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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Our findings of a low total magnesium content in the dense fraction (over 1.118 g ml-1) of sickle cell anaemia (SS) red cells seemed inconsistent with the low Mg2+ permeability and outward Mg2+ gradient seen in normal red cells, and prompted studies of the Mg2+ permeability and equilibria in the SS cells. 2. Deoxygenation and sickling induced Mg2+ permeabilization in SS cells, supporting non-specificity of the sickling-induced cation permeabilization, previously described for Na+, K+ and Ca2+. The extent of Mg2+ permeabilization was comparable in SS cells with normal or high density. 3. Compared with normal-density SS cells and normal red cells, the dense SS cells showed a much larger increase in the fraction of ionized magnesium ([Mg2+]i) on deoxygenation, resulting in [Mg2+]i levels sufficient to reverse the normal inward direction of the transmembrane Mg2+ gradient. 4. The molar ratio of 2,3-diphosphoglycerate (2,3-DPG) to haemoglobin was markedly reduced in the dense SS cells. Since 2,3-DPG and ATP are the main cytoplasmic Mg2+ buffers, their further reduction upon binding to deoxyhaemoglobin accounts for the high [Mg2+]i in the deoxygenated dense SS cells; the resulting outward electrochemical Mg2+ gradient, together with sickling-induced Mg2+ permeabilization, could explain the decreased total magnesium content of these cells. 5. The above findings suggested that the documented low sodium pump fluxes in dense SS cells may result from an increased Mg2+:ATP ratio, which is known to inhibit Na(+)-K+ exchange fluxes through the sodium pump. If so, deoxygenation, by increasing the Mg2+:ATP ratio, should inhibit the pump further, whereas increasing ATP should relieve the inhibition. Experiments designed to test this possibility showed that in these dense SS cells, the ouabain-sensitive K(86Rb) influx was low in oxygenated cells, was reduced further by deoxygenation, but was substantially increased after treatment with inosine, pyruvate and phosphate to increase their organic phosphate pool. These results were thus consistent with such a mechanism for Na+ pump inhibition in the dense SS cells.
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PMID:Deoxygenation permeabilizes sickle cell anaemia red cells to magnesium and reverses its gradient in the dense cells. 221 97

Intracellular calcium regulates a number of membrane functions in the erythrocyte, including control of shape, membrane lipid composition and cation permeability. Measurement of total red cell calcium has yielded values between 5 and 15 nmol/ml cells, and these low values in part reflect the absence of Ca2+ -containing organelles. Most intracellular Ca2+ is bound and the low cell ionized Ca2+ concentration (approximately 0.2 microM) is maintained by a combination of low membrane permeability and a powerful Ca2+ -pump. This pump has been identified with a (Ca2+ + Mg2+)-stimulated ATPase, and both Ca2+ transport and ATP splitting are stimulated by calmodulin, a low molecular weight protein which binds Ca2+ avidly and activates many Ca2+ -dependent enzymes. Both high and low affinity kinetics for Ca2+ pumping have been demonstrated, depending on the extent of binding of calmodulin to the pump. A stoichiometry of either 1 or 2 Ca2+ ions pumped per ATP molecule split has been shown, and the value may vary with the level of intracellular Ca2+. Phenothiazines, such as chlorpromazine inhibit the Ca2+ -pump by antagonizing the increment in activity produced by calmodulin. The passive inward leak of Ca2+ into erythrocytes can be quantitated by 45Ca2+ uptake into red cells whose Ca2+ -pump has been inhibited. Estimates of the Ca2+ permeability, based on unidirectional influx, yield values many orders of magnitude lower than for nucleated cells. Influx of Ca2+ into human erythrocytes occurs by a facilitated diffusion process, which can be inhibited by phenothiazines and the cinchona alkaloids. Calcium affects many membrane functions including cation permeability, lipid composition and some cytoskeletal interactions which may determine cell shape. Any rise in intracellular Ca2+ activates a specific K+ channel which normally makes little contribution to K+ fluxes. Kinetic studies of this process demonstrate either high or low affinity Ca2+ -activation of K+ efflux, with low affinity of the channel to Ca2+ being the probable state in vivo. Propranolol is the best known activator of Ca2+ -stimulated K+ efflux, although the mechanism of stimulation is unclear. Like other tissues, red cells possess a Ca2+ -activated phosphoinositol phosphodiesterase. Although it has been suggested that the echinocytic shape change induced by Ca2+ is due to the hydrolysis of polyphosphoinositides, it seems more likely that this shape change results from an effect of Ca2+ on the macromolecular interactions of the cytoskeleton. Abnormal Ca2+ permeability may contribute to red cell destruction in a variety of diseases. For example, in sickle cell anemia a large Ca2+ influx occurs when cells are sickled under deoxy conditions, and moreover, the ability of the Ca2+ -pump to extrude the increment of cell Ca2+ is impaired. Thus, red cell Ca2+ is increased 3-7-fold above normal and this may contribute to the short survival of sickle red cells...
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PMID:Calcium ions, drug action and the red cell membrane. 629 89

A vasodilating Ca2+ channel blocker, bencyclane, was used in 18 patients with homozygous sickle cell anaemia (SCD) to test the possible anti-sickling effect. With bencyclane intervention the Na(+)-K+ ATPase activity increased from 256 +/- 29 to 331 +/- 37 nmol Pi/mg protein/h (P < 0.0001) and the Ca(2+)-Mg2+ ATPase level increased from 172 +/- 12 to 222 +/- 44 nmol Pi/mg protein/h (P < 0.0001). The intracytoplasmic Ca2+ concentration reduced from 3.5 +/- 0.6 to 2.7 +/- 0.25 mumol/l (P < 0.0001). The patient's blood contained fewer irreversibly sickled cells (ISCs) (a reduction from 21.4% to 14.4%) (P < 0.05). At the same time MCHC of the erythrocytes decreased from 34.5 to 33.0 g/dl (P < 0.05). Bencyclane appears to be a promising anti-sickling agent that can be used orally in SCD.
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PMID:Bencyclane as an anti-sickling agent. 860 94

A prominent feature of sickle cell disease is the presence of cells with markedly increased sickle cell hemoglobin concentration, as a consequence of the loss of potassium, chloride, and water from the erythrocyte. Because of the extreme dependency of the kinetic of polymerization on sickle cell hemoglobin concentration, these dehydrated erythrocytes have an increased tendency to polymerize and sickle. Thus blockade of the loss of potassium from the erythrocyte should prevent the increase in sickle cell hemoglobin concentration and reduce sickling. The availability of this potential therapeutic option is based on a detailed knowledge of the mechanisms leading to cell dehydration. Two ion transport pathways, the K-Cl cotransport and the Ca(2+)-activated K+ channel, play a prominent role in the dehydration of sickle erythrocytes. Possible therapeutic strategies include inhibition of K-Cl cotransport by increasing erythrocyte Mg2+ content and inhibition of the Ca(2+)-activated K channel by oral administration of clotrimazole.
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PMID:Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. 937 83

An array of sickle cell syndromes has been obtained in transgenic mice, expressing HbS or super HbS, from the asymptomatic phenotype similar to the human A/S state to a syndrome more severe than the human homozygous S/S state, inducing 100% fetal death. Anemia was observed in SAD and SAD (beta th/ beta +) neonates and disappeared during postnatal development. In adults, many features of sickle cell disease are found in transgenic mice, especially in SAD and SAD (beta th/ beta +) mice, including abnormal hemolysis, vasoocclusion, microthrombosis, infarct, priapism, chronic organ defects, and death on hypoxia. These mouse models are relevant to the study of the pathophysiology of sickle cell disease and the induction of vasoocclusion and to evaluate new therapeutic approaches in vivo. Clotrimazole and Mg2+ restore hydration of sickle cells and 12 C79 protected SAD mice from lethal acute hypoxia.
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PMID:Transgenic mouse models of sickle cell disease. 937 66

1. K+ influx and efflux were measured in normal (HbA) and sickle (HbS) red blood cells to investigate the interaction of swelling, H+ ions and urea with O2 (0 to 150 mmHg O2) in the presence of ouabain and bumetanide (both 100 microM). 2. In HbA cells, K+-C1- cotransport was O2 dependent. At low oxygen tensions (PO2s) the transporter was inactive and refractory to low pH, swelling or urea. 3. C1--independent K+ influxes in sickle cells were elevated at low PO2s, as previously reported. C1--dependent K+ influxes were large at both high and low PO2s, whether stimulated by swelling, H+ ions or urea. In the absence of O2, C1--dependent K+ influxes were similar in magnitude to those measured at high PO2s. The minimum for C1--dependent K+ influx was observed at PO2s of about 40-70 mmHg. 4. K+ efflux from HbS cells was stimulated by the addition of urea (500 mM). The rate constants were of similar magnitude whether measured at high PO2 or in the absence of O2, and were predominantly C1- dependent under both conditions. 5. In HbS red blood cells, reduction of extracellular Ca2+, addition of 1 mM Mg2+ or nitrendipine (10 microM) to the saline had no effect. Inhibitors of K+-C1- cotransport, [(dihydroindenyl)oxy] alkanoic acid (DIOA; 100 microM) or calyculin A (0.1 microM), inhibited influxes by a similar magnitude to C1- substitution. 6. Results are significant for the pathophysiology of sickle cell disease. Low pH and urea are able to stimulate KC1 loss from sickle cells, leading to cellular dehydration, even in regions of low PO2.
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PMID:Differential oxygen sensitivity of the K+-Cl- cotransporter in normal and sickle human red blood cells. 967 56

The intracellular concentration of Hb S is an important determinant of the kinetic of polymer formation and cell sickling. A variable fraction of dense, dehydrated erythrocytes with high Hb S concentration is seen in the blood of patients with sickle cell disease; these dense cells play an important role in the pathophysiology of the vasoocclusive events of sickle cell disease, due to their higher tendency to polymerize and sickle. Sickle cell dehydration is due to loss of K+, Cl-, and water: the two major determinant pathways of dehydration of sickle erythrocytes are the Ca2+-activated K+ channel (IK1 or Gardos channel) and the K-Cl cotransport (KCC). Specific inhibitors of these pathways being tested in patients with sickle cell disease are Mg2+ pidolate, which inhibits KCC by increasing the sickle cell content of Mg2+, and clotrimazole and derivatives of clotrimazole metabolites, which specifically block the Gardos channel. An inhibitor of Cl- conductance has been shown to reduce dehydration in a transgenic mouse model of sickle cell disease but has not been tested in humans. If clinical efficacy and benefit are demonstrated, an inhibitor of cell dehydration could be used in patients as a single agent or in combination with existing therapies, such as hydroxyurea.
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PMID:Therapeutic strategies for prevention of sickle cell dehydration. 1135 64

The aim of this paper is to discuss, on the basis of an extensive literature review, the role of magnesium in health and disease. Magnesium is an essential cation playing a crucial role in many physiological functions. It is critical in energy-requiring metabolic processes, in protein synthesis, membrane integrity, nervous tissue conduction, neuromuscular excitability, muscle contraction, hormone secretion, and in intermediary metabolism. Serum magnesium concentration is maintained within a narrow range by the small intestine and kidney which both increase their fractional magnesium absorption under conditions of magnesium deprivation. If magnesium depletion continues, the bone store helps to maintain serum magnesium concentration by exchanging part of its content with extracellular fluid. The abundance of magnesium within cells is consistent with its relevant role in regulating tissue and cell functions. Recent data suggest that large fluxes of magnesium can cross the cell plasma membrane in either direction following a variety of hormonal and non-hormonal stimuli, resulting in major changes in total and, to a lesser extent, in free magnesium content within tissues. Imbalances of magnesium are common and are associated with a great number of pathological situations responsible for human morbidity and mortality. A large part of the population may have an inadequate magnesium intake, and in particular elderly subjects and athletes may be prone to chronic latent magnesium deficiency. Magnesium deficit is frequently observed in alcoholics and diabetic patients, in whom a combination of factors contributes to its pathogenesis. We will discuss some of the aspects of the involvement of magnesium in the etiology of some pathological situations, such as cardiovascular diseases, diabetes, pre-eclampsia, eclampsia, sickle cell disease and chronic alcoholism.
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PMID:Role of cellular magnesium in health and human disease. 1476 64

Erythrocyte magnesium (Mg2+) deficiency has been demonstrated in sickle cell disease to contribute to erythrocyte dehydration, K loss, and thus sickling. No studies have assessed the functional properties of the Na/Mg exchanger in sickle cell disease. Using Mg(2+)-loaded erythrocytes, we measured Mg2+ efflux induced by extracellular Na+. We estimated that the Na/Mg exchanger had higher maximal velocity, higher affinity for Na+, and lower cooperativity for Mg2+ in sickle than in normal erythrocytes. The activity of the exchanger was markedly decreased by hypotonic and hypertonic conditions in normal erythrocytes but not in sickle erythrocytes. Studies of density-separated erythrocytes showed that the activity of the exchanger decreased as the mean cellular hemoglobin concentration increased in normal but not in sickle erythrocytes. Inhibition of protein kinase C (PKC) activity by calphostin C and chelerythrine increased the activity of the exchanger in normal but not in sickle erythrocytes. Inhibition of serine/threonine phosphatases did not affect the activity of the exchanger in either normal or sickle erythrocytes. Altogether, these data indicate that the Na/Mg exchanger is abnormally regulated in sickle erythrocytes. Therefore, Mg2+ depletion in sickle erythrocytes might be mediated by an up-regulated Na/Mg exchanger, possibly by dephosphorylation of the transporter or a closely associated regulator.
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PMID:Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes. 1535 77

Following the generation of transgenic mouse models of sickle cell disease, pre-clinical trials have shown the beneficial effects of various potential therapeutic molecules for the acute or chronic manifestations of the disease. Several molecules are upon evaluation in phase I to phase III clinical trials. These therapeutic approaches target: 1) membrane cation transport systems and channels involved in sickle cell dehydration; 2) adherence of erythrocytes to endothelium; 3) activation of circulating and endothelial cells participating in the vasoocclusive events and local ischemia. The Gardos channel (calcium activated potassium channel KCNN4) is inhibited by the clotrimazole metabolite ICA17043, in phase III trial. The K-Cl co-transport (KCC1/3/4) activated by the depletion of erythrocyte magnesium is inhibited by Magnesium pidolate; dipyridamole inhibits ion transports upon deoxygenation. Sulfasalazyne (inhibitor of the NF-jB pathway) inhibits the abnormal activation of endothelial cells. Nitric oxide (NO) is the most potent vasodilator. It prevents the activation of leucocytes, platelets and endothelial cells in patients with sickle cell disease and vascular remodelling. The L-arginine, the NO precursor, provides could be beneficial in sickle cell patients.
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PMID:[Clinical trials of new therapeutic pharmacology for sickle cell disease]. 1744 60


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