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. 1994 Mar;111(3):873–879. doi: 10.1111/j.1476-5381.1994.tb14819.x

Effects of disopyramide and flecainide on the kinetics of inward rectifier potassium channels in rabbit heart muscle.

D K Martin 1, Y Nakaya 1, K R Wyse 1, T J Campbell 1
PMCID: PMC1910107  PMID: 8019764

Abstract

1. Standard patch-clamp techniques were used to study the interaction of therapeutic concentrations of flecainide and disopyramide with single inwardly-rectifying potassium channels in cell-attached membrane patches from rabbit ventricular myocytes. 2. Under drug-free conditions, the potassium channels had a conductance of 31 +/- 2 pS (n = 13), a mean open time of 230 +/- 6 ms (n = 11) recorded at the resting cell potential, and an open probability of 0.66 +/- 0.20 (n = 39). The resting potential of the cells studied was -68.5 +/- 3.6 mV (n = 32). 3. Disopyramide did not reduce the open probability of the channel when the cell was voltage-clamped at the resting cell potential. However, disopyramide increased the mean open time of the channel, recorded at the resting cell potential, by 15% at 5 microM and by 29% at 20 microM. The action potential prolonging actions of disopyramide in therapeutic concentrations appear not to be due to blocking the inward rectifier K+ channel. 4. Flecainide (3.0 microM, but not at 0.5 microM) decreased the open probability without changing the conductance of the channel, at 3 microM (51.0 +/- 7.2%, n = 6, P = 0.03) at the resting cell potential. Flecainide increased the mean open time of the channel, recorded at the resting cell potential, by 12% at 3.0 microM. 5. We propose that flecainide stabilized the inward rectifier K+ channel in an inactivated state, without plugging the conducting pore.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Arena J. P., Walsh K. B., Kass R. S. Measurement, block, and modulation of potassium channel currents in the heart. Prog Clin Biol Res. 1990;334:43–63. [PubMed] [Google Scholar]
  2. Balser J. R., Roden D. M., Bennett P. B. Single inward rectifier potassium channels in guinea pig ventricular myocytes. Effects of quinidine. Biophys J. 1991 Jan;59(1):150–161. doi: 10.1016/S0006-3495(91)82207-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barry P. H., Lynch J. W. Liquid junction potentials and small cell effects in patch-clamp analysis. J Membr Biol. 1991 Apr;121(2):101–117. doi: 10.1007/BF01870526. [DOI] [PubMed] [Google Scholar]
  4. Campbell T. J. Class III antiarrhythmic action: the way forward? Med J Aust. 1993 Jun 7;158(11):732–733. doi: 10.5694/j.1326-5377.1993.tb121952.x. [DOI] [PubMed] [Google Scholar]
  5. Campbell T. J. Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res. 1983 Jun;17(6):344–352. doi: 10.1093/cvr/17.6.344. [DOI] [PubMed] [Google Scholar]
  6. Colatsky T. J., Follmer C. H., Starmer C. F. Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation. 1990 Dec;82(6):2235–2242. doi: 10.1161/01.cir.82.6.2235. [DOI] [PubMed] [Google Scholar]
  7. Coraboeuf E., Deroubaix E., Escande D., Coulombe A. Comparative effects of three class I antiarrhythmic drugs on plateau and pacemaker currents of sheep cardiac Purkinje fibres. Cardiovasc Res. 1988 Jun;22(6):375–384. doi: 10.1093/cvr/22.6.375. [DOI] [PubMed] [Google Scholar]
  8. Coraboeuf E. Ionic basis of electrical activity in cardiac tissues. Am J Physiol. 1978 Feb;234(2):H101–H116. doi: 10.1152/ajpheart.1978.234.2.H101. [DOI] [PubMed] [Google Scholar]
  9. DiFrancesco D. A study of the ionic nature of the pace-maker current in calf Purkinje fibres. J Physiol. 1981 May;314:377–393. doi: 10.1113/jphysiol.1981.sp013714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Echt D. S., Liebson P. R., Mitchell L. B., Peters R. W., Obias-Manno D., Barker A. H., Arensberg D., Baker A., Friedman L., Greene H. L. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781–788. doi: 10.1056/NEJM199103213241201. [DOI] [PubMed] [Google Scholar]
  11. Elharrar V. Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1988 Jul;246(1):235–242. [PubMed] [Google Scholar]
  12. Escande D., Cavero I. K+ channel openers and 'natural' cardioprotection. Trends Pharmacol Sci. 1992 Jul;13(7):269–272. doi: 10.1016/0165-6147(92)90083-i. [DOI] [PubMed] [Google Scholar]
  13. Follmer C. H., Colatsky T. J. Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. Circulation. 1990 Jul;82(1):289–293. doi: 10.1161/01.cir.82.1.289. [DOI] [PubMed] [Google Scholar]
  14. Hodges M., Haugland J. M., Granrud G., Conard G. J., Asinger R. W., Mikell F. L., Krejci J. Suppression of ventricular ectopic depolarizations by flecainide acetate, a new antiarrhythmic agent. Circulation. 1982 May;65(5):879–885. doi: 10.1161/01.cir.65.5.879. [DOI] [PubMed] [Google Scholar]
  15. Hondeghem L. M. Development of class III antiarrhythmic agents. J Cardiovasc Pharmacol. 1992;20 (Suppl 2):S17–S22. [PubMed] [Google Scholar]
  16. Ikeda N., Singh B. N., Davis L. D., Hauswirth O. Effects of flecainide on the electrophysiologic properties of isolated canine and rabbit myocardial fibers. J Am Coll Cardiol. 1985 Feb;5(2 Pt 1):303–310. doi: 10.1016/s0735-1097(85)80051-6. [DOI] [PubMed] [Google Scholar]
  17. Josephson I. R., Brown A. M. Inwardly rectifying single-channel and whole cell K+ currents in rat ventricular myocytes. J Membr Biol. 1986;94(1):19–35. doi: 10.1007/BF01901010. [DOI] [PubMed] [Google Scholar]
  18. Martin C. L., Chinn K. Contribution of delayed rectifier and inward rectifier to repolarization of the action potential: pharmacologic separation. J Cardiovasc Pharmacol. 1992 May;19(5):830–837. doi: 10.1097/00005344-199205000-00022. [DOI] [PubMed] [Google Scholar]
  19. Matsuda H. Open-state substructure of inwardly rectifying potassium channels revealed by magnesium block in guinea-pig heart cells. J Physiol. 1988 Mar;397:237–258. doi: 10.1113/jphysiol.1988.sp016998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. McManus O. B., Blatz A. L., Magleby K. L. Sampling, log binning, fitting, and plotting durations of open and shut intervals from single channels and the effects of noise. Pflugers Arch. 1987 Nov;410(4-5):530–553. doi: 10.1007/BF00586537. [DOI] [PubMed] [Google Scholar]
  21. Niarchos A. P. Disopyramide: serum level and arrhythmia conversion. Am Heart J. 1976 Jul;92(1):57–64. doi: 10.1016/s0002-8703(76)80403-6. [DOI] [PubMed] [Google Scholar]
  22. Noble D. The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol. 1984 Aug;353:1–50. doi: 10.1113/jphysiol.1984.sp015320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Patlak J., Horn R. Effect of N-bromoacetamide on single sodium channel currents in excised membrane patches. J Gen Physiol. 1982 Mar;79(3):333–351. doi: 10.1085/jgp.79.3.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rees S. A., Curtis M. J. Specific IK1 blockade: a new antiarrhythmic mechanism? Effect of RP58866 on ventricular arrhythmias in rat, rabbit, and primate. Circulation. 1993 Jun;87(6):1979–1989. doi: 10.1161/01.cir.87.6.1979. [DOI] [PubMed] [Google Scholar]
  25. Sakmann B., Trube G. Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol. 1984 Feb;347:641–657. doi: 10.1113/jphysiol.1984.sp015088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sakmann B., Trube G. Voltage-dependent inactivation of inward-rectifying single-channel currents in the guinea-pig heart cell membrane. J Physiol. 1984 Feb;347:659–683. doi: 10.1113/jphysiol.1984.sp015089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shimoni Y., Clark R. B., Giles W. R. Role of an inwardly rectifying potassium current in rabbit ventricular action potential. J Physiol. 1992 Mar;448:709–727. doi: 10.1113/jphysiol.1992.sp019066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wang Z. G., Pelletier L. C., Talajic M., Nattel S. Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. Circulation. 1990 Jul;82(1):274–283. doi: 10.1161/01.cir.82.1.274. [DOI] [PubMed] [Google Scholar]
  29. Wu B., Sato T., Kiyosue T., Arita M. Blockade of 2,4-dinitrophenol induced ATP sensitive potassium current in guinea pig ventricular myocytes by class I antiarrhythmic drugs. Cardiovasc Res. 1992 Nov;26(11):1095–1101. doi: 10.1093/cvr/26.11.1095. [DOI] [PubMed] [Google Scholar]
  30. Wyse K. R., Ye V., Campbell T. J. Action potential prolongation exhibits simple dose-dependence for sotalol, but reverse dose-dependence for quinidine and disopyramide: implications for proarrhythmia due to triggered activity. J Cardiovasc Pharmacol. 1993 Feb;21(2):316–322. doi: 10.1097/00005344-199302000-00019. [DOI] [PubMed] [Google Scholar]

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