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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-05-1433. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1433v1 101/6/2412    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stocker, J. W. Articles by Brugnara, C. Search for Related Content PubMed PubMed Citation Articles by Stocker, J. W. Articles by Brugnara, C. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 March 2003, Vol. 101, No. 6, pp. 2412-2418 RED CELLS ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice Jonathan W. Stocker, Lucia De Franceschi, Grant A. McNaughton-Smith, Roberto Corrocher, Yves Beuzard, and Carlo Brugnara From the Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy; Experimental Laboratory of Gene Therapy, Hospital St Louis, Paris, France; Departments of Laboratory Medicine and Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA; and Icagen, Inc, Research Triangle Park, NC. A prominent feature of sickle cell anemia is the presence of dehydrated red blood cells (RBCs) in circulation. Loss of potassium (K+), chloride (Cl), and water from RBCs is thought to contribute to the production of these dehydrated cells. One main route of K+ loss in the RBC is the Gardos channel, a calcium (Ca2+)-activated K+ channel. Clotrimazole (CLT), an inhibitor of the Gardos channel, has been shown to reduce RBC dehydration in vitro and in vivo. We have developed a chemically novel compound, ICA-17043, that has greater potency and selectivity than CLT in inhibiting the Gardos channel. ICA-17043 blocked Ca2+-induced rubidium flux from human RBCs with an IC50 value of 11 ± 2 nM (CLT IC50 = 100 ± 12 nM) and inhibited RBC dehydration with an IC50 of 30 ± 20 nM. In a transgenic mouse model of sickle cell disease (SAD), treatment with ICA-17043 (10 mg/kg orally, twice a day) for 21 days showed a marked and constant inhibition of the Gardos channel activity (with an average inhibition of 90% ± 27%, P < .005), an increase in RBC K+ content (from 392 ± 19.9 to 479.2 ± 40 mmol/kg hemoglobin [Hb], P < .005), a significant increase in hematocrit (Hct) (from 0.435 ± 0.007 to 0.509 ± 0.022 [43.5% ± 0.7% to 50.9% ± 2.2%], P < .005), a decrease in mean corpuscular hemoglobin concentration (MCHC) (from 340 ± 9.0 to 300 ± 15 g/L [34.0 ± 0.9 to 30 ± 1.5 g/dL], P < .05), and a left-shift in RBC density curves. These data indicate that ICA-17043 is a potent inhibitor of the Gardos channel and ameliorates RBC dehydration in the SAD mouse. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. I. Ataga, W. R. Smith, L. M. 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