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-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125-187.5 micrograms daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated 3H-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. 3H-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 digoxin antibody fragments, respectively. Thus, the present study indicates a approximately 13% occupancy of skeletal muscle digitalis glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle digitalis 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 lateralis of the digitalized patients, which may be of importance for skeletal muscle incapacity in heart failure.
Department of Medicine B, Rigshospitalet, Copenhagen University School of Medicine, Denmark.
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Schmidt
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Holm-Nielsen
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Kjeldsen
D000368:Aged; D000918:Antibody Specificity; D004071:Digitalis Glycosides / Q000378:metabolism / Q000494:pharmacology; D004077:Digoxin / Q000378:metabolism / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure*; D010042:Ouabain / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D004071:Digitalis Glycosides; D007140:Immunoglobulin Fab Fragments; D011955:Receptors, Drug; C027082:digitalis receptor; C050199:digoxin antibodies Fab fragments; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase