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首页> 外文期刊>Cell communication & adhesion >Effects of the New Antiarrhythmic Peptide ZP123 on Epicardial Activation and Repolarization Pattern
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Effects of the New Antiarrhythmic Peptide ZP123 on Epicardial Activation and Repolarization Pattern

机译：新型抗心律不齐肽ZP123对心外膜激活和复极模式的影响

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Antiarrhythmic peptides such as AAP10 (Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH_2) have antiarrhythmic properties related to their stimulatory effect on gap junctional coupling. However, most of these peptides are not stable in enzymatic environment which limits studies with these compounds in vivo. ZP123 is a new antiarrhythmic peptide constructed using a retro-all-D-amino acid design of the AAP10 template (Ac-D-Tyr-D-Pro-D-4Hyp-Gly-D-Ala-Gly-NH_2). The aim of this study was to compare the effects of AAP10 and ZP123 on epicardial activation and repolarization patterns in isolated perfused rabbit hearts. In addition, we tested the effect of these compounds on PKC activation in cultured HeLa-Cx43 cells. Rabbit hearts were perfused according to the Langendorff technique with Tyrode solution at constant pressure (70 cm H_2O). After 45 min equilibration, either AAP10 (n = 7) or ZP123 (n = 7) was infused intracoronarily in concentrations of 0.1, 1, 10, 100, and 1000 nM (15 min for each concentration) in the presence of 0.05% bovine serum albumine. 256 AgCl electrodes were attached to the hearts surface and connected to the inputs of a 256 channel mapping system in a unipolar circuit (4 kHz/channel, 0.04 mV vertical resolution, 1 mm spatial resolution). For each electrode the activation and repolarization timepoint were determined. We found that both peptides significantly reduced epicardial dispersion by a maximum of about 20% thereby enhancing the homogeneity of epicardial action potential duration, while the action potential duration itself was not affected. The beat-to-beat variability of the epicardial activation pat-tern was stabilized by both peptides as compared to an untreated time-control series. Other parameters such as LVP, CF, heart rate, or total activation time were not effected by either of the peptides. In a second protocol, rectangular pulses were delivered to the back wall and the propagation velocity was determined longitudinal and transversal to the fiber axis. We found an increase in both longitudinal and transversal conduction velocity. Using a commercial PKC assay on HeLa-Cx43 cells we found that 50 nM AAP10 and 50 nM ZP123 increased activity by 99 ±6% and 146 ±54%, respectively. The PKC activation induced by either of these compounds was completely blocked using the selective PKCa inhibitor GCP54345. We conclude that AAP10 and ZP123 have similar effects in vitro, but the superior enzymatic stability of ZP123 makes this compound the preferred substance for in vivo studies of antiarrhythmic peptides.
机译：抗心律不齐的肽，如AAP10（Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH_2）具有抗心律不齐的性质，与它们对间隙连接偶联的刺激作用有关。然而，大多数这些肽在酶促环境中不稳定，这限制了在体内对这些化合物的研究。 ZP123是一种新的抗心律失常肽，它使用AAP10模板的逆向全D氨基酸设计（Ac-D-Tyr-D-Pro-D-4Hyp-Gly-D-Ala-Gly-NH_2）构建。这项研究的目的是比较AAP10和ZP123对离体灌注兔心脏的心外膜激活和复极模式的影响。此外，我们测试了这些化合物对培养的HeLa-Cx43细胞中PKC活化的影响。根据Langendorff技术，在恒定压力（70 cm H_2O）下用Tyrode溶液灌注兔心脏。平衡45分钟后，在存在0.05％牛的情况下，分别以0.1、1、10、100和1000 nM的浓度（每个浓度15分钟）冠状动脉内注入AAP10（n = 7）或ZP123（n = 7）。血清白蛋白。将256个AgCl电极连接到心脏表面，并连接到单极电路中的256通道映射系统的输入（每通道4 kHz，垂直分辨率0.04 mV，空间分辨率1 mm）。对于每个电极，确定活化和复极化时间点。我们发现，两种肽均最大程度地降低了心外膜分散性，最大减少了约20％，从而增强了心外膜动作电位持续时间的均匀性，而动作电位持续时间本身并未受到影响。与未处理的时间对照系列相比，两种肽均稳定了心外膜激活模式的心跳变化。其他参数（例如LVP，CF，心率或总激活时间）不受任何一种肽的影响。在第二种方案中，将矩形脉冲传送到后壁，并确定传播速度是纵向的还是横向于纤维轴。我们发现纵向和横向传导速度均增加。在HeLa-Cx43细胞上使用商业PKC分析，我们发现50 nM AAP10和50 nM ZP123分别将活性提高了99±6％和146±54％。使用选择性PKCa抑制剂GCP54345完全阻止了这两种化合物诱导的PKC活化。我们得出的结论是，AAP10和ZP123在体外具有相似的作用，但是ZP123优异的酶稳定性使该化合物成为抗心律失常肽体内研究的首选物质。

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