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PubMed1979

Direct photoaffinity labeling of the primary region of the ouabain binding site of (Na+ + K+)-ATPase with [3H]ouabain, [3H]digitoxin and [3H]digitoxigenin.

The tritiated cardiotonic steroids, ouabain, digitoxin, and digitoxigenin are shown to photolabel the large polypeptide but not the glycoprotein or proteolipid component of the (Na+ + K+)-ATPase when they are bound to the inhibitory site and exposed to light of 220 or 254 nm. The extent of photolabeling is low, less than 1%, and is limited by photocross-linking of the enzyme. The mechanism of photoincorporation does not appear to be either photolysis of the lactone ring in ouabain or photolysis of tryptophan or tyrosine residues in the polypeptide.

Affinity Labels↗
PubMed1990

Chelation of mercury by ouabain-sensitive and ouabain-resistant renal Na,K-ATPase.

The SH-reactive HgCl2 inhibits the Na,K-ATPase activity potently in a manner antagonized only partially by EDTA or cysteine; solely dimercaprol, a dithiol antidote for mercury, blocks the HgCl2 effects entirely as confirmed also by 203Hg-binding experiments. The results reveal the presence of a chelating component in pure Na,K-ATPase with an affinity for mercury superior to EDTA. The mercury-sensitivity of the Na,K-ATPase is not related to the ouabain-sensitivity. This criterion will be useful for the distinction between ouabain-like and mercury-like inhibitors from body fluids and tissues.

Animals↗
PubMed1990

Energy transfer via cell-to-cell junctions. Ouabain-resistant cells maintain a membrane potential in ouabain-sensitive cells.

Animal cell cooperation has been studied in a mixed cell culture. Membrane potentials of human embryonic cells and hamster BHK-21 cells were recorded by intracellular microelectrodes. The Na+/K(+)-ATPase inhibitor ouabain (1 x 10(-6) M; 2 h) caused strong depolarisation of the human cells in pure culture. The same treatment reduced only slightly the membrane potential in the hamster cells in pure or mixed cultures, as well as in the human cells in mixed culture. The above data can be explained by effective ion fluxes through heterotypic gap junctions in mixed culture. Thus, in the presence of ouabain the Na+/K(+)-ATPase of hamster cells creates transmembrane differences of the electrochemical potential of ions not only in the hamster cells, but in the human cells as well.

Animals↗
PubMed2006

Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension.

The genetic and environmental heterogeneity of essential hypertension is responsible for the individual variability of antihypertensive therapy. An understanding of the molecular mechanisms underlying hypertension and related organ complications is a key aspect for developing new, effective, and safe antihypertensive agents able to cure the cause of the disease. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+ reabsorption observed in essential hypertension: the polymorphism of the cytoskeletal protein alpha-adducin and the increased circulating levels of endogenous ouabain (EO). Both lead to increased activity and expression of the renal Na+-K+ pump, the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a new oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, Rostafuroxin antagonizes EO triggering of the Src-epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+ pump, and ERK tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate Rostafuroxin as the first example of a new class of antihypertensive agents designed to antagonize adducin and EO-hypertensive mechanisms.

Androstanols↗
PubMed1975

The nature of the transport adenosine triphosphatase-digitalis complex. VIII. The relationship between in vivo-formed (3-H-ouabain-Na+, K+-adenosine triphosphatase) complex and ouabain-induced positive inotropism.

Ouabain interaction with a possible pharmacologic receptor, Na+, K+-adenosine triphosphatase (Na+, K+-ATPase), has been assessed by continual perfusion of canine hearts with various concentrations of both unlabeled and 3-H-ouabain. A positive dose-related correlation between enzyme inhibition, increased contractile force and drug binding to the enzyme has been established. The complex formed between 3-H-oubain and Na+, K+-ATPase in vivo appears to have the same characteristics as that formed in vitro, suggesting that the nature of both complexes is the same. These data are consistent with the concept that Na+, K+-ATPase may be an important pharmacologic receptor for cardiac glycosides.

Adenosine Triphosphatases↗
PubMed1978

Factors affecting the relative magnitudes of the ouabain-sensitive and the ouabain-insensitive fluxes of thallium ion in erythrocytes.

A maximal rate of the ouabain-sensitive 204-Tl influx in human erythrocytes can be attained at trace concentrations of Tl+ in Mg2+ isotonic media free of K+ and Na+. The maximal influx of Tl+ from isotonic Mg(NO3)2 at 20 degrees C and pH 7.4 was 0.45 mM.l(-1).h-1 with a Km of 0.025 mM. In contrast to the active influx of Tl+, the passive Tl+ fluxes were neither saturated nor influenced by external cations in the range of concentrations of Tl+ and K+ studied. The rate constants of Tl+ passive fluxes in human and cat erythrocytes can be related to pH by the equation log kin(OUT)= -A + B.pH, where A and B are empirical constants for particular conditions. The apparent activation energy was 16 and 11 kcal/mol in sulphate and nitrate media, respectively. Tl+ and the alkali metal cations seem to overcome a common barrier in the erythrocyte membrane. Nevertheless, the rate of the passive penetration of Tl+ is about two orders of magnitude faster than those of K+ or Rb+. An extra non-Coulombic interaction between Tl+ and membrane ligands appears to be involved providing an accumulation of Tl+ somewhere in the vicinity of the membrane barrier and increasing the diffusion fluxes of Tl+ in both directions.

Animals↗
PubMed1979

An ouabain-insensitive Na-ATPase of the arterial vascular muscle cell and its relation to ouabain-sensitive Na,K-ATPase.

A Na+-stimulated, Mg++-requiring ATPase (Na-ATPase), which is insensitive to ouabain, has been demonstrated in the carotis and coronary arteries of different species. In dependence on the sodium concentration half-maximal activities of Na-ATPase are found in the range from 16 to 24 mM Na+. A replacement of Mg++ by Ca++ leads to a partial loss of activity. It does not, however, change its sensitivity to sodium. Compared to Na,K-ATPase, the Na-ATPase shows a considerably lower sensitivity to calcium. p-Chloro-mercuribenzoate, N-ethylmaleinimide, chloropromazine, sodium fluoride, ethanol and sodium azide influence the activity of the Na-ATPase in a characteristic way corresponding to the reactivity of Na,K-ATPase. Noradrenaline and isoprenaline do not lead to any significant change of its activity. The possible separate existence of a Na-ATPase independent of Na,K-ATPase, as well as its potential importance for cellular metabolism are discussed.

Adenosine Triphosphatases↗
PubMed1980

Comparison of adriamycin- and ouabain-induced cytotoxicity and inhibition of 86rubidium transport in wild-type and ouabain-resistant C3H/10T1/2 mouse fibroblasts.

Ouabain (OUA) inhibited 86Rb uptake (50% inhibitory concentration = 0.8 X 10(-4) M) over concentration ranges close to those at which it caused a reversible cytotoxicity (50% lethal dose = 2.5 X 10(-4) M) in growing wild-type C3H/10T1/2 cells. On the other hand, Adriamycin (ADM) inhibited 86Rb uptake (50% inhibitory concentration = 2 X 10(-3) M) but at concentrations 10(4)-fold higher than those causing irreversible cytotoxicity in growing wild-type cells (50% lethal dose = 3 X 10(-8) M). While OUA inhibited 86Rb uptake more in wild-type cells than in a OUA-resistant mutant, ADM inhibited 86Rb uptake to the same extent in confluent wild-type and OUA-resistant cells. Further, three OUA-resistant mutants were not cross-resistant to ADM- or daunomycin (DM)-induced cytotoxicity during log phase or to ADM-induced cytotoxicity at confluence. In addition, ADM, DM, or 5-iminodaunomycin did not displace the cardiac glycosides digoxin or digitoxin from their respective antibody complexes. The order of potency of anthracycline derivatives in inhibiting 86Rb uptake in confluent wild-type cells was the same as their order of inhibiting the growth of wild-type cells and in detaching confluent wild-type cells (DM > ADM > 5-iminodaunomycin) but did not correlate with their cardiotoxic potentials (ADM > DM > 5-iminodaunomycin). Therefore, in this model system, ADM cytotoxicity is mediated differently from OUA cytotoxicity. Further, we find no biological evidence consistent withADM binding to the OUA site on the cell surface (Na+-K+) adenosine triphosphatase and therefore no evidence in this model system that ADM cardiotoxicity could be a digitalis-type toxicity per se.

Animals↗