therapy resulted in a statistically significantly lower mortality rate than would be expected in MH patients. The study supports animal data suggesting that dantrolene is specific in reversing MH.
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Dantrolene Sodium
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Departments of Anesthesiology and Orthopedics, Stanford University School of Medicine, Stanford, California
Malignant hyperthermia
Dantrolene Sodium
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Dantrolene Sodium
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Halothane-induced contractures in isolated muscle fibers from swine susceptible to malignant hyperthermia (MHS) were significantly less when fibers were incubated in KRB plus 6.2 x 10(-6) M dantrolene sodium prior to the administration of 4 per cent halothane. Administration of dantrolene sodium at the time of maximum contraction to NHS fibers in which contractures had been induced by halothane significantly increased the rate of relaxation of these fibers compared with similar fibers not treated with dantrolene sodium. This study indicates possible prophylactic and therapeutic value of dantrolene sodium in malignant hyperthermia and suggests that the previously reported effectiveness of dantrolene sodium in preventing and treating halothane-induced contractures may be due, at least in part, to its direct effect on muscles.
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Abstract Malignant hyperthermia (MH) is a hereditary myopathy, triggered when susceptible patients are exposed to a depolarizing muscle relaxant and/or potent volatile anesthetics. We have studied the effects of dantrolene on the free [Ca 2+ ] i of intercostal muscle biopsies obtained from two MH‐susceptible patients before and after administration of dantrolene orally (2.5 mg/kg for 3 days) and intravenously (1.0 mg/kg 2 hours before the biopsy). The free [Ca 2+ ] i was measured by Ca 2+ ‐selective microelectrodes. The mean resting free [Ca 2+ ] i in the MH‐susceptible muscle before dantrolene treatment was 0.42 ± 0.01 μ M (mean ± SEM, n = 12). The administration of dantrolene reduced this value to 0.27 ± 0.01 μ M ( n = 14). There was no detectable difference in the resting membrane potential after dantrolene. These results represent the first direct demonstration that dantrolene is able to reduc the resting free [Ca 2+ ] i in skeletal muscle of MH‐susceptible patients.
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