Publication Date:
2006-11-16
Description:
Vaso-occlusive (VOC) crisis is a major manifestation of sickle cell disease (SCD) leading to acute organ damages. Increased levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, have been reported in SCD patients. In addition, ETB receptor has been identified in red blood cells (RBCs) membrane and in vitro, ET-1 increases the activity of Gardos channel in sickle RBCs, which is important in generation of dehydrated sickle RBCs. First, we evaluated the effects of the dual-endothelin-receptor (ETR) antagonist bosentan in vitro on mouse RBCs from transgenic SAD mice and in vivo on hypoxic model of acute sickle VOCs. ET-1 (500 nM) significantly increased Gardos channel activity in SAD mouse RBCs, this was prevented by bosentan (10 μM). We next evaluated the in vivo effects of bosentan (100 mg/kg/d by gavage for 14 days) in both control and SAD mice. Under normoxic condition, bosentan did not modify either RBCs density profiles or RBCs K+ content in SAD mice, suggesting that ET-1 may not contribute to sickle cell dehydration in the steady state. The bosentan-treated mice were then exposed to hypoxia (8%, 18 hrs). We first evaluated the cardiac output and renal artery blood flow (RBF) by ultrasound color imaging. In SAD mice only, hypoxia induced a marked reduction in RBF (− 40%; p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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