Structure-activity relationships of ET-1 and selected analogues in the isolated guinea pig trachea: evidence for the existence of different ETB receptor subtypes.
We tested endothelin-1 (ET-1) derivatives on the guinea pig trachea (GPT) and compared their biologic activities to ET-1 in this tissue and to published reports using similar analogues in different assay systems, such as vascular smooth-muscle preparations. Six ET-1 analogues with no intramolecular disulfide bridges and/or with the substitution of one or more amino acids at position 7 and/or 21 were synthesized. Oxidation of the Met7 or formylation of the indole moeity of the Trp21 did not affect the biologic activity of ET-1 on the trachea. Acetamidomethylation of the Cys1-15 decreased the potency and intrinsic activity, but not as much as had been reported on vascular preparations. However, modifications involving one or both disulfide bridges, combined with formylation of the Trp21, yielded analogues with very weak contractile activity. These findings, when compared with the biologic activity of ET-1 analogues in other assay systems, suggest that a different population of receptors, probably non-ETA (i.e., an ETB subtype different from the one reported to be involved in ET-1-induced binding or activities in rabbit pulmonary artery or in rat cerebellum or vasculature) is present and responsible for ET-1-induced bronchoconstriction on the GPT.
Battistini
B
B
Département de Pharmacologie, Faculté de Médecine, Université de Sherbrooke, Canada.
Germain
M
M
Fournier
A
A
Sirois
P
P
D000595:Amino Acid Sequence; D000818:Animals; D004220:Disulfides / Q000737:chemistry; D016232:Endothelins / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
D004220:Disulfides; D016232:Endothelins; D017466:Receptors, Endothelin