Dantrolene, sodium salt

Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity.[Pubmed:11278295]

J Biol Chem. 2001 Apr 27;276(17):13810-6.

As an inhibitor of Ca(2+) release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca(2+) signaling and a lifesaving treatment for the pharmacogenetic disorder malignant hyperthermia. However, the molecular basis and specificity of the actions of dantrolene on RYR channels have remained in question. Here we utilize [(3)H]ryanodine binding to further investigate the actions of dantrolene on the three mammalian RYR isoforms. The inhibition of the pig skeletal muscle RYR1 by dantrolene (10 microm) was associated with a 3-fold increase in the K(d) of [(3)H]ryanodine binding to sarcoplasmic reticulum (SR) vesicles such that dantrolene effectively reversed the 3-fold decrease in the K(d) for [(3)H]ryanodine binding resulting from the malignant hyperthermia RYR1 Arg(615) --> Cys mutation. Dantrolene inhibition of the RYR1 was dependent on the presence of the adenine nucleotide and calmodulin and reflected a selective decrease in the apparent affinity of RYR1 activation sites for Ca(2+) relative to Mg(2+). In contrast to the RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene, both in native cardiac SR vesicles and when heterologously expressed in HEK-293 cells. By comparison, the RYR3 isoform expressed in HEK-293 cells was significantly inhibited by dantrolene, and the extent of RYR3 inhibition was similar to that displayed by the RYR1 in native SR vesicles. Our results thus indicate that both the RYR1 and the RYR3, but not the RYR2, may be targets for dantrolene inhibition in vivo.

Dantrolene inhibits long-term depression and depotentiation of synaptic transmission in the rat dentate gyrus.[Pubmed:8577362]

Neuroscience. 1995 Oct;68(3):621-4.

The involvement of Ca release from intracellular stores in the induction of long-term depression and depotentiation of excitatory synaptic transmission was investigated in the rat dentate gyrus using dantrolene, an agent known to block Ca release via the ryanodine receptor. In control slices, low-frequency stimulation (1 Hz for 15 min) induced robust long-term depression of baseline field excitatory postsynaptic potentials and depotentiation of previously established long-term potentiation. Dantrolene (50 microM) was found to block completely both long-term depression of baseline responses and depotentiation. Moreover, long-term potentiation induced by high-frequency stimulation was enhanced in the presence of dantrolene.

Dantrolene ameliorates the metabolic hallmarks of sepsis in rats and improves survival in a mouse model of endotoxemia.[Pubmed:8159702]

Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3039-43.

Sepsis is the systemic inflammatory response resulting from serious infection and is the most common cause of death in intensive care units. Intracellular free calcium concentration ([Ca2+]i) is an important regulator of numerous cellular processes and when increased excessively may act as a potent cellular toxin. To determine if [Ca2+]i is responsible for the major metabolic changes which are hallmarks of sepsis, we examined if sodium dantrolene, a drug which decreases release of calcium from sarcoplasmic reticulum, affected the metabolic abnormalities in plasma and epitrochlearis muscles of rats made septic by cecal ligation and perforation. Dantrolene when added in vitro or when given in vivo decreases many of the metabolic hallmarks of sepsis--i.e., muscle protein breakdown approximately 30%, muscle glucose transport approximately 38%, muscle lactate formation approximately 28%, and plasma lactate approximately 29% (P < 0.05). In addition, we examined the ability of dantrolene to improve survival in a mouse model of endotoxemia. Dantrolene caused > 2-fold improvement in survival when it was administered concurrently with endotoxin (54% vs. 20% survival in dantrolene-treated and control mice, respectively (P < 0.001). Our results are consistent with the hypothesis that an increase in [Ca2+]i plays an important role in the metabolic abnormalities which occur during sepsis and that dantrolene administration may be an effective therapeutic strategy.