Local venous response to N-desethylamiodarone in humans

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.

The dorsal hand vein compliance technique was applied in 36 healthy male volunteers. In hand veins preconstricted with the alpha1-adrenergic receptor agonist phenylephrine or prostaglandin F2alpha, 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 alpha-tocopherol. Additional experiments were carried out in bovine aortic endothelial cells to explore the effects of N-desethylamiodarone on the intracellular Ca2+ concentration ([Ca2+]i).

N-Desethylamiodarone produced dose-dependent venodilation (47% +/- 4% maximum). In vitro, 10 micromol/L N-desethylamiodarone caused a sustained increase of the endothelial [Ca2+]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 alpha-tocopherol and N-desethylamiodarone reduced the maximum N-desethylamiodarone-induced venodilation to 11% +/- 4%.

In concentrations estimated to be in the therapeutic range, N-desethylamiodarone dilates preconstricted human hand veins in vivo and increases endothelial [Ca2+]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).