DOI: 10.5176/2345-783X_PHARMA15.48
Authors: Christine M. Loescher and L. Michelle Gibson
Abstract:
The effect of dantrolene sodium on force production and calcium movements associated with sarcoplasmic reticulum (SR) were investigated in rat and sheep heart preparations. Cardiac contractility was not altered in functionally skinned right ventricular trabeculae from the rat when exposed to calcium activating solutions in the presence of ca. 35 μM dantrolene. There was no significant shift in the relative force versus pCa relation for cardiac preparations, slow twitch (soleus) or fast twitch (edl) muscle (P ≥ 0.05). Calcium loading and release were measured initially using the caffeine-induced force transient in rat heart preparations. Dantrolene (35μM) increased the caffeine-induced force transient for a range of calcium concentrations used to load the SR (pCa range 6.32 to 6.03) for 2 minutes, but was only significantly greater than control at pCa 6.24 (P < 0.05). When SR calcium loading and release were investigated in chemically skinned, isolated ventricular myocytes from sheep heart, 1μM dantrolene caused a significant (P < 0.05) increase in caffeine –induced SR calcium release after loading at pCa 6.55 or pCa 6.24 for 3 minutes. At higher calcium concentrations (pCa 6.03 and pCa 5.83) this property was lost and the peak calcium returned to those seen in control conditions. When 1 μM dantrolene was present only in the caffeine-releasing solution, there was no potentiation of SR calcium release until pCa 5.83 was used to load the SR (P < 0.05). Finally using purified calsequestrin 2 (CASQ2) the effect of dantrolene (concentration range 1.0 to 30μM) on calcium binding was assessed by using the native fluorescence changes of CASQ2 as it binds calcium. There was a dose–dependent increase in calcium binding by CASQ2 with 30μM dantrolene causing a 6-fold increase in calcium bound to CASQ2. We suggest that alterations in CASQ2 calcium binding in the presence of dantrolene is entirely possible in situ (as it is highly lipophilic) and is in part responsible for the improvement in SR calcium release in conjunction with its effects on the myoplasmic face of the ryanodine receptor (RyR2), but this is dependent on the calcium loading conditions.
Keywords: dantrolene; cardiac; mammalian; sarcoplasmic reticulum (SR), calsequestrin, ryanodine receptor
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