Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal tubular secretion of digoxin appears to be one of the main ports of elimination of the glycoside from the body. Because of its narrow therapeutic window and severe toxicity, the mechanisms of tubular handling of digoxin are important. Moreover, several drugs which are commonly administered with digoxin, including quinidine, spironolactone, verapamil and amiodarone have been shown to decrease renal clearance of digoxin without affecting GFR. We studied the handling of digoxin using in vitro and in vivo approaches. The handling of the glycoside by the brush border suggests passive reabsorption which is not enhanced by commonly coadministered drugs. Digoxin binding to the antiluminal (basal) membrane suggests that the secretion of the glycoside may not involve the pharmacologic receptor, the Na+, K+, ATPase. Using the multiple indicator dilution technique, we could directly show the two steps of secretion of digoxin: Its sequestration from the postglomerular circulation, and its appearance in the urine after transtubular transport. Digoxin transport is not inhibited by a cationic or anionic molecule (PAH and tolazoline). It is possible that digoxin is secreted by a yet unidentified transport mechanism.
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PMID:Cellular mechanisms of digoxin transport and toxic interactions in the kidney. 353 41

A woman died after drinking herbal tea prepared from oleander (Nerium oleander) leaves. This case demonstrates the cross-reactivity between the cardiac glycosides in oleander and the digoxin radioimmunoassay. Digoxin-specific Fab antibody fragments have not been used in oleander poisoning, but these might prove to be lifesaving. Treatment of oleander toxicity is aimed at controlling arrhythmias and hyperkalemia; inactivation of the Na-K ATPase pump, however, can make treatment difficult.
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PMID:Oleander tea: herbal draught of death. 403 13

The ability of digoxin and a 4-aminocardenolide, ASI-222, to alter atrioventricular nodal refractory period (AVRP) was determined as a function of the maximum subarrhythmic dose (MSAD) in the dog anesthetized with morphine-pentobarbital. ASI-222, a highly polar and potent inhibitor of Na+, K+-adenosine triphosphatase produces a cardiotoxicity in dogs prominently involving atrioventricular nodal blockade rather than ventricular premature ectopic beats and tachycardia seen with digoxin. AVRP was assessed with trains of electrically isolated stimuli of decreasing pulse interval delivered to the right atria. Digoxin and ASI-222 were infused i.v. at rates which produced cardiac arrhythmias in about 100 min in dogs either: 1) with intact nerves, 2) pretreated with atropine, 3) without reflex receptors (without vagus and carotid sinus nerves, 4) without cardiac sympathetic nerves and adrenals or 5) pretreated with metoprolol. In dogs with intact nerves, ASI-222 produced greater increases in AVRP than digoxin at fractions of the MSAD; however, both glycoside produced a similar elevation at the MSAD (approximately equal to 30% increase). Atropine did not alter the AVRP response to ASI-222 but prevented the lengthening due to digoxin except for that which occurred near the MSAD. Removal of reflex receptor afferents (and vagi) had an effect similar to atropine on the AVRP response to digoxin, but completely prevented any response to ASI-222. Prior sympathectomy or beta adrenergic blockade abolished the AVRP response to ASI-222 but did not alter the responses to digoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of an aminocardenolide and digoxin upon atrioventricular refractory period in the dog. 407 25

The purpose of this study was to see whether the receptor for cardiac glycosides might be localized upon or within the plasma membrane of digitalis-sensitive cells. Ouabain and digoxin were joined covalently to several large protein molecules. These macromolecular conjugates are too large to enter intact cells; consequently, any pharmacologic or biochemical effects which they display should arise from interaction with a cell surface receptor. Conjugates were tested in several cardiac glycoside-sensitive systems: (a), contractility response of isolated cardiac muscle; (b), active (86)Rb(+) uptake by red cells; (c), enzymatic activity of isolated myocardial microsomal (Na(+) + K(+))-activated adenosine triphosphatase (ATPase); and (d), enzymatic activity of solubilized red cell (Na(+) + K(+))-activated ATPase. Results demonstrated that in all of these systems, the macromolecular-glycoside conjugates were 100- to 1000-fold less active than the free glycosides. Careful chromatographic examination of the various conjugates revealed that they contained a small but persistent free cardiac glycoside contaminant. The amount of this species ranged from 0.1 to 1.0% of the total macromolecule-bound glycoside, and its presence fully explains the levels of biologic activity observed with the conjugates. To try to minimize steric factors which could interfere with glycoside-receptor interaction, digoxin and ouabain were also coupled to macromolecule via long, flexible polyamide side-chains. These extended chain conjugates, in which the cardiac glycoside potentially lay some 30 A removed from the surface of the macromolecule, also exhibited negligible digitalis-like effects when tested upon isolated cardiac muscle, red cell (86)Rb(+) uptake, and enzymatic activity of cardiac microsomal (Na(+) + K(+))-ATPase. However, the extended chain conjugates were fully active when examined with the solubilized red cell (Na(+) + K(+))-ATPase system. To further ensure that the chemical reactions used to couple macromolecule to glycoside did not inactivate the drug, all conjugates were subjected to extensive proteolytic digests exhibited full pharmacologic activity. Digoxin was also coupled to the tripeptide alanylglycylglycine, and the resulting conjugate was fully active. Taken together, these results suggest that if the receptor(s) for cardiac glycosides is associated with the plasma membrane, then it may lie deep within it.
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PMID:Studies on the localization of the cardiac glycoside receptor. 426 Jun 87

Na+-K+-ATPase activity, as measured by erythrocytic 86Rb uptake and number Digoxin Binding Sites were evaluated in 34 obese patients and in 39 control subjects. No differences were found in 86Rb uptake and Digoxin Binding Sites between obese and controls. Likewise no differences were found between obese patients on their spontaneous caloric intake and those studied during various hypocaloric regimens. Finally, no relationship between thyroid hormone serum concentrations and ATPase activity was found in the group of obese patients.
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PMID:Erythrocyte Na+-ATPase in obese patients. 609 23

This study was designed to determine whether digoxin therapy in the canine heart failing because of mitral regurgitation (MR) provides only hemodynamic benefit and accompanying subjective improvement or if it also reverses the changes in intracellular Ca++ and sarcolemmal Na+-K+-ATPase. The dogs were divided into four groups: control, MR of 3 months' duration, MR of 6 months', and digoxin treatment for 3 months after 3 months of MR. Six months of MR produced a marked decrease in the index of myocardial contractility and function associated with a decrease in intracellular Ca++ and Na+, and an increase in intracellular K+, extracellular space, sarcolemmal Na+-K+-ATPase, and Mg++-ATPase. Digoxin treatment tended to return the changes in the index of myocardial contractility and cardiac function, intracellular Ca++, Na+, K+, extracellular space, and sarcolemmal Na+-K+-ATPase of the failing heart toward control levels. Digoxin treatment did not affect Mg++-ATPase. The right ventricle, which did not fail, also did not show any significant changes in the parameters measured. The results showed that digoxin treatment not only improved the index of myocardial contractility and cardiac function of the failing heart but also tended to return the electrolytes and sarcolemmal Na+-K+-ATPase toward control levels.
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PMID:Effects of chronic digoxin treatment on cardiac function, electrolytes, and sarcolemmal ATPase in the canine failing heart due to chronic mitral regurgitation. 609 32

The distribution of 3H-digoxin has been measured in a large number of tissues from the central, autonomic, and peripheral nervous system after the induction of ventricular tachycardia by infusing digoxin into anesthetized dogs. In most parts of the nervous system the tissue digoxin concentration was close to that in the cerebrospinal fluid. Digoxin accumulation in the choroid plexus probably represented a labeling of adenosine triphosphatase. There was a markedly higher concentration of digoxin in the neurohypophysis than in the adenohypophysis, and the very high levels in the neurohypophysis are hard to explain. There may be a relationship between the pituitary and the hypothalamic digoxin levels, although the concentration in the latter was unimpressive. The fornix showed a modest increase in 3H-digoxin concentration and may play a role, as its efferent discharge goes to the hypothalamus. The high concentration of digoxin in the area postrema suggests that this central nervous system structure is responsible, at least in part, for producing digoxin-induced cardiac arrhythmias. It may act as a sensing organ sensitive to blood digoxin concentration. Either it is the only central nervous structure implicated, or it is involved together with the fornix-hypothalamus-hypophysis pathways. Further proof is given for the importance of the autonomic nervous system in cardiac arrhythmias by the high digoxin levels in the superior cervical sympathetic ganglion and adrenal medulla.
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PMID:3H-digoxin distribution in the nervous system in ventricular tachycardia. 617 30

Digoxin therapy has been made more rational by the measurement of serum digoxin concentrations. However, difficulties remain because of the overlap between "therapeutic" and "toxic" serum concentrations and the lack of an obvious therapeutic endpoint in many patients. An assay which measures the degree of interaction between digoxin and its putative receptor, the membrane Na+, K+-ATPase, might be capable of resolving some of these difficulties. Therefore, as a first approach in this direction we evaluated the relationship between serum digoxin concentration and the degree of inhibition of RBC ghost Na+, K+-ATPase activity in patients receiving digoxin therapy. Utilizing an improved micro-assay technique, Na+, K+-ATPase activity was determined in aliquots of RBC ghosts before and after removal of bound digoxin. In 27 patients a significant relationship was present between serum digoxin concentration and the degree of RBC ghost Na+, K+-ATPase inhibition. However, at any serum digoxin concentration, there was a variation in the magnitude of enzyme inhibition from patient to patient. This study confirms the feasibility of determining the degree of in vivo RBC Na+, K+-ATPase inhibition in man and demonstrates, for the first time, a highly significant but somewhat variable relationship between serum digoxin concentrations and the magnitude of RBC digoxin receptor inactivation. This quantitative, functional, individualized assay of digoxin effects may prove to be of clinical value in the future.
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PMID:Erythrocyte Na+, K+-ATPase and serum digoxin concentrations. 630 31

Blood pressure and digitalis-like substance were measured in the plasma of control, salt-treated, and DOCA-salt treated rats. Blood pressure in DOCA-salt treated rats was significantly higher than that of either control or salt-treated animals. Digitalis-like activity was measured by two methods, radioimmunoassay for digoxin, and a receptor binding assay employing a rat brain synaptosomal membrane fraction. Digoxin-like immunoreactivity in plasma was not detected in either control or salt-treated rats, but was detected in DOCA-salt treated rats. Receptor binding activity in salt-treated rats was slightly but significantly higher than that of control rats. In DOCA-salt treated rats, receptor binding activity was significantly higher than that of salt-treated rats. Partial purification of the digitalis-like substance in plasma was performed by gel filtration using Sephadex G-25. Two peaks containing digoxin-like immunoreactivity were observed. Receptor binding activity, as well as Na+-K+ ATPase inhibitory activity, was detected only in the second peak, in which approximately 70% of the digoxin-like immunoreactivity was eluted. These results indicate that a circulating digitalis-like substance is increased in DOCA-salt hypertension.
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PMID:Circulating digitalis-like substance is increased in DOCA-salt hypertension. 633 39

Digoxin serum concentrations were measured by a routine radioimmunoassay in 30 neonates not receiving digoxin; nonetheless, digoxin levels were between 0.17 nM and 1.64nM (means = 0.64nM +/- 0.27 nM). There was a negative correlation between gestational age and concentration of an endogenous digoxin-like substance (EDLS). Neonates less than or equal to 32 wk gestational age had higher levels of EDLS than neonates greater than 32 wk old. EDLS concentrations were compared in 22 mothers and their 24 offspring and were higher in all newborn infants (0.34nM +/- 0.09nM and 0.15nM +/- 0.08nM). EDLS was shown to inhibit Na+-K+-adenosinetriphosphatase activity by measurement of 86Rb uptake in erythrocytes exposed to sera samples from 30 infants in the study. EDLS levels greater than 0.6 ng/ml were associated with lesser 86Rb uptake. Simulation kinetics suggest that the presence of 0.6nM EDLS would lengthen the digoxin t1/2 by 64%, reduce the volume of distribution by 23%, and lower clearance by 53% if the peak "true" digoxin level were 2 ng/ml. EDLS concentrations of 1.5 ng/ml would increase the t1/2 by 207% while reducing the volume of distribution by 43% and clearance by 81%. These considerations cast serious doubts on the validity of currently accepted digoxin kinetics and dosing in preterm infants.
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PMID:Significance of the endogenous digoxin-like substance in infants and mothers. 654 74


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