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

P. D. Allen, J. R. Lopez, V. Sanchez, J. F. Ryan, F. A. Sreter

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)132-138
Number of pages7
JournalAnesthesiology
Volume76
Issue number1
StatePublished - 1992
Externally publishedYes

Fingerprint

Malignant Hyperthermia
Skeletal Muscle Fibers
Swine
Dantrolene
Skeletal Muscle
Halothane
Succinylcholine
azumolene
Muscles
Microelectrodes
Poland
China
Homeostasis

Keywords

  • Ions, calcium: intracellular
  • Malignant hyperthermia, treatment: dantrolene; EU 4093
  • Measurement technique: ion-selective microelectrode
  • Skeletal muscle

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Allen, P. D., Lopez, J. R., Sanchez, V., Ryan, J. F., & Sreter, F. A. (1992). EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine. Anesthesiology, 76(1), 132-138.

EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine. / Allen, P. D.; Lopez, J. R.; Sanchez, V.; Ryan, J. F.; Sreter, F. A.

In: Anesthesiology, Vol. 76, No. 1, 1992, p. 132-138.

Research output: Contribution to journalArticle

Allen, PD, Lopez, JR, Sanchez, V, Ryan, JF & Sreter, FA 1992, 'EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine', Anesthesiology, vol. 76, no. 1, pp. 132-138.
Allen, P. D. ; Lopez, J. R. ; Sanchez, V. ; Ryan, J. F. ; Sreter, F. A. / EU 4093 decreases intracellular [Ca2+] in skeletal muscle fibers from control and malignant hyperthermia-susceptible swine. In: Anesthesiology. 1992 ; Vol. 76, No. 1. pp. 132-138.
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AU - Sreter, F. A.

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AB - 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.

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