title: I(Ks) restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation.
abstract: In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I(Ks) blockade versus I(Kr) blockade and late-I(Na) augmentation, under the influence of beta-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I(Ks) was blocked by HMR1556, I(Kr) by dofetilide. Late I(Na) was augmented by sea anemone toxin-II. Isoproterenol was added for beta-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca(2+). SEA0400 partially inhibited the Na(+)-Ca(2+) exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Sigma(|APD90; i+1 minus APD90; i|)/[nbeatsx radical2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I(Kr) blockade and late-I(Na) augmentation, especially at slow pacing rates. beta-adrenergic stimulation restabilized these BVR changes. In contrast, I(Ks) blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during beta-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, beta-adrenergic receptor stimulation exaggerates BVR during I(Ks) blockade, indicating a BVR-stabilizing role of beta-adrenergic-sensitive I(Ks). Loss of I(Ks) plus overriding of Ca(2+)-dependent membrane currents, including inward Na(+)-Ca(2)(+) exchange current, conspire to proarrhythmic BVR under these conditions.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Johnson
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.forename: Chris E
authors.initials: CE
authors.lastname: Pollard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.forename: Harry J G M
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007473:Ion Channels / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D007473:Ion Channels; D010627:Phenethylamines; D010647:Phenyl Ethers; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D012964:Sodium; D007545:Isoproterenol; C063533:dofetilide; D011188:Potassium; D002118:Calcium