Effect of diltiazem and dantrolene on the contractility of isolated malignant hyperpyrexia-susceptible porcine skeletal muscle.
Diltiazem inhibited and antagonized the abnormal contractures induced by halothane, caffeine and potassium chloride in isolated skeletal muscle from pigs susceptible to malignant hyperpyrexia (MHS). Contractile responses to caffeine and electrical stimulation also were suppressed by diltiazem in control tissue. Similar effects were obtained in the presence of dantrolene. In both MHS and control preparations, diltiazem antagonized caffeine-induced contractures in the presence of maximal effective concentrations of dantrolene, and the converse was true also. In MHS and control preparations detubulated by glycerol, diltiazem did not inhibit or antagonize caffeine-induced contractures while dantrolene did. Diltiazem seems to modify contractile responses at the level of the transverse tubule membrane by inhibiting the inward flow of extracellular Ca2+, while dantrolene inhibits Ca2+ release directly from the sarcoplasmic reticulum. Ca2+ influx through transverse tubules may be important in the aetiology of the MH syndrome.
Foster
P S
PS
Department of Medicine and Clinical Science, John Curtin School of Medicine Research, Australian National University, Canberra.
Denborough
M A
MA
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D008305:Malignant Hyperthermia / Q000503:physiopathology*; D009119:Muscle Contraction / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D013552:Swine
D002110:Caffeine; D011189:Potassium Chloride; D004110:Diltiazem; D003620:Dantrolene; D006221:Halothane