Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ET(B) receptors in the guinea pig perfused lung.
Maturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ET(A) and ET(B)) to produce its effects. In the guinea pig, the systemic administration of ET-1 produces a bronchoconstrictor response that is mediated indirectly via the release of thromboxane A(2) through ET(B) receptor activation. A new potent metabolite of big ET-1, ET-1 (1-31), has been reported to act as an ET(A) receptor selective agonist. In this study we investigated the effects of ET-1 (1-31), compared with ET-1, on the release of eicosanoids in the isolated and perfused guinea pig lung. We also clarified the implication of ET receptors in these effects using selective ET(A) or ET(B) receptor antagonists, BQ-123 and BQ-788 respectively. Finally, using the neutral endopeptidase 24.11 (NEP 24.11) inhibitor, thiorphan, we determined the involvement of this enzyme on ET-1 (1-31) effects. Infusion of ET-1 (1-31) (50 nM) stimulates a marked release of thromboxane A(2) and prostacyclin equivalent to that observed with a ten times lower concentration of ET-1 (5 nM). BQ-788 (5 nM and 10 nM), but not BQ-123 (1 microM), decreases the release of thromboxane A(2) and prostacyclin triggered by both agonists. Interestingly, thiorphan (25 microM) abolishes the eicosanoid-releasing properties of big ET-1 (100 nM) and ET-1 (1-31). This study demonstrates that ET-1 (1-31) is less potent than ET-1 in stimulating the release of eicosanoids through ET(B) receptor activation in the guinea pig perfused lung. Moreover, the inhibitory properties of thiorphan indicate the possible existence of a bioactive metabolite of ET-1 (1-31). We therefore suggest that NEP 24.11 in the pulmonary vasculature, is implicated in the cleavage of ET-1 (1-31) to produce ET-1 which will further act on both ET receptors.
Department of Pharmacology, IPS, Medical School, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, Québec J1H 5N4, Canada.
Mirco
M
Plante
Jean-Claude
JC
Honoré
Witold
W
Neugebauer
Pedro
P
D'Orléans-Juste
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000378:metabolism; D000818:Animals; D015777:Eicosanoids / Q000032:analysis / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000031:analogs & derivatives; D016232:Endothelins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D015244:Thiorphan / Q000494:pharmacology; D013928:Thromboxane A2 / Q000032:analysis / Q000378:metabolism
D015777:Eicosanoids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C114932:endothelin-1 (1-31); C086539:BQ 788; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D015244:Thiorphan; D015260:Neprilysin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)