Calcium release near L-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog.

Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca(2+) handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca(2+) release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca(2+)]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca(2+) release increased both APD and BVR. Inhibition of Ca(2+) release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na(+)/Ca(2+) exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca(2+). Buffering of Ca(2+) transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca(2+) transients modulated BVR to a larger extent than the cytosolic Ca(2+) transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca(2+) release, which may act through modulation of the l-type Ca(2+) current in a subsarcolemmal microdomain.

Antoons G ，Johnson DM ，Dries E ，Santiago DJ ，Ozdemir S ，Lenaerts I ，Beekman JD ，Houtman MJ ，Sipido KR ，Vos MA ... -  《-》

Window Ca2+ current and its modulation by Ca2+ release in hypertrophied cardiac myocytes from dogs with chronic atrioventricular block.

Antoons G ，Volders PG ，Stankovicova T ，Bito V ，Stengl M ，Vos MA ，Sipido KR ... -  《-》

I(Ks) 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 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.

Johnson DM ，Heijman J ，Pollard CE ，Valentin JP ，Crijns HJ ，Abi-Gerges N ，Volders PG ... -  《-》

The Na+/Ca2+ exchange blocker SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in canine ventricular cardiomyocytes.

Birinyi P ，Tóth A ，Jóna I ，Acsai K ，Almássy J ，Nagy N ，Prorok J ，Gherasim I ，Papp Z ，Hertelendi Z ，Szentandrássy N ，Bányász T ，Fülöp F ，Papp JG ，Varró A ，Nánási PP ，Magyar J ... -  《CARDIOVASCULAR RESEARCH》

Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation.

Johnson DM ，Heijman J ，Bode EF ，Greensmith DJ ，van der Linde H ，Abi-Gerges N ，Eisner DA ，Trafford AW ，Volders PG ... -  《-》