The effect of azumolene on hypercontractility and sarcoplasmic reticulum Ca(2+)-dependent ATPase activity of malignant hyperpyrexia-susceptible porcine skeletal muscle.
1. Azumolene sodium is a new water-soluble derivative of dantrolene sodium that also acts as a skeletal-muscle relaxant. 2. Azumolene (6 mumol/L) inhibited the hypercontractility induced separately by 3% halothane, 2 mmol/L caffeine and 80 mmol/L potassium chloride in isolated malignant hyperpyrexia (MH)-susceptible muscle. Azumolene was equipotent with dantrolene in inhibiting the abnormal responses. 3. Like dantrolene, azumolene (6 mumol/L) not only prevented but reversed the abnormal contractures induced by halothane and caffeine. Contracture responses to caffeine were also modified by azumolene in control preparations. 4. In the presence of maximal effective concentrations of dantrolene, azumolene failed to further relax caffeine-induced contractures, and the converse was also true. This was observed in both MH-susceptible and control preparations. 5. Sarcoplasmic reticulum Ca(2+)-dependent ATPase activity from MH-susceptible and control muscle was not affected by azumolene. 6. Like dantrolene, azumolene may inhibit Ca2+ release directly from the sarcoplasmic reticulum and be of therapeutic value for the treatment of MH.
Foster
P S
PS
Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra.
Hopkinson
K C
KC
Payne
N
N
Denborough
M A
MA
D000818:Animals; D002110:Caffeine / Q000009:adverse effects; D000252:Calcium-Transporting ATPases / Q000187:drug effects* / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D006221:Halothane / Q000009:adverse effects; D007093:Imidazoles / Q000494:pharmacology*; D008305:Malignant Hyperthermia / Q000188:drug therapy* / Q000201:enzymology; D009119:Muscle Contraction / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009132:Muscles / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D010080:Oxazoles / Q000494:pharmacology*; D011189:Potassium Chloride / Q000009:adverse effects; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology
D007093:Imidazoles; D009125:Muscle Relaxants, Central; D010080:Oxazoles; D002110:Caffeine; C061387:azumolene; D011189:Potassium Chloride; D000252:Calcium-Transporting ATPases; D003620:Dantrolene; D006221:Halothane