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 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)

• Authors: P D Allen, J R López, V Sánchez, J F Ryan, F A Sreter
• Journal: Anesthesiology (Anesthesiology) Vol. 76 Issue 1 Pg. 132-8 (Jan 1992) ISSN: 0003-3022 [Print] United States
• PMID: 1729917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Imidazoles
• Muscle Relaxants, Central
• Oxazoles
• azumolene
• Calcium
• Halothane

Topics

• Animals
• Calcium (metabolism)
• Disease Susceptibility
• Dose-Response Relationship, Drug
• Halothane
• Imidazoles (administration & dosage, pharmacology)
• Malignant Hyperthermia (metabolism, prevention & control)
• Membrane Potentials
• Microelectrodes
• Muscle Relaxants, Central (pharmacology)
• Muscles (metabolism)
• Oxazoles (administration & dosage, pharmacology)
• Swine