Nicotine Is a Potent Blocker of the Cardiac A-Type K+ Channels : Effects on Cloned Kv4.3 Channels and Native Transient Outward Current

H. Wang, H. Shi, L. Zhang, M. Pourrier, B. Yang, S. Nattel, Z. Wang
2000 Circulation  
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 ϩ current (I to ) were studied by use of
more » ... e-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC 50 ) was 40Ϯ4 nmol/L, and the current was abolished by 100 mol/L nicotine. The IC 50 for block of native I to was 270Ϯ43 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 ϩ 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. (Circulation. 2000;102:1165-1171.)
doi:10.1161/01.cir.102.10.1165 pmid:10973847 fatcat:x42hl4fcyvaxvjdz55binnlhxa