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)

Disruption of cellular acid-base status alters the host defence functions of alveolar macrophages (m phi). These pH effects might be mediated by pH-sensitive changes in the signalling pathways of the effector functions of m phi. The present study examined the effects of intracellular pH (pH(i)) on the free cytosolic calcium concentration ([Ca(2+)](i)), an important second messenger for cell functions. [Ca(2+)](i) and pH(i) of rabbit resident alveolar m phi were measured using fluorescent dyes. With extracellular pH (pH(o)) of 7.4, the steady-state pH(i) and [Ca(2+)](i) were approx. 7.14 and 123 nM respectively. Incubation at pH(o) 6.8 caused a sustained cytosolic acidosis, but did not affect [Ca(2+)](i). Likewise, [Ca(2+)](i) was unchanged when m phi at pH(o) 7.4 were acidified using bafilomycin A(1) or sodium propionate. In contrast, [Ca(2+)](i) was markedly sensitive to cytosolic alkalosis. Exposure to NH(4)Cl at pH(o) 7.4 caused transient increases in both pH(i) and [Ca(2+)](i). The Ca(2+) response was mediated by release of intracellular Ca(2+) from thapsigargin-sensitive stores and was potentiated by capacitative entry of extracellular Ca(2+). Incubation at high pH(o) values (>7.4) produced sustained increases in pH(i) and [Ca(2+)](i). The sustained elevation of [Ca(2+)](i) was consistent with pH-sensitive inhibition of plasma-membrane Ca(2+)-ATPase. The response to high pH(o) was unaffected by blockade of L-type or receptor-operated Ca(2+) channels with nifedipine or SKF-96365, and was independent of extracellular Na(+). The findings indicate that pH impacts cytosolic Ca(2+) homoeostasis at multiple levels. The data suggest that cellular acid-base status can influence Ca(2+)-dependent signalling events in resident alveolar m phi, especially during alkaline disruptions of pH(i).
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PMID:Cell alkalosis elevates cytosolic Ca2+ in rabbit resident alveolar macrophages. 1259 69

It is well-known that pH changes can influence a lot of cellular processes. In this work, we have specifically studied the influence of alkalinization, which can be developed in spinal cord neurons during hyperventilation (respiratory alkalosis) and chronic renal failure (metabolic alkalosis) on calcium homeostasis. Application of Tyrode solution with increased pH (pH = 8.8) to secondary sensory neurons isolated from rat spinal dorsal horn induced elevation of intracellular free calcium concentration in the cytosol ([Ca2+]i) if applied after membrane depolarization. Repetitive application of alkaline solution led to disappearance of such elevations. Depletion of endoplasmic reticulum (ER) calcium stores by 30 mM caffeine almost completely blocked the effect of elevated extracellular pH. If caffeine-induced [Ca2+]i transients were evoked during alkalinization, their amplitudes were decreased by 41%. Preapplication of 500 nM ionomycin resulted in disappearance of alkalinization-induced [Ca2+]i transients, whereas prolonged applications (for 20 min) of 200 nM thapsigargin, a blocker of Ca2+ ATPase of the endoplasmic reticulum, resulted in disappearance of the rapid phase of the [Ca2+]i transients induced by alkalinization. Preapplication of the mitochondrial protonophore CCCP (10 microM) also induced changes in the alkalinization-induced calcium response--it lost its peak and was transformed into an irregular wave terminating in several seconds. The data obtained indicate that alkalinization induces an increase of [Ca2+]i level in the investigated neurons via a combined action of both intracellular Ca2+-accumulating structures--the endoplasmic reticulum and mitochondria. This suggestion was supported by morphological data that both structures in these neurons are tightly connected and may interact during release of accumulated calcium ions.
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PMID:Alkalinization-induced changes in intracellular calcium in rat spinal cord neurons. 1545 60

Metabolic alkalosis is a common feature of hypokalemic hypertensive syndromes associated with angiotensin II excess. The alkalosis-generating effect of angiotensin II is usually ascribed to its stimulatory effect on aldosterone secretion, a hormone that upregulates collecting duct hydrogen ion secretion. We studied the effect of angiotensin II infusions on the expression of B1 and a4 protein, subunits of the renal H+-ATPase in adrenalectomized rats. Adrenalectomized rats were given either angiotensin II or vehicle for 7 days via osmotic mini-pumps. H+-ATPase B1 protein expression was evaluated by Western blot analysis in isolated medulla and cortex plasma membrane preparations from one kidney, whereas the contralateral kidney was used for immunostaining. By Western blotting, the relative abundance of B1 protein was 2-fold higher in renal medulla membranes from rats with intact adrenal glands (sham surgery) than from adrenalectomized rats (219+/-47%, n=12; P<0.05). In contrast to renal medulla, adrenalectomy did not significantly alter the relative abundance of B1 protein in renal cortex. Angiotensin II also did not significantly alter the relative levels of B1 protein in the cortex, but it increased it significantly in renal medullary membranes (231+/-56%, n=8; P<0.005). Moreover, enhanced H+-ATPase B1 subunit protein immunoreactivity was found in medullary collecting duct segments of rats infused with angiotensin II. In contrast to B1, expression of a4, another subunit of the H+-ATPase was not altered by adrenalectomy or angiotensin II. We conclude that adrenalectomy decreases whereas angiotensin II increases H+-ATPase B1 subunit expression in medullary, but not in cortical collecting ducts. By increasing the relative abundance of the B1 subunit of H+-ATPase in the collecting duct, angiotensin II excess may lead to increased hydrogen ion secretion and thus metabolic alkalosis-a common feature of hypertensive syndromes associated with angiotensin II overactivity.
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PMID:Angiotensin II increases H+-ATPase B1 subunit expression in medullary collecting ducts. 1569 54

Acid-base disturbances, such as metabolic or respiratory alkalosis, are relatively common in critically ill patients. We examined the effects of alkalosis (hypocapnic or metabolic alkalosis) on alveolar fluid reabsorption in the isolated and continuously perfused rat lung model. We found that alveolar fluid reabsorption after 1 hour was impaired by low levels of CO2 partial pressure (PCO2; 10 and 20 mm Hg) independent of pH levels (7.7 or 7.4). In addition, PCO2 higher than 30 mm Hg or metabolic alkalosis did not have an effect on this process. The hypocapnia-mediated decrease of alveolar fluid reabsorption was associated with decreased Na,K-ATPase activity and protein abundance at the basolateral membranes of distal airspaces. The effect of low PCO2 on alveolar fluid reabsorption was reversible because clearance normalized after correcting the PCO2 back to normal levels. These data suggest that hypocapnic but not metabolic alkalosis impairs alveolar fluid reabsorption. Conceivably, correction of hypocapnic alkalosis in critically ill patients may contribute to the normalization of lung ability to clear edema.
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PMID:Hypocapnic but not metabolic alkalosis impairs alveolar fluid reabsorption. 1576 29

This review summarizes results 87Rb MRS/I studies of K+ transport in mammalian cells, organs and in vivo. It provides a brief description of K+ transport systems, their interactions with Rb+ and evidence that Rb+ is a best K+ congener. 87Rb MR studies have focused mostly on isolated perfused rat and pig hearts and to a lesser extent on kidney, skeletal muscle, salivary gland and red blood cells. The method has been used for three purposes: measurements of kinetics of unidirectional Rb+ uptake and efflux and steady-state Rb+ levels. In cardiovascular studies Rb+ has been used in the absence of shift reagent taking advantage of the predominantly intracellular Rb+/K+ distribution (approximately 20:1). Pharmacological analysis of Rb+ uptake and efflux allowed assessment of the contributions of various transporters to the total Rb+ fluxes in rat hearts. It was confirmed that Na+/K+ ATPase is responsible for the majority of K+ influx since Rb+ uptake is 80% ouabain-sensitive and dependent on the intracellular [Na+]. Energy deprivation caused by low-flow ischemia or metabolic inhibition reduced Rb+ uptake rate. Under normal conditions, Rb+ efflux is mediated mainly by voltage-gated K+ channels with a small contribution from the K+/Na+/2Cl- cotransporter. Intracellular alkalosis and osmotic swelling stimulated Rb+ efflux by activation of the putative K+/H+ antiporter. Activity of ATP-sensitive K+ (K(ATP)) channels was revealed by metabolic (2,4-dinitrophenol, ischemia) or pharmacological (K(ATP) opener, P-1075) stimulation of Rb+ efflux, which was reversed by the K(ATP) blocker, glibenclamide. Mitochondrial K+ transport was evaluated in hearts with saponin-permeabilized myocytes and under hypothermic conditions.Three-dimensional (3-D) spectroscopic MRI of isolated beating pig hearts has been used to obtain time series of Rb+ maps of normal and ischemic/infarcted hearts, which showed lower image intensity in the damaged area. Kinetics of Rb+ uptake in the ischemic areas depended on both regional flow and metabolism. The adrenergic agonist dobutamine stimulated Rb+ uptake in normal areas and did not affect uptake in ischemic areas. Drugs that may affect passive Rb+ transport (bumetanide, pinacidil, glibenclamide) did not change Rb+ uptake either in the normal or ischemic zones. 87Rb-MRI was also able to localize ischemia and infarction in blood-perfused hearts. 87Rb MRS/I is an excellent non-invasive research tool for studies of K+ transport in isolated organs and in vivo.
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PMID:Rubidium-87 magnetic resonance spectroscopy and imaging for analysis of mammalian K+ transport. 1577 Jun 27

A model of rat early distal convoluted tubule (DCT) is developed in conjunction with a kinetic representation of the thiazide-sensitive NaCl cotransporter (TSC). Realistic constraints on cell membrane electrical conductance require that most of the peritubular Cl(-) reabsorption proceeds via a KCl cotransporter,along with most of the K(+) recycled from the Na-K-ATPase. The model tubule reproduces the saturable Cl(-) reabsorption of DCT but not the micropuncture finding of linear Na(+) flux in response to load, more likely a feature of late DCT (CNT). As in proximal tubule, early DCT HCO(3)(-) reabsorption is mediated by a luminal Na(+)/H(+) exchanger (NHE), but in contrast to proximal tubule, the DCT exchanger is operating closer to equilibrium. In the model DCT, two consequences of the lesser driving force for NHE exchange are an acidic cytosol and wider swings in NHE flux with perturbations of luminal composition. Variations in luminal NaCl provide a challenge to cell volume, which can be blunted by volume dependence of the KCl cotransporter. Cell swelling can also be induced by increases in peritubular K(+) concentration. In this case, volume-dependent inhibition of TSC could provide volume homeostasis that also enhances distal Na(+) delivery, and ultimately enhances renal K(+) excretion. In the model DCT, proton secretion is blunted by peritubular HCO(3)(-), so that there is little contribution by this segment to the maintenance of metabolic alkalosis. During alkalosis, the model predicts that increasing luminal NaCl concentration enhances NHE flux, so that these calculations provide no support for a role of early DCT in recovery from Cl(-) depletion alkalosis.
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PMID:A mathematical model of rat distal convoluted tubule. I. Cotransporter function in early DCT. 1585 59

Slc26a4 (Pds) encodes pendrin, a Cl(-)/HCO(3)(-) exchanger expressed in the apical region of type B and non-A, non-B cells, which mediates secretion of OH(-) equivalents. Thus genetic disruption of Slc26a4 leads to systemic alkalosis in some treatment models. However, humans and mice with genetic disruption of Slc26a4 have normal acid-base balance under basal conditions. Thus we asked: 1) Is net acid excretion altered in Slc26a4 (-/-) mice under basal conditions? 2) In the absence of pendrin-mediated OH(-) secretion, are increases in intracellular and systemic pH minimized through changes in intercalated cell subtype abundance or intercalated cell H(+)/OH(-) transporter expression? To answer these questions, net acid excretion and H(+)/OH(-) transporter expression were examined in Slc26a4 (-/-) and Slc26a4 (+/+) mice using balance studies, immunolocalization, and immunoblotting. Excretion of ammonium, titratable acid, and citrate were the same in Slc26a4 null and wild-type mice. However, urinary pH and Pco(2) were much lower in Slc26a4 null relative to wild-type mice due to reduced urinary buffering of secreted H(+) by HCO(3)(-). Abundance of non-A, but not type A intercalated cells, was reduced within the cortical collecting ducts of Slc26a4 null mice. Moreover, kidneys from Slc26a4 null mice had reduced H(+)-ATPase, NBC3 and RhBG total protein expression, particularly within type B and non-A, non-B intercalated cells, although RhCG protein expression was unchanged. Reduced intercalated cell H(+)/OH(-) transporter expression is observed in Slc26a4 null mice, which likely attenuates the rise in intracellular and systemic pH expected with genetic disruption of Slc26a4.
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PMID:Intercalated cell H+/OH- transporter expression is reduced in Slc26a4 null mice. 1614 65

Several hormones regulate Na(+), K(+)-ATPase content in the muscle cell membrane, which is essential for maintaining muscle cell excitability. Chronic glucocorticoid excess is associated with muscle weakness and reduced endurance. We hypothesized that chronic glucocorticoid excess affects Na(+), K(+)-ATPase content in canine skeletal muscle, and contributes to reduced endurance and muscle weakness associated with pituitary-dependent hyperadrenocorticism (PDH) in dogs. Therefore, Na(+), K(+)-ATPase content in skeletal muscle was evaluated before and after hypophysectomy and hormone replacement (cortisone and l-thyroxin) in dogs with PDH (n=13), and in healthy controls (n=6). In addition, baseline and exercise-induced changes in plasma electrolyte concentrations and acid-base balance were evaluated before and after hypophysectomy in dogs with PDH. Na(+), K(+)-ATPase content of gluteal muscle in dogs with PDH was significantly lower than in control dogs (201+/-13pmol/g versus 260+/-8pmol/g wet weight; P<0.01). Similar differences were found in palatine muscle. After hypophysectomy and on hormone replacement, Na(+), K(+)-ATPase was increased (234+/-7pmol/g wet weight). Both plasma pH and base excess in dogs with PDH (7.44+/-0.01; 1.7+/-0.6mmol/l, respectively) were significantly higher (P<0.05) than after hypophysectomy and hormone replacement (7.41+/-0.01; -0.2+/-0.4mmol/l, respectively). Exercise induced respiratory alkalosis, but did not result in hyperkalemia in dogs with PDH. In conclusion, chronic glucocorticoid excess in dogs with PDH is associated with decreased Na(+), K(+)-ATPase content in skeletal muscle. This may contribute to reduce endurance in canine PDH, although dogs with PDH did not exhibit exercise-induced hyperkalemia. Na(+), K(+)-ATPase content normalized to values statistically not different from healthy controls after hypophysectomy and hormone replacement.
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PMID:Na(+), K(+)-ATPase content in skeletal muscle of dogs with pituitary-dependent hyperadrenocorticism. 1620 54

Alkalosis enhances human exercise performance, and reduces K+ loss in contracting rat muscle. We investigated alkalosis effects on K+ regulation, ionic regulation and fatigue during intense exercise in nine untrained volunteers. Concentric finger flexions were conducted at 75% peak work rate (3 W) until fatigue, under alkalosis (Alk, NaHCO3, 0.3 g kg(-1)) and control (Con, CaCO3) conditions, 1 month apart in a randomised, double-blind, crossover design. Deep antecubital venous (v) and radial arterial (a) blood was drawn at rest, during exercise and recovery, to determine arterio-venous differences for electrolytes, fluid shifts, acid-base and gas exchange. Finger flexion exercise barely perturbed arterial plasma ions and acid-base status, but induced marked arterio-venous changes. Alk elevated [HCO3-] and PCO2, and lowered [H+] (P < 0.05). Time to fatigue increased substantially during Alk (25 +/- 8%, P < 0.05), whilst both [K+]a and [K+]v were reduced (P < 0.01) and [K+]a-v during exercise tended to be greater (P= 0.056, n= 8). Muscle K+ efflux at fatigue was greater in Alk (21.2+/- 7.6 micromol min(-1), 32 +/- 7%, P < 0.05, n= 6), but peak K+ uptake rate was elevated during recovery (15 +/- 7%, P < 0.05) suggesting increased muscle Na+,K+-ATPase activity. Alk induced greater [Na+]a, [Cl-]v, muscle Cl- influx and muscle lactate concentration ([Lac-]) efflux during exercise and recovery (P < 0.05). The lower circulating [K+] and greater muscle K+ uptake, Na+ delivery and Cl- uptake with Alk, are all consistent with preservation of membrane excitability during exercise. This suggests that lesser exercise-induced membrane depolarization may be an important mechanism underlying enhanced exercise performance with Alk. Thus Alk was associated with improved regulation of K+, Na+, Cl- and Lac-.
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PMID:Alkalosis increases muscle K+ release, but lowers plasma [K+] and delays fatigue during dynamic forearm exercise. 1623 79

Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation mainly in the proximal tubule and bicarbonate generation predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na-H antiporter and to a smaller extent by the H-ATPase. The principal factors affecting HCO 3 reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na delivery and reabsorption, aldosterone, arterial pH, and arterial pCO2. To generate metabolic alkalosis, either a gain of base or a loss of acid, must occur. The loss of acid may be via the GI tract or by the kidney. Excess base may be gained by oral or parenteral HCO 3 administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate (GFR), volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelma's Syndromes. The effects of metabolic alkalosis on the body are varied and include effects on the central nervous system, myocardium, skeletal muscle, and the liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors promoting alkalosis and in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis.
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PMID:Metabolic alkalosis. 1673 46


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