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.

Endothelin: 30 Years From Discovery to Therapy

“…[338][339][340] Established antiarrhythmics, such as amiodarone, may exert antiarrhythmic effects indirectly in part by inhibiting ET-1 synthesis. 341 Clinical studies found that selective ET A -receptor blockade in patients with chronic CAD causes changes in QT and QTc intervals, indicating a role for endothelin in cardiac conduction in humans. 342…”

Antioxidant Activity and Sex Differences of Acute Vascular Effects of Amiodarone in Advanced Atherosclerosis

“…This notion is supported by experimental studies in which rhythmic contractions of human coronary arteries have been shown to involve Ca 2+ and endothelin receptor signaling 35,36 ; thus, it is possible that the effect of amiodarone on phasic contractions in atherosclerotic arteries was, at least in part, due to interference with any of these mechanisms. 41,42 Interestingly and unexpectedly, the amplitude of phasic contractions was greater in females than in males, suggesting that endogenous sex hormones determine the magnitude of vascular oscillations. Functional abnormalities of microvessels also occur in patients with variant angina and may contribute to myocardial ischemia.…”