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)

Digitalis glycosides are specific inhibitors of the sodium pump. While their effects on isolated Na,K-ATPase, an enzymatic representation of the sodium pump, can be quantified easily and precisely, estimation of their effects on the sodium pump and evaluation of the physiological significance of sodium pump inhibition are complicated by several factors. In isolated Na,K-ATPase, the specific binding of cardiac glycosides observed in the presence of Mg2+ and ATP is stimulated by Na+. In intact myocardial cells, conditions which enhance Na+ influx, and hence the amount of Na+ to be transported by the sodium pump, such as stimulation at high frequencies, presence of monensin (a sodium ionophore), batrachotoxin or grayanotoxin I, enhance the glycoside binding to the sodium pump. In left atrial muscle preparations isolated from the guinea-pig heart and stimulated at 0.5 Hz, binding of ouabain to glycoside binding sites on Na,K-ATPase was eliminated by lowering the extracellular Na+ concentration from 145 to 27 mM, a condition reported to lower the intracellular Na+ concentration by more than 60%. When ouabain exposure of atrial muscle preparations was restricted to the quiescent period, glycoside binding to the sodium pump was minimal. Monensin, however, caused ouabain to bind to the sodium pump in quiescent preparations. These results indicate that glycoside binding to the sodium pump is enhanced by intracellular Na+. In addition to enhancing the glycoside binding to the sodium pump, an elevation of intracellular Na+ reduces the reserve capacity of the sodium pump and therefore increases the sensitivity of the myocardium to sodium pump inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The dual effect of sodium ion on the digitalis-sodium pump interaction. 609 4

Although the positive inotropic effect of cardiac glycosides correlates well with inhibition of Na+ pump activity in many preparations, digitalis at low concentrations (10(-9) to 10(-8) M) may produce an apparent stimulation of monovalent cation transport in isolated intact myocardium or produce an inotropic effect that does not correlate with pump inhibition. Digitalis is known to modify tissue metabolism of endogenous neurotransmitters that may affect inotropic state, Na,K-ATPase activity, and K+ permeability. We examined the interactions of low concentrations of ouabain with adrenergic and cholinergic influences in isolated guinea pig left atria stimulated at 3.3 Hz in which inotropic state and monovalent cation transport (measured as 86Rb+ uptake) were assessed simultaneously. Ouabain (10(-9) M) stimulated Rb+ transport (+25%) without an inotropic response; the stimulatory effect on transport was abolished by propranolol or atropine pretreatment. In atria pretreated with atropine, 10(-8) M ouabain produced a small positive inotropic effect (+10%) without measurable associated Na+-K+ pump inhibition. This inotropic response was abolished in catecholamine-depleted atria. Ouabain (10(-7) M) always produced a positive inotropic response (about +25%) independent of catecholamine depletion, beta-adrenergic blockade, or muscarinic blockade, but Rb+ uptake inhibition was observed only in beta-adrenergically-blocked atria. In all preparations, ouabain concentrations greater than 10(-7) M caused an inotropic response associated with pump inhibition. At concentrations 3 X 10(-7) M and higher, mechanical toxicity was observed in all preparations except those pretreated with propranolol. Incubation with low concentrations of ouabain did not modify the inotropic response to isoproterenol. At concentrations of isoproterenol sufficient to stimulate Rb+ transport by 25%, there was a large (+80%) inotropic response. We conclude first, that, in guinea pig atria exposed to ouabain, the mechanism as well as the extent of inotropic response and of monovalent cation transport modification is concentration dependent, second, that at low concentrations (1-10 X 10(-9) M), in vitro inotropic and monovalent cation transport responses are in part mediated by an effect of ouabain on endogenous neurotransmitters; and third, that in this preparation at concentrations between 10(-9) and 10(-7) M ouabain, monovalent cation transport as measured by tissue 86Rb+ uptake does not correlate with inotropic response.
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PMID:Active transport and inotropic state in guinea pig left atrium. 629 9

Digitalis sensitivity of the heart is increased in patients with ischemic heart disease. Whether this elevation of digitalis sensitivity occurs as the result of ischemia-induced changes in the cardiac tissue and whether changes in the sarcolemmal Na,K-adenosine triphosphatase (ATPase) or reserve capacity of the sodium pump are responsible for the increased digitalis sensitivity were examined using isolated heart preparations obtained from guinea pigs. Ligation of the left anterior descending coronary artery (LAD) in Langendorff preparations 40 min before perfusion with a toxic concentration (either 1.8 or 2.5 microM) of digoxin decreased the time to the onset of arrhythmias. LAD-ligation by itself did not cause arrhythmias. The time to the onset of arrhythmias during digoxin perfusion was slightly longer in preparations obtained from reserpine-treated animals; however, the reserpine pretreatment failed to alter the effect of LAD ligation on digitalis sensitivity, indicating that the release of catecholamines is not involved in the sensitization. The effects of ischemia on Na,K-ATPase and sodium pump activities, glycoside binding to the enzyme and reserve capacity of the sodium pump were examined in globally ischemic Langendorff preparations. The preparations were perfused with a Krebs-Henseleit bicarbonate buffer solution (pH 7.4) saturated with a 95% O2-5% CO2 gas mixture at a control flow rate of 2.5 ml/g of tissue per min or at 5 or 0% of the control flow rate. After 6 hr of zero perfusion, Na,K-ATPase activity and the number of specific ouabain binding sites were reduced in ventricular muscle homogenates. However, the remaining Na,K-ATPase was not altered in its sensitivity to dihydrodigoxin-induced inhibition or affinity of binding sites for ouabain, sodium or potassium. Similar results were observed after reperfusion following 2 or 5 hr of zero perfusion. A 5% perfusion for 2 or 6 hr, or zero perfusion for 2 hr failed to affect Na,K-ATPase activity in muscle homogenates. Sodium pump activity in ventricular slices, estimated from the ouabain-sensitive 86Rb+ uptake, was unchanged after 5% perfusion or zero perfusion for 2 hr, but was significantly reduced after a 20-min reperfusion following 2 hr of zero perfusion. Reserve capacity of the sodium pump, as estimated from the differences in 42K+ uptake by right ventricular strips under 1.5 and 7 Hz stimulation, was unaffected by 2 hr of 5% perfusion. These results indicate that coronary artery occlusion enhances the arrhythmogenic action of digitalis in isolated heart preparations. This change in digitalis sensitivity produced by 40 min of occlusion cannot be explained by reductions in Na,K-ATPase activity or sodium pump reserve capacity as 2 hr of zero perfusion does not alter Na,K-ATPase or sodium pump activity in ventricular tissue.
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PMID:Ischemia-induced enhancement of digitalis sensitivity in isolated guinea-pig heart. 630 6

Digitalis compounds that are extensively used in the treatment of cardiovascular disorders are known to bind specifically at the extracellular side of (Na+,K+)ATPase. We have recently reported the synthesis of [3H]p- nitrophenyltriazene -ouabain, a derivative of ouabain, which specifically alkylates the catalytic chain of the (Na+,K+)ATPase at a defined region of the sequence. The peptidic segment involved in the binding of digitalis to (Na+,K+)ATPase has been located after mild trypsin treatment of the labeled enzyme. In the presence of 100 mM KCl, tryptic fragmentation results in two peptide fragments of mol. wt. 58 000 and 41 000, respectively. The radioactive probe labeled only the 41 000 fragment indicating that the digitalis binding site is located on the 41 000 domain situated at the N-terminal part of the sequence of the alpha-subunit.
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PMID:Identification of the segment of the catalytic subunit of (Na+,K+)ATPase containing the digitalis binding site. 632 11

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

The aims of treatment of chronic heart failure are to improve the symptoms and the quality of life, reduce mortality and prevent left ventricular dysfunction. Before the first symptom occurs, neurohormonal activation takes place (increased catecholamines and atrial natriuretic peptide levels). Diuretics improve symptoms and are irreplaceable for the elimination of salt and water overload. Loop diuretics are used more often than the thiazides. Their deleterious effects on electrolyte balance are well known. The fact that they activate the renin angiotensin system is a more recent acquisition; the increase in plasma renin activity is a poor prognostic factor. Diuretics potentialize the vasodilator effect of angiotensin converting enzyme inhibitors which inhibit the neurohumoral activation induced by the diuretics. This therapeutic association is very logical, effective and allows reduction in the dosage of the diuretic. To date, there are no large scale controlled studies of the effects of diuretics on mortality. Spironolactone corrects hypokalaemia and hypomagnesaemia induced by loop diuretics. Moreover, it has been shown experimentally in renovascular hypertension and in hyperaldosteronism, that this molecule can prevent myocardial fibrosis, a factor which leads to ventricular dysfunction. The RALES study will analyse the effect of associating spironolactone to diuretic and ACE inhibitor therapy on the mortality of patients in NYHA classes III-IV. The value of digitalis in heart failure patients with sinus rhythm is a classical controversy. Digitalis has a positive inotropic effect (inhibition of NaK-dependent ATPase). More recently, a favourable neurohormonal effect has been reported; digitalis decreases the activation of the sympathetic and renin-angiotensin systems.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Classic treatment of chronic heart insufficiency. What if new?]. 748 8

Digitalis-like compounds (DLC), normal constituents of animal tissues, are possible regulators of the Na+,K(+)-ATPase implicated in water and salt homeostasis. DLC are present in toad (Bufo viridis) tissues. Although DLC highest levels were found in toad skin, it was also detected in plasma and many internal organs. The abundant distribution and the different levels of DLC in various tissues exclude the possibility that toxicity is the only function of these compounds in the toad. The concentration of DLC in toad plasma is 30 microM, out of which 25-30% is bound to plasma proteins. Fractionation of toad plasma proteins on a G-100 Sephadex column followed by the extraction of DLC from the plasma proteins revealed that DLC are bound primarily to proteins of 48,000-53,000 Da. These results establish the existence of bufodienolide-binding protein(s) in animal plasma.
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PMID:Digitalis-like compounds in the toad Bufo viridis: interactions with plasma proteins. 750 11

Digitalis-like compounds in bovine lens capsule, cortex and nucleus were determined quantitatively, following extraction, by their ability to inhibit [3H]ouabain binding to red blood cells. These compounds were found to be highly concentrated in the epithelium capsule and were significantly diminished in the cortex and nucleus. Na+, K+-ATPase density in the different regions was determined by [3H]ouabain binding to membranes and by autoradiography of lens slices. The highest concentration of [3H]ouabain-binding sites was observed to occur in membranes prepared from the epithelial cells of the capsule, and was almost 100- and 200-fold higher than the concentrations observed in membranes prepared from fiber cells of the cortex and nucleus, respectively. In the autoradiography studies, strong labeling of [3H]ouabain appeared in the epithelial cell zone, and only weak specific labeling appeared in the lens cortex and nucleus. Almost all (99%) of the Na+,K+-ATPase specific activity was found to be in the capsule epithelium and only 0.5% was measured in the cortex and no activity was detected in the nucleus. These results indicate that the digitalis-like compounds and Na+, K+-ATPase are concentrated in the lens capsule epithelium and are present only at low levels in the cortex and nucleus, thus implying that the lens capsular epithelial layer is the major region of the lens responsible for the homeostasis of ions and water in this tissue.
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PMID:Digitalis-like compounds and Na+, K+-ATPase activity in bovine lens. 900 Apr 21

In dogs, it has been reported that acute ischemia or severe and terminal heart failure results in a selective reduction of myocardial alpha 3 isoform of Na, K-ATPase activity. The aim of this study was to evaluate if a similar change in the two canine digitalis receptor isoforms occurs following 4 weeks of rapid ventricular pacing-induced heart failure without profound necrosis. Heart failure was induced in dogs by rapid ventricular pacing (240 beats x min-1). Digitalis receptors were quantitated by [3H]-ouabain binding with isolated microsomal membranes from sham-operated (n = 3) and heart failure dogs (n = 4) and by Western blot analysis using specific alpha 1 and alpha 3 polyclonal antibodies. In kinetic studies, similar dissociation rates of 19 to 22 x 10(-4) s-1 and 1.3 to 2.4 x 10(-4) s-1 corresponding to high and low affinity sites respectively, were found in sham-operated and CHF dogs. Immunoblotting showed similar abundance of alpha 1 isoform in the two groups; however, levels of alpha 3 were increased by at least 50% in pacing-induced heart failure animals. In conclusion, heart failure selectively modulates the expression of cardiac alpha 3 isoform in dogs.
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PMID:Canine cardiac digitalis receptors are preserved in congestive heart failure induced by rapid ventricular pacing. 902 7

Clinical electrophysiological effects of magnesium (Mg2+) are known for more than 60 years. Mg2+ is a cation to be found ubiquitously in the human body and is involved in more than 300 different enzymatic reactions. However, so far this ion has not been established as a standard therapeutic tool for the treatment of supraventricular tachyarrhythmia. This may be explained by the inconsistent efficacy of Mg2+, partly in relationship to a given plasma Mg(2+)-concentration, partly caused by the uncertainty regarding the dosage and injection rate or the unawareness of the clinical effects of the cation. Mg2+ influences myocardial metabolism by its effects on contractility and electrical activity. Both effects are closely linked. About 12% of cardiac Mg2+ is found in the mitochondria and 2 to 3% in the myofibrils. A large portion is incorporated in adenosin mono-, di- and triphosphate. Mg2+ affects intracellular calcium by inhibiting the influx of calcium into the myocyte through sarcolemmal channels, by modulation of cyclic AMP and by competing with calcium for binding to a single high affinity site on actin. Mg2+ has been linked to a naturally occurring calcium channel blocker. Furthermore Mg2+ blocks the outward current through some potassium channels resulting in an inward rectification of these channels. This suggests that internal magnesium functions as a potassium channel-blocking agent. Early afterdepolarizations are oscillations in the membrane potential and lead to triggered activity and therefore are the electrophysiological substrate of "torsade de pointes" type of ventricular flutter. Mg2+ is able to inhibit both early afterdepolarizations and tachyarrhythmias. Additionally Mg2+ interferes with the sodium-potassium-ATPase system by stabilizing the transmembrane gradient of both cations. Mg2+ deficiency alters this balance and leads to increased neuromuscular excitability. Digitalis is able to block the sodium-potassium-ATPase system, which can be cancelled by Mg2+. Thus the first clinical reports of the therapeutic use of Mg2+ refer to digitalis-induced atrial arrhythmia and ventricular ectopy which could be converted to sinus-rhythm or suppressed by the intravenous application of Mg2+ in 1935. Some years later, the first successful termination of paroxysmal supraventricular and ventricular tachycardia following application of 1.5 to 3 g of Mg2+ was published. But only in the late eighties, systematic studies of the electrophysiological effects of Mg2+ were performed and clinical use was first tested in random fashion in the nineties. Summarizing studies in older patients with different heart diseases and young healthy volunteers the most pronounced and clinically important effect seems to be related to the modulation of the AV node function. The prolongation of the PR interval by 7 to 12% without changing significantly heart rate, QRS duration and QT duration, can be considered a consistent and reproducible effect of Mg2+. In electrophysiological studies a prolongation of the AH interval by 8 to 18%, of the Wenckebach cycle length by up to 20% and of the refractory period of the AV node by 6 to 20% is usually observed, but no change of the retrograde conduction, or the HV interval can be found. Furthermore sinus node recovery time increases by 10% and sinuatrial conduction time by up to 25%. There is no significant effect on intraventricular conduction and atrial and ventricular refractory period. Additionally no significant effect on the anterograde and retrograde refractory period of accessory pathways could be measured; however in some cases (up to 40%) an anterograde block in the accessory pathway may be observed after intravenous Mg(2+)-injection. For the treatment of paroxysmal atrioventricular tachycardia like AV-nodal reentrant tachycardia or orthodromic atrioventricular reentrant tachycardia in WPW syndrome, Mg2+ has been applied in a limited number of recent prospective but uncontrolled studies. Recently, an
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PMID:[Clinico-electrophysiologic effects of magnesium, especially in supraventricular tachycardia]. 933 91


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