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ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice.
- Source :
-
Blood [Blood] 2003 Mar 15; Vol. 101 (6), pp. 2412-8. Date of Electronic Publication: 2002 Nov 14. - Publication Year :
- 2003
-
Abstract
- 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 (Ca(2+))-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 Ca(2+)-induced rubidium flux from human RBCs with an IC(50) value of 11 +/- 2 nM (CLT IC(50) = 100 +/- 12 nM) and inhibited RBC dehydration with an IC(50) 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.
- Subjects :
- Acetamides chemistry
Acetamides therapeutic use
Anemia, Sickle Cell drug therapy
Animals
Calcium pharmacology
Clotrimazole chemistry
Clotrimazole pharmacology
Clotrimazole therapeutic use
Erythrocytes drug effects
Erythrocytes physiology
Female
Humans
Hypoxia
Male
Mice
Mice, Transgenic
Potassium Channels, Calcium-Activated metabolism
Rubidium blood
Trityl Compounds chemistry
Trityl Compounds therapeutic use
Acetamides pharmacology
Anemia, Sickle Cell blood
Calcium Channel Blockers pharmacology
Erythrocytes chemistry
Potassium Channels, Calcium-Activated antagonists & inhibitors
Trityl Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 101
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 12433690
- Full Text :
- https://doi.org/10.1182/blood-2002-05-1433