1,721,006 research outputs found
Red blood cell indices, cation content, and membrane cation transports
No full textIn sickle cell disease, in the homozygous state, the increased heterogeneity of erythrocytes results mainly from membrane defects secondary to Hb S polymerization and the increased survival of F cells. The density distribution curve, using phthalate esters or the red blood cell indices measured with the H*3 system, are useful methods for the hematological follow-up of patients under specific therapies. The methods evaluating the red blood cell cation contents and the abnormal membrane potassium transport pathways are also described, in order to evaluate agents which can restore normal hemoglobin concentration and water content in dehydrated sickle cells
Sulfhydryl oxidation and activation of red cell K(+)-Cl- cotransport in the transgenic SAD mouse
No full textThe SAD mouse is characterized by the expression of human SAD hemoglobin (Hb), a super S Hb with a higher tendency to polymerize than HbS due to the presence of two additional mutations, Antilles beta 23Ile and D Punjab beta 121Glu. Monovalent cation transport was studied in erythrocytes from SAD-1 (Hb SAD = 19%) and beta-thal/SAD-1 (Hb SAD = 26%) mice. Erythrocytes containing Hb SAD exhibited dehydration, increased maximal rate of Na(+)-K+ pump, unchanged Rb+ flux via the Gardos channel, and increased K(+)-Cl- cotransport. K(+)-Cl- cotransport was defined as Cl(-)-dependent (substitution with sulfamate or methanesulfonate) okadaic acid-sensitive K+ efflux. Volume regulatory decrease via K(+)-Cl- cotransport was also increased in swollen SAD erythrocytes compared with controls. K(+)-Cl- cotransport was stimulated by staurosporine in all mouse strains, but the extent of stimulation was reduced in beta-thal/SAD-1 mice. Treatment with dithiothreitol reduced K(+)-Cl- cotransport activity in SAD-1 and beta-thal/SAD-1 mice to levels similar to that of control strains, indicating that reversible sulfhydryl oxidation contributes to the activated state of K(+)-Cl- cotransport in mouse erythrocytes that express transgenic human Hb SAD
Dietary magnesium supplementation ameliorates anemia in a mouse model of beta-thalassemia
No full textTo ascertain the quantitative effect on the disease beta-thalassemia of a low-magnesium (Mg) diet compared with a high-Mg diet and a standard-Mg diet, we studied the effect these diets had over a 4-week period on beta-thalassemic (beta thal) mice compared with normal C57BL/6 mice used as controls. The low-Mg diet consisted of 6 +/- 2 mg Mg/kg body weight/d, the high-Mg diet 1,000 +/- 20 mg Mg/kg body weight/d, and the standard-Mg diet 400 +/- 20 mg Mg/kg body weight/d. Beta thal mice that were fed the low-Mg diet became more anemic, had reduced serum and erythrocyte Mg, and had decreased erythrocyte K. Their K-Cl cotransport increased, followed by commensurate cell dehydration. The high-Mg group showed a significant improvement of the anemia, increased serum and erythrocyte Mg, increased erythrocyte Mg, increased erythrocyte K, reduced K-Cl cotransport, and diminished cell dehydration. C57BL/6 control mice that received the low-Mg diet experienced anemia with erythrocyte dehydration, whereas the high-Mg diet had little effect on the hematologic parameters. Beta thal and C57BL/6 control mice that were fed a standard diet showed no changes. These results indicate that dietary Mg supplementation corrects hypomagnesemia and improves anemia in murine beta thal and should be assessed in human beta-thalassemia
Modulation of erythrocyte potassium chloride cotransport, potassium content, and density by dietary magnesium intake in transgenic SAD mouse
No full textK+ efflux in deoxygenated sickle cells in the presence or absence of DIOA, a specific inhibitor of the [K+, Cl-] cotransport system
No full textThe ouabain bumetanide resistant (OBR) K+ efflux was investigated in deoxygenated sickle cells in comparison to oxygenated ones, by using a specific inhibitor of the [K+, Cl-] co-transport system, [(DihydroIndenyl)Oxy] Alkanoic acid (DIOA). A DIOA sensitive and a DIOA resistant K+ efflux were measured in deoxygenated sickle cells. The DIOA sensitive K+ efflux shared the properties of the [K+, Cl-] co-transport system, being stimulated by decreased pH and hypoosmolarity. This DIOA sensitive K+ efflux represented 70% of the total K+ efflux at pH 7.0 and at low pO2 (10-15 mmHg). Thus, a small reduction in Ph effectively stimulated the [K+, Cl-] co-transport system in deoxygenated condition, and this may contribute significantly to the sickle cell dehydration. We conclude that at pH lower than 7.4, the [K+, Cl-] co-transport system is permanently activated in sickle cells and leads to sickle cell dehydration in both oxygenated and deoxygenated conditions
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.
No full textPrevention 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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