ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice.

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.

• Authors: Jonathan W Stocker, Lucia De Franceschi, Grant A McNaughton-Smith, Roberto Corrocher, Yves Beuzard, Carlo Brugnara
• Journal: Blood (Blood) Vol. 101 Issue 6 Pg. 2412-8 (Mar 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12433690 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acetamides
• Calcium Channel Blockers
• Potassium Channels, Calcium-Activated
• Trityl Compounds
• Clotrimazole
• Rubidium
• Calcium
• senicapoc

Topics

• Acetamides (chemistry, pharmacology, therapeutic use)
• Anemia, Sickle Cell (blood, drug therapy)
• Animals
• Calcium (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Clotrimazole (chemistry, pharmacology, therapeutic use)
• Erythrocytes (chemistry, drug effects, physiology)
• Female
• Humans
• Hypoxia
• Male
• Mice
• Mice, Transgenic
• Potassium Channels, Calcium-Activated (antagonists & inhibitors, metabolism)
• Rubidium (blood)
• Trityl Compounds (chemistry, pharmacology, therapeutic use)