Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists

Abstract

Elevated plasma levels of cytokines such as endothelin-1 (ET-1) have been shown to be associated with sickle cell disease (SCD). However, the role of ET-1 in the pathophysiology of SCD is not entirely clear. I now show that treatment of SAD mice, a transgenic mouse model of SCD, with BQ-788 (0.33 mg·kg−1·day−1intraperitoneally for 14 days), an ET-1 receptor B (ETB) antagonist, induced a significant decrease in Gardos channel activity (1.7 ± 0.1 to 1.0 ± 0.4 mmol·1013cell−1·h−1, n = 3, P = 0.019) and reduced the erythrocyte density profile by decreasing the mean density (D50; n = 4, P = 0.012). These effects were not observed in mice treated with BQ-123, an ET-1 receptor A (ETA) antagonist. A mixture of both antagonists induced a similar change in density profile as with BQ-788 alone that was associated with an increase in mean cellular volume and a decrease in corpuscular hemoglobin concentration mean. I also observed in vitro effects of ET-1 on human sickle erythrocyte dehydration that was blocked by BQ-788 and a mixture of ETB/ETAantagonists but not by ETAantagonist alone. These results show that erythrocyte hydration status in vivo is mediated via activation of the ETBreceptor, leading to Gardos channel modulation in SCD.