Pharmacological Blockade of IKs Destabilizes Spiral-Wave Reentry Under β-Adrenergic Stimulation in Favor of Its Early Termination

Journal of Pharmacological Sciences

Hiroki Takanari²  Sara Kato²  Tobias Opthof⁵  Tomoyuki Suzuki²  Shin Inada¹  Itsuo Kodama²  Kazuo Nakazawa¹  Takashi Ashihara⁴  Ichiro Sakuma³  Yusuke Okuno²  Yoshio Takemoto²  Haruo Honjo²  Kaichiro Kamiya² 

[1] National Cardiovascular Center, Research Institute, Japan;Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan;Graduate School of Engineering, The University of Tokyo, Japan;Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan;Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, The Netherlands

关键词: β-adrenergic stimulation;    IKs;    spiral-wave reentry;    optical mapping;    ventricular tachycardia;   

DOI  :  10.1254/jphs.12008FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(46)Cited-By(1)Supplementary materials(1)We tested a hypothesis that an enhancement of IKs may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, 0.1 μM) significantly shortened action potential duration (APD); chromanol 293B (30 μM), a selective IKs-blocker, reversed the APD shortening. VTs induced in the presence of ISP lasted longer than in the control, and this was reversed by 293B. E-4031 (0.1 μM), a selective IKr-blocker, did not cause such reversal. Spiral-wave (SW) reentry with ISP was characterized by more stable rotation around a shorter functional block line (FBL) than in the control. After application of 293B, SW reentry was destabilized, and rotation around a longer FBL with prominent drift reappeared. The APD abbreviation by ISP close to the rotation center was more pronounced than in the periphery, leading to an opposite APD gradient (center < periphery) compared with controls. This effect was also reversed by 293B. In conclusion, β-adrenergic stimulation stabilizes SW reentry most likely though an enhancement of IKs. Blockade of IKs may be a promising therapeutic modality in prevention of ventricular tachyarrhythmias under high sympathetic activity.

【 授权许可】

Unknown