title: Amiodarone acutely inhibits vascular activity of endothelin-converting enzymes.
abstract: Endothelin has been implicated in arrhythmogenesis. Amiodarone, initially developed for the treatment of angina pectoris, is a potent inhibitor of ventricular arrhythmias. We investigated whether amiodarone (34 microg/mL) affects the vascular endothelin system of healthy Wistar-Kyoto rats. Contractility to big endothelin-1 and endothelin-1 was determined in aortic and carotid artery rings suspended in organ chambers. Functional activity of endothelin-converting enzymes was calculated for each concentration, and endothelin-converting enzyme-1 gene expression was analyzed using real-time polymerase chain reaction. Activity of functional endothelin-converting enzymes was sevenfold higher in the carotid artery than in the aorta (P < 0.001). Contractions to big endothelin-1 (0.1 micromol/L) were attenuated by amiodarone in the carotid artery (50 +/- 9% vs 90 +/- 8%, P < 0.01) but not in the aorta. Accordingly, contractility to endothelin-1 (0.1 micromol/L) was decreased by amiodarone in carotid rings only (105 +/- 7% vs 132 +/- 6%, P < 0.01). After acute exposure to amiodarone, functional activity of endothelin-converting enzymes at 0.1 micromol/L was slightly increased in the aorta (17 +/- 2% vs 11 +/- 2%, P < 0.05), but decreased in the carotid artery (40 +/- 9% vs 76 +/- 5%, P < 0.05). Endothelin-converting enzyme-1 mRNA expression in the aorta was not affected by amiodarone treatment. Thus, amiodarone acutely affects the activity of vascular endothelin-converting enzymes depending on the anatomical localization of the artery. Acute effects of amiodarone on endothelin-converting enzymes may contribute to its antiarrhythmic properties.
authors.affiliation: Medizinishe Poliklinik and Departement für Innere Medizin, Universitätsspital Zürich, Zürich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Traupe
authors.forename: Matthias
authors.initials: M
authors.lastname: Lang
authors.forename: Jana
authors.initials: J
authors.lastname: Ortmann
authors.forename: Mario
authors.initials: M
authors.lastname: Keller
authors.forename: Eva
authors.initials: E
authors.lastname: Fojtu
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Vetter
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D019332:Endothelin-1; D011480:Protease Inhibitors; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000638:Amiodarone