Isolation of a urinary digitalis-like factor indistinguishable from digoxin

Goto, Atsuo; Ishiguro, Taro; Yamada, Kaoru; Ishii, Masao; Yoshioka, Masanori; Eguchi, Chikahiko; Shimora, M; Sugimoto, Tsuneaki

doi:10.1016/s0006-291x(05)80898-8

Cited by 126 publications

(46 citation statements)

References 10 publications

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“…The results of the treatments with nucleases and phospholipase C also suggest that a nucleic acid or a lysophospholipid is not responsible for this inhibitory activity. Furthermore, the inhibitory activity was stable in boiling water for 10 min, whereas heating at 150" C for 30 min, acid hydrolysis for an extremely short period and alkaline hydrolysis partially destroyed the inhibitory activity. Strong acid hydrolysis (6 M HCl at 11 5" C for 6 h and 21 h) almost completely destroyed the inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

“…A number of investigators have attempted to isolate and identify an endogenous counterpart to the cardiac glycosides from a variety of sources, such as plasma [30 -32, 461, urine [9,10,30], cerebrospinal fluid [47], hypothalamus [I 3,151 and adrenal gland [35]. Although several compounds have been isolated and identified as endogenous substances with the inhibitor activity, most of them have been shown to be nonspecific, low-affinity inhibitors for Na+,K+-ATPase.…”

Section: Discussionmentioning

confidence: 99%

“…Although several compounds have been isolated and identified as endogenous substances with the inhibitor activity, most of them have been shown to be nonspecific, low-affinity inhibitors for Na+,K+-ATPase. Recently specific inhibitors have been successfully isolated which show hlgh affinity for the ATPase [35,48 -501, and digoxin [30] and ouabain 1311 have been identified as the endogenous substances. However, scepticism remains as to whether these substances are produced in vertebrates because they are known to be produced only in plants, and the enzymes required for de novo synthesis of a cardiac glycoside have not yet been detected in mammalian tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Non-peptide, low-molecular-mass Na+,K+-ATPase inhibitors were also found in human urine [8 -101, and one of them has been identified as digoxin [30]. Another was reported to have a character identical to ouabain [48].…”

Section: Discussionmentioning

confidence: 99%

“…Although bufotoxins have been shown to exhibit more potent cardiotonic, natriuretic and diuretic action in some animals than the plant-derived cardiac glycosides, such as ouabain [28, 291, they have not yet been identified in mammals. Recently, two such substances have been isolated from human materials and identified as digoxin [30] and ouabain [31]. However, it remains controversial whether synthetic pathways for both digoxin and ouabain exist in human tissues and whether they act as regulators of sodium homeostasis.…”

mentioning

confidence: 99%

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Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine

Tamura

Harris

Konishi

et al. 1993

European Journal of Biochemistry

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A Na+,K+-ATPase inhibitor was purified from 88.6 1 pig urine with a yield of approximately 10 pg. It inhibits the ouabain-sensitive uptake of "Rb into human erythrocytes and the specific binding of ouabain to Na+,K+-ATPase. It also exhibits cross-reactivity to anti-ouabain serum. The purification procedure consisted of adsorption chromatography on an Amberlite XAD-2 column, preparative scale CI8 low-pressure liquid chromatography (LPLC), and five steps of HPLC with five different types of reverse-phase columns. The dose dependence of the purified substance for the inhibition of ouabain-sensitive Na+,K ' -ATPase activity and 86Rb uptake into human erythrocytes, and for the ouabain-displacing activity, paralleled those of ouabain, spanning two orders of magnitude in concentration range. However, the curve obtained from the cross-immunoreactivity with antiouabain serum did not parallel that of ouabain. The inhibitory potencies of the purified substance against the Na+-pump and ouabain-binding were diminished with increasing K' concentration, exhibiting characteristics typical of cardiac glycosides. This substance had no effect on Ca2 +-ATPase activity in human erythrocyte plasma membrane and skeletal-muscle sarcoplasmic reticulum, nor on Mg2+-ATPase activity. Acid treatment with 6 M HC1 at 115°C for less than 1 min destroyed approximately 82% of the inhibitory activity of the purified substance against Na+-pump activity. Alkaline treatment with 0.2 M NaOH at 23°C for 2 h and heat treatment at 150°C for 30 min

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine

Tamura

Harris

Konishi

et al. 1993

European Journal of Biochemistry

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Digitalisforschung in Berlin‐Buch – Rückblick und Ausblick

et al. 1995

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Der Arzt William Withering führte 1785 mit seinem Buch „An Account of the Foxglove and some of its Medical Uses”︁ Präparate aus Digitalisblättern in die Therapie der Wassersucht (des Herzversagens) ein und erklärte: „The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.”︁ Diese Bemerkungen sind hier vom Seniorautor angeführt, da er die Schwierigkeit sieht, einen ausgewogenen Bericht über sein lebenslanges Forschungsprojekt zur Digitalis‐Weiterentwicklung zu bieten. Seine Entscheidung, sich der Digitalisforschung zu widmen, entstand am Krankenbett, an dem er als Arzt die furchtbaren Endstadien des Herzversagens erlebte, in denen für die Kranken keine wirkliche Hilfe mehr möglich ist. Unglücklicherweise paßte dieses Vorhaben nicht in das vom Wissenschaftsministerium der DDR dekretierte Forschungsprogramm, so daß er das Digitalisprojekt zugunsten von Biomembran‐Untersuchungen einstellen sollte. Glücklicherweise entging er dem Verdikt durch Etikettierung der digitalisartig wirkenden Steroide als chemische Sonden für die Zellmembran‐lokalisierte Na+/K+ ‐transportierende ATPase, die er gerade als den Digitalisrezeptor erkannt hatte. Über die Arbeit der Autoren wird hier erstmals im Zusammenhang berichtet. Ziel des Überblicks ist, die Forschung für die Lösung einer großen Aufgabe zu fördern: die Entwicklung von Steroidwirkstoffen zur Verhinderung und Heilung der Herzinsuffizienz.

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Digitalis Research in Berlin–Buch—Retrospective and Perspective Views

Repke¹,

Megges²,

Weiland³

et al. 1995

Angew. Chem. Int. Ed. Engl.

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“The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.” These declarations, which stem from the famous book “An Account of the Foxglove and some of its Medical Uses” by physician William Withering in 1785 in which he introduced preparations from digitalis leaves in the therapy of dropsy (cardiac failure), are cited here by the senior author because of his awareness of the difficulties in presenting a balanced report on his life‐long research project on the further development of digitalis. His decision to devote himself to digitalis research originated at the bedside, when as a physician he experienced the grim final stages of cardiac failure in which no real help for the patients is possible. Unfortunately, his research project did not fit into the research program decreed by the Ministry of Science of the German Democratic Republic, so that he was ordered to stop the digitalis project in favor of biomembrane studies. Fortunately, he got round the ban simply by labeling the digitalis‐like acting steroids as probes for the cell membrane‐located Na+/K+‐transporting ATPase which he had just recognized as the digitalis target (receptor) enzyme. These and other ventures by the authors are collated here for the first time. The aim of this review is to foster straightforward research for solving a major challenge: the development of steroidal drugs for the prevention and cure of cardiac failure.

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Isolation of a urinary digitalis-like factor indistinguishable from digoxin

Cited by 126 publications

References 10 publications

Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine

Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine

Digitalisforschung in Berlin‐Buch – Rückblick und Ausblick

Digitalis Research in Berlin–Buch—Retrospective and Perspective Views

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Isolation of a urinary digitalis-like factor indistinguishable from digoxin

Cited by 126 publications

References 10 publications

Isolation and characterization of an endogenous Na+,K+ ‐ATPase‐specific inhibitor from pig urine

Isolation and characterization of an endogenous Na+,K+ ‐ATPase‐specific inhibitor from pig urine

Digitalisforschung in Berlin‐Buch – Rückblick und Ausblick

Digitalis Research in Berlin–Buch—Retrospective and Perspective Views

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Product

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Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine

Isolation and characterization of an endogenous Na⁺,K⁺ ‐ATPase‐specific inhibitor from pig urine