The effect of EU4093 (azumolene sodium) on the contraction of intrafusal muscle in the soleus muscle of the anaesthetized rat

Abstract

1 EU4093 (azumolene sodium) is a direct acting, skeletal muscle relaxant with structural similarities to dantrolene sodium in that the para-nitro phenyl group of dantrolene sodium is replaced by a para-bromo phenyl group. 2 The effect of EU4093 on the twitch of the intact rat soleus preparation is nearly maximal at a dose of 20mgkg-'. This dose of EU4093 reduces the amplitude of the twitch to 31.9% of the control value. By comparison, dantrolene sodium reduced the twitch amplitude to 31.3% of the control value at a dose of 5 mg kg-1. 3 The contraction of intrafusal muscle as measured by the response of spindle afferent discharge was also reduced by EU4093. 4 The most significant difference between the effect of EU4093 and dantrolene sodium on the contraction of intrafusal muscle was that EU4093 had an appreciable depressant action at high stimulation frequencies at which dantrolene sodium had only a minimal relaxant effect on the intrafusal muscle contraction. 5 The significance of this difference in the actions of EU4093 and dantrolene sodium is discussed in terms of the possible effect of the drug in the intact animal and human patient. It is concluded that, because the discharge frequency is not likely to move into the high frequency range at which dantrolene sodium and EU4093 have significantly different effects, the overall effect of these two drugs is likely to be similar.

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

“…To date, the only effective treatment for MH is dantrolene sodium, a skeletal muscle relaxant, which suppresses the uncontrolled rise in myoplasmic Ca 2ϩ , presumably by targeting RyR1 and suppressing its Ca 2ϩ channel activity (10 -12). Azumolene sodium is a structurally similar, equipotent analog of dantrolene, with an ϳ30-fold greater water solubility (13,14).…”

“…To date, the only effective treatment for MH is dantrolene sodium, a skeletal muscle relaxant, which suppresses the uncontrolled rise in myoplasmic Ca 2ϩ , presumably by targeting RyR1 and suppressing its Ca 2ϩ channel activity (10 -12). Azumolene sodium is a structurally similar, equipotent analog of dantrolene, with an ϳ30-fold greater water solubility (13,14).Whereas hyperactivity or leakiness of the RyR1 channel has been described as the primary physiological defect in MH-susceptible muscle, the molecular mechanism underlying the suppression of [ -sensitive fluorescence measurements of RyR1-dependent intracellular Ca 2ϩ transients and extracellular Ca 2ϩ entry via SOCE, we show that azumolene inhibits SOCE both in skeletal muscle fibers and in cultured cells expressing RyR1. Our results reveal two modes of SOCE activation.…”

The Effect of Azumolene on Hypercontractility and Sarcoplasmic Reticulum Ca2+‐dependent Atpase Activity of Malignant Hyperpyrexiasusceptible Porcine Skeletal Muscle

“…Dantrolene decreases halothane-induced calcium release from MH-susceptible porcine SR (Ohnishi et al 1983) and modifies caffeine contractures in detubulated MHsusceptible porcine muscle (Foster & Denborough 1989), indicating that dantrolene can act directly on the SR. Like dantrolene, azumolene does not stimulate the Ca2+-transport pump of the SR. Azumolene did not potentiate SR Ca2+-dependent ATPase activity from MH-susceptible or control muscle. Azumolene and dantrolene also have similar effects on the contractile characteristics of intrafusal muscle from intact rat soleus preparations (Leslie & Part 1989). Moreover, in the presence of maximal effective concentrations of dantrolene, azumolene does not induce relaxation of caffeine contractures and vice versa, indicating that both muscle relaxants modify contracture at the same site.…”

Effects of azumolene on Ryanodine binding to sarcoplasmic reticulum of normal and malignant hyperthermia susceptible swine skeletal muscles

“…Partial inhibition of halothane-induced Ca 2+ release from MHS SR by dantrolene-Na was reported previously (Ohnishi et al, 1983). Azumolene,[1][2][3][4][5]-2-oxazolyl] methylene]amino]-2,4-imidazolidinedione, is a water soluble dantrolene analogue having the useful greater water solubility than dantrolene (Fletcher et al, 1988;Leslie and Part, 1989;Dershwitz and Sreter, 1990). However, no study has yet been carried out on the effects of azumolene on Ca 2+ release channel in the isolated pig skeletal SR vesicles.…”