Sulmazole (AR-L 115BS) activates the sheep cardiac muscle sarcoplasmic reticulum calcium-release channel in the presence and absence of calcium.
The properties of calcium-release channels of sheep cardiac muscle junctional sarcoplasmic reticulum (SR), have been investigated under voltage-clamp conditions following the fusion of isolated membrane vesicles with planar phospholipid bilayers. In the presence of activating calcium on the cytosolic side of the membrane, additions of the benzimidazole derivative sulmazole (AR-L 115BS) increased the open probability (Po) of the channel reaching saturating values of 1.0 at 3 mM sulmazole. The drug did not affect single-channel conductance and activation was readily reversible. Analysis of channel open and closed lifetimes suggested that low concentrations of sulmazole (0.1 mM) may sensitize the channel to activating calcium, while at higher concentrations (1 mM and above), calcium and sulmazole act synergistically to produce a unique gating scheme for the channel. Millimolar concentrations of sulmazole also stimulate a degree of channel opening at subactivating (60 pM) calcium concentrations. Openings occurring under these conditions show very different kinetics to those of the calcium-activated channel but have an identical single-channel conductance and are modified by ATP, magnesium, ruthenium red and ryanodine in a similar manner to the calcium-activated channel. The release of calcium from the SR following the activation of the calcium-release channel by sulmazole may contribute to the positive inotropic action of this drug on mammalian cardiac muscle.
Department of Cardiac Medicine, National Heart & Lung Institute, University of London, United Kingdom.
A J
AJ
Williams
S R
SR
Holmberg
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D012430:Ruthenium Red / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012756:Sheep
D015220:Calcium Channels; D002316:Cardiotonic Agents; D007093:Imidazoles; D012430:Ruthenium Red; D012433:Ryanodine; D000255:Adenosine Triphosphate; C029758:sulmazole; D008274:Magnesium; D002118:Calcium