Role of positions 9 and 10 in the endothelin molecule for biological activity and discrimination of receptor subtypes.
The importance of residues 9 and 10 in endothelin-1 was assessed by studying the responses of the guinea-pig ileum to [Ala9]endothelin-1 and [Ala10]endothelin-1. Both analogues induced relaxation followed by contraction. [Ala9]Endothelin-1 showed similar ED50 values and maximum response to those of endothelin-1, whereas [Ala10]endothelin-1 showed a larger ED50 value and was a partial agonist. Endothelin-1 and [Ala10]endothelin-1 induced similar degrees of tachyphylaxis, whereas [Ala9]endothelin-1 induced very little tachyphylaxis, indicating that Lys9 is important for inducing tachyphylaxis. Apamin inhibited the relaxation induced by endothelin-1 and [Ala9]endothelin-1 but not that induced by [Ala10]endothelin-1. BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu), a specific endothelin ETA receptor antagonist, inhibited [Ala9]endothelin-1-, but not [Ala10]endothelin-1-induced contraction. Cross-tachyphylaxis and additivity studies indicated that [Ala9]endothelin-1, like endothelin-1, acts at the endothelin ETA receptor, whereas [Ala10]endothelin-1 behaved as an endothelin ETB receptor agonist, like sarafotoxin S6c. Thus, the residue at position 10 plays a significant role in receptor activation and is a candidate for further exploration of receptor antagonism.
Miasiro
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N
Department of Biophysics, Escola Paulista de Medicina, São Paulo, Brazil.
De Castiglione
R
R
Paiva
A C
AC
D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007551:Isotonic Contraction / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism; D013618:Tachyphylaxis / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C095657:endothelin-1, Ala(10)-; C095658:endothelin-1, Ala(9)-; D001030:Apamin; D012964:Sodium; C072247:cyclo(Trp-Asp-Pro-Val-Leu)