Endothelin receptor antagonism prevents vaso-occlusion induced hemodynamic changes, reduces renal and lung damage and abrogates hypoxia-induced mortality in experimental sickle cell disease

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused byvasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictorpathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. Wereport here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damagein a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantialincrease in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. Thisincrease was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropicbeneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation,dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress.Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings inmice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organdamage in sickle-cell patients.