Inhibition of ETP-508 on vasoconstriction induced by endothelin

摘要

Endothelin (ET) is a potent vasoactive and mitogenic peptide that is synthesized and released by endothelia cells. It exists in three isoforms, ET-1, ET-2, and ET-3, and ET-1 appears to be the most important in vascular regulation. ET-1 constricts pulmonary arteries under resting conditions but may have vasodilator actions when administered to preconstricted arteries. These opposing effects have been ascribed to the different actions of the ET receptors. It has been reported that ET receptors are able to be classified into two subtypes, endothelin A (ET_A) receptor which mediates vasoconstricttion and mitogenic actions, and the endothelin B (ET_B) receptor. The ET_B receptor has also two subtypes: ET_(B1), which mediates vasodilation, at least partially via increase in release of nitric oxide and prostacyclin, and ET_(B2), which mediates vasoconstrictive actions. More recently, interest has focus on the role of endothelins, particularly ET-1 which stimulates growth of cultured cardiomyocytes and cardiac fibroblasts. Many studies have found that a blockade of ET-1 receptors strongly reduced the onset of hypoxia-induced pulmonary hypertension. Consequently, several investigators suggest that ET-1 might play a role in the pathophysiology of pulmonary hypertension. The development of selective ET antagonist is essential to understand the pathophysiological roles of ET and could lead to new therapeutic approaches. In this study, the biological activities of ETP-508, which synthesized by ourselves and was a highly selective ET_A receptor ligand based on our receptor binding results, were evaluated in vitro and in vivo.