Effects of azimilide on the muscarinic acetylcholine receptor-operated K+ current and experimental atrial fibrillation in guinea-pig hearts.
Effects of azimilide, a class III antiarrhythmic drug, on the acetylcholine (ACh) receptor-operated K+ current (I K.ACh) and the delayed rectifier K+ current (IK) were examined in guinea-pig atrial cells using patch-clamp techniques. Effects of azimilide on experimental atrial fibrillation (AF) were also examined in isolated guinea-pig hearts. In single atrial myocytes, azimilide inhibited both the rapid (IKr) and slow component of IK (IKs). Azimilide inhibited the I K.ACh induced by carbachol (CCh, 1 microM), adenosine (10 microM), and intracellular loading of GTPgammaS (100 microM) in a concentration-dependent manner. The IC50 values of azimilide for inhibiting the CCh-, adenosine-, and GTPgammaS-induced I K.ACh were 1.25, 29.1, and 20.9 microM, respectively, suggesting that azimilide inhibits I K.ACh mainly by blocking the muscarinic receptors. Azimilide concentration-dependently (0.3 - 10 microM) prolonged the action potential duration (APD) in the absence and presence of muscarinic stimulation. In isolated hearts, perfusion of CCh shortened the duration of the monophasic action potential (MAP) and effective refractory period (ERP) of the left atrium and lowered the atrial fibrillation threshold (AFT). Addition of azimilide inhibited the induction of AF by prolonging the duration of MAP and ERP. The I K.ACh inhibition by azimilide may at least in part contribute to the effectiveness to prevent parasympathetic-type AF.
Nishida
Atsushi
A
Department of Pharmacology, Chiba University Graduate School of Medicine, Inohana 1-8-1, Chiba 260-8670, Japan.
Reien
Yoshie
Y
Ogura
Takehiko
T
Uemura
Hiroko
H
Tamagawa
Masaji
M
Yabana
Hideo
H
Nakaya
Haruaki
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000517:prevention & control*; D002217:Carbachol / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D051668:Delayed Rectifier Potassium Channels; D006827:Hydantoins; D048289:Imidazolidines; D018727:Muscarinic Antagonists; D010879:Piperazines; D026902:Potassium Channel Blockers; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C086123:azimilide; D002217:Carbachol