title: Direct block of inward rectifier potassium channels by nicotine.
abstract: 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.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Xu
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
mesh_terms: 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
chemical_list: D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011978:Receptors, Nicotinic; D009538:Nicotine