Sexual dimorphisms of atherosclerosis and the susceptibility to arrhythmias and antiarrhythmic treatment have been reported. This study investigated acute effects of amiodarone on endothelium-dependent relaxation in the aorta of male and female apoE0 mice with advanced atherosclerosis. Amiodarone tissue uptake was quantified by high-performance liquid chromatography, and xanthine oxidase-dependent superoxide anion formation was investigated in vitro in presence or absence of amiodarone. Incubation with amiodarone for 30 min improved endothelium-dependent relaxation, which was associated with rapid vascular accumulation of amiodarone (P < 0.001) that was sex-dependent. In males, reduced endothelium-dependent relaxation was improved by amiodarone (from 88 +/- 3% to 100 +/- 2%, P < 0.01). Spontaneous phasic contractions, which were greater in females than in males (P < 0.001), were completely abolished by amiodarone (P < 0.0001). Amiodarone also inhibited generation of superoxide anion (P < 0.0001). These data show that amiodarone rapidly accumulates in atherosclerotic vascular tissue, abolishes vascular autorhythmicity, and improves endothelium-dependent function in atherosclerotic arteries. Antioxidant and vasodilator effects following amiodarone administration may contribute to its antiarrhythmic effects.
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.
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