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)

The receptor for cardiac glycosides probably is identical with the (Na+ + K+)-ATPase (approximately 250 000 Daltons). Its affinity for the therapeutically used glycosides is extremely different in different species (KD approximately 10(-9)M (human heart) - approximately 10(-7)M (rat heart]. In the latter, two distinct receptor types have been demonstrated (high- and low-affinity receptors) with different effects. In the human heart, there may be two cardiac glycoside receptors as well, although this has not been proved as yet. The number of cardiac glycoside receptors and their affinity is regulated in certain states and diseases. An increased receptor density is found in hyperthyroid states, in chronic hypokalaemia and in chronic digitalis treatment. A decreased number is measured in ischemic heart disease, in dilated cardiomyopathy and in hypothyroidism. Parallel to the decreased receptor density the maximal cardiac glycoside induced positive inotropy is reduced. Pronounced toxicity occurs, if the digitalis dose is increased in spite of missing effects.
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PMID:[Changes of affinity and capacity of cardiac glycoside receptors]. 391 28

Impairment of mitochondrial respiration in acute myocardial ischemia was studied in the inner and outer layers of canine heart muscle by the determination of oxidative phosphorylation and several respiratory enzymatic activities of isolated mitochondria. As early as 15 min after coronary ligation, the respiratory control ratio decreased as the result of a reduction in the oxygen consumption rate in state 3 to 72% of the control ratio in the inner layer. However, in the outer layer, it dropped to 74% after 1 to 2 hours. The oxygen consumption rate in state 4 and the ADP/O ratio were not significantly altered in both cardiac sublayers. In parallel with a decrease in oxygen consumption rate in state 3, Mg++-dependent ATPase and DNP-stimulated ATPase activities of isolated mitochondria reduced significantly in both sublayers, followed by a sequential increase in Mg++-dependent ATPase activity. Succinate dehydrogenase activity increased in ischemia for 3 hours in the inner layer, and for 6 hours in the outer layer, respectively; cytochrome oxidase activity reduced in both sublayers during the same period. Mitochondrial respiration is impaired in acute myocardial ischemia much earlier in the inner layer by a decrease in oxygen consumption rate in state 3, and there is a chronological delay in the development of ischemic mitochondrial changes in the outer myocardium.
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PMID:Regional changes in mitochondrial respiration in acute myocardial ischemia. Comparison of the inner and outer heart muscles. 609 79

alpha-Adrenergic blockade with phentolamine or prazosin but not beta-adrenergic blockade reduces premature ventricular complexes and abolished ventricular fibrillation induced by coronary artery ligation or reperfusion in cats. The protective influences were independent of regional coronary flow or systemic hemodynamics. Efferent sympathetic nerve stimulation increased the idioventricular rate (IVR) prior to myocardial ischemia, a response blocked by propranolol, whereas during reperfusion the increased IVR was abolished only by alpha-blockade. Enhanced alpha-adrenergic responsiveness during reperfusion was also apparent with the alpha-agonist methoxamine. More recently we have demonstrated that alpha-adrenergic receptors, assessed by ligand binding with 3H-prazosin, increased nearly twofold in ischemic myocardium by 30 minutes (Bmax = 14 + 2 to 27 + 3 fmol/mg prot) and remain elevated during early reperfusion (12 + 1 to 18 + 1) before returning to control values by 15 minutes after reperfusion. 3H-DHA binding or Na+- -K+ adenosine triphosphatase activity was not altered at any time, indicating the specificity of the alteration. Thus enhanced alpha-adrenergic receptors and suggests the potential use of alpha-adrenergic blockade as one intervention to alleviate these malignant dysrhythmias.
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PMID:Enhanced alpha-adrenergic responsiveness in ischemic myocardium: role of alpha-adrenergic blockade. 611 77

Coronary heart diseases (CHD) have high indices of mortality and morbidity. A number of CHD and myocardial ischaemic syndromes such as unstable angina pectoris, sudden death ischaemic heart disease, acute myocardial infarction and ventricular arrhythmias have been associated with losses of myocardial magnesium and potassium. Mg++ ions are essential for regulation of Na+ and K+ transport across cell membranes, including those found in cardiac and vascular smooth muscle cells. Mg++ activates an Na+-K+-ATPase pump which in turn plays a major role in regulating Na+-K+ transport. Loss of cellular Mg++ results in loss of critically important phosphagens: MgATP and creatine phosphate. Thus, under conditions where cellular Mg++ is depleted (e.g. hypoxia, ischaemia, anoxia), the Na+-K+ pump and phosphagen stores will be compromised, leading to alterations in resting membrane potentials. Cellular Mg++ depletion has been found to result in concomitant depletion of K+ in a number of cells, including cardiac and vascular muscles. The consequences of these events are often production of cardiac arrhythmias. Myocardial and vascular injury lead to disturbances in electrolyte transport across cell membranes, whereby Na+ and Ca++ uptakes are enhanced and, just prior or concomitantly, Mg++ and K+ are lost. Such electrolyte disturbances often lead to necrotic foci. Considerable evidence has accumulated to indicate that the extracellular concentration of Mg++ is important in control of arterial tone and blood pressure via pressure via regulation of vascular membrane Mg++-Ca++ exchange sites. A reduction in the extracellular Mg++ concentration can produce hypertension, coronary vasospasm and potentiation of vasoconstrictor agents by allowing excess entry of Ca++; concomitantly, the potency of vasodilator agents is reduced. Alterations in vascular membrane Mg++ results in arterial and arteriolar membranes which are 'leaky', thus contributing to the cellular reduction in K+ and gain of Na+ and Ca+. Alterations in extracellular K+ or Na+ concentrations over physiological ranges, in the face of a Mg++ deficit, can exacerbate the coronary vasospasm noted with reduction in only extracellular Mg++. Since free Mg++ ions are necessary for maintaining Ca+ ions (both plasma membrane-bound and sarcoplasmic reticulum membrane-bound via Ca++ ATPases), intracellular free Mg++ would rise in conditions which result in cellular loss of Mg++, thereby exacerbating and contributing to elevation of blood pressure and coronary vasospasm.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Magnesium, electrolyte transport and coronary vascular tone. 614 22

Ultracytochemical changes in ATPase activity of ischemic myocardial cells were studied in the dog heart by electron microscopy in the early stage of myocardial infarction and compared to the fine structural alterations in the ischemic myocardium. 1) In the normal myocardial cell, ATPase activity was observed intensely in the terminal cisternae (TC) of the sarcoplasmic reticulum (SR), and moderately in the myofilaments in the longitudinal SR and around the gap junctions of the intercalated discs. 2) The most striking change in the ischemic myocardial cells was the reduction in the ATPase reaction product in the TC of the SR and along the gap junctions 60 min after coronary ligation, simultaneously with swelling of the TC and the appearance of mitochondrial dense deposits. The reaction product began to decrease at 30 min on the myofilaments, and for 3 to 12 hours no reaction product was observed except irreversible morphologic changes in 60 to 70% of the longitudinal SR in the ischemic subendocardial cells. 3) A decrease in ATPase activity was recognized in the early stage of myocardial ischemia simultaneously with the fine structural changes of myocardial cells and it is considered to be one of the signs of ischemic irreversibility.
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PMID:Electron microscopic studies on the ATPase activity in myocardial infarction -changes in the early myocardial infarction. 621 2

The molecular consequences of acute myocardial ischemia induced in rabbit hearts by ligation of the left circumflex branch of the coronary artery were assessed in terms of the biochemical properties of subcellular organelles. Mitochondrial alteration, as reflected in progressive decrease in the activity of azide-sensitive ATPase, was apparent as early as 5 min postligation, but the activity of another mitochondrial enzyme, cytochrome c oxidase, was unchanged, even following 60 min of coronary ligation. Sarcolemmal Na+K+-ATPase exhibited a time course of inactivation similar to that of the mitochondrial ATPase, but differed from the latter in that the impairment was not reversed on reperfusion. Cellular levels of ATP, which decreased in parallel with the loss of ATPase activities, also remained depressed following reperfusion. Decreases in lysosomal enzyme latency were noted, but these occurred somewhat later than the sarcolemmal and mitochondrial alterations. Attempts to demonstrate the production of a population of labile lysosomal structures during ischemia were unsuccessful. Similarly, no alterations in the gel electrophoretic profiles of proteins or in the P phosphatidylcholine/P phosphatidylethanolamine ratio of isolated mitochondrial or sarcolemmal membranes from hearts subjected to ischemia and (or) subsequent reperfusion could be found. It is suggested that sarcolemmal Na+,K+-ATPase may serve as a sensitive and readily quantifiable index of irreversible cellular necrosis and, therefore, be of value in assessing the possible beneficial effects of pharmacological interventions.
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PMID:Membrane alterations in acute myocardial ischemia. 625 43

We have investigated alterations in sarcolemmal function that occur during myocardial ischemia. Rabbit ventricles were incubated at 37 degrees C for time periods ranging from 5 min to 2 h. The ischemic tissue was homogenized, and activities of the sarcolemmal enzymes Na+-K+-ATPase, K+-p-nitrophenylphosphatase (K+-pNPPase), and adenylate cyclase were measured in the crude homogenate. Na+-K+-ATPase and K+-pNPPase were substantially inhibited after only 10 min of ischemia, and activities for all three enzymes declined progressively up to 1 h of ischemia, when activities were 37-59% of control. Highly purified sarcolemmal membranes prepared from control tissue and myocardium that had been made ischemic for 1 h showed similar purification of sarcolemmal enzymes, passive Ca2+ binding, and passive permeability to Ca2+. However, the velocity of Na+-Ca2+ exchange in ischemic sarcolemmal vesicles was reduced approximately 50% due to a reduction in Vmax. Although the parallel decline in activities of several sarcolemmal functions might suggest a change in membrane structure, phospholipid and cholesterol contents in ischemic sarcolemma were the same as control.
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PMID:Sodium-calcium exchange and sarcolemmal enzymes in ischemic rabbit hearts. 628 34

A local increase in the extracellular potassium concentration [K+]o, up to about 8 meq/liter either by topical application or intra-arterial infusion of K+ salts, causes arteriolar dilation and decreased resistance to blood flow in systemic vascular beds. Isolated vascular smooth muscle responds to a similar increase in [K+] in the bathing fluid with relaxation if the preparation has some initial active tension. Reduction in [K+] over physiological ranges produces arteriolar constriction and increased resistance to blood flow. K+ vasodilation is accompanied by hyperpolarization of the smooth muscle cell whereas the vasoconstriction is accompanied by depolarization. All these responses can be blocked by ouabain, a potent Na+, K+-ATPase inhibitor. It is therefore thought that K+ vasodilation results from stimulation of the electrogenic Na+-K+ pump whereas the vasoconstriction results from inhibition of this pump. A number of conditions that alter resistance also alter interstitial fluid [K+]. These include exercise, myocardial ischemia, epileptic convulsions, and evoked electrical activity of the somatomotor cortex. Certain findings, including those during administration of ouabain, suggest that changes in [K+] contribute significantly to some of the changes in resistance.
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PMID:Potassium effects on contraction in arterial smooth muscle mediated by Na+, K+-ATPase. 629 24

Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. The activities of the five mitochondrial inner membrane enzyme complexes of electron transport and coupled oxidative phosphorylation were assayed as a function of time of ischemia or autolysis. While the activities of complex II (succinate-CoQ reductase) and IV (cytochrome c oxidase) were completely stable, that of complex I (NADH-CoQ reductase) decreased markedly, but largely only after 20 min of ischemia or autolysis. At 20 min and beyond, the decrease in the activity of complex I paralleled closely the decrease in whole mitochondrial oxygen uptake with NAD-linked substrates in both models. The activity of complex III (CoQH2-c reductase) decreased at a more gradual rate during ischemia or autolysis, and its rate of decrease paralleled that of succinate-supported oxygen uptake. The activity of complex V (oligomycin-sensitive ATPase) decreased most rapidly (by 40% in only 5 min of autolysis) but nearly leveled off beyond 20 min in the two models. A strikingly similar pattern of differential enzyme lability was observed in isolated control mitochondria incubated at lowered pH values. The results demonstrate 1) differential enzyme lability within the mitochondrial inner membrane, 2) a connection between severity of acidosis and the degree of enzyme activity loss, and 3) the usefulness of simple tissue autolysis as an analogue of in situ myocardial ischemia.
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PMID:Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. 630 12

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


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