Ji Yuan, Varkevisser Rosanne, Opacic Dragan, Bossu Alexandre, Kuiper Marion, Beekman Jet D M, Yang Sihyung, Khan Azinwi Phina, Dobrev Dobromir, Voigt Niels, Wang Michael Zhuo, Verheule Sander, Vos Marc A, van der Heyden Marcel A G
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
Br J Pharmacol. 2017 Aug;174(15):2576-2590. doi: 10.1111/bph.13869. Epub 2017 Jun 28.
The density of the inward rectifier current (I ) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re-entry. The synthetic compound pentamidine analogue 6 (PA-6) is a selective and potent I inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, using established models in large animals.
PA-6 was applied i.v. in anaesthetized goats with rapid pacing-induced AF and anaesthetized dogs with chronic atrio-ventricular (AV) block. Electrophysiological and pharmacological parameters were determined.
PA-6 (2.5 mg·kg ·10 min ) induced cardioversion to sinus rhythm (SR) in 5/6 goats and prolonged AF cycle length. AF complexity decreased significantly before cardioversion. PA-6 accumulated in cardiac tissue with ratios between skeletal muscle : atrial muscle : ventricular muscle of approximately 1:8:21. In SR dogs, PA-6 peak plasma levels 10 min post infusion were 5.5 ± 0.9 μM, PA-6 did not induce significant prolongation of QTc and did not affect heart rate, PQ or QRS duration. In dogs with chronic AV block, PA-6 did not affect QRS but lengthened QTc during the experiment, but not chronically. PA-6 did not induce TdP arrhythmias in nine animals (0/9) in contrast to dofetilide (5/9). PA-6 (200 nM) inhibited I , but not I , in human isolated atrial cardiomyocytes.
PA-6 restored SR in goats with persistent AF and, in dogs with chronic AV block, prolonged QT intervals, without inducing TdP arrhythmias. Our results demonstrate cardiac safety and good anti-AF properties for PA-6.
内向整流电流（I ）密度在心房颤动（AF）时增加，缩短有效不应期，从而促进心房折返。合成化合物喷他脒类似物6（PA - 6）是一种选择性且强效的I 抑制剂。我们使用大型动物的既定模型测试了PA - 6的抗AF疗效和潜在的促心律失常作用。
将PA - 6静脉注射到快速起搏诱导AF的麻醉山羊和慢性房室（AV）阻滞的麻醉犬体内。测定电生理和药理学参数。
PA - 6（2.5 mg·kg ·10 min ）使6只山羊中的5只恢复为窦性心律（SR），并延长了AF周期长度。在恢复为SR之前，AF的复杂性显著降低。PA - 6在心脏组织中蓄积，骨骼肌：心房肌：心室肌的比例约为1:8:21。在SR犬中，输注后10分钟PA - 6的血浆峰值水平为5.5±0.9 μM，PA - 6未引起QTc显著延长，也不影响心率、PQ或QRS时限。在慢性AV阻滞的犬中，PA - 6在实验期间不影响QRS，但延长了QTc，但长期来看无此影响。与多非利特（5/9）不同，PA - 6在9只动物中未诱发尖端扭转型室性心动过速（TdP）心律失常（0/9）。PA - 6（200 nM）抑制人离体心房心肌细胞中的I ，但不抑制I 。
PA - 6使持续性AF的山羊恢复为SR，并且在慢性AV阻滞的犬中延长了QT间期，而不诱发TdP心律失常。我们的结果证明了PA - 6的心脏安全性和良好的抗AF特性。
