How to determine cardiac ion channels targeted by drugs using the isolated rabbit ventricular wedge model

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• 作者：Guizhi Liu^a ; ^b ; Tong Liu^c ; Daniel Cohen^b ; Tengxian Liu^b ; Gan-Xin Yan^b ; ^d ; ^{yanganxin@comcast.net" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Rabbit ventricular wedge assay ; Drug safety ; Tp-e/QT ratio ; IKr blocker ; QT-BCL slope ; Positive staircase response of contractility ; Use-dependency ; Calcium channel blocker ; Potassium channel activator
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：September-October 2016
• 年：2016
• 卷：81
• 期：Complete
• 页码：161-170
• 全文大小：1332 K

文摘

The rabbit left ventricular wedge (RLVW) has been demonstrated as a highly sensitive and specific preclinical model in assessing drug-induced QT prolongation and proarrhythmias. However, there is a need to determine drugs' cardiac ion channel profiles beyond QT measurement. In this study, we present an approach to determine cardiac ion channels targeted by drugs with analyzing a few key ECG parameters plus a contractility parameter obtained from the RLVW.

Methods

The RLVW assay was used for testing 18 drugs with well-known ion channel profiles. A transmural ECG and isometric contractility were recorded. Five parameters including QRS, QT, T_p-e/QT ratio, QT-BCL slope and the positive staircase response of contractility were analyzed.

Results

There were distinguished drug-induced ECG and contractility changes from which targeted cardiac ion channels by drugs could be determined. Inhibition of sodium channel resulted in rate-dependent QRS widening, QT and T_p-e shortening and a reduced QT-BCL slope. Although both I_Kr and I_Ks blockers prolonged QT interval, I_Kr blockers but not I_Ks increased T_p-e/QT ratio. Both potassium channel openers and calcium channel blockers markedly shortened QT and T_p-e intervals, but only calcium channel blockers could reverse the positive staircase response of contractility.

Discussion

The results in the present study are correlated closely to the drugs' well-known clinical profiles. This indicates that the RLVW assay with an adequate experimental protocol plus analysis of 5 key parameters is highly valuable in preclinical assessment of drug candidates for their detailed ion channel activities, proarrhythmic risks and other adverse effects. The limitations of the RLVW assay are also addressed.