Direct block of inward rectifier potassium channels by nicotine.
Nicotine has been shown to depolarize membrane potential and to lengthen action potential duration in isolated cardiac preparations. To investigate whether this is a consequence of direct interaction of nicotine with inward rectifier K(+) channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K(+) channels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inward rectifier K(+) current I(K1) in canine ventricular myocytes. Nicotine suppressed Kir2.1-expressed currents at varying potentials negative to -20 mV, with more pronounced effects on the outward current between -70 and -20 mV relative to the inward current at hyperpolarized potentials (below -70 mV). The inhibition was concentration dependent. For the outward currents recorded at -50 mV, the IC50 was 165 +/- 18 microM. Similar effects of nicotine were observed for Kir2.2. A more potent effect was seen with I(K1) in canine myocytes. Significant blockade ( approximately 60%) was found at a concentration as low as 0.5 microM and the IC50 was 4.0 +/- 0.4 microM. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. Antagonists of nicotinic receptors (mecamylamine, 100 microM), muscarinic receptors (atropine, 1 microM), and beta-adrenergic receptors (propranolol, 1 microM) all failed to restore the depressed currents, suggesting that nicotine acted directly on Kir channels, independent of catecholamine release. This property of nicotine may explain its membrane-depolarizing and action potential duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias.
Wang
H
H
Research Center, Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
Yang
B
B
Zhang
L
L
Xu
D
D
Wang
Z
Z
D000818:Animals; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D009538:Nicotine / Q000633:toxicity*; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011978:Receptors, Nicotinic / Q000502:physiology; D014982:Xenopus laevis
D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011978:Receptors, Nicotinic; D009538:Nicotine