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Digoxin activates sarcoplasmic reticulum Ca 2+ ‐release channels: a possible role in cardiac inotropy
Author(s) -
McGarry Stephen J.,
Williams Alan J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13503.x
Subject(s) - digoxin , chemistry , endoplasmic reticulum , cardiac muscle , vesicle , biophysics , skeletal muscle , membrane channel , medicine , membrane , biochemistry , biology , heart failure
1 The effect of digoxin on rapid 45 Ca 2+ efflux from cardiac and skeletal sarcoplasmic reticulum (SR) vesicles was investigated. Additionally the interaction of digoxin with single cardiac and skeletal muscle SR Ca 2+ ‐release channels incorporated into planar phospholipid bilayers and held under voltage clamp was determined. 2 Digoxin (1 n m ) increased the initial rate and amount of Ca 2+ ‐induced release of 45 Ca 2+ from cardiac SR vesicles, passively loaded with 45 CaCl 2 , at an extravesicular [Ca 2+ ] of 0.1 μ m . The efflux in the presence and absence of digoxin was inhibited at p m extravesicular Ca 2+ and blocked by 5 m m Mg 2+ . 3 To elucidate the mechanism of action of digoxin, single‐channel recording was used. Digoxin (1–20 n m ) increased single‐channel open probability ( P o ) when added to the cytosolic but not the luminal face of the cardiac channel in the presence of sub‐maximally activating Ca 2+ (0.1 μ m −10 μ m ) with an EC 50 of 0.91 n m at 10 μ m Ca 2+ . The mechanisms underlying the action of digoxin appear to be concentration‐dependent. The activation observed at 1 n m digoxin appears to be consistent with the sensitization of the channel to the effects of Ca 2+ . At higher concentrations the drug appears to interact synergistically with Ca 2+ to produce values of P o considerably greater than those seen with Ca 2+ as the sole activating ligand. 4 Digoxin had no effect on single‐channel conductance or the Ca 2+ /Tris permeability ratio. In channels activated by digoxin the P o was decreased by Mg 2+ . Single‐channels were characteristically modified to a long lasting open, but reduced, conductance state when 100 n m ryanodine was added to the cytosolic side of the channel. 5 Activation of the cardiac SR Ca 2+ ‐release channel was observed with similar concentrations of digitoxin, however, higher concentrations of ouabain were required to increase P o . In contrast, a steroid which is not positively inotropic, chlormadinone acetate, had no effect on either cardiac or skeletal SR Ca 2+ ‐release channel activity. 6 At concentrations up to 1 μ m , digoxin had no effect on Ca 2+ ‐induced 45 Ca 2+ efflux from skeletal muscle SR vesicles nor did it affect skeletal SR Ca 2+ ‐release channel P o , reflecting a difference between the cardiac and skeletal isoforms of the Ca 2+ ‐release channel. 7 Since activation of the cardiac SR Ca 2+ ‐release channel occurs within the range of concentrations of digoxin encountered therapeutically, it is possible that activation of this channel contributes to the positive inotropic effect observed with this drug. Further, activation of the channel by higher concentrations of digoxin may contribute to the toxic effects seen clinically.