Direct block of inward rectifier potassium channels by nicotine

Nicotine has been shown to depolarize membrane potential and to lengthen ac tion potential duration in isolated cardiac preparations. To investigate wh ether this is a consequence of direct interaction of nicotine with inward r ectifier K+ channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K+ c hannels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inw ard rectifier K+ current I-K1 in canine ventricular myocytes. Nicotine supp ressed 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 recor ded at -50 mV, the IC50 was 165 +/- 18 mu M. Similar effects of nicotine we re observed for Kir2.2. A more potent effect was seen with I-K1 in canine m yocytes. Significant blockade (similar to 60%) was found at a concentration as low as 0.5 mu M and the IC50 was 4.0 +/- 0.4 mu M. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. An tagonists of nicotinic receptors (mecamylamine, 100 mu M), muscarinic recep tors (atropine, 1 mu M), and beta-adrenergic receptors (propranolol, 1 mu M ) all failed to restore the depressed currents, suggesting that nicotine ac ted directly on Kir channels, independent of catecholamine release. This pr operty of nicotine may explain its membrane-depolarizing and action potenti al duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias. (C) 2000 Acad emic Press.