Endogenous Digitalis-like Substance Research Articles

Biological activity of partially purified digitalis-like substance and Na-K-ATPase inhibitor in rats.

In order to study the biological activity of endogenous digitalis-like substance (DLS) and Na-K-ATPase inhibitor (ATPI), human urine was partially purified and administered to rats, and its effects on the urinary volume, urinary Na excretion and blood pressure (BP) were determined. In addition, the effect on myocardial Na-K-ATPase activity was also measured. After the extraction of 40L of urine with a reversed phase cartridge column (S-fraction), 20 ml of chloroform was added and extraction was repeated. The chloroform layer was applied to an open silica gel column, and at a fraction with ethylacetate: methanol (60: 40, T-1 fraction), DLS and ATPI were eluted at the highest concentration. The water layer was treated with charcoal (D-1 fraction). The acute administration of K-1, T-1 fraction to rats in vivo caused significant rises in urinary volume, urinary Na excretion and BP. In chronic administration of K-1 fraction, urinary Na excretion was significantly elevated and myocardial Na-K-ATPase activity was also significantly suppressed. These results suggest that DLS and ATPI cause increase in the urinary volume and urinary Na excretion and also possess a hypertensive action; and moreover, these substance may affect the heart like cardiotonic steroids and regulate BP by increasing cardiac contractility.

Morphological evidence of endogenous digitalis-like substance (EDLS) in the rat and macaque hypothalamus, using digoxin-immunohistochemistry.

Morphological investigation of the endogenous digitals-like substance (EDLS) characterized as a natriuretic humoral agent has not been carried out to date; but EDLS can be detected indirectly by immunohistochemistry using cross-reactivity with digoxin-antibody. In this report, the brain and other organs of the rat and macaque were immunostained using commercially supplied digoxin-specific antibodies. The immunoreactive substances were mainly observed in the neurons of hypothalamic paraventricular and supraoptic nuclei, and varicose fibers in some areas of the hypothalamus and infundibulum. No immunopositive substances were detected in the pituitary anterior lobe, adrenal gland, or kidney of the rat.

Endogenous digitalis-like substance in cardiovascular disease

Endogenous digitalis-like substance in cardiovascular disease

Evidence for a digitalis-like substance in the hypothalamopituitary axis in rats: implications in the central cardiovascular regulation associated with an excess intake of sodium.

The origin and the physiological role of an endogenous digitalis-like substance were investigated by measuring both the digoxin-like substance by a digoxin radioimmunoassay (RIA) and the inhibitory activity on the ouabain sensitive Na+,K+-ATPase in rats. The digitalis-like substance was in high concentration in the pituitary, and in decreasing concentration in the hypothalamus, adrenal and the other organs as measured by RIA using an antibody raised from a goat. However, the adrenal showed the highest content of digitalis-like substance as measured by the antibody raised from a rabbit. The plasma level markedly decreased during a 2-week sodium-loading, and the adrenal content decreased markedly on hypophysectomy as measured with the rabbit-antibody. Therefore, the substance measured with the rabbit-antibody must be one of ACTH-dependent adrenal steroids. The inhibitory activity on the Na+,K+-ATPase was high in the pituitary gland, and was decreased in order of the adrenal, hypothalamus and other organs. The 2-week sodium-loading increased both the content in the pituitary gland and the output in the urine, and decreased the hypothalamic content. Immunohistochemical staining of the hypothalamus with the antibody revealed that the immunoreactivity is restricted to the neurons of the paraventricular nucleus, supraoptic nucleus, magnocellular accessory nuclei and extended their fibers reaching to the inner layer of the median eminence. To determine the role of the substance in the brain, the crude extract dissolved in artificial cerebrospinal fluid was injected into the lateral ventricle; vasopressor responses, tachycardia and hyperactivity of the splanchnic nerve lasting for more than 30 min were recorded, which resembled the responses to ouabain injected similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic drugs--digitalis.

Digitalis glycosides inhibit Na+K+-ATPase in the cells and have been used for scientific studies of cation transport over cell membranes. Furthermore, digitalis has a positive inotropic and antiarrhythmogenic effect. Specific binding sites for digitalis glycosides have been observed in erythrocytes, the myocardium and the central nervous system. Transcellular transport of digoxin has been found in the kidney, since digoxin is excreted by tubular secretion. Recent studies have discovered an endogenous digitalis-like substance both inhibiting Na-K-ATPase and displacing digoxin from specific binding sites at the erythrocytes. The concentration of this component in plasma seems to be higher in hypertension than in normotension. Future studies will have to disclose other effects of this substance in order to evaluate whether it can be used as a drug in heart failure.

Effects of extracts of rat brain on the digitalis receptor

There is a possibility that an endogenous substance exists which interacts with the ouabain binding site on Na +, K +-ATPase. Recently, several reports have appeared suggesting the presence of an endogenous digitalis-like substance in acid-acetone extracts of brain. We have demonstrated that in preparing an acid-acetone extract, peroxidized lipids and lysophospholipids are produced, both of which inhibit Na +, K +-ATPase, thereby complicating interpretation. Preliminary evidence suggests, however, that when rat brains are extracted with an aqueous -acetone mixture under nitrogen, a principle is obtained which specifically inhibits Na +, K +-ATPase.

Involvement of endogenous digitalis-like substance in genesis of deoxycorticosterone-salt hypertension

In an attempt to evaluate the role of endogenous digitalis-like substance in the genesis of deoxycorticosterone (DOCA) -salt hypertension, the effects of intravenous anti-digoxin antibody on the blood pressure response were observed in male Wistar rats that underwent heminephrectomy followed by treatment with DOCA and saline. Administration of anti-digoxin antibody caused a marked decrease in the blood pressure which continued for about an hour. Such a change in the blood pressure was not observed in pertinent control animals. Thus, it seems that endogenous digitalis-like substance plays an important role in the genesis of DOCA-salt hypertension.

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

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) hypothesis2–4. 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.

The salt-fed animal as a test object for pressor substances in the blood of hypertensive animals.

ArticleThe Salt-Fed Animal as a Test Object for Pressor Substances in the Blood of Hypertensive AnimalsDavid B. Gordon, Douglas R. Drury, and Shawn SchapiroDavid B. GordonFrom the Department of Physiology, School of Medicine, University of Southern California, Los Angeles, California, Douglas R. DruryFrom the Department of Physiology, School of Medicine, University of Southern California, Los Angeles, California, and Shawn SchapiroFrom the Department of Physiology, School of Medicine, University of Southern California, Los Angeles, CaliforniaPublished Online:30 Sep 1953https://doi.org/10.1152/ajplegacy.1953.175.1.123MoreSectionsPDF (987 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByLingonberry juice negates the effects of a high salt diet on vascular function and low-grade inflammationJournal of Functional Foods, Vol. 7Chapter 25 Cardiac glycosidesEndogenous Regulation of Sodium Pump ActivityThe Mechanism of Sodium-Dependent Low Renin HypertensionRole of an Ouabain-Like Humoral Agent and the Sodium-Potassium Pump in Low-Renin HypertensionHumoral factors and the sodium-potassium pump in low renin hypertensionKlinische Wochenschrift, Vol. 60, No. 19Evidence for a vascular sensitizing factor in plasma of saline-loaded dogs.Hypertension, Vol. 4, No. 5Involvement of endogenous digitalis-like substance in genesis of deoxycorticosterone-salt hypertensionLife Sciences, Vol. 30, No. 21Mechanism, prevention and therapy of sodium-dependent hypertensionThe American Journal of Medicine, Vol. 69, No. 5Humoral factors and the sodium-potassium pump in volume expanded hypertensionLife Sciences, Vol. 24, No. 23The Toxicity of Salt26 September 2008 | CRC Critical Reviews in Toxicology, Vol. 5, No. 4The Sodium-Potassium Pump in Volume Expanded Hypertension3 July 2009 | Clinical and Experimental Hypertension, Vol. 1, No. 3High sodium-low potassium environment and hypertensionThe American Journal of Cardiology, Vol. 38, No. 6A viewpoint concerning the enigma of hypertensionThe American Journal of Medicine, Vol. 52, No. 5Physiologie und Pathologie des Renin/Angiotensin-SystemsStudies on the Mechanism of an Eclampsia-Like Syndrome in RatsAmerican Journal of Obstetrics and Gynecology, Vol. 69, No. 3 More from this issue > Volume 175Issue 1September 1953Pages 123-128 Copyright & PermissionsCopyright © 1953 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1953.175.1.123PubMed13114364History Received 9 June 1953 Published online 30 September 1953 Published in print 30 September 1953 Metrics