Conversion of Big Endothelin-1 and Characterization of Its Contractile Effects on Isolated Human Placental Arteries

• Published in: Gynecologic and obstetric investigation Vol. 45; no. 1; pp. 1 - 6
• Main Authors: Hanson, Gunilla C., Wide-Swenson, Dag, Andersson, Karl-Erik, Lindberg, B. Fredrik
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Karger 01.01.1998; S. Karger AG
• Subjects: Arteries - drug effects; Arteries - metabolism; Biological and medical sciences; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1 - drug effects; Endothelin-1 - metabolism; Endothelins - drug effects; Endothelins - metabolism; Endothelins - pharmacology; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Glycopeptides - pharmacology; Humans; Membrane Proteins - drug effects; Membrane Proteins - metabolism; Mother. Fetoplacental unit. Mammary gland. Milk; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Original Paper; Osmolar Concentration; Peptide Fragments - pharmacology; Peptides, Cyclic - pharmacology; Placenta - blood supply; Placenta - drug effects; Placenta - metabolism; Pregnancy. Parturition. Lactation; Protein Precursors - drug effects; Protein Precursors - metabolism; Trypsin Inhibitors - pharmacology; Umbilical Arteries - drug effects; Umbilical Arteries - metabolism; Vertebrates: reproduction; Protein precursors; Receptors; Placenta; Endothelin; Metalloproteinases; Arteries; Human; Enzyme; Peptide hormone; Vasoconstriction; Conversion; In vitro; Metalloproteins; Artery; Vascularization; Peptidases; Hydrolases; Vasoconstrictor agent; Fetoplacental unit
• ISSN: 0378-7346; 1423-002X
• DOI: 10.1159/000009913

Objectives: To study the conversion of human big endothelin-1 (bigET-1) to endothelin-1 (ET-1) and to characterize contractile ET-1 receptors in human placental arteries. Methods: BigET-1 was incubated with artery membranes and the formation of ET-1 was investigated. ET-1 and bigET-1-induced contractile responses were studied in the absence or presence of the metalloprotease inhibitor phosphoramidon, the ET A -receptor antagonist BQ 123, or the ET B -receptor antagonists IRL 1038 and RES 701-1. Results: The artery membranes hydrolysed bigET-1 to ET-1 through a partly phosphoramidon-sensitive pathway. The contractile responses to ET-1 and bigET-1 were similar, with pEC 50% values of 8.1 ± 0.2 and 7.8 ± 0.1, respectively (NS; n = 17). Phosphoramidon decreased pEC 50% for bigET-1-evoked contractions (p < 0.05; n = 8), without affecting the response to ET-1. A Schild plot of BQ 123 effects on ET-1 and bigET-1-induced contractions resulted in identical pA 2 values and a slope of 0.56 ± 0.2 and 0.47 ± 0.01, respectively. IRL 1038 and RES 701-1 did not affect the contractile responses. Conclusion: BigET-1-evoked contractions in isolated human placental arteries depend on a rapid and metalloprotease-dependent hydrolytic conversion to ET-1, which in turn causes a, mainly ET A -receptor-mediated, contraction.