Department of Physiology and Biophysics, Rush University Medical Center, Chicago, Illinois.
Am J Physiol Heart Circ Physiol. 2020 May 1;318(5):H1245-H1255. doi: 10.1152/ajpheart.00650.2019. Epub 2020 Apr 10.
Carvedilol is an FDA-approved β-blocker commonly used for treatment of high blood pressure, congestive heart failure, and cardiac tachyarrhythmias, including atrial fibrillation. We investigated at the cellular level the mechanisms through which carvedilol interferes with sarcoplasmic reticulum (SR) Ca release during excitation-contraction coupling (ECC) in single rabbit atrial myocytes. Carvedilol caused concentration-dependent (1-10 µM) failure of SR Ca release. Failure of ECC and Ca release was the result of dose-dependent inhibition of voltage-gated Na () and L-type Ca () currents that are responsible for the rapid depolarization phase of the cardiac action potential (AP) and the initiation of Ca-induced Ca release from the SR, respectively. Carvedilol (1 µM) led to AP duration shortening, AP failures, and peak inhibition by ~80%, whereas was not markedly affected. Carvedilol (10 µM) blocked almost completely and reduced by ~40%. No effect on Ca-transient amplitude, , and was observed in control experiments with the β-blocker metoprolol, suggesting that the carvedilol effect on ECC is unlikely the result of its β-blocking property. The effects of carvedilol (1 µM) on subcellular SR Ca release was spatially inhomogeneous, where a selective inhibition of peripheral subsarcolemmal Ca release from the junctional SR accounted for the cell-averaged reduction in Ca-transient amplitude. Furthermore, carvedilol significantly reduced the probability of spontaneous arrhythmogenic Ca waves without changes of SR Ca load. The data suggest a profound antiarrhythmic action of carvedilol in atrial myocytes resulting from an inhibitory effect on the SR Ca release channel. Here we show that the clinically widely used β-blocker carvedilol has profound effects on Ca signaling and ion currents, but also antiarrhythmic effects in adult atrial myocytes. Carvedilol inhibits sodium and calcium currents and leads to failure of ECC but also prevents spontaneous Ca release from cellular sarcoplasmic reticulum (SR) Ca stores in form of arrhythmogenic Ca waves. The antiarrhythmic effect occurs by carvedilol acting directly on the SR ryanodine receptor Ca release channel.
卡维地洛是一种获得美国食品药品监督管理局批准的β受体阻滞剂，常用于治疗高血压、充血性心力衰竭和心脏心动过速，包括心房颤动。我们在单细胞水平上研究了卡维地洛在兔心房肌细胞兴奋-收缩偶联（ECC）过程中如何干扰肌浆网（SR）Ca 释放的机制。卡维地洛引起浓度依赖性（1-10 μM）的 SR Ca 释放失败。ECC 和 Ca 释放失败是由于电压门控 Na(+)（）和 L 型 Ca(+)（）电流的剂量依赖性抑制所致，这些电流分别负责心脏动作电位（AP）的快速去极化相和 Ca 诱导的从 SR 释放 Ca。卡维地洛（1 μM）导致 AP 持续时间缩短、AP 失败和峰值抑制约 80%，而对 Ca 没有明显影响。卡维地洛（10 μM）几乎完全阻断 Ca 电流，并减少约 40%。在对照实验中，β受体阻滞剂美托洛尔对钙瞬变幅度、没有影响，表明卡维地洛对 ECC 的作用不太可能是其β阻断特性的结果。在控制实验中，卡维地洛（1 μM）对亚细胞 SR Ca 释放的影响是空间不均匀的，其中选择性抑制连接 SR 的周边肌浆网 Ca 释放导致 Ca 瞬变幅度的细胞平均减少。此外，卡维地洛显著降低自发性心律失常性 Ca 波的发生概率，而不会改变 SR Ca 负荷。这些数据表明卡维地洛在心房肌细胞中具有显著的抗心律失常作用，这是由于对 SR Ca 释放通道的抑制作用。在这里，我们表明，临床上广泛使用的β受体阻滞剂卡维地洛对 Ca 信号和离子电流有深远影响，但也对成年人心房肌细胞具有抗心律失常作用。卡维地洛抑制钠和钙电流，导致 ECC 失败，但也防止自发性 Ca 从细胞肌浆网（SR）Ca 库中释放，形成心律失常性 Ca 波。抗心律失常作用是通过卡维地洛直接作用于 SR ryanodine 受体 Ca 释放通道而产生的。
