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 125I-labeled endothelin (ET)-1 to bovine cerebellar membranes. ETB receptors are predominant in bovine cerebellum. However, in bovine lung membranes, where both ETA and ETB receptors are expressed, RES-701-1 inhibited 125I-ET-1 binding by up to 70%; RES-701-1, in the presence of the ETA-selective antagonist BQ-123 at 1 microM, displaced 125I-ET-1 binding completely. With membranes from transfected Chinese hamster ovary cells expressing the human ETA or ETB receptors, RES-701-1 inhibited 125I-ET-1 binding to the ETB receptor with an IC50 value of 10 nM but had no effect on 125I-ET-1 binding to the ETA receptor. Thus, RES-701-1 is highly specific for the ETB receptor; it has no effect on a number of other receptors. RES-701-1 selectively inhibited the ET-1-induced increase in intracellular Ca2+ concentration in COS-7 cells expressing the ETB receptor but did not inhibit the Ca2+ transient in ETA-expressing cells. When injected intravenously (250 nmol/kg) into anesthetized rats, RES-701-1 abolished the initial depressor response to ET-1 but enhanced the subsequent pressor response. These results suggest that RES-701-1 is a potent and specific antagonist for the ETB receptor and that RES-701-1 will be a powerful tool for understanding the physiological roles of this receptor.
Tanaka
T
T
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Japan.
Tsukuda
E
E
Nozawa
M
M
Nonaka
H
H
Ohno
T
T
Kase
H
H
Yamada
K
K
Matsuda
Y
Y
D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D016232:Endothelins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017466:Receptors, Endothelin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C087120:RES 701-1; D002118:Calcium