Separate sites for the dantrolene-induced inhibition of contracture of the rat diaphragm preparation due to depolarization or to caffeine.
Addition of dantrolene 8.5 x 10(-5) M caused a mono-exponential decay of the depolarization contractures caused by inhibition of the sarcolemmal Na,K-ATPase with propranolol 1 mM or by depolarization of the sarcolemma and T tubular membranes with KCl 100 mM. The half-times of the inhibitory effects were 6 s for the propranolol contracture and 11 s for the KCl contracture. The inhibition of both contractures was complete. Inhibition of the caffeine (10 mM) contracture was bi-exponential with half-times of 45 s and 9.5 min. Inhibition was incomplete; 29.6 +/- 5.0% of the contracture tension could not be inhibited. The inhibition of twitch contractions was similar to that of the caffeine contracture, with half-times of 48 s and 9.1 min, and 20.6 +/- 1.2% of the initial twitch tension could not be inhibited. The contracture tensions induced by release of Ca from the mitochondria with dicumarol, and by actin-myosin binding with the sulfhydryl inhibitor, N-ethyl-maleimide, could not be inhibited by dantrolene. The present results indicate that dantrolene inhibits depolarization signals from the sarcolemma and the T tubular membranes, in addition to inhibition of the coupling between the T tubules and the sarcoplasmic reticulum, and of the release of Ca from the sarcoplasmic reticulum. All these effects of dantrolene may contribute to its therapeutic effect in malignant hyperthermia.
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Department of Physiology and Biochemistry, Dental Faculty, University of Oslo, Blindern, Norway.
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D003620:Dantrolene / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D001728:Dicumarol / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D005033:Ethylmaleimide / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002110:Caffeine; D011189:Potassium Chloride; D001728:Dicumarol; D011433:Propranolol; D003620:Dantrolene; D005033:Ethylmaleimide