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Local venous response to N‐desethylamiodarone in humans
Author(s) -
Grossmann Matthias,
Dobrev Dobromir,
Himmel Herbert M.,
Kirch Wilhelm
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.103822
Subject(s) - phenylephrine , vasodilation , cyclooxygenase , medicine , nitric oxide , umbilical vein , pharmacology , agonist , anesthesia , chemistry , endocrinology , receptor , blood pressure , in vitro , biochemistry , enzyme
Objective Amiodarone, a class III antiarrhythmic agent, is a potent vasodilator in vivo. Its main metabolite, N ‐desethylamiodarone, contributes to the antiarrhythmic action of amiodarone after long‐term treatment. It is unknown whether N ‐desethylamiodarone has acute vascular effects. The aim of this study was to explore the mechanism of action of N ‐desethylamiodarone in human hand veins. Methods : The dorsal hand vein compliance technique was applied in 36 healthy male volunteers. In hand veins preconstricted with the α 1 –adrenergic receptor agonist phenylephrine or prostaglandin F 2 α , N ‐desethylamiodarone and an inhibitor of nitric oxide formation ( N G ‐monomethyl‐ L ‐arginine, L ‐NMMA) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, N ‐desethylamiodarone was infused after oral treatment with hydrocortisone or coinfused with α‐tocopherol. Additional experiments were carried out in bovine aortic endothelial cells to explore the effects of N ‐desethylamiodarone on the intracellular Ca 2+ concentration ([Ca 2+ ] i ). Results N‐Desethylamiodarone produced dose‐dependent venodilation (47% ± 4% maximum). In vitro, 10 μmol/L N ‐desethylamiodarone caused a sustained increase of the endothelial [Ca 2+ ] i . Pretreatment of the volunteers with acetylsalicylic acid reduced the maximum N ‐desethylamiodarone–induced venodilation to 22% ± 8%; L ‐NMMA reduced the maximum N ‐desethylamiodarone–induced venodilation to 18% ± 11%. Pretreatment with acetylsalicylic acid and coinfusion of N ‐desethylamiodarone and L ‐NMMA abolished the venodilation, whereas hydrocortisone had no effect. Coinfusion of α‐tocopherol and N ‐desethylamiodarone reduced the maximum N ‐desethylamiodarone–induced venodilation to 11% ± 4%. Conclusions In concentrations estimated to be in the therapeutic range, N ‐desethylamiodarone dilates preconstricted human hand veins in vivo and increases endothelial [Ca 2+ ] i in vitro. Subsequently the cyclooxygenase (COX‐1) and the endothelial nitric oxide synthase pathways are activated. The resulting venodilation does not involve inflammatory cytokines, inducible nitric oxide synthase, or inducible cyclooxygenase (COX‐2). Clinical Pharmacology & Therapeutics (2000) 67 , 22–31; doi: 10.1067/mcp.2000.103822