HUMAN SKELETAL-MUSCLE DIGITALIS GLYCOSIDE RECEPTORS (NA,K-ATPASE) - IMPORTANCE DURING DIGITALIZATION

The aims of the present study were to evaluate in humans the putative importance of skeletal muscle digitalis glycoside receptors (Na,K-ATPa se) in the volume of distribution of digoxin and to assess whether the rapeutic digoxin exposure might cause digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained post mortem from 11 long-term (9 months to 9 years) digitalized (125-187.5 mug daily) and eight undigitalized subjects. In intact samples from di gitalized patients, vanadate-facilitated H-3-ouabain binding increased 15% (p < 0.02) from 150 +/- 18 to 173 +/- 13 pmol/g wet wt. (mean +/- SEM) after clearing receptors of bound digoxin by washing samples in excess specific digoxin antibody fragments. H-3-ouabain binding in the untreated group was 257 +/- 28 and 274 +/- 26 pmol/g wet wt. (7%, p > 0.30) before and after washing in specific dogoxin antibody fragments , respectively. Thus, the present study indicates a approximately 13% occupancy of skeletal muscle digitalis glycoside receptors with digoxi n during digitalization. In light of the large skeletal muscle contrib ution to body mass, this indicates that the skeletal muscle Na,K-ATPas e pool constitutes a major volume of distribution for digoxin during d igitalization. The results gave no indication of skeletal muscle digit alis glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p < 0.005) digitalis glycoside receptor concentration in the vastus latera lis of the digitalized patients, which may be of importance for skelet al muscle incapacity in heart failure.