致Torsagenic药物影响的心脏离子通道mRNA表达的快速变化影响大鼠心脏对β肾上腺素能刺激诱导的心律失常的易感性。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Katarina Hadova, Jana Kmecova, Katarina Ochodnicka-Mackovicova, Eva Kralova, Gabriel Doka, Lenka Bies Pivackova, Peter Vavrinec, Tatiana Stankovicova, Peter Krenek, Jan Klimas
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引用次数: 0

摘要

药物诱导的长QT综合征(LQTS)和尖端扭转(TdP)是药物开发中的严重问题。尽管大鼠是一种有用的科学工具,但与体型较大的物种不同,它们的心脏通常对致扭转药物没有反应。因此,人们对它们对药物引起的心律失常的抵抗力知之甚少。在这里,我们用抑制快速延迟整流电流(Ikr)的抗生素克拉霉素(CLA)、环路利尿剂呋塞米(FUR)或它们的组合(CLA + FUR),并检查用异丙肾上腺素刺激后的功能和分子异常。克拉霉素和速尿口服给药,间隔12小时,共7天 天。为了评估电不稳定性,在基础条件下以及随后在β肾上腺素能刺激下,使用Langendorff灌注心脏法在体内或离体记录心电图(ECG)。使用实时定量PCR测量左心室组织中的基因表达。事实上,FUR和CLA + FUR大鼠表现出低钾血症。CLA和CLA + FUR治疗导致药物诱导的LQTS,甚至在一个CLA中出现TdP发作 + FUR大鼠。联合治疗失调了几个离子通道亚基的基因表达,包括KCNQ1、钙通道和Na+/K + -ATP酶亚基,而两种单一疗法都没有影响。与CLA内的其他大鼠相比,具有记录的TdP的大鼠在离子通道基因表达方面表现出差异 + FUR集团。在离体灌注心脏中未检测到心电图变化。因此,我们报道了在大鼠中同时给予克拉霉素和呋塞米诱导QT延长的心脏离子通道重编程的快速协调,这可能是它们避免β-肾上腺素能刺激引发心律失常的能力的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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