Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart.
Amiodarone, a powerful antiarrhythmic compound, possesses coronary and peripheral vasodilator properties. The mechanisms responsible for these effects remain incompletely understood. In the present study, the coronary effects of amiodarone and dronedarone, a non-iodinated amiodarone-like compound, were investigated in isolated guinea pig hearts perfused at constant flow with high K+ solution (40 mM). Amiodarone (0.01-10 microM), dronedarone (0.01-1 microM) and verapamil (0.01-10 microM) induced concentration-dependent decreases in coronary perfusion pressure. Amiodarone- and dronedarone-mediated reductions in coronary perfusion pressure were not modified by a cyclooxygenase inhibitor, indomethacin (3 microM). L-Nitro-L-arginine (L-NOARG; 3-100 microM) caused a rightward shift of concentration-response curves to amiodarone and dronedarone in a dose-dependent way; L-arginine, a nitric oxide (NO) precursor, reversed this effect. Furthermore, when guinea pigs were treated with NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), amiodarone could not reduce coronary perfusion pressure. NO synthase inhibition did not affect the coronary perfusion pressure response to verapamil. 1H-[1,2,4]Oxadiazole (4,3-a) quinoxalin-1-one (ODQ), a specific inhibitor of the guanylyl cyclase, inhibited the effects of amiodarone but not those of verapamil. In the presence of L-NOARG and ODQ, and in hearts from animals treated with L-NAME, a decrease in coronary perfusion pressure was still observed at the highest concentration of dronedarone. These results show that, in guinea pig hearts, the coronary vasodilation induced by amiodarone highly depends on nitric oxide. Dronedarone differs from amiodarone by a remaining relaxant effect, refractory to inhibition of NO synthase pathway, probably due to its Ca+ antagonist properties.
Cardiovascular Thrombosis Department, Sanofi-Synthelabo Recherche, 371, rue du Pr. J. Blayac, 34184, Montpellier cedex 04, France. pierre.guiraudou@sanofi-synthelabo.com
Pierre
P
Guiraudou
Sylvie Cosnier
SC
Pucheu
Regine
R
Gayraud
Patrick
P
Gautier
Alain
A
Roccon
Jean Marc
JM
Herbert
Dino
D
Nisato
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D009569:Nitric Oxide; D000077764:Dronedarone; D000638:Amiodarone; D019331:NG-Nitroarginine Methyl Ester