title: Big-endothelin-1 contracts rat isolated uterus via a phosphoramidon-sensitive endothelin ETA receptor-mediated mechanism.
abstract: The presence of a phosphoramidon-sensitive endothelin-1-converting enzyme was investigated in the rat isolated uterus. Endothelin-1 and its precursor, big-endothelin-1, increased the rate of spontaneous contractions and caused tonic contractions. Responses to big-endothelin-1 had a slower start than those to endothelin-1. The tonic contraction induced by big-endothelin-1 (10 nM) was nearly abolished by phosphoramidon (100 microM), but the response to an equieffective concentration of endothelin-1 (3 nM) was not affected. Big-endothelin-1 (EC50 6.7 nM) was only 7-fold less potent than endothelin-1 (EC50 0.9 nM), whereas endothelin-3 was much less potent (EC50 > 100 nM). The endothelin ETA receptor antagonist, BQ-123 (40, 150 and 600 nM), induced graded rightward shifts of the concentration-response curve for endothelin-1. Schild analysis yielded a straight line with a slope not different from unity, and a pA2 value of 7.76. At 100 nM, BQ-123 specifically blocked responses to both endothelin-1 (3 nM) and big-endothelin-1 (10 nM), without modifying those to oxytocin (5 nM), acetylcholine (3 microM) or bradykinin (0.5 nM). Our results suggest the presence of phosphoramidon-sensitive endothelin-converting enzyme and demonstrate the occurrence of functional endothelin ETA receptors in the rat uterus.
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, Brazil.
authors.forename: G A
authors.initials: GA
authors.lastname: Rae
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology*; D066298:In Vitro Techniques; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011498:Protein Precursors; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon