Paradoxical potentiation of stimulated insulin release by dantrolene in rat pancreatic islets.
Dantrolene sodium, used clinically as a muscle relaxant because of its ability to block Ca2+ efflux from sarcoplasmic reticulum, was used to study the role of intracellular stored Ca2+ in the stimulation of insulin release from rat pancreatic islets. Under basal conditions (2.8 mM glucose), dantrolene (25 microM) decreased 45Ca2+ efflux by 40% without affecting the rate of insulin release. When the islets were exposed to a submaximal stimulatory concentration of glucose (8.3 mM), dantrolene potentiated insulin release. When a supermaximal concentration of glucose (33.3 mM) was used, dantrolene neither increased nor decreased the maximal rate of insulin release. In all cases studied, 45Ca2+ efflux was depressed by dantrolene. 3-Isobutyl-1-methyl-xanthine (IBMX) a phosphodiesterase inhibitor, stimulated insulin release and caused a transient increase in 45Ca2+ efflux from preloaded islets in accord with the idea that it mobilizes Ca2+ from an intracellular store. Dantrolene inhibited IBMX-induced 45Ca2+ efflux and potentiated IBMX-stimulated insulin release. That dantrolene acts to trap calcium in stores is supported by wash-out experiments in which, under basal conditions, removal of the drug after a preincubation period increased both insulin release and 45Ca2+ efflux. The apparent contradiction that a calcium store blocker potentiates insulin release is reconciled by the hypothesis that dantrolene, by filling intracellular Ca2+ stores, causes them to regulate cytosolic Ca2+ at a higher set point.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D003620:Dantrolene / Q000494:pharmacology*; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels / Q000187:drug effects; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical
D007328:Insulin; D007473:Ion Channels; D003620:Dantrolene; D005947:Glucose; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine