Endogenous digitalis-like substance in plasma of volume-expanded dogs

Abstract

Considerable evidence supports the hypothesis that renal sodium excretion is partly regulated by a humoral agent released or activated by extracellular fluid volume (ECFY) expansion¹, including the demonstration of biological activities in extracts of plasma and urine which support the natriuretic hormone (NH) hypothesis^2–4. NH is a low molecular weight peptide formed from a precursor in plasma⁵, which inhibits sodium transport (anti-natriferic activity) in isolated toad bladder, an analogue of the distal renal tubule and collecting duct. Other evidence indicates that NH can inhibit renal (Na⁺+ K⁺) ATPase⁶, which suggests that it might be an endogenous digitalis-like substance. Although an immunoreactive ouabain-like substance has been demonstrated in amphibian plasma⁷, none has been reported in mammals. To identify an endogenous digitalis-like substance, we used an approach suggested by the work of Spector and his collaborators, who demonstrated that biological substances which bind to the same receptors as drugs, such as endogenous opioids⁸ and benzodiazepines⁹, may compete with antibodies specific for the drugs. Hough and Edwardson¹⁰ showed that antibodies to thaumatin, a sweet-tasting plant protein, also bind non-protein sweet substances in a linearly related fashion to the sweetness of the compound, suggesting that the antibody binding site may be similar to the sweet taste receptor. Based on these observations, we postulated that if NH were an endogenous digitalis-like substance, it might bind to antibodies specific for digitalis glycosides. We report here the preliminary isolation of a substance in plasma of dogs which competes with digoxin for two specific digoxin antibodies and is an inhibitor of (Na⁺ + K⁺) ATPase activity. Increased amounts of this factor are found in plasma of volume-expanded dogs, suggesting it is the putative NH.