Local venous response to N-desethylamiodarone in humans.
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 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).


RESULTS
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%.


CONCLUSIONS
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).
Grossmann
M
M
Institute of Clinical Pharmacology and the Department of Pharmacology and Toxicology, Medical Faculty of the University of Technology, Dresden, Germany. mgrossma@rcs.urz.tudresden.de
Dobrev
D
D
Himmel
H M
HM
Kirch
W
W
D000328:Adult; D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006225:Hand / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012016:Reference Values; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014680:Veins / Q000187:drug effects*
D014665:Vasodilator Agents; C036116:desethylamiodarone; D000638:Amiodarone; D002118:Calcium