Oncotarget

Research Papers:

Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts

Gary Tse, Tong Liu, Guangping Li, Wendy Keung, Jie Ming Yeo, Yin Wah Fiona Chan, Bryan P. Yan, Yat Sun Chan, Sunny Hei Wong, Ronald A. Li, Jichao Zhao, William K.K. Wu _ and Wing Tak Wong

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Oncotarget. 2017; 8:85341-85352. https://doi.org/10.18632/oncotarget.19675

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Abstract

Gary Tse1,2, Tong Liu3, Guangping Li3, Wendy Keung4, Jie Ming Yeo5, Yin Wah Fiona Chan6, Bryan P. Yan1, Yat Sun Chan1, Sunny Hei Wong1,2, Ronald A. Li7, Jichao Zhao8, William K.K. Wu9 and Wing Tak Wong10

1Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China

2Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China

3Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China

4Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong, China

5Faculty of Medicine, Imperial College London, London, UK

6School of Biological Sciences, University of Cambridge, Cambridge, UK

7Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Solna, Sweden

8Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand

9Department of Anaesthesia and Intensive Care, State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

10School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China

Correspondence to:

William K.K. Wu, email: [email protected]

Wing Tak Wong, email: [email protected]

Keywords: heptanol, conduction, repolarization, extrasystolic stimulation, S1S2 restitution

Abbreviations: APD: action potential duration; CV: conduction velocity; DIcrit: critical diastolic interval; ERP: effective refractory period; VERP: ventricular effective refractory period

Received: April 25, 2017     Accepted: May 23, 2017     Published: July 28, 2017

ABSTRACT

Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher’s exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.


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