The Journal of Physiological Sciences

, Volume 64, Issue 3, pp 185–193 | Cite as

Role of slow delayed rectifying potassium current in dynamics of repolarization and electrical memory in swine ventricles

  • Linyuan Jing
  • Kathleen Brownson
  • Abhijit PatwardhanEmail author
Original Paper


Dynamics of repolarization, quantified as restitution and electrical memory, impact conduction stability. Relatively less is known about role of slow delayed rectifying potassium current, I Ks, in dynamics of repolarization and memory compared to the rapidly activating current I Kr. Trans-membrane potentials were recorded from right ventricular tissues from pigs during reduction (chromanol 293B) and increases in I Ks (mefenamic acid). A novel pacing protocol was used to explicitly control diastolic intervals to quantify memory. Restitution hysteresis, a consequence of memory, increased after chromanol 293B (loop thickness and area increased 27 and 38 %) and decreased after mefenamic acid (52 and 53 %). Standard and dynamic restitutions showed an increase in average slope after chromanol 293B and a decrease after mefenamic acid. Increase in slope and memory are hypothesized to have opposite effects on electrical stability; therefore, these results suggest that reduction and enhancement of I Ks likely also have offsetting components that affect stability.


Slow delayed rectifier potassium current Restitution Action potential duration Cardiac memory Hysteresis Ventricular arrhythmia 



Slow delayed rectifier potassium current


Action potential


Rapid delayed rectifier potassium current


Action potential duration


Cycle length


Diastolic interval


Transmembrane potential


Torsades de Pointes



Supported by grants from the National Science Foundation (0730450, 0814194) and the Commonwealth of Kentucky.


  1. 1.
    Abi-Gerges N, Small BG, Lawrence CL, Hammond TG, Valentin JP, Pollard CE (2006) Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender. Br J Pharmacol 147(6):653–660. doi: 10.1038/sj.bjp.0706491 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Hayakawa EH, Furutani M, Matsuoka R, Takakuwa Y (2011) Comparison of protein behavior between wild-type and G601S hERG in living cells by fluorescence correlation spectroscopy. J Physiol Sci 61(4):313–319. doi: 10.1007/s12576-011-0150-2 PubMedCrossRefGoogle Scholar
  3. 3.
    Cheng JH, Kodama I (2004) Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin 25(2):137–145PubMedGoogle Scholar
  4. 4.
    Lu Z, Kamiya K, Opthof T, Yasui K, Kodama I (2001) Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans. Circulation 104(8):951–956PubMedCrossRefGoogle Scholar
  5. 5.
    Singh BN (1988) Control of cardiac arrhythmias by lengthening repolarization. Futura, Mount KiscoGoogle Scholar
  6. 6.
    Singh BN, Vaughan Williams EM (1970) A third class of anti-arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ, 1999 and AH 3474. Br J Pharmacol 39(4):675–687PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Stengl M, Volders PG, Thomsen MB, Spatjens RL, Sipido KR, Vos MA (2003) Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol 551(Pt 3):777–786. doi: 10.1113/jphysiol.2003.044040 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Magyar J, Horvath B, Banyasz T, Szentandrassy N, Birinyi P, Varro A, Szakonyi Z, Fulop F, Nanasi PP (2006) L-364,373 fails to activate the slow delayed rectifier K+ current in canine ventricular cardiomyocytes. Naunyn-Schmiedeberg’s Arch Pharmacol 373(1):85–89. doi: 10.1007/s00210-006-0047-4 CrossRefGoogle Scholar
  9. 9.
    Cherry EM, Fenton FH (2004) Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects. Am J Physiol Heart Circ Physiol 286(6):H2332–H2341. doi: 10.1152/ajpheart.00747.2003 PubMedCrossRefGoogle Scholar
  10. 10.
    Choi BR, Liu T, Salama G (2004) Adaptation of cardiac action potential durations to stimulation history with random diastolic intervals. J Cardiovasc Electrophysiol 15(10):1188–1197. doi: 10.1046/j.1540-8167.2004.04070.x PubMedCrossRefGoogle Scholar
  11. 11.
    Jordan PN, Christini DJ (2004) Determining the effects of memory and action potential duration alternans on cardiac restitution using a constant-memory restitution protocol. Physiol Meas 25(4):1013–1024PubMedCrossRefGoogle Scholar
  12. 12.
    Wu R, Patwardhan A (2004) Restitution of action potential duration during sequential changes in diastolic intervals shows multimodal behavior. Circ Res 94(5):634–641. doi: 10.1161/01.RES.0000119322.87051.A9 PubMedCrossRefGoogle Scholar
  13. 13.
    Wu R, Patwardhan A (2007) Effects of rapid and slow potassium repolarization currents and calcium dynamics on hysteresis in restitution of action potential duration. J Electrocardiol 40(2):188–199. doi: 10.1016/j.jelectrocard.2006.01.001 PubMedCrossRefGoogle Scholar
  14. 14.
    Bosch RF, Gaspo R, Busch AE, Lang HJ, Li GR, Nattel S (1998) Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res 38(2):441–450PubMedCrossRefGoogle Scholar
  15. 15.
    Sun ZQ, Thomas GP, Antzelevitch C (2001) Chromanol 293B inhibits slowly activating delayed rectifier and transient outward currents in canine left ventricular myocytes. J Cardiovasc Electrophysiol 12(4):472–478PubMedCrossRefGoogle Scholar
  16. 16.
    Guerard NC, Traebert M, Suter W, Dumotier BM (2008) Selective block of IKs plays a significant role in MAP triangulation induced by IKr block in isolated rabbit heart. J Pharmacol Toxicol Methods 58(1):32–40. doi: 10.1016/j.vascn.2008.05.129 PubMedCrossRefGoogle Scholar
  17. 17.
    Jost N, Virag L, Bitay M, Takacs J, Lengyel C, Biliczki P, Nagy Z, Bogats G, Lathrop DA, Papp JG, Varro A (2005) Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation 112(10):1392–1399. doi: 10.1161/CIRCULATIONAHA.105.550111 PubMedCrossRefGoogle Scholar
  18. 18.
    Liu Z, Du L, Li M (2012) Update on the slow delayed rectifier potassium current (I(Ks)): role in modulating cardiac function. Curr Med Chem 19(9):1405–1420PubMedCrossRefGoogle Scholar
  19. 19.
    Volders PG, Stengl M, van Opstal JM, Gerlach U, Spatjens RL, Beekman JD, Sipido KR, Vos MA (2003) Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation. Circulation 107(21):2753–2760. doi: 10.1161/01.CIR.0000068344.54010.B3 PubMedCrossRefGoogle Scholar
  20. 20.
    Salata JJ, Jurkiewicz NK, Wang J, Evans BE, Orme HT, Sanguinetti MC (1998) A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol 54(1):220–230PubMedGoogle Scholar
  21. 21.
    Xu X, Salata JJ, Wang J, Wu Y, Yan GX, Liu T, Marinchak RA, Kowey PR (2002) Increasing I(Ks) corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy. Am J Physiol Heart Circ Physiol 283(2):H664–H670. doi: 10.1152/ajpheart.00076.2002 PubMedGoogle Scholar
  22. 22.
    Banville I, Chattipakorn N, Gray RA (2004) Restitution dynamics during pacing and arrhythmias in isolated pig hearts. J Cardiovasc Electrophysiol 15(4):455–463. doi: 10.1046/j.1540-8167.2004.03330.x PubMedCrossRefGoogle Scholar
  23. 23.
    Caldwell BJ, Legrice IJ, Hooks DA, Tai DC, Pullan AJ, Smaill BH (2005) Intramural measurement of transmembrane potential in the isolated pig heart: validation of a novel technique. J Cardiovasc Electrophysiol 16(9):1001–1010. doi: 10.1111/j.1540-8167.2005.40558.x PubMedCrossRefGoogle Scholar
  24. 24.
    Jiang H, Zhao D, Cui B, Lu Z, Lu J, Chen F, Bao M (2008) Electrical restitution determined by epicardial contact mapping and surface electrocardiogram: its role in ventricular fibrillation inducibility in swine. J Electrocardiol 41(2):152–159. doi: 10.1016/j.jelectrocard.2007.10.001 PubMedCrossRefGoogle Scholar
  25. 25.
    Ristagno G, Yu T, Quan WL, Freeman G, Li YQ (2013) Current is better than energy as predictor of success for biphasic defibrillatory shocks in a porcine model of ventricular fibrillation. Resuscitation 84(5):678–683. doi: 10.1016/j.resuscitation.2012.09.029 PubMedCrossRefGoogle Scholar
  26. 26.
    Voroshilovsky O, Qu Z, Lee MH, Ohara T, Fishbein GA, Huang HL, Swerdlow CD, Lin SF, Garfinkel A, Weiss JN, Karagueuzian HS, Chen PS (2000) Mechanisms of ventricular fibrillation induction by 60-Hz alternating current in isolated swine right ventricle. Circulation 102(13):1569–1574PubMedCrossRefGoogle Scholar
  27. 27.
    Walcott GP, Kroll MW, Ideker RE (2011) Ventricular fibrillation threshold of rapid short pulses. Conf Proc IEEE Eng Med Biol Soc 2011:255–258. doi: 10.1109/IEMBS.2011.6090049 PubMedGoogle Scholar
  28. 28.
    Koller ML, Riccio ML, Gilmour RF Jr (1998) Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation. Am J Physiol 275(5 Pt 2):H1635–H1642PubMedGoogle Scholar
  29. 29.
    Guzman KM, Jing L, Patwardhan A (2010) Effects of changes in the L-type calcium current on hysteresis in restitution of action potential duration. Pacing Clin Electrophysiol 33(4):451–459. doi: 10.1111/j.1540-8159.2009.02637.x PubMedCrossRefGoogle Scholar
  30. 30.
    Jing L, Chourasia S, Patwardhan A (2010) Heterogeneous memory in restitution of action potential duration in pig ventricles. J Electrocardiol 43(5):425–432. doi: 10.1016/j.jelectrocard.2010.02.006 PubMedCrossRefGoogle Scholar
  31. 31.
    Pruvot EJ, Katra RP, Rosenbaum DS, Laurita KR (2004) Role of calcium cycling versus restitution in the mechanism of repolarization alternans. Circ Res 94(8):1083–1090. doi: 10.1161/01.RES.0000125629.72053.95 PubMedCrossRefGoogle Scholar
  32. 32.
    Nattel S, Zeng FD (1984) Frequency-dependent effects of antiarrhythmic drugs on action potential duration and refractoriness of canine cardiac Purkinje fibers. J Pharmacol Exp Ther 229(1):283–291PubMedGoogle Scholar
  33. 33.
    Barhanin J, Attali B, Lazdunski M (1998) IKs, a slow and intriguing cardiac K+ channel and its associated long QT diseases. Trends Cardiovasc Med 8(5):207–214PubMedCrossRefGoogle Scholar
  34. 34.
    Inanobe A, Kamiya N, Murakami S, Fukunishi Y, Nakamura H, Kurachi Y (2008) In silico prediction of the chemical block of human ether-a-go–go-related gene (hERG) K+ current. J Physiol Sci 58(7):459–470. doi: 10.2170/physiolsci.RV-0114-08-07-R1 PubMedCrossRefGoogle Scholar
  35. 35.
    Laursen M, Olesen SP, Grunnet M, Mow T, Jespersen T (2011) Characterization of cardiac repolarization in the Gottingen minipig. J Pharmacol Toxicol Methods 63(2):186–195. doi: 10.1016/j.vascn.2010.10.001 PubMedCrossRefGoogle Scholar
  36. 36.
    Lengyel C, Iost N, Virag L, Varro A, Lathrop DA, Papp JG (2001) Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration. Br J Pharmacol 132(1):101–110. doi: 10.1038/sj.bjp.0703777 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Karma A (1994) Electrical alternans and spiral wave breakup in cardiac tissue. Chaos 4(3):461–472. doi: 10.1063/1.166024 PubMedCrossRefGoogle Scholar
  38. 38.
    Qu Z, Garfinkel A, Chen PS, Weiss JN (2000) Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation 102(14):1664–1670PubMedCrossRefGoogle Scholar
  39. 39.
    Chialvo DR, Michaels DC, Jalife J (1990) Supernormal excitability as a mechanism of chaotic dynamics of activation in cardiac Purkinje-Fibers. Circ Res 66(2):525–545PubMedCrossRefGoogle Scholar
  40. 40.
    Pajouh M, Wilson LD, Poelzing S, Johnson NJ, Rosenbaum DS (2005) IKs blockade reduces dispersion of repolarization in heart failure. Heart Rhythm 2(7):731–738. doi: 10.1016/j.hrthm.2005.04.015 PubMedCrossRefGoogle Scholar
  41. 41.
    Cheng HC, Incardona J (2009) Models of torsades de pointes: effects of FPL64176, DPI201106, dofetilide, and chromanol 293B in isolated rabbit and guinea pig hearts. J Pharmacol Toxicol Methods 60(2):174–184. doi: 10.1016/j.vascn.2009.05.010 PubMedCrossRefGoogle Scholar
  42. 42.
    Jost N, Papp JG, Varro A (2007) Slow delayed rectifier potassium current (IKs) and the repolarization reserve. Ann Noninvasive Electrocardiol 12(1):64–78. doi: 10.1111/j.1542-474X.2007.00140.x PubMedCrossRefGoogle Scholar
  43. 43.
    Busch AE, Busch GL, Ford E, Suessbrich H, Lang HJ, Greger R, Kunzelmann K, Attali B, Stuhmer W (1997) The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. Br J Pharmacol 122(2):187–189. doi: 10.1038/sj.bjp.0701434 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Busch AE, Herzer T, Wagner CA, Schmidt F, Raber G, Waldegger S, Lang F (1994) Positive regulation by chloride channel blockers of I-Sk channels expressed in Xenopus oocytes. Mol Pharmacol 46(4):750–753PubMedGoogle Scholar
  45. 45.
    Bryant SM, Wan X, Shipsey SJ, Hart G (1998) Regional differences in the delayed rectifier current (IKr and IKs) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig. Cardiovasc Res 40(2):322–331PubMedCrossRefGoogle Scholar
  46. 46.
    Cheng J, Kamiya K, Liu W, Tsuji Y, Toyama J, Kodama I (1999) Heterogeneous distribution of the two components of delayed rectifier K+ current: a potential mechanism of the proarrhythmic effects of methanesulfonanilideclass III agents. Cardiovasc Res 43(1):135–147PubMedCrossRefGoogle Scholar
  47. 47.
    Liu DW, Antzelevitch C (1995) Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res 76(3):351–365PubMedCrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2014

Authors and Affiliations

  • Linyuan Jing
    • 1
  • Kathleen Brownson
    • 1
  • Abhijit Patwardhan
    • 1
    Email author
  1. 1.Department of Biomedical EngineeringUniversity of KentuckyLexingtonUSA

Personalised recommendations