Two receptor subtypes are involved in the contractile component of the guinea pig ileum responses to endothelins.
Endothelin-1 (ET-1) and endothelin-3 (ET-3) induced a biphasic response (relaxation and contraction) in the guinea pig ileum. Short-term activation of protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu) inhibited the contractile but not the relaxing component of the responses, as did H-7. Long-term pretreatment with PDBu reversed the short-term inhibition but did not affect the tachyphylaxis induced by ET-1. These results suggest that PKC contributes to ET-1 contraction but not to tachyphylaxis. The ETA antagonist BQ-123, at 34 nM, competitively inhibited ET-1 contraction, but at 340 nM the inhibition was noncompetitive. Dose-response curves for ET-1 relaxation were shifted to the left. For ET-3, BQ-123 (340 nM) only decreased the maximal contractile response of the dose-response curve without affecting the relaxation. We suggest that in this tissue there is one receptor for ET-1-induced contraction, which is competitively antagonized by BQ-123, and another one for ET-3-induced contraction, which is noncompetitively antagonized by BQ-123.
Miasiro
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N
Department of Biophysics, Escola Paulista de Medicina, São Paulo, Brazil.
Paiva
A C
AC
Ihara
M
M
Yano
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000595:Amino Acid Sequence; D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007546:Isoquinolines; D010456:Peptides, Cyclic; D010879:Piperazines; D017466:Receptors, Endothelin; D015240:Phorbol 12,13-Dibutyrate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; C072247:cyclo(Trp-Asp-Pro-Val-Leu)