ROLE of POSITION-9 and POSITION-10 in the ENDOTHELIN MOLECULE for BIOLOGICAL-ACTIVITY and DISCRIMINATION of RECEPTOR SUBTYPES

ROLE of POSITION-9 and POSITION-10 in the ENDOTHELIN MOLECULE for BIOLOGICAL-ACTIVITY and DISCRIMINATION of RECEPTOR SUBTYPES

Autor Miasiro, N. Google Scholar
Decastiglione, R. Google Scholar
Paiva, ACM Google Scholar
Instituição Universidade Federal de São Paulo (UNIFESP)
PHARMACIA FARMITALIA CARLO ERBA
Resumo The importance of residues 9 and 10 in endothelin-1 was assessed by studying the responses of the guinea-pig ileum to [Ala(9)]endothelin-1 and [Ala(10)]endothelin-1. Both analogues induced relaxation followed by contraction. [Ala(9)]Endothelin-1 showed similar ED(50) values and maximum response to those of endothelin-1, whereas [Ala(10)]endothelin-1 showed a larger ED(50) value and was a partial agonist. Endothelin-1 and [Ala(10)]endothelin-1 induced similar degrees of tachyphylaxis, whereas [Ala(9)]endothelin-1 induced very little tachyphylaxis, indicating that Lys(9) is important for inducing tachyphylaxis. Apamin inhibited the relaxation induced by endothelin-1 and [Ala(9)]endothelin-1 but not that induced by [Ala(10)]endothelin-1. BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu), a specific endothelin ET(A) receptor antagonist, inhibited [Ala(9)]endothelin-1-, but not [Ala(10)]endothelin-1-induced contraction. Cross-tachyphylaxis and additivity studies indicated that [Ala(9)]endothelin-1, like endothelin-1, acts at the endothelin ET(A) receptor, whereas [Ala(10)]endothelin-1 behaved as an endothelin ET(B) 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.
Palavra-chave ENDOTHELIN
ALANINE ANALOG
RECEPTOR SUBTYPE
ILEUM, GUINEA-PIG
SARAFOTOXIN S6C
TACHYPHYLAXIS
Idioma Inglês
Data de publicação 1995-05-15
Publicado em European Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 278, n. 2, p. 103-109, 1995.
ISSN 0014-2999 (Sherpa/Romeo, fator de impacto)
Publicador Elsevier B.V.
Extensão 103-109
Fonte http://dx.doi.org/10.1016/0014-2999(95)00109-X
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:A1995QZ62500003
Endereço permanente http://repositorio.unifesp.br/handle/11600/25494

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