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European Heart Journal 2001 22(11):955-963; doi:10.1053/euhj.2000.2499
Copyright © 2001 by the European Society of Cardiology.
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Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts

M.W Veldkampa, A.O Verkerkb, A.C.G van Ginnekena, A Baartscheera, C Schumachera, N de Jongec, J.M.T de Bakkerd,e and T Opthofd,f1

a Experimental and Molecular Cardiology Group, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, the Netherlands
b Department of Physiology, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, the Netherlands
c Department of Cardiac Transplantation, University Medical Center Utrecht, the Netherlands
d Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
e Interuniversity Cardiovascular Institute, the Netherlands

revised October 10, 2000; accepted October 11, 2000

Abstract

Aims Congestive heart failure is characterized by high levels of norepinephrine which is considered to be arrhythmogenic. It is unclear whether increased norepinephrine is only a marker of the severity of heart failure or whether it directly triggers ventricular arrhythmias.

Methods and Results Ventricular myocytes were isolated from eight explanted hearts of patients with end-stage heart failure (ischaemic or dilated cardiomyopathy). With the whole-cell configuration of the patch–clamp technique the effect of 1µmol.l–1norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256±25pF (n=26) and action potential duration (APD90) during control conditions was 620±45ms at 1Hz (n=14). Norepinephrine induced action potential prolongation in all cells and early afterdepolarizations in 50% of them. Norepinephrine significantly increased the calcium current but had no effect on the delayed rectifier current, the inward rectifier current or the transient outward current. Norepinephrine also significantly increased the steady-state calcium window-current measured between –40 and 0mV.

Conclusions In contrast to many animal species, norepinephrine induces action potential prolongation in ventricular myocytes from human failing hearts, as well as early afterdepolarization, by an increase in both the calcium peak current and window current. Thus norepinephrine seems to be an important arrhythmogenic factor in congestive heart failure.

Key Words: Heart failure, norepinephrine, myocytes, arrhythmias, action potential duration

f1 Correspondence: Tobias Opthof, Department of Medical Physiology, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands.

References

  1. Messerli FH, Ventura OH, Elilardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med. 1984;77:18–22[CrossRef][Web of Science][Medline]
  2. Levy D, Anderson K, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1987;60:560–565[CrossRef][Web of Science][Medline]
  3. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819–823[Abstract]
  4. Francis GS. Neurohormonal mechanisms involved in congestive heart failure. Am J Cardiol. 1985;55:15A–22A[Medline]
  5. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol. 1986;57:3B–7B[CrossRef][Medline]
  6. Parmley W. Factors causing arrhythmias in chronic congestive heart failure. Am Heart J. 1987;114:1267–1272[CrossRef][Web of Science][Medline]
  7. Kameyama M, Hescheler F, Hofmann F, Trautwein W. On the mechanism of ß -adrenergic regulation of the Ca channel in the guinea pig heart. Pflügers Arch. 1985;405:285–293[CrossRef][Web of Science][Medline]
  8. Bennet PB, Begenisich TB. Catecholamines modulate the delayed rectifying potassium current (IK) in guinea pig ventricular myocytes. Pflügers Arch. 1987;410:217–219[CrossRef][Web of Science][Medline]
  9. Nakayama T, Fozzard HA. Adrenergic modulation of the transient outward current in isolated canine Purkinje cells. Circ Res. 1988;62:162–172[Abstract/Free Full Text]
  10. Harvey RD, Hume JR. Autonomic regulation of a chloride current in heart. Science. 1989;244:983–985[Abstract/Free Full Text]
  11. Opthof T, Janse MJ, Breithardt G, Kléber AG, Kottkamp H, Vanoli E. The role of basic arrhythmia research: the continued need for experiments in the intact heart and organism. Eur Heart J. 1995;16:1469–1475[Free Full Text]
  12. Jakob H, Nawrath H, Rupp J. Adrenoceptor-mediated changes of action potential and force of contraction in human isolated ventricular heart muscle. Br J Pharmacol. 1988;94:584–590[Web of Science][Medline]
  13. Mitchell MR, Powell T, Sturridge MF, Terrar DA, Twist VW. Electrical properties and response to noradrenaline of individual heart cells isolated from human ventricular tissue. Cardiovasc Res. 1986;20:869–876[Web of Science][Medline]
  14. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res. 1994;28:933–946[Free Full Text]
  15. Bristow MR, Hershberger RE, Port JD. ß-Adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation. 1990;82:12–15
  16. Veldkamp MW, van Ginneken AC, Opthof T, Bouman LN. Delayed rectifier channels in human ventricular myocytes. Circulation. 1995;92:3497–3504[Abstract/Free Full Text]
  17. ter Welle HF, Baartscheer A, Fiolet JWT, Schumacher CA. The cytoplasmic free energy of ATP hydrolysis in isolated rod-shaped rat ventricular myocytes. J Mol Cell Cardiol. 1988;20:435–441[CrossRef][Web of Science][Medline]
  18. Hamill O, Marty A, Neher E, Sakmann B. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch. 1981;391:85–100[CrossRef][Web of Science][Medline]
  19. Follmer CH, Lodge NJ, Cullininan CA, Colatsky TJ. Modulation of the delayed rectifier, IK, by cadmium in cat ventricular myocytes. Am J Physiol. 1992;262:C75–83[Web of Science][Medline]
  20. Quadbeck J, Reiter M. Cardiac action potential and inotropic effect of noradrenaline and calcium. Naunyn Schmiedeberg's Arch Pharmacol. 1975;286:337–351[CrossRef][Web of Science][Medline]
  21. Marchi S, Szabo B, Lazzara R. Adrenergic induction of delayed afterdepolarizations in ventricular myocardial cells: induction and modulation. J Cardiovasc Electrophysiol. 1991;2:476–491[CrossRef]
  22. Verkerk AO, van Ginneken ACG, Veldkamp MW, Bouman LN. Effects of constant inward current and norepinephrine on the electrophysiology of isolated rabbit ventricular myocytes. Pflügers Arch. 1996;432:R5 (16)
  23. Brooks CMcC, Hoffman BF, Suckling IE, Orias O. The effects of heart rate, action of autonomic nerves and chemical mediators on cardiac excitability. Excitability of the heart. New York, London: Grune and Stratton; 1955. p. 188–234
  24. Matsumara M, Takaori S. The effect of drugs on the cardiac membrane potentials in the rabbit. Jpn J Pharmacol. 1959;8:134–142
  25. Braveny P, Simurdova M, Sumbera J. Effect of epinephrine on the duration of action potential of papillary muscles. Experientia. 1974;30:166–167[CrossRef][Web of Science][Medline]
  26. Dukes ID, Vaughan Williams EM. Effects of selective {alpha}1-, {alpha}2-, ß1- and ß2-adrenoceptor stimulation on potentials and contractions in the rabbit heart. J Physiol. 1984;355:523–546[Abstract/Free Full Text]
  27. Opthof T, Coronel R, Vermeulen JT, Verberne HJ, Van Capelle FJL, Janse MJ. Dispersion of refractoriness in normal and ischaemic canine ventricle: effects of sympathetic stimulation. Cardiovasc Res. 1993;27:1954–1960[Abstract/Free Full Text]
  28. Verkerk AO, Veldkamp MW, De Jonge N, Wilders R, Van Ginneken ACG. Injury current modulates afterdepolarizations in single human ventricular cells. Cardiovasc Res. 2000;47:124–132[Abstract/Free Full Text]
  29. Wit, AL, Hoffman, BF, Rosen, MR, Electrophysiology and pharmacology of cardiac arrhythmias IX, Cardiac electrophysiologic effects of beta adrenergic receptor stimulation and blockade. Part C, Am Heart J, 1975, 90, 795, 803
  30. Stern S, Eisenberg S. The effect of propranolol (Inderal) on the electrocardiogram of normal subjects. Am Heart J. 1969;77:192–195[CrossRef][Web of Science][Medline]
  31. Seides SF, Jospehson ME, Batsford WP, Weisfogel GM, Lau SH, Damato AN. The electrophysiology of propranolol in man. Am Heart J. 1974;88:733–741[CrossRef][Web of Science][Medline]
  32. Edvardsson N, Olsson SB. Effects of acute and chronic beta-receptor blockade on ventricular repolarisation in man. Br Heart J. 1981;45:628–636[Abstract/Free Full Text]
  33. Duff HJ, Roden DM, Brorson L. Electrophysiologic actions of high plasma concentrations of propranolol in human subjects. J Am Coll Cardiol. 1983;2:1134–1140[Abstract]
  34. Endresen K, Amlie JP. Effects of propranolol on ventricular repolarization in man. Eur J Clin Pharmacol. 1990;39:123–125[CrossRef][Web of Science][Medline]
  35. Malik M. QT dispersion: time for an obituary? Eur Heart J. 2000;21:955–957[Free Full Text]
  36. van Ginneken AC, Jongsma HJ. Slow inward current in aggregates of neonatal rat heart cells and its contribution to the steady state current-voltage relationship. Pflügers Arch. 1983;397:265–271[CrossRef][Web of Science][Medline]
  37. Bénitah J-P, Bailly P, D'Agrosa M-C, Da Ponte J-P, Delgado C, Lorente P. Slow inward current in single cells isolated from adult human ventricles. Pflügers Arch. 1992;421:176–187[CrossRef][Web of Science][Medline]
  38. Ouadid H, Albat B, Nargeot J. Calcium currents in diseased human cardiac cells. J Cardiovasc Pharmacol. 1995;25:282–291[Web of Science][Medline]
  39. Mewes T, Ravens U. L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. J Mol Cell Cardiol. 1994;26:1307–1320[CrossRef][Web of Science][Medline]
  40. Maltsev VA, Sabbah HN, Higgins RSD, Silverman N, Lesch M, Undrovinas AI. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation. 1998;98:2545–2552[Abstract/Free Full Text]
  41. Li Q, Biagi B, Hohl C, Starling R, Stokes B, Altschuld R. Effects of isoproterenol and caffeine on calcium transients and action potentials in human ventricular myocytes. Prog Clin Biol Res. 1990;327:743–750[Medline]
  42. Marban E, Robinson SW, Wier WG. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest. 1986;78:1185–1192[Web of Science][Medline]
  43. Priori SG, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol. 1990;258:H1796–1805[Web of Science][Medline]
  44. January CT, Riddle JM. Early afterdepolarizations: Mechanism of induction and block. Circ Res. 1989;64:977–990[Abstract/Free Full Text]
  45. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: Mechanism and rate dependence. Biophys J. 1995;68:949–964[Web of Science][Medline]
  46. Uzzaman M, Honjo H, Takagishi Y. Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension. Circ Res. 2000;86:871–878[Abstract/Free Full Text]
  47. Jongsma HJ, Wilders R. Gap junctions in cardiovascular disease. Circ Res. 2000;86:1193–1197[Abstract/Free Full Text]
  48. Wit, AL, Rosen, MR, Afterdepolarizations and triggered activity, Fozzard, HA, The heart and cardiovascular system, New York, Raven Press, 1986, 1449, 90

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