PDE8 Inhibition and Its Impact on ICa,L in Persistent Atrial Fibrillation: Evaluation of PDE8 as a Potential Drug Target.

IF 2.6 4区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of Cardiovascular Pharmacology Pub Date : 2024-09-13 DOI:10.1097/fjc.0000000000001630

Djemail Ismaili,Johannes Petersen,Carl Schulz,Thomas Eschenhagen,Jussi T Koivumäki,Torsten Christ

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引用次数: 0

Abstract

Atrial fibrillation (AF) poses a significant therapeutic challenge with drug interventions showing only limited success. Phosphodiesterases (PDE) regulate cardiac electrical stability and may represent an interesting target. Recently, PDE8 inhibition was proposed as an antiarrhythmic intervention by increasing L-type Ca2+ current (ICa,L) and action potential duration (APD). However, the effect size of PDE8 inhibition on ICa,L and APD seems discrepant and effects on force are unknown. We investigated the impact of PDE8 inhibition on force using PF-04957325 in right atrial appendages, obtained from patients in sinus rhythm (SR) and with persistent AF (peAF) undergoing cardiac surgery. A computational model was employed to predict the effects of PDE8 inhibition on APD in SR and peAF. Results showed no increase in force after exposure to increasing concentrations of the PDE8 inhibitor PF-04957325 in either SR or peAF tissues. Furthermore, PDE8 inhibition did not affect the potency or efficacy of norepinephrine-induced inotropic effects in either group. Arrhythmic events triggered by norepinephrine were observed in both SR and peAF, but their frequency remained unaffected by PF-04957325 treatment. Computational modeling predicted that the reported increase in ICa,L induced by PDE8 inhibition would lead to substantial APD prolongation at all repolarization states, particularly in peAF. Our findings indicate that PDE8 inhibition does not significantly impact force or arrhythmogenicity in human atrial tissue.

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PDE8 抑制及其对持续性心房颤动 ICa,L 的影响：评估作为潜在药物靶点的 PDE8。

心房颤动（房颤）给治疗带来了巨大挑战，药物干预的效果有限。磷酸二酯酶（PDE）调节心电稳定性，可能是一个有趣的靶点。最近，有人提出通过增加 L 型 Ca2+ 电流（ICa,L）和动作电位持续时间（APD）来抑制 PDE8，从而达到抗心律失常的目的。然而，PDE8 抑制对 ICa,L 和 APD 的影响大小似乎并不一致，对力量的影响也不清楚。我们在接受心脏手术的窦性心律（SR）和持续性房颤（peAF）患者的右心房阑尾中使用 PF-04957325 研究了 PDE8 抑制对力量的影响。采用计算模型预测了 PDE8 抑制对 SR 和 peAF 的 APD 的影响。结果显示，在SR和peAF组织中暴露于浓度不断增加的PDE8抑制剂PF-04957325后，肌力没有增加。此外，PDE8 抑制剂对去甲肾上腺素诱导的肌力作用的效力和效果均无影响。在 SR 和 peAF 中都观察到了由去甲肾上腺素引发的心律失常事件，但其频率不受 PF-04957325 治疗的影响。计算模型预测，PDE8 抑制引起的 ICa,L 增加将导致所有复极化状态下 APD 的大幅延长，尤其是在 peAF 中。我们的研究结果表明，PDE8 抑制不会对人体心房组织的力量或心律失常发生率产生重大影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cardiovascular Pharmacology 医学-心血管系统

CiteScore

5.10

自引率

3.30%

发文量

367

审稿时长

1 months

期刊介绍： Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.