EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine.
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 Ca(2+)-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Allen
P D
PD
Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts 02115.
López
J R
JR
Sánchez
V
V
Ryan
J F
JF
Sreter
F A
FA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D006221:Halothane; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008305:Malignant Hyperthermia / Q000378:metabolism* / Q000517:prevention & control; D008564:Membrane Potentials; D008839:Microelectrodes; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009132:Muscles / Q000378:metabolism*; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013552:Swine
D007093:Imidazoles; D009125:Muscle Relaxants, Central; D010080:Oxazoles; C061387:azumolene; D002118:Calcium; D006221:Halothane