Effects of polyunsaturated fatty acids on cardiac voltage-activated K+ currents in adult ferret cardiomyocytes

( views:59, downloads:0 )
James P.MORGAN()
Alexander LEAF()
Journal Title:
Volume 54, Issue 04, 2002
Key Word:
cardiomyocytes;potassium channels;arrhythmia;polyunsaturated fatty acids

Abstract: This study was carried out in adult ferret cardiomyocytes to investigate the effects of the n-3 polyunsaturated fatty acids (PUFAs) on voltage-gated K+ currents. We report that the two outward K+ currents: the transient outward K+ current (Ito) and the delayed rectifier K+ current (IK), are both inhibited by the n-3 PUFAs, while the inwardly rectifying K+ current (IK1) is unaffected by the n-3 PUFAs. Docosahexaenoic acid (C22:6n-3, DHA) produced a concentration-dependent suppression of Ito and IK in adult ferret cardiomyocytes with an IC50 of 7.5 and 20 μmol/L, respectively; but not IK1. In addition, eicosapentaenoic acid (C20:5n-3, EPA) had the effects on the three K+ channels similar to DHA. Arachidonic acid (C20:4n-6, AA) at 5 or 10 μmol/L, after an initial inhibitory effect on IK, caused an activation of IK,AA which was prevented by pretreatment with indomethacin, a cyclooxygenase inhibitor. Monounsaturated and saturated fatty acids, which are not antiarrhythmic, lack the effects on these K+ currents. Our results demonstrate that the n-3 PUFAs inhibit cardiac Ito and IK with much less potency compared to their effects on cardiac Na+ and Ca2+ currents as we reported previously. This inhibition of the cardiac ion currents by the n-3 PUFAs may contribute to their antiarrhythmic actions.

  • [1]McLennan, PL, Abeywardena MY, Charnock JS. Influence of dietary lipids on arrhythmias and infarction after coronary artery ligation in rats. Can J Physiol Pharmacol, 1985,63:1411~1417.
  • [2]McLennan PL, Bride TM, Abeywardena MY, Charnock JS. Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey. Am Heart J, 1992,123:1555~1561.
  • [3]Hock CE, Beck LD, Bodine LC, Reibel DK. Influence of dietary n-3 fatty acids on myocardial ischemia and re-perfusion. Am J Physiol (Heart and Circ Physiol), 1990,259:H1518~H1526.
  • [4]Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation, 1999,99(18):2452~2457.
  • [5]Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PW, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet, 1989, 334:757~761.
  • [6]de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, Guidollet J, Toubout P, Delaye J. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet,1994,343:1454~1459.
  • [7]Siscovick DS, Raghunathan TE, King I, Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J Am Med Assoc, 1995,274:1363~1367.
  • [8]Kang JX, Leaf A. Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes. Proc Natl Acad Sci (USA),1994,91:9886~9890.
  • [9]Kang JX, Xiao YF, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci (USA), 1995,92:3997~4001.
  • [10]Xiao YF, Kang JX, Morgan JP, Leaf A. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci (USA), 1995,92:11000~11004.
  • [11]Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci (USA), 1997,94:4182~4187.
  • [12]Kang JX, Leaf A. Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proc Natl Acad Sci (USA), 1996,93:3542~3546.
  • [13]Xiao YF, McArdle JJ. Elevated density and altered pharmacologic properties of myocardial calcium current of the spontaneously hypertensive rat. J Hypertens, 1994,12:783~790.
  • [14]Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pfluegers Arch, 1981,391:85~100.
  • [15]Tohse N, Kameyama M, Sekiguchi K, Shearman MS, Kanno M. Protein kinase C activation enhances the delayed rectifier potassium current in guinea-pig heart cells. J Mol Cell Cardiol, 1990,22:725~734.
  • [16]Linden DJ, Routtenberg A. Cis-fatty acids, which activate protein kinase C, attenuate Na+ and Ca2+ currents in mouse neuroblastoma cells. J Physiol (Lond), 1989,419:95~119.
  • [17]Tobias LD, Hamilton JG. The effect of 5,8,11,14-eicosatetraynoic on lipid metabolism. Lipids, 1978,14:181~193.
  • [18]Kang JX, Leaf A. Protective effects of All-trans-retinoic acid against cardiac arrhythmias induced by isoproterenol, lysophosphatidylcholine or ischemia and reperfusion. J Cardiovasc Pharmacol, 1995, 26:943~948.
  • [19]Xiao YF, Wright SN, Wang GK, Morgan JP, Leaf A. Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the α-subunit of the human cardiac Na+ channel. Proc. Natl Acad Sci (USA), 1998,95:2680~2685.
  • [20]Xiao YF, Wright SN, Wang GK, Morgan JP, Leaf A. Coexpression with the ?1 subunit modifies the kinetics and fatty-acid block of hH1? Na+ channels. Am J Physiol (Heart and Circ. Physiol.), 2000,279:H35~H46.
  • [21]Xiao YF, Ke Q, Wang SY, Auktor K, Yang Y, Wang GK, Morgan JP, Leaf A. Single point mutations affect fatty acid block of human myocardial sodium channel alpha subunit Na+ channels. Proc Natl Acad Sci (USA), 2001,98:3606~3611.
  • [22]Bogdanov KY, Spurgeon HA, Vinogradova TM, Lakatta EG. Modulation of the transient outward current in adult rat ventricular myocytes by polyunsaturated fatty acids. Am J Physiol (Heart and Circ. Physiol.), 1998,274:H571~H579.
  • [23]Honore E, Barhanin J, Attali B, Lesage F, Lazdunski M. External blockade of the major cardiac delayed-rectifier K+ (Kv1.5) by polyunsaturated fatty acids. Proc Natl Acad Sci (USA), 1994,91:1937~1941.
  • [24]Poling JS, Karanian JW, Salem N Jr, Stefano V. Time- and voltage-dependent block of delayed rectifier potassium channels by docosahexaenoic acid. Mol Pharmacol, 1995, 47:381~390.
  • [25]Catterall WA. Structure and function of voltage-sensitive ion channels. Science, 1989, 242:50~61.
  • [26]Noma A, Nakayama T, Kurachi Y, Irisawa H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol, 1984, 34:245~254.
  • [27]Chung S, Jung W, Lee MY. Inward and outward rectifying potassium currents set membrane potentials in activated rat microglia. Neurosci Lett, 1999,262:121~124.
  • [28]Mubagwa K, Flameng W, Carmeliet E. Resting and action potentials of nonischemic and chronically ischemic human ventricular muscle. J Cardiovasc Electrophysiol, 1994,5:659~671.
  • [29]Pancrazio JJ, Frazer MJ, Lynch C. Barbiturate anesthetics depress the resting K+ conductance of myocardium. J Pharmacol Exp Ther, 1993,265:358~365.
  • [30]Hallaq H, Smith T W, Leaf A. Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids. Proc Natl Acad Sci (USA), 1992,89:1760~1764.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615 Email:yiyao@wanfangdata.com.cn