EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine

Abstract

The mechanisms causing the malignant hyperthermia (MH) syndrome are related to a malfunction of intracellular Ca2+ homeostasis and can be prevented or reversed by dantrolene. EU 4093 (Azumolene®, 1-[[[5-(4-bromophenyl)-2-oxyzolyl]methylene] amino]-2-4-imidazolidinedione) is a 30-fold more water-soluble analogue of dantrolene that is believed to have the same effects as dantrolene on the intracellular free Ca2+ concentration ([Ca2+](i)) in skeletal muscle and that should have similar efficacy in treating and preventing the clinical manifestations of MH in response to a halothane/succinylcholine challenge. To test this hypothesis, experiments were carried out in four controls (Yorkshire) and eight MH-susceptible crossbreed swine (Poland China x Pietrain). The resting [Ca2+](i) in normal muscle fibers measured by Ca2+-selective microelectrodes was 111 ± 12 nM (mean ± standard deviation, n = 30), whereas in the MH muscles the resting [Ca2+](i) was 395 ± 36 nM, (n = 28) (P = 0.0001). EU 4093 decreased [Ca2+](i) in MH-susceptible skeletal muscle in a dose-related fashion from 207 to 38 nM after 0.5 to 2.0 mg/kg, respectively, and had a similar effect in control skeletal muscle (58 to 30 nM) after the same doses. In MH-susceptible swine, a dose of 2.0 mg/kg was successful in preventing any clinical signs of the MH syndrome during a subsequent halothane/succinylcholine challenge. A dose of 0.5 mg/kg was able to attenuate but not reverse the clinical signs of the MH syndrome after a halothane challenge, whereas a dose of 1.0 mg/kg was completely successful in reversing this effect in all subjects. These results indicate that EU 4093 is able to decrease the resting [Ca2+](i) in normal and MH-susceptible skeletal muscle and prevent and treat the clinical MH syndrome. These data suggest that it has a mechanism of action similar to that of dantrolene.