RES-701-1, A NOVEL, POTENT, ENDOTHELIN TYPE-B RECEPTOR-SELECTIVE ANTAGONIST OF MICROBIAL ORIGIN

The unique cyclic peptide designated RES-701-1 blocked the binding of I-125-labeled endothelin (ET)-1 to bovine cerebellar membranes. ET(B) receptors are predominant in bovine cerebellum. However, in bovine lun g membranes, where both ET(A) and ET(B) receptors are expressed, RES-7 01-1 inhibited I-125-ET-1 binding by up to 70%; RES-701-1, in the pres ence of the ET(A)-selective antagonist BQ-123 at 1 mu M, displaced I-1 25-ET-1 binding completely. With membranes from transfected Chinese ha mster ovary cells expressing the human ET(A) or ET(B) receptors, RES-7 01-1 inhibited I-125-ET-1 binding to the ET(B) receptor with an IC50 v alue of 10 nM but had no effect on I-125-ET-1 binding to the ET(A) rec eptor. Thus, RES-701-1 is highly specific for the ET(B) receptor; it h as no effect on a number of other receptors. RES-701-1 selectively inh ibited the ET-1-induced increase in intracellular Ca2+ concentration i n COS-7 cells expressing the ET(B) receptor but did not inhibit the Ca 2+ transient in ET(A)-expressing cells. When injected intravenously (2 50 nmol/kg) into anesthetized rats, RES-701-1 abolished the initial de pressor response to ET-1 but enhanced the subsequent presser response. These results suggest that RES-701-1 is a potent and specific antagon ist for the ET(B) receptor and that RES-701-1 will be a powerful tool for understanding the physiological roles of this receptor.