To study the ionic basis of salt sensitivity in hypertension, 19F-, 13P-, and 23Na-nuclear magnetic resonance techniques were used to measure cytosolic free calcium (Cai), pH (pHi), free magnesium (Mgi), and sodium (Nai) in erythrocytes of essential hypertensive subjects (n = 19). Individuals were studied for 2 mo each on low- (UNaV 200 meq/d) salt diets, with the concomitant administration of nifedipine (10 mg t.i.d.) or placebo tablets for 1 mo of each diet. Salt loading elevated Cai and Nai while suppressing Mgi and pHi; these changes occurred predominantly in salt-sensitive subjects (n = 9). Nifedipine blunted the pressor response to salt loading > 50% (delta diastolic BP [high-low salt vs placebo] = 5 +/- 2 vs 14 +/- 2 mmHg, P < 0.05) and reversed salt-induced ionic changes, lowering Cai and elevating Mgi and pHi. Regardless of the definition of salt sensitivity, continuous relationships were observed between the pressure response to salt loading, the levels of Cai (r = 0.726, P < 0.001), Nai (r = 0.747, P < 0.001), and pHi (r = -0.754, P < 0.001), and the salt-induced change in Mgi (r = -0.757, P < 0.001). Altogether, these results emphasize the reciprocal and coordinate nature of intracellular ionic changes in response to dietary salt loading and calcium channel blockade in essential hypertension. They suggest that salt sensitivity is mediated by cellular calcium accumulation from the extracellular space, in association with magnesium depletion and acidification. Lastly, interpretation of intracellular ion measurements in the future will require concurrent assessment of dietary salt intake.

/pdf/intracellular-ionic-consequences-of-dietary-salt-loading-in-2nuxe3j06c.pdf

Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

Sickle cell anemia is characterized by the presence of dense dehydrated erythrocytes that have lost most of their K content. Due to the unique dependence of Hb S polymerization on intracellular Hb S concentration, preventing this dehydration should markedly reduce polymerization. The erythrocyte intermediate conductance Ca-activated K channel (hSK4 or KCNN4), first described by Gardos, has been shown to be a major pathway for sickle cell dehydration. Studies with the imidazole antimycotic clotrimazole have shown reduction of sickle cell dehydration in vivo in a small number of patients with sickle cell disease; dose-limiting gastrointestinal and liver toxicities were observed. Based on the chemical structure of clotrimazole metabolites, a novel Gardos channel inhibitor, ICA-17043, has been developed. It has shown substantial activity both in vitro and in vivo in transgenic sickle mice. ICA-17043 is currently in phase 2 human trials. Another potential therapeutic target is the K-Cl cotransport. When sickle erythrocytes are exposed to relatively acidic conditions, they undergo cell shrinkage via activation of this pathway. K-Cl cotransport can be blocked by increasing the abnormally low erythrocyte Mg content of sickle erythrocytes. Oral Mg supplementation has been shown to reduce sickle cell dehydration in vivo in transgenic sickle mice and in patients in two separate clinical trials. Oral Mg pidolate is being tested in clinical trials in homozygous sickle cell disease and in Hb S/HbC (SC) disease, either as a single agent or in combination with hydroxyurea. The ongoing trials will determine the clinical effectiveness of therapies aimed at preventing sickle erythrocyte dehydration.

Sickle cell disease: from membrane pathophysiology to novel therapies for prevention of erythrocyte dehydration.

Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), which has the unique property of polymerizing when deoxygenated. The sickling process is markedly accelerated when intracellular concentration of HbS is increased. Due to the unique dependence of HbS polymerization on its cell concentration, a slight reduction in HbS concentration is likely to have a beneficial effect on the kinetic of polymerization and on the generation of dense, dehydrated red cells. The pathophysiology of acute and chronic clinical manifestations of SCD is strictly related to the hemoglobin cyclic polymerization, to the generation of dense, dehydrated red cells and to the interaction between sickle red cells and abnormal activated vascular endothelial cells. In the present paper we have reviewed the principal therapeutic strategies and we have explored the future treatment options for sickle cell disease. Therapy of sickle cell disease is based on two major goals. The first one is the decrease in intracellular HbS concentration obtained with agents activating fetal hemoglobin synthesis, such as hydroxyurea (HU) or with erythrocyte-active agents blocking different red cell membrane ion pathways and preventing sickle cell dehydration. The second one is based on therapeutic strategies, which may reduce sickle cell-endothelial adhesive events.

https://haematologica.org/article/download/3007/11025

Established and experimental treatments for sickle cell disease.

The calcium homeostasis of normal human red cells may appear deceptively simple Mature red cells lack Ca2+-accumulating organelles and Ca2+ signalling functions Their total calcium content and Ca2+ permeability (PCa) are extremely low, and they have minimal cytoplasmic Ca2+ buffering capacity compared to other cell types One property red cells share with all prokaryots and eukaryots is a low cytoplasmic ionized Ca2+ concentration ([Ca2*]i) The low [Ca2+]i represents the balance between passive Ca2+ influx and active Ca2+ extrusion Passive Ca2+ influx is through low capacity transport pathways with carrier properties (Ferreira and Lew 1977; Lew and Ferreira 1978; Desai et al 1991a) Active Ca2+ extrusion is mediated by a large-capacity (high-Vmax), ATP-fuelled P-type pump (PMCA), expressed with genomic variants 1 and 4 (Schatzmann 1966, 1982; Schatzmann and Vin-cenzi 1969; Rega and Garrahan 1986; Wang et al 1992; Carafoli 1992, 1997) Thus, as with the resting [Ca2+]i level in other cell types, the physiological low-[Ca2+]i condition of red cells is probably maintained within very narrow margins throughout their life-span (-120 days) There have been claims that the Ca2+ permeability, and hence [Ca2+]i, may increase in physiological conditions, transiently during shear stress in the microcirculation (Larsen et al 1981), or terminally, as part of red cell programmed death (Lew and Beauge 1979; Romero and Romero 1999a), and the evidence for and against will be discussed below

Calcium Homeostasis in Normal and Abnormal Human Red Cells

The sickling process causes secondary changes in cell shape, size, cation and water content, and membrane structure that contribute to the impairment of intrinsic cell deformability (Figure 2). This rheological defect is partially compensated by a low haematocrit, which moderates the rise in whole-blood viscosity, and by a rise in cardiac output which increases capillary flow velocity (Berger and King, 1982). A delicate balance exists between these mechanisms and any local disturbance of this balance by pathological changes in factors extrinsic to the sickle cell (Figure 2) can precipitate vaso-occlusion. There is still considerable controversy over the site (arteriolar, capillary, or venular) of vaso-occlusion, the type of sickle cell (reversibly sickled or irreversibly sickled) that is primarily involved, and the relative importance of extra-erythrocytic precipitating factors such as stasis, hypoxia, hyperosmolality, acidosis, alteration in temperature, acute-phase rise in plasma proteins and leukocytes, prothrombotic changes in coagulation factors and platelets, and adhesion of blood cells to vascular endothelium (Figure 2). A low-grade hypercoagulable state has been described in patients with SS (Leichtman and Brewer, 1978; Richardson et al, 1979) which may be related to the procoagulant effect of the shift of phosphatidyl serine to the outer lipid bilayer of the sickle cell (Chiu et al, 1981; Franck et al, 1985). Platelets appear to accumulate at sites of vaso-occlusion (Siegel et al, 1985) and their migration to the vessel wall may be enhanced by the presence of poorly deformable erythrocytes (Aarts et al, 1984). Endothelial cell damage in the arterial or venous circulation may also contribute (Klug et al, 1982). Thus vaso-occlusion appears to result from a complex interaction between blood cells, plasma proteins and endothelium and any one of several precipitating factors may disturb the fragile steady state and cause a painful crisis. The study of sickle cells by rheological methods has considerable potential for investigating the pathophysiology of vaso-occlusive episodes in the SCD and for monitoring, both in vitro and ex vivo, the efficacy of antisickling compounds. Because of the multiple intrinsic and extrinsic factors that contribute to the rheological defect, it is not yet known which of these should be the primary target for an antisickling agent. In-vitro rheological studies in which different metabolic stresses can be applied to intact sickle cells in the presence of a putative antisickling drug should help to answer this question.(ABSTRACT TRUNCATED AT 400 WORDS)

6 Rheology of the sickle cell disorders

Cytosolic free calcium levels in sickle red blood cells

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Cytosolic free calcium levels in sickle red blood cells