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

Several hemoglobinopathies are associated with abnormalities in the permeability of the red cell membrane, in some cases leading to permanent alterations of the intracellular milieu. Homozygous sickle cell disease is the most thoroughly studied example. Deoxygenation of sickle cells causes a transient increase in the permeability to monovalent cations and Ca; prolonged deoxygenation can lead to a permanent accumulation of Ca and loss of total cations and water. Although the mechanisms for the permeability changes are not yet defined, mechanical stress on the membrane, with subsequent damages by excess Ca or membrane-associated hemoglobin have been suggested to play a role. Loss of cell water and increase in mean cell hemoglobin concentration causes massive reduction of cell deformability in the oxygenated state and makes the hemoglobin more likely to undergo sickling because of the strong concentration dependence of the sickling process. Limited evidence suggests the occurrence of permeability defects in other hemoglobinopathies and the thalassemias. The suggested alterations range from a slight increase in K permeability of incubated thalassemia cells to substantial dehydration of cells from patients with homozygous hemoglobin C disease. Oxidative damage to the membrane, involving an abnormal hemoglobin-membrane association, may underly the permeability changes in these cells.
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PMID:The effect of abnormal hemoglobins on the membrane regulation of cell hydration. 703 77

1. The effects of indomethacin on water excretion during both vasopressin stimulation and inhibition were studied in control subjects and in patients with sickle cell anaemia. 2. In the control group as well as in the group of patients with sickle cell anaemia sodium and urea retention occurred after indomethacin in the water-depleted state. During water loading, indomethacin induced sodium retention without urea reabsorption. 3. In healthy volunteers indomethacin increased urinary osmolality during water deprivation, but not after water loading. In contrast, in patients with sickle cell anaemia indomethacin caused a rise in urinary osmolality during water loading, but not after deprivation. 4. The findings support the view that indomethacin promotes solute reabsorption in the distal tubule. 5. From our observations we conclude that renal prostaglandins are not involved in the urinary concentrating defect of patients with sickle cell anaemia. On the other hand, the normal diluting capacity in sickle cell anaemia appears to depend on renal prostaglandins.
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PMID:The influence of indomethacin on renal concentrating and diluting capacity in sickle cell nephropathy. 708 65

Irreversibly sickled cells (ISC) are considered to be a hallmark of sickle cell disease, yet their number in peripheral blood smears varies greatly among different homozygous SS patients. This variation has suggested a role for ISC in the varying clinical manifestations of the disease. Efforts to determine the role of ISC have been complicated by the difficulty in standardizing the quantification of these cells. For this reason, we have attempted to develop an alternative method of quantification that would be less variable than the microscopic counting of cells on blood smears. Because ISC are dehydrated dense cells, a measurement based on cell density seemed an attractive alternative approach. Analysis of whole blood samples on a simple, 2-step density gradient, spun in a microhematocrit centrifuge, showed a strong correlation between the proportion of high density cells and the percentage of morphologically identified ISC. Parallel ektacytometric measurements of cell deformability, another parameter that reflects the low water content and high MCHC of ISC, were also strongly correlated with ISC counts. These findings suggest that either of these measurements, sensitive to the special physical properties of ISC, could be used as an objective substitute for the microscopic counting of ISC.
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PMID:A simple laboratory alternative to irreversibly sickled cell (ISC) counts. 710 92

Mean cell hemoglobin concentration (MCHC) is thought to have an important influence in sickle cell disease, both through the strong dependence of sickling rates on hemoglobin S concentration, and through the profoundly limiting effect of high MCHC on the rheologic competence of oxygenated, irreversibly sickled cells (ISC). Recent studies have tested the ability of antidiuretic hormone to reduce sickle cell MCHC by reducing plasma sodium (Na) and osmolality. An alternative means of reducing MCHC is to elevate intracellular cation content, rather than to depress extracellular cation concentration. In an effort to do this, we have treated sickle cells with Monensin, an antibiotic that selectively enhances membrane Na permeability. At submicromolar concentrations, Monensin substantially reduced the MCHC of whole sickle blood and isolated ISC, causing an improvement in cell deformability. Monensin's effectiveness in producing a controlled increase in erythrocyte water content suggests that agents that selectively increase membrane Na permeability could be therapeutically useful.
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PMID:Hydration of sickle cells using the sodium ionophore Monensin. A model for therapy. 713 Mar 94

L-Phenylalanine benzyl ester (Phe-Bz) and a number of ester analogues prevent sickling of erythrocytes from sickle cell disease patients. The compounds tested exhibit anti-sickling activity in the concentration range 0.5-3.0 mM. A general feature of these compounds is the presence of two aromatic rings in their molecular structure. The anti-sickling agents rapidly enter the erythrocyte and are hydrolysed to their component molecules. Incubation of human erythrocytes with 3.0 mM L-phenylalanine for 30 min at 37 degrees C results in accumulation of 2.0 mmol L-phenylanine/l cells, while incubation of erythrocytes with 3.0 mM Phe-Bz under similar conditions results in the production of 4.0 mmol L-phenylalanine/l cells and an equivalent amount of benzyl alcohol. Both L-phenylalanine and benzyl alcohol are inhibitors of the gelation of deoxyhaemoglobin S (deoxy-HbS) in vitro. Moreover, Phe-Bz and related anti-sickling agents fluidize the lipid bilayer of the erythrocyte membrane, inhibiting several transport systems, including those for L-phenylalanine, uridine and sulphate ions, as well as the Na+ pump and the Na+/K+ cotransporter, but increasing the passive influx and efflux of both cations and anions. The accumulation of Phe-Bz hydrolysis products within the erythrocyte together with the effects of Phe-Bz on cation permeability result in the influx of water causing the cell to swell. Thus, treatment of erythrocytes with 3.0 mM Phe-Bz at 37 degrees C for 30 min causes an increase in mean cell volume of 14.8%, decreasing the mean intracellular haemoglobin concentration from 34 to 29.6 g%. The increase in cell volume caused by Phe-Bz and its analogues together with the direct effects of their hydrolysis products on HbS probably act in concert to bring about the anti-sickling effect.
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PMID:Mode of transport and possible mechanism of action of L-phenylalanine benzyl ester as an anti-sickling agent. 715 85

Arterial blood pressures (BPs) in 187 adult patients with sickle cell disease, casually recorded during hospitalization or clinic visits, were compared with BPs from age- and sex-matched populations of black Americans. The BPs in those with sickle cell disease were significantly lower than those in the control populations in all ages and did not demonstrate the expected rise with advancing age. In these patients, there was no difference between BP and sex, degree of anemia, or hemoglobin genotype. Four patients had diastolic and two had systolic hypertension. The prevalence of hypertension was significantly less than that in the block population. These BP findings in sickle cell disease may be due to the renal tubular defect responsible for increased sodium and water excretion, which may blunt the plasma volume expansion necessary for sustained hypertension and thus promote lower arterial pressures, similar to that situation observed in patients with salt-losing nephritis.
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PMID:Arterial blood pressure in adults with sickle cell disease. 723 8

Cetiedil has been reported to relieve painful crises in sickle cell anemia and to have antisickling properties in vitro. The drug alters neither oxygen affinity nor the solubility of deoxyhemoglobin S. Because the viscosity of the erythrocyte interior and the kinetics of gelation are dependent on the concentration of hemoglobin, we postulated that cetiedil might inhibit sickling by modifying erythrocyte sodium or potassium movements in a manner that would increase cell water content and thus dilute the cell hemoglobin. The drug has two such effects: it inhibits the specific increase in potassium permeability that follows a rise in cytoplasmic calcium concentration and it causes a rise in passive sodium movements. These effects are further evidence that cell ion and water movements may be important in the process of sickling and suggest a mechanism for the results reported with cetiedil.
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PMID:Effect of cetiedil, an in vitro antisickling agent, on erythrocyte membrane cation permeability. 729 48

The size of choroid plexuses and cerebral ventricles relative to brain varies widely among vertebrates. The functional significance of this variability has attracted little attention since Herrick's original proposal that large choroid plexuses might enhance oxygen delivery to the brain and therefore be of adaptive value in the transition of vertebrates from water to air breathing. We compared choroid plexus and brain weight or ventricular and brain volume in 40 species from nine vertebrate groups. Both choroid plexus weight and ventricular volume were unrelated to brain size. Plexus weight ranged from 0 to 5.2% of brain weight and ventricular volume from 0.9 to 132% of brain volume. Amid this diversity the dipnoans, chondrosteans, holosteans, amphibians, and crossopterygian examined in this study are exceptional in uniformly having large plexuses. The adaptive significance of large choroid plexuses may lie in the presence of specific homeostatic mechanisms and their role in the response to the increases in PCO2 that accompany the transition to air breathing.
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PMID:On the anatomic relation of choroid plexus to brain: a comparative study. 735 50

The incubation of red blood cells in high concentrations of sodium bicarbonate produces a net influx of salt and water resulting in the dilution of cell hemoglobin. After reinfusion into the donor, cells swollen in this manner can be readily identified in peripheral blood samples by their low density on phthalate gradients. It is proposed that this manipulation of cell water content may have therapeutic implications for sickle cell disease, since the rate of deoxyhemoglobin S gelation is retarded by small reductions in hemoglobin concentration.
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PMID:Cell density profile as a measure of erythrocyte hydration: therapeutic alteration of salt and water content in normal and SS red blood cells. 739 91

Prevention of red cell K+ and water loss is a therapeutic strategy for sickle cell disease. We have investigated in vitro and in vivo the effects of clotrimazole (CLT) and miconazole (MIC) on transgenic mice red cells expressing hemoglobin SAD. CLT blocked the Gardos channel (ID50 75 +/- 22 nM; n = 3) and the A23187-induced dehydration of Hbbs/Hbbthal SAD 1 mouse erythrocytes in vitro. Oral treatment with CLT (160 mg/kg per d) and MIC (100 mg/kg per d) inhibited the Gardos channel in both SAD 1 and control (Hbbs/Hbbthal) mice. In the SAD 1 mice only, cell K+ content increased, and mean corpuscular hemoglobin concentration and cell density decreased. After 7 d of treatment, the hematocrit of SAD 1, CLT-treated animals also increased. All changes were fully reversible. Long-term treatments of SAD 1 mice with oral CLT (80 mg/kg per d for 28 d) lead to sustained increases in cell K+ content and hematocrit and sustained decreases in mean corpuscular hemoglobin concentration and cell density, with no changes in animals treated with vehicle alone. Thus, CLT and MIC can reverse dehydration and K+ loss of SAD 1 mouse erythrocytes in vitro and in vivo, further supporting the potential utility of these drugs in the treatment of sickle cell anemia.
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PMID:Treatment with oral clotrimazole blocks Ca(2+)-activated K+ transport and reverses erythrocyte dehydration in transgenic SAD mice. A model for therapy of sickle cell disease. 751 89


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