Endogenous digitalis-like factors: in vitro comparison of biological and immunological activities of peptide and steroid candidates.
Endogenous substances that modulate the activity of (Na+ + K+)-ATPase through interaction at the cardiac glycoside site have been postulated. Reports of digitalis-like biological and immunological activity exhibited by certain ACTH/MSH peptides and 14-OH steroids make these compounds potential candidates as endogenous digitalis-like factors. We tested several ACTH/MSH peptides and 14 alpha-OH steroids in four in vitro assays and detected no significant cardiac glycoside-like activity. On the other hand, chlormadinone acetate, a progesterone derivative shown to bind with high affinity to the digitalis receptor, was nearly equipotent to digoxigenin in a [3H]ouabain radioreceptor assay. In a [3H]digoxin radioimmunoassay, however, digoxigenin and digoxin were equipotent but chlormadinone acetate was inactive. A clear dissociation between radioreceptor assay and radioimmunoassay activity was also observed using 15 beta-OH-progesterone. Our findings indicate that (a) ACTH/MSH peptides and 14 alpha-OH steroids are not viable candidates as endogenous digitalis-like factors, (b) digoxin antibodies are not necessarily directed at molecular determinants critical for biological activity, and (c) among the compounds reported to exhibit digitalis-like activity and postulated to share structural features with an endogenous steroidal digitalis-like factor, only chlormadinone acetate and its congeners appear to constitute tenable models.
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D002301:Cardiac Glycosides / Q000494:pharmacology*; D004077:Digoxin / Q000032:analysis / Q000378:metabolism; D004285:Dogs; D006914:Hydroxysteroids / Q000494:pharmacology*; D066298:In Vitro Techniques; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D010042:Ouabain / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011863:Radioimmunoassay; D011955:Receptors, Drug / Q000187:drug effects; D012413:Rubidium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D002301:Cardiac Glycosides; D006914:Hydroxysteroids; D010446:Peptide Fragments; D011955:Receptors, Drug; C027082:digitalis receptor; D010042:Ouabain; D004077:Digoxin; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; D000254:Sodium-Potassium-Exchanging ATPase; D012413:Rubidium