IKs restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation

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 IKs blockade versus IKr blockade and late-INa augmentation, under the influence of β-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. IKs was blocked by HMR1556, IKr by dofetilide. Late INa was augmented by sea anemone toxin-II. Isoproterenol was added for β-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca2+. SEA0400 partially inhibited the Na+–Ca2+ exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Σ(|APD90; i + 1 minus APD90; i|) / [nbeats × √ 2] for 30 consecutive action potentials. Baseline BVR was significantly increased by IKr blockade and late-INa augmentation, especially at slow pacing rates. β-adrenergic stimulation restabilized these BVR changes. In contrast, IKs blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during β-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, β-adrenergic receptor stimulation exaggerates BVR during IKs blockade, indicating a BVR-stabilizing role of β-adrenergic-sensitive IKs. Loss of IKs plus overriding of Ca2+-dependent membrane currents, including inward Na+–Ca2+ exchange current, conspire to proarrhythmic BVR under these conditions.