Nicotine is a potent blocker of the cardiac A-type K+ channels - Effects on cloned Kv4.3 channels and native transient outward current

Background-Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aim ed at establishing ionic mechanisms underlying potential electrophysiologic al effects of nicotine. Methods and Results-Effects of nicotine on Kv4.3 and Kv4.2 channels express ed in Xenopus oocytes were studied at the whole-cell and single-channel lev els. The effects of nicotine on the transient outward K+ current (I-to) wer e studied by use of whole-cell patch-clamp techniques in canine Ventricular myocytes. Nicotine potently inhibited Kv4 current, The concentration for h alf-maximal inhibition (ICS,) was 40+/-4 nmoI/L, and the current was abolis hed by 100 mu mol/L nicotine. The ICS, for block of native I-to was 270+/-4 3 nmol/L. The steady-state activation properties of Kv4.3 and I-to were una ltered 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 d ue to tonic block and 60% was attributable to use-dependent block. Activati on, 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 nicot ine 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 acti on may contribute to the ability of nicotine to affect cardiac electrophysi ology and induce arrhythmias.