Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease.
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The dehydration of sickle red blood cells (RBCs) through the Ca-activated K channel depends on the parallel movement of Cl ions. To study whether Cl-conductance block might prevent dehydration of sickle RBCs, a novel Cl-conductance inhibitor (NS3623) was characterized in vitro using RBCs from healthy donors and sickle cell patients and in vivo using normal mice and a transgenic mouse model of sickle cell disease (SAD mice). In vitro, NS3623 reversibly blocked human RBC Cl-conductance (g(Cl)) with an IC(50) value of 210 nmol/L and a maximal block of 95%. In vivo, NS3623 inhibited RBC g(Cl) after oral administration to normal mice (ED(50) = 25 mg/kg). Although g(Cl), at a single dose of 100 mg/kg, was still 70% inhibited 5 hours after dosing, the inhibition disappeared after 24 hours. Repeated administration of 100 mg/kg twice a day for 10 days caused no adverse effects; therefore, this regimen was chosen as the highest dosing for the SAD mice. SAD mice were treated for 3 weeks with 2 daily administrations of 10, 35, and 100 mg/kg NS3623, respectively. The hematocrit increased, and the mean corpuscular hemoglobin concentration decreased in all groups with a concomitant increase in the intracellular cation content. A loss of the densest red cell population was observed in conjunction with a shift from a high proportion of sickled to well-hydrated discoid erythrocytes, with some echinocytes present at the highest dosage. These data indicate feasibility for the potential use of Cl-conductance blockers to treat human sickle cell disease. (+info)
Differentiation of brain angiotensin type 1a and 1b receptor mRNAs: A specific effect of dehydration.
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The objective was to examine the effect of dehydration on the expression of the angiotensin type 1 (AT(1)) receptor subtype mRNAs in mice by using an in situ hybridization method. The method used free-floating brain sections with (35)S-labeled probes specific for the untranslated 5' (AT(1a)) and 3' (AT(1b)) regions. AT(1a) and AT(1b) mRNA levels in the subfornical organ (SFO) and anterior third ventricle (AV3V) were quantified by using a phosphor-imaging system. Emulsion autoradiography with cresyl violet counterstaining was used to show cellular expression. Adult male C57BL mice (25 to 30 g) were given water ad libitum or were deprived of water for 48 hours. Dehydration produced increases in plasma osmolality (349+/-6 versus 314+/-4 mOsm/kg) and hematocrit (58+/-2% versus 47+/-1%). In situ hybridization showed that there was expression of AT(1a) and of AT(1b) mRNA in SFO and AV3V. Dehydration produced an increase in AT(1a) mRNA in both regions, with no changes noted for AT(1b). AT(1a) mRNA was increased in the AV3V region from 0.3+/-0.2 to 0.7+/-0.2 muCi/g and in the SFO from 0.6+/-0.3 to 1.0+/-0.2 muCi/g. These results provide information regarding the localization and physiological importance of a subset of angiotensin receptors that are important in volume and blood pressure regulation. AT(1a) and AT(1b) mRNAs showed a similar pattern of expression in rostral forebrain osmosensitive regions. However, osmotic/volume stimulation with dehydration produced specific activation of AT(1a) receptors. This verifies the role of AT(1a) receptors in volume regulation but raises a question concerning the physiological role of the AT(1b) subtype. (+info)
Pharmacologic activities of aged garlic extract in comparison with other garlic preparations.
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We investigated the pharmacologic activities of four garlic preparations, raw garlic juice (RGJ), heated garlic juice (HGJ), dehydrated garlic powder (DGP) and aged garlic extract (AGE). The study used three animal models, i.e., testicular hypogonadism (hypospermatogensis and impotence) induced by warm water treatment, intoxication of acetaldehyde and growth of inoculated tumor cells. RGJ was found to be effective only in recovery of testicular function. The efficacy of HGJ was observed in three models; however, it did not improve impotence. DGP was effective in recovery of spermatogenesis and stimulated acetaldehyde detoxification. Significant beneficial effects of AGE were found in all three models. Although all four garlic preparations significantly enhanced natural killer (NK) and killer cell activities of the spleen cells of tumor-bearing mice, only AGE and HGJ inhibited the growth of inoculated tumor cells. These results suggest that different types of garlic preparations have different pharmacologic properties, and among the four garlic preparations studied, AGE could be the most useful garlic preparation. (+info)
A commentary on the effects of garlic extraction and formulation on product composition.
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The garlic (Allium sativa L.) bulb has been used as a food and condiment for centuries throughout the entire world and in Egypt for perhaps 5000 years. Since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994 by the U.S. Congress, it has been claimed that garlic dietary supplements possess health benefits. Support for this claim is not the primary objective of this publication. The primary objective of this article is to demonstrate that the prediction of a potential health benefit(s) from garlic is largely dependent on the process used to produce a product. (+info)
Complication of suprapubic bladder aspiration.
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Suprapubic abscess formation was seen in 2 babies after attempted suprapubic bladder puncture. In both cases the baby was grossly dehydrated and gut contents were aspirated. Though this complication is rare, it should be remembered, as with all investigations, that a definite indication should be present before suprapubic aspiration is undertaken. (+info)
Chemical characteristics of dimer interfaces in the legume lectin family.
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The Erythrina corallodendron lectin (EcorL) crystallizes in monoclinic and hexagonal crystal forms. Comparison of the newly determined hexagonal form (PDB code 1fyu) with the monoclinic form shows that the dimeric structure of EcorL reflects the inherent biological structure of the protein and is not an artifact of the crystal packing. To further understand the factors determining the dimerization modes of legume lectins, EcorL, concanavalin A (ConA), and Griffonia simplicifolia (GS4) were taken as representatives of the three unique dimers found in the family. Six virtual homodimers were generated. The hydropathy, amino acid composition, and solvation energy were calculated for all nine homodimers. Each of the three native dimers has a distinct chemical composition. EcorL has a dominant hydrophobic component, and ConA has a strong polar component, but in GS4 the three components contribute equally to the interface. This distribution pattern at the interface is unique to the native dimers and distinct from the partition observed in the virtual dimers. Amino acid composition of other members of the family that dimerize like EcorL or ConA maintain the same pattern of amino acids distribution observed in EcorL and ConA. However, lectins that dimerize like GS4 do not show a particularly distinct distribution. In all cases, the calculated solvation energy of the native dimer was lower than that of the virtual dimers, suggesting that the observed mode of dimerization is the most stable organization for the given sequence and tertiary structure. The dimerization type cannot be predicted by sequence analysis. (+info)
Garlic prevents ultrastructural alterations caused by dehydration in mouse cerebral microvessels.
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Dehydration is known to significantly reduce both the time required for the first platelet aggregate and the time to full occlusion in photochemically-induced thrombosis, in vivo. Ultrastructural changes that contribute to such events remain unknown. Therefore, the effect of water deprivation for 24 hr, (as a model for dehydration) on the ultrastructure of mouse pial microvessels was investigated. The possible beneficial effect of garlic in preventing such ultrastructural changes was also investigated. Four groups of TO strain: control, control-garlic treated, dehydrated, and dehydrated-garlic treated male mice, 10/group, were used. Dehydration was induced by water deprivation for 24 hr. Garlic solution was i.p. injected at 0.1 ml/10g body weight. In urethane-anesthetized (2 mg/g, i.p.) mice, topical and transvessel bimodal fixation of pial microvessels was done with a phosphate buffered mixture of glutaraldehyde and paraformaldehyde, followed by a conventional electron microscopy procedure. Examination of control cerebral pial microvessels showed no evidence of cellular damage. Membranes of endothelial cells were intact. Within pial microvessels there was no evidence of platelet aggregation. Garlic treatments did not cause any ultrastructure abnormalities in control mice. Compared with control, dehydration caused the appearance of thrombi that consisted of platelet aggregates. Discoid platelets containing granules, spheroid degranulated platelets, and those with large pseudopodia were present in 80% of dehydrated mice. The venular endothelial surface of dehydrated mice revealed dilated profiles of endoplasmic reticulum and variously shaped vacuoles. Swelling of nuclear envelopes and mitochondrial distension were also present in dehydrated mice. Concomitant garlic treatment prevented most of these ultrastructural changes. These findings demonstrated the extent of damage to the pial microvessels in response to water deprivation and demonstrated the beneficial effect of garlic as a possible mean of protection against oncoming vascular pathology. (+info)
Interstitial fluid pressure surrounding rat mesenteric venules during changes in fluid filtration.
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The interstitial fluid pressure (P(isf)) has been measured in the exposed superfused mesenteries of anaesthetised rats using the micropipette servo-null technique. When mesenteries were superfused with Ringer-Locke solutions, P(isf) was close to atmospheric pressure with mean +/- S.E.M. values of -0.46 +/- 0.14 cmH(2)O (n = 22). Superfusing with paraffin oil did not alter P(isf) significantly, but P(isf) could be lowered considerably by removing fluid from the upper surface of the mesentery. Measurements of P(isf) were also made in the tissues immediately outside mesenteric venules as the pressure inside these vessels and the filtration of fluid through their walls was varied. No significant changes in perivascular P(isf) could be detected even though the intravascular pressure varied from 20 to 70 cmH(2)O. Addition of histamine or the mast cell degranulating agent compound 48/80 to the superfusate had no significant effect on P(isf). The findings are relevant to experiments on the permeability of single perfused mesenteric microvessels. They strengthen the assumption, which is made in these studies, that P(isf) is close to atmospheric pressure and does not change significantly with changes in the filtration and reabsorption of fluid through the vessel walls. Experimental Physiology (2001) 86.1, 33-38. (+info)