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(Circulation. 2000;102:1165.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Nicotine Is a Potent Blocker of the Cardiac A-Type K⁺ Channels

Effects on Cloned Kv4.3 Channels and Native Transient Outward Current

Huizhen Wang, MD, MSc; Hong Shi, MD; Liming Zhang, MD; Marc Pourrier, BSc; Baofeng Yang, MD, PhD; Stanley Nattel, MD; Zhiguo Wang, PhD

From the Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal (H.W., H.S., L.Z., M.P., S.N., Z.W.), and Department of Pharmacology and Therapeutics, McGill University (S.N.), Montreal, Quebec, Canada, and the Department of Pharmacology, Harbin Medical University, Harbin, China (B.Y., Z.W.).

Correspondence to Dr Zhiguo Wang, Montreal Heart Institute, 5000 Belanger E, Montreal, Quebec, Canada H1T 1C8. E-mail wangz{at}icm.umontreal.ca

Background—Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aimed at establishing ionic mechanisms underlying potential electrophysiological effects of nicotine.

Methods and Results—Effects of nicotine on Kv4.3 and Kv4.2 channels expressed in Xenopus oocytes were studied at the whole-cell and single-channel levels. The effects of nicotine on the transient outward K⁺ current (I_to) were studied by use of whole-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC₅₀) was 40±4 nmol/L, and the current was abolished by 100 µmol/L nicotine. The IC₅₀ for block of native I_to was 270±43 nmol/L. The steady-state activation properties of Kv4.3 and I_to were unaltered by nicotine, whereas positive shifts of the inactivation curves were observed. Of the total inhibition of Kv4.3 and I_to by nicotine, 40% was due to tonic block and 60% was attributable to use-dependent block. Activation, inactivation, and reactivation kinetics were not significantly changed by nicotine. Nicotine reduced single-channel conductance, open probability, and open time but increased the closed time of Kv4.3. The effects of nicotine were not altered by antagonists to various neurotransmitter receptors, indicating direct effects on I_to channels.

Conclusions—Nicotine is a potent inhibitor of cardiac A-type K⁺ channels, with blockade probably due to block of closed and open channels. This action may contribute to the ability of nicotine to affect cardiac electrophysiology and induce arrhythmias.

Key Words: nicotine • ion channels • potassium

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