Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle.

Abstract

Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. The twitches of extensor digitorum longus and soleus muscles from mice were inhibited by azumolene with IC(50) of 2.8 +/- 0.8 and 2.4 +/- 0.6 microM, respectively. The IC(50) of dantrolene sodium in these muscles was 1.6 +/- 0.4 and 3.5 +/- 1.2 microM, respectively, with no difference in comparison to azumolene. Previous in vitro exposure of mouse soleus muscle to azumolene and dantrolene sodium (10 microM) significantly inhibited 8 mM caffeine-induced contractures. Azumolene was just effective as dantrolene sodium in relaxing caffeine-induced contractures of mouse soleus muscle. Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC(50) of 1.2 +/- 0.1 and 1.5 +/- 0.2 mg/kg for azumolene and dantrolene sodium, respectively. Azumolene, 10 microM, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro. These studies provide evidence that azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that azumolene should be efficacious for treatment/prevention of malignant hyperthermia.

• Authors: Roberto Takashi Sudo, Paula Lima do Carmo, Margarete Manhães Trachez, Gisele Zapata-Sudo
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 102 Issue 3 Pg. 308-16 (Mar 2008) ISSN: 1742-7843 [Electronic] England
• PMID: 18047479 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Muscle Relaxants, Central
• Oxazoles
• azumolene
• Dantrolene

Topics

• Animals
• Dantrolene (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Guinea Pigs
• Humans
• Imidazoles (administration & dosage, pharmacology)
• In Vitro Techniques
• Inhibitory Concentration 50
• Male
• Malignant Hyperthermia (drug therapy)
• Mice
• Muscle Contraction (drug effects)
• Muscle Relaxants, Central (administration & dosage, pharmacology)
• Muscle, Skeletal (drug effects, metabolism)
• Oxazoles (administration & dosage, pharmacology)
• Solubility