부산대학교 도서관

Endothelin-1 (ET-1) is a potent mitogen and modulator of vascular tone. It is synthesized and released from endothelial cells and acts upon two receptor subtypes designated as ET[subA] and ET[subB]. In this study, a series of potent dipeptide sulfonamide dual-endothelin ET[subA] /ET[subB] receptor antagonists were prepared to investigate their potential benefit in vascular diseases. CGS 31398 inhibited [[sup125]I]ET-1 binding to human ET[subA] and ET[subB] receptors expressed in Chinese hamster ovary (CHO) cells (ET[subA] /CHO, ET[subB] /CHO) with respective IC[sub50] values of 0.26 and 0.12 nM. However, in anesthetized rats, this compound markedly potentiated ET-1-induced renal vascular resistance, a response normally observed with selective ET[subB] receptor antagonists. To determine whether species differences account for these results, a direct comparison was made between binding to rat and rabbit aortic membranes versus functional antagonism in isolated rat aortic rings. It was found that CGS 31398 had potent affinity for the ET[subA] receptor in rat and rabbit aorta with IC[sub50] values of 0.87 and 0.79 nM, respectively. Inhibition of ET-1-induced contractions of rat aorta by the compound was considerably weaker than expected (pK[subB] = 6.4), while that of sarafotoxin S6c induced contraction of dog saphenous vein (100% inhibition at 100 nM) was consistent with corresponding binding data. These results suggest that although CGS 31398 is a potent dual inhibitor of ET[subA]/ET[subB] receptor binding, it surprisingly displays potent ET[subB] and weak ET[subA] receptor antagonism in functional assays. [ABSTRACT FROM AUTHOR]