Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease.

Abstract

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial 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 in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.

• Authors: Nathalie Sabaa, Lucia de Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, Haythem Debbabi, Ariane Galaup, Micheline Maier-Redelsperger, Sophie Vandermeersch, Aldo Scarpa, Anne Janin, Bernard Levy, Robert Girot, Yves Beuzard, Christophe Leboeuf, Annie Henri, Stéphane Germain, Jean-Claude Dussaule, Pierre-Louis Tharaux
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 118 Issue 5 Pg. 1924-33 (May 2008) ISSN: 0021-9738 [Print] United States
• PMID: 18382768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Endothelin Receptor Antagonists
• Endothelin-1
• Receptors, Endothelin
• Sulfonamides
• Bosentan

Topics

• Anemia, Sickle Cell (metabolism, mortality, pathology, physiopathology)
• Animals
• Antihypertensive Agents (therapeutic use)
• Bosentan
• Disease Models, Animal
• Endothelin Receptor Antagonists
• Endothelin-1 (genetics, metabolism)
• Hemodynamics
• Humans
• Hypoxia
• Kidney (cytology, metabolism, pathology, physiology)
• Lung (cytology, metabolism)
• Mice
• Mice, Inbred C57BL
• Neutrophils (metabolism)
• Receptors, Endothelin (genetics, metabolism)
• Regional Blood Flow
• Renal Circulation (physiology)
• Sulfonamides (therapeutic use)
• Vasoconstriction (physiology)