Amiodarone is a potent calmodulin antagonist.
The possible interaction between amiodarone, a potent antiarrhythmic and antianginal agent, and calmodulin (CaM) was investigated by three avenues of approach: (a) Effect of amiodarone on cardiac and vascular Ca2+/calmodulin-activated cyclic nucleotide phosphodiesterase (CaM-PDE); (b) Effect on the CaM-activated (Ca2+ + Mg2+)-ATPase from human erythrocytes; (c) Direct interaction between amiodarone and calmodulin measured by the effect of the drug on the fluorescence of 9-anthroylcholine (9AC) bound to calmodulin. Results show that amiodarone did not interact with basal activities of CaM-PDE and other isolated CaM-insensitive PDE forms as well as with (Ca2+ + Mg2+)-ATPase. Amiodarone inhibited calmodulin-activation of aortic CaM-PDE (Ki = 650 nM, substrate cGMP) and calmodulin-activation of erythrocyte ghosts (Ca2+ + Mg2+)-ATPase (IC50 = 4.5 microM) in an apparently competitive manner. Amiodarone decreased the fluorescence of the hydrophobic probe 9AC bound to calmodulin (IC50 = 5 microM). It is concluded that amiodarone is a potent calmodulin antagonist.
Nokin
P
P
Sanofi-Labaz Research Center, Brussels, Belgium.
Blondiaux
J P
JP
Schaeffer
P
P
Jungbluth
L
L
Lugnier
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002417:Cattle; D004910:Erythrocyte Membrane / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors; D013050:Spectrometry, Fluorescence
D002147:Calmodulin; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D000638:Amiodarone