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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 (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 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. Social Bookmarking                   What's this? Submitted May 17, 2002 Accepted November 2, 2002 ICA-17043, a novel Gardos channel blocker, prevents sickle 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 New Product Development, Icagen Inc., Durham, NC, USA 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, MA, USA * Corresponding author; email: jstocker{at}icagen.com. 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, which 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. Transgenic sickle (SAD) mice treated with ICA-17043 (10 mg/kg po, bid) for 21 days showed a marked and constant inhibition of the Gardos channel activity (with an average inhibition of 90 ± 27%, p<0.005), an increase in RBC K+ content (from 392 ± 19.9 to 479.2 ± 40 mmol/kg Hb, p<0.005), a significant increase in hematocrit (Hct) (from 43.5 ± 0.7 to 50.9 ± 2.2%, p<0.005), a decrease in mean corpuscular hemoglobin concentration (MCHC) (from 34.0 ± 0.9 to 30 ± 1.5 g/dL, p<0.05), 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. 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. De Castro, P. Swerdlow, Y. Saunthararajah, O. Castro, E. Vichinsky, A. Kutlar, E. P. Orringer, G. C. Rigdon, et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia Blood, April 15, 2008; 111(8): 3991 - 3997. [Abstract] [Full Text] [PDF] A. Rivera Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists Am J Physiol Cell Physiol, September 1, 2007; 293(3): C960 - C966. [Abstract] [Full Text] [PDF] L. De Franceschi, A. Rivera, M. D. Fleming, M. Honczarenko, L. L. Peters, P. Gascard, N. Mohandas, and C. 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