PMID- 12433690
OWN - NLM
STAT- MEDLINE
DCOM- 20030407
LR  - 20220408
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 101
IP  - 6
DP  - 2003 Mar 15
TI  - ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell 
      dehydration in vitro and in vivo in SAD mice.
PG  - 2412-8
AB  - 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.
FAU - Stocker, Jonathan W
AU  - Stocker JW
AD  - Department of Clinical and Experimental Medicine, University of Verona, Verona, 
      Italy. jstocker@icagen.com
FAU - De Franceschi, Lucia
AU  - De Franceschi L
FAU - McNaughton-Smith, Grant A
AU  - McNaughton-Smith GA
FAU - Corrocher, Roberto
AU  - Corrocher R
FAU - Beuzard, Yves
AU  - Beuzard Y
FAU - Brugnara, Carlo
AU  - Brugnara C
LA  - eng
GR  - DK 50422/DK/NIDDK NIH HHS/United States
GR  - HL 15157/HL/NHLBI NIH HHS/United States
GR  - HL 58930/HL/NHLBI NIH HHS/United States
GR  - HL 64885/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021114
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Acetamides)
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Potassium Channels, Calcium-Activated)
RN  - 0 (Trityl Compounds)
RN  - G07GZ97H65 (Clotrimazole)
RN  - MLT4718TJW (Rubidium)
RN  - SY7Q814VUP (Calcium)
RN  - TS6G201A6Q (senicapoc)
SB  - IM
MH  - Acetamides/chemistry/*pharmacology/therapeutic use
MH  - Anemia, Sickle Cell/*blood/drug therapy
MH  - Animals
MH  - Calcium/pharmacology
MH  - Calcium Channel Blockers/*pharmacology
MH  - Clotrimazole/chemistry/pharmacology/therapeutic use
MH  - Erythrocytes/*chemistry/drug effects/physiology
MH  - Female
MH  - Humans
MH  - Hypoxia
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Potassium Channels, Calcium-Activated/*antagonists & inhibitors/metabolism
MH  - Rubidium/blood
MH  - Trityl Compounds/chemistry/*pharmacology/therapeutic use
EDAT- 2002/11/16 04:00
MHDA- 2003/04/08 05:00
CRDT- 2002/11/16 04:00
PHST- 2002/11/16 04:00 [pubmed]
PHST- 2003/04/08 05:00 [medline]
PHST- 2002/11/16 04:00 [entrez]
AID - S0006-4971(20)57366-7 [pii]
AID - 10.1182/blood-2002-05-1433 [doi]
PST - ppublish
SO  - Blood. 2003 Mar 15;101(6):2412-8. doi: 10.1182/blood-2002-05-1433. Epub 2002 Nov 
      14.