Effects of 2,3-butanedione 2-monoxime on Ca2+ release channels (ryanodine receptors) of cardiac and skeletal muscle.

Single channel and [3H]ryanodine binding measurements were performed to test for a direct functional interaction between 2,3-butanedione 2-monoxime (BDM) and the skeletal and cardiac muscle sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors). Single channel measurements were carried out in symmetric 0.25 m KCl media using the planar lipid bilayer method. BDM (1-10 mm) activated suboptimally Ca2+-activated (0.5-1 microM free Ca2+) single, purified and native cardiac and skeletal release channels in a concentration-dependent manner by increasing the number of channel events without a change of single channel conductances. BDM activated the two channel isoforms when added to either side of the bilayer. At a maximally activating cytosolic Ca2+ concentration of 20 microM, BDM was without effect on the cardiac channel, whereas it inhibited skeletal channel activities with IC50 approximately 2.5 mm. In agreement with single channel measurements, high-affinity [3H]ryanodine binding to the two channel isoforms was increased in a concentration-dependent manner at </=1 microM Ca2+. BDM was without a noticeable effect at low (</=0.01 microM) Ca2+ concentrations. At 20 microM Ca2+, BDM inhibited the skeletal but not cardiac channel. These results suggest that BDM regulates the Ca2+ release channels from the sarcoplasmic reticulum of skeletal and cardiac muscle in a concentration, Ca2+ and tissue-dependent manner.