Skip to main content
SpringerLink
Log in

Targeting Ischemic Ventricular Arrhythmias

  • Protocol
Cardiac Drug Development Guide

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

The purpose of this chapter is to ask why there has been so little success in developing new antiarrhythmic drugs and what can we do to increase our chances of success. Failure has been a fairly common theme in attempts to produce new antiarrhythmic drugs, particularly for lethal ventricular arrhythmias. The chapter considers old and new ways of finding novel drugs for lethal ventricular arrhythmias as a result of myocardial ischemia and infarction and describes new compounds selective for ischemia-induced ventricular tachycardia and fibrillation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

REFERENCES

  1. Fogel, R. I. and Prystowsky, E. N. (2000) Management of malignant ventricular arrhythmias and cardiac arrest. Crit. Care Med. (10 Suppl), N165–N169.

    Google Scholar 

  2. Atlee, J. L. (2001) Cardiac arrhythmias: Drugs and devices. Curr. Opin. Anaesthesiol. 14, 3–9.

    PubMed  CAS  Google Scholar 

  3. Steinberg, J. S., Martins, J., Sadanandan, S., et al. and the AVID Investigators. (2001) Antiarrhythmic drug use in the implantable defribillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study. Am. Heart. J. 142, 520–529.

    PubMed  CAS  Google Scholar 

  4. Echt, D. S., Liebson, P. R., Mitchell, L. B., et al. and the CAST Investigators. (1991) Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 324, 781–788.

    PubMed  CAS  Google Scholar 

  5. Waldo, A. L., Camm, A. J., deRuyter, H, et al. for the SWORD Investigators (1996) Effect of d-sotolol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. N. Engl. J. Med. 348, 7–12.

    CAS  Google Scholar 

  6. Cairns, J. A., Connolly, S. J., Roberts, R., and Gent, M. (1997) Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 349, 675–682.

    PubMed  CAS  Google Scholar 

  7. Julian, D. G., Camm, A. J., Frangin G, Janse, M. J., Munoz A, Schwartz, P. J., et al. (1997) Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 349, 667–674.

    PubMed  CAS  Google Scholar 

  8. Clare, J. J., Tate, S. N., Nobbs, M., and Romanos, M. A. (2000) Voltage gated sodium channels as therapeutic targets. Drug Dis. Today 5, 506–520.

    CAS  Google Scholar 

  9. Curran, M. (1998) Potassium ion channels and human disease: Phenotypes to drug targets. Curr. Opin. Biotech. 9, 565–572.

    PubMed  CAS  Google Scholar 

  10. Jalife, J. (2000) Ventricular fibrillation: Mechanisms of initiation and maintenance. Annu. Rev. Physiol. 62, 25–5.

    PubMed  CAS  Google Scholar 

  11. Nattel, S., Li, D., and Lue, L. (2000) Basic mechanisms of atrial fibrillation: Very new insights into very old ideas. Annu. Rev. Physiol. 62, 51–77.

    PubMed  CAS  Google Scholar 

  12. Ramaswamy, K. and Hamdan, M. H. (2000) Ischemia, metabolic disturbances and arrhythmogenesis: Mechanisms and management. Crit. Care Med. 28 (10 Suppl), N151–N156.

    PubMed  CAS  Google Scholar 

  13. Roden, D. M., Balser, J. R., George, Jr, J. L., and Anderson, M. (2002) Cardiac ion Channels. Annu. Rev. Physiol. 64, 431–475.

    PubMed  CAS  Google Scholar 

  14. Carmeliet, E. (1999) Cardiac ion currents and acute ischemia: From channels to arrhythmias. Physiol. Rev. 79, 917–1017.

    PubMed  CAS  Google Scholar 

  15. Curtis, M. J., Pugsley, M. K., and Walker, M. J. A. (1993) Endogenous chemical mediators of ventricular arrhythmias in ischaemic heart disease. Circ. Res. 27, 703–719.

    CAS  Google Scholar 

  16. Vaughn-Williams, E. M. (1970) Classification of antiarrhythmic drugs, in Symposium on Cardiac Arrhythmias (Sandoe, E., Flenstedt-Johnson, E., and Oleson, K. H., eds), Sodertalje, Sweden, AB Astra, pp. 440–469.

    Google Scholar 

  17. Members of the Sicillian Gambit. (1991) The Sicilian gambit: A new approach to classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 84, 1831–1851.

    Google Scholar 

  18. Zipes, D. P. and Wellens, H. J. (2000) What have we learned about cardiac arrhythmias? Circulation 102(Suppl 4), 52–57.

    Google Scholar 

  19. Huikuri, H. V., Castellanos, A., and Myerburg, R. J. (2001) Sudden death due to cardiac arrhythmias. N. Engl. J. Med. 345, 1473–482.

    PubMed  CAS  Google Scholar 

  20. Priori, S. G., Aliot, E., and Blømstrom-Lundqvist, C. (2002) Task Force on Sudden Cardiac Death, European Society of Cardiology: Summary of recommendations. Europace 4, 3–18.

    PubMed  CAS  Google Scholar 

  21. Johnson, K. M., MacLeod, B. A., and Walker, M. J. A. (1983) Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can. J. Physiol. 61, 1340–1353.

    Google Scholar 

  22. Inoue, F., MacLeod, B. A., and Walker, M. J. A. (1984) Intracellular potential changes following coronary occlusion in isolated perfused rat hearts. Can. J. Physiol. 62, 658–664.

    CAS  Google Scholar 

  23. Johnson, K. M., MacLeod, B. A., and Walker, M. J. A. (1981) ECG and other responses to ligation of a coronary artery in the conscious rat, in The Rat Electrocardiogram in Pharmacology and Toxicology (Budden, R., Detweiler, D. K., and Zbinden, G., eds), Pergammon Press, New York, pp. 243–252.

    Google Scholar 

  24. Xie, F., Qu., K, Garfinkel, A., and Weiss, J. N. (2001) Effects of simulated ischemia on spiral wave stability. Am. J. Physiol. 280, H1667–H1673.

    CAS  Google Scholar 

  25. Chaudhry, G. M., and Haffajee, C. I. (2000) Antiarrhythmic agents and proarrhythmia. Crit. Care Med. 28 (Suppl), N158–N164.

    PubMed  CAS  Google Scholar 

  26. Barrett, T. D., Hayes, E. S., and Walker, M. J. A. (1995) Lack of selectivity for ventricular and ischaemic tissue limits the antiarrhythmic actions of lidocaine, quinidine and flecainide against ischaemia induced arrhythmias. Eur. J. Pharmacol. 285, 229–238.

    PubMed  CAS  Google Scholar 

  27. Farkas, A. and Curtis, M. J. (2002) Limited antifibrillatory effectiveness of clinically relevant concentrations of class I antiarrhythmics in isolated perfused rat hearts. J. Cardiovasc. Pharmacol. 39, 412–424.

    PubMed  CAS  Google Scholar 

  28. Carson, D. L., Cardinal, R., Savard, P., et al. (1986) Relationship between an arrhythmogenic action of lidocaine and its effects of excitation patterns in acutely ischemic porcine myocardium. J. Cardiovasc. Pharmacol. 8, 126–136.

    PubMed  CAS  Google Scholar 

  29. Barrett, T. D., MacLeod, B. A., and Walker, M. J. A. (2000) RSD 1019 suppresses ischemia-induced monophasic action potential shortening and arrhythmias in anesthetized rabbits. Br. J. Pharmacol. 131, 405–414.

    PubMed  CAS  Google Scholar 

  30. Barrett, T. D., Hayes, E. S., Yong, S. L., et al. (2000) Ischaemia selectivity confers efficacy for suppression of ischaemia-induced arrhythmias in rats. Eur. J. Pharmacol. 398, 365–374.

    PubMed  CAS  Google Scholar 

  31. Igwemezie, L. W., Beatch, G. N., McErlane, K. M., and Walker, M. J. A. (1992) Mexilitine’s antifibrillatory actions are limited by the occurrence of convulsions in conscious animals. Eur. J. Pharmacol. 210, 271–277.

    PubMed  CAS  Google Scholar 

  32. Pike, G. K., Bretag, A. H., and Roberts, M. L. (1993) Modification of the transient outward current of rat atrial myocytes by metabolic inhibition and oxidant stress. J. Physiol. 470, 365–382.

    PubMed  CAS  Google Scholar 

  33. Scholz, W., Albus, U., Counillon, L., et al. (1995) Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc. Res. 29, 260–268.

    PubMed  CAS  Google Scholar 

  34. Eigel, B. N. and Hadley, R. W. (1999) Contribution of the Na+ channel and Na+/H+ exchanger. Heart Circ. Physiol. 277, H1817–H1822.

    CAS  Google Scholar 

  35. Hendrikx, M., Mubagwa, K. Verdonck, F., et al. (1994) New Na+/H+ exchange inhibitor HOE 694 improves postischemic function and high-energy phosphate resynthesis and reduces Ca2+ overload in isolated perfused rabbit heart. Circulation 89, 2787–2798.

    PubMed  CAS  Google Scholar 

  36. Xue, Y. X., Aye, N. N., and Hashimoto, K. (1996) Antiarrhythmic effects of HOE642, a novel Na+-H+ exchange inhibitor, on ventricular arrhythmias in animal hearts. Eur. J. Pharmacol. 317, 309–316.

    PubMed  CAS  Google Scholar 

  37. Aye, N. N., Xue, Y. X., and Hashimoto, K. (1997) Antiarrhythmic effects of cariporide, a novel Na+-H+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts. Eur. J. Pharmacol. 339, 121–127.

    PubMed  CAS  Google Scholar 

  38. Gumina, R. J., Daemmgen, J., and Gross, G. J. (2000) Inhibition of the Na+/H+ exchanger attenuates phase 1b ischemic arrhythmias and reperfusion-induced ventricular fibrillation. Eur. J. Pharmacol. 396, 119–124.

    PubMed  CAS  Google Scholar 

  39. Avkiran, M. (1999) Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia. Am. J. Cardiol. 83, 10G–17G.

    PubMed  CAS  Google Scholar 

  40. Chin, B. and Lip, G. Y. (2000) Cariporide (Aventis). Curr. Opin. Invest. Drugs 1, 340–346.

    CAS  Google Scholar 

  41. Karmazyn, M. (2000) Pharmacology and clinical assessment of cariporide for the treatment coronary artery diseases. Expert Opin. Invest. Drugs 9, 1099–1108.

    CAS  Google Scholar 

  42. Wirth, K. J., Maier, T., and Busch, A. E. (2001) NHE1-inhibitor cariporide prevents the transient reperfusion-induced shortening of the monophasic action potential after coronary ischemia in pigs. Basic Res. Cardiol. 96, 192–197.

    PubMed  CAS  Google Scholar 

  43. Gazmuri, R. J., Hoffner, E., Kalcheim, J., et al. (2001) Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal flux. J. Lab. Clin. Med. 137, 43–55.

    PubMed  CAS  Google Scholar 

  44. Theroux, P., Chaitman, B. R., Danchin, N., et al. (2000) Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation 102, 3032–3038.

    PubMed  CAS  Google Scholar 

  45. Zeymer, U., Suryapranata, H., Monassier, J. P., et al. (2001) The Na+/H+ exchange inhibitor Eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the ESCAMI trial [abstract]. Eur. Heart J. 22, 640.

    Google Scholar 

  46. Banno, H., Fujiwara, J., Hosoya, J., Kitamori, T., Mori, H., Yamashita, H., Ikeda, F. (1999) Effects of MS-31—038, a novel Na+/H+ exchange inhibitor, on the myocardial infarct size in rats after postischemic administration. Arzneimittelforschung 49, 304–310.

    PubMed  CAS  Google Scholar 

  47. Lorrain, J., Briand, V., Favennec, E., et al. (2000) Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger. Br. J. Pharmacol. 131, 1188–1194.

    PubMed  CAS  Google Scholar 

  48. Aihara, K., Hisa, H., Sato, T., et al. (2000) Cardioprotective effect of TY-12533, a novel Na(+)/H(+) exchange inhibitor, on ischemia/reperfusion injury. Eur. J. Pharmacol. 404, 221–229.

    PubMed  CAS  Google Scholar 

  49. Gazmuri, R. J., Ayoub, I. M., Kolarova, J. D., and Karmazyn, M. (2002) Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1. Crit. Care Med. 30(Suppl. 4), S166–S171.

    PubMed  CAS  Google Scholar 

  50. Marban, E., Kitakaze, M., Koretsune, Y., et al. (1990) Quantification of [Ca2+]I in perfused hearts. Critical evaluation of the 5 F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ. Res. 66, 1255–1267.

    PubMed  CAS  Google Scholar 

  51. Gambassi, G., Hansford, R. G., Sollott, S. J., et al. (1993) Effects of acidosis on resting cytosolic and mitochondrial Ca2+ in mammalian myocardium. J. Gen. Physiol. 102, 575–597.

    PubMed  CAS  Google Scholar 

  52. Smith, G. L. and Allen, D. G. (1988) Effects of metabolic blockade on intracellular calcium concentration in isolated ferret ventricular muscle. Circ. Res. 62, 1223–1236.

    PubMed  CAS  Google Scholar 

  53. Tani, M. and Neely, J. R. (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ. Res. 65, 1045–1056.

    PubMed  CAS  Google Scholar 

  54. Yashar, P. R., Fransua, M, and Frishman, W. H. (1998) The sodium-calcium ion membrane exchanger: Physiologic significance and pharmacologic implications. J. Clin. Pharmacol. 38, 393–401.

    PubMed  CAS  Google Scholar 

  55. Trafford, A. W, Diaz, M. E., Negretti, N., and Eisener, D. A. (1997) Enhanced Ca2+ current and decreased Ca2+ efflux restore sarcoplasmic reticulum Ca2+ content after depletion. Circ. Res. 81, 477–484.

    PubMed  CAS  Google Scholar 

  56. Weber, C. R., Piacentino III, V., Ginsburg, K. S., et al. (2002) Na+-Ca2+ exchange current and submembrane [Ca2+] during the cardiac action potential. Circ. Res. 90, 182–189.

    PubMed  CAS  Google Scholar 

  57. Philipson, K. D., Bersohn, M. M., and Nishimoto, A. Y. (1982) Effects of pH on Na+/Ca2+ exchange in canine cardiac sarcolemmal vesicles. Circ. Res. 50, 287–293.

    PubMed  CAS  Google Scholar 

  58. Coetzee, W. A., Ichihawa, H., and Hearse, D. J. (1994) Oxidant stress inhibits Na-Ca exchange current in cardiac myocytes: mediation by sulfhydryl groups? Am. J. Physiol. 266, H909–H919.

    PubMed  CAS  Google Scholar 

  59. Bassani, J. W., Bassani, R. A., and Bers, D. M. (1993) Ca2+ cycling between sarcoplasmic reticulum and mitochondria in rabbit cardiac myocytes. J. Physiol. (Lond.) 460, 603–621.

    CAS  Google Scholar 

  60. Watano, T., Harada, Y., Harada, K., and Nishimura, N. (1999) Effect of Na+/Ca2+ exchange inhibitor, KB-R7943, on ouabain-induced arrhythmias in guinea-pigs. Br. J. Pharmacol. 127, 1846–1850.

    PubMed  CAS  Google Scholar 

  61. Mukai, M., Terada, H., Sugiyama, S., et al. (2000) Effects of a selective inhibitor of Na+/Ca2+ exchange, KB-R7943, on reoxygenation-induced injuries in guinea pig papillary muscles. J. Cardiovasc. Pharmacol. 35, 121–128.

    PubMed  CAS  Google Scholar 

  62. Elias, C. L., Lukas, A., Shurraw, S., et al. (2001) Inhibition of Na+/Ca2+ exchange by KB-R7943: Transport mode selectivity and antiarrhythmic consequences. Am. J. Physiol. 281, H1334–H1345.

    CAS  Google Scholar 

  63. Curtis, M. J., MacLeod, B. A., and Walker, M. J. A. (1984) Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat. Br. J. Pharmacol. 83, 373–385.

    PubMed  CAS  Google Scholar 

  64. Walker, M. J. A. and Chia, S. K. L. (1989) Calcium channel blockers as antiarrhythmics. Cardiovasc. Drug Rev. 73, 265–284.

    Google Scholar 

  65. MacLeod, B. A. and Walker, M. J. A. (1990) Rat models for studying arrhythmic and other adverse responses to myocardial ischemia: Beneficial actions of calcium channel blockade, in Calcium Channel Modulations in Heart and Smooth Muscle: Basic Mechanisms and Pharmacological Aspects (Abraham, and Amitai, G., eds), Alan, R. Liss Inc, New York, pp. 339–352.

    Google Scholar 

  66. Curtis, M. J. (1990) Calcium antagonists and coronary artery disease: An opportunity missed? J. Neural. Trans. 31 (Suppl), 17–38.

    CAS  Google Scholar 

  67. Lee, J. A., and Allen, D. G. (1992) Changes in intracellular free calcium concentration during long exposures to simulated ischemia in isolated mammalian ventricular muscle. Circ. Res. 21, 58–69.

    Google Scholar 

  68. Tani, M. and Neely, J. R. (1990) Mechanisms of reduced reperfusion injury by low Ca2+ and/or high K+. Am. J. Physiol. 258, H1025–H1031.

    PubMed  CAS  Google Scholar 

  69. Wagner, S., Wu, S. T., Parmley, W. W., and Wikman Coffelt, J. (1990) Influence of ischemia on [Ca2+]i transients following drug therapy in hearts from aortic constricted rats. Cell Calcium 11, 431–444.

    Google Scholar 

  70. Mohabir, R., Lee, H. C., Kurz, R. W., and Clusin, W. T. (1991) Effects of ischemia and hypercarbic acidosis on myocyte calcium transients, contraction, and pHi in perfused rabbit hearts. Circ. Res. 69, 1525–1537.

    PubMed  CAS  Google Scholar 

  71. Thandroyen, F. T., McCarthy, J., Burton, K. M., and Opie, L. H. (1988) Ryanodine and caffeine prevent ventricular arrhythmias during acute myocardial ischemia and reperfusion in rat heart. Circ. Res. 62, 306–314.

    PubMed  CAS  Google Scholar 

  72. Terzic, A., Jahangir, A., and Kurachi, Y. (1995) Cardiac ATP-sensitive K+ channels: Regulation by intracellular nucleotides and K+ channel-opening drugs. Am. J. Physiol. 269, C525–C545.

    PubMed  CAS  Google Scholar 

  73. Yan, G. X., Yamada, K. A., Kleber, A. G., et al. (1993) Dissociation between cellular K+ loss, reduction in repolarization time, and tissue ATP levels during myocardial hypoxia and ischemia. Circ. Res. 72, 560–570.

    PubMed  CAS  Google Scholar 

  74. Noma, A. (1983) ATP-regulated K+ channels in cardiac muscle. Nature 305, 147–148.

    PubMed  CAS  Google Scholar 

  75. Trube, G., and Hescheler, D. J. (1984) Inward-rectifying channels in isolated patches of the heart cell membrane: ATP-dependence and comparison with cell-attached patches. Pflugers Arch. 401, 178–184.

    PubMed  CAS  Google Scholar 

  76. Wilde, A. A. M. and Janse, M. J. (1994) Electrophysiological effects of ATP sensitive channel modulation: Implications for arrhythmogenesis. Cardiovasc. Res. 28, 16–24.

    PubMed  CAS  Google Scholar 

  77. Kantor, P. F., Coetzee, W. A., Carmeliet, E. E., et al. (1990) Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea. Circ. Res. 66, 478–485.

    PubMed  CAS  Google Scholar 

  78. Gwilt, M., Norton, B., and Henderson, C. G. (1993) Pharmacological studies of K+ loss from ischaemic myocardium in vitro: Roles of ATP-dependent K+ channels and lactate-coupled efflux. Eur. J. Pharmacol. 236, 107–112.

    PubMed  CAS  Google Scholar 

  79. Barrett, T. D. and Walker, M. J.A. (1998) Glibenclamide does not prevent action potential shortening induced by ischemia in anesthetized rabbits but reduces ischemia-induced arrhythmias. J. Mol. Cell. Cardiol. 30, 999–1008.

    PubMed  CAS  Google Scholar 

  80. Adams, D., Crome, R., Lad, N., et al. (1990) Failure of the ATP-dependent K+ channel inhibitor, glibenclamide, to reduce reperfusion-induced or ischaemia arrhythmias in rat hearts. Br. J. Pharmacol. 100, P438.

    Google Scholar 

  81. Rees, S. A. and Curtis, M. J. (1995) Pharmacological analysis in rat of the role of the ATP-sensitive potassium channel as a potential target for antifibrillatory intervention in acute myocardial ischemia. J. Cardiovasc. Pharmacol. 26, 280–288.

    PubMed  CAS  Google Scholar 

  82. Fujita, A. and Kurachi, Y. (2000) Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol. Ther. 85, 35–53.

    Google Scholar 

  83. Friedrich, M., Benndorf, K.,. Schwalb, M., and Hirche, H. (1990) Effects of anoxia on K and Ca currents in isolated guinea pig cardiocytes. Pflugers Arch. 416, 207–209.

    PubMed  CAS  Google Scholar 

  84. Gasser, R. N. and Vaughn-Jones, R. D. (1990) Mechanism of potassium efflux and action potential shortening during ischaemia in isolated mammalian cardiac muscle. J. Physiol. (Lond.) 431, 713–741.

    CAS  Google Scholar 

  85. Sato T, Sasaki N, Seharaseyon J, O’Rourke B, and Marban, E. (2000) Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection. Circulation 101, 2418–2423.

    PubMed  CAS  Google Scholar 

  86. Asemu., Papousek, E., Ostadal, B., and Kolar, F. (1999) Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K+ (ATP) channel. J. Mol. Cell Cardiol. 31, 1821–1831.

    PubMed  CAS  Google Scholar 

  87. Workman, A. J., MacKenzie, I., and Northover, B. J. (2000) Do KATP channel channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart. Basic Res. Cardiol. 95, 250–260.

    PubMed  CAS  Google Scholar 

  88. Terzic, A., Tung, R. T., and Kurachi, Y. (1994a) Nucleotide regulation of ATP sensitive potassium channels. Cardiovasc. Res. 28, 746–753.

    PubMed  CAS  Google Scholar 

  89. Han, J., Kim, E., Lee, S. H., Yoo, S., et al. (1998) cGMP facilitates calcium current via cGMP-dependent protein kinase in isolated rabbit ventricular myocytes. Pflugers Arch. 435, 388–393.

    PubMed  CAS  Google Scholar 

  90. Fan, Z. and Makielski, J. C. (1993) Intracellular H+ and Ca2+ modulation of trypsin-modified ATP-sensitive K+ channels in rabbit ventricular myocytes. Circ. Res. 72, 715–722.

    PubMed  CAS  Google Scholar 

  91. Jabr, R. I. and Cole, W. C. (1993) Alterations in electrical activity and membrane currents induced by intracellular oxygen-derived free radical stress in guinea pig venticular myocytes. Circ. Res. 72, 1229–1244.

    PubMed  CAS  Google Scholar 

  92. Terzic, A., Tung, R. T., Inanobe, A., et al. (1994b) G proteins activate ATP-sensitive K+ channels by antagonizing ATP-dependent gating. Neuron 12, 885–893.

    PubMed  CAS  Google Scholar 

  93. Han, J., Kim, E., Ho, W. K., and Earm, Y. E. (1996) Blockade of the ATP-sensitive potassium channel by taurine in rabbit ventricular myocytes. J. Mol. Cell. Cardiol. 28, 2043–2050.

    PubMed  CAS  Google Scholar 

  94. Van Wagoner, D. R. (1993) Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ. Res. 72, 973–983.

    PubMed  Google Scholar 

  95. Vegh, A., Gyorgyi, K., Papp, J. G., et al. (1996) Nicorandil suppressed ventricular arrhythmias in a canine model of myocardial ischemia. Eur. J. Pharmacol. 305, 163–168.

    PubMed  CAS  Google Scholar 

  96. Dhein, S., Pejman, P., and Krusemann, K. (2000) Effects of the I(K. ATP) blockers glibenclamide and HMR1883 on cardiac electrophysiology during ischemia and reperfusion. Eur. J. Pharmacol. 398, 273–284.

    PubMed  CAS  Google Scholar 

  97. Hirche, H., Franz, C., Bos, L., et al. (1980) Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J. Mol. Cell. Cardiol. 12, 579–593.

    PubMed  CAS  Google Scholar 

  98. Curtis, M. J. and Hearse, D. J. (1989) Ischaemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: Implications for mechanisms of initiation and maintenance of ventricular fibrillation. J. Mol. Cell Cardiol. 21, 21–40.

    PubMed  CAS  Google Scholar 

  99. Curtis, M. J. (1991) The rabbit dual coronary perfusion model: A new method for assessing the pathological relevance of individual products of the ischaemic milieu: Role of potassium in arrhythmogenesis. Cardiovasc. Res. 25, 1010–1022.

    PubMed  CAS  Google Scholar 

  100. Saint, K. M., Abraham, S., MacLeod, B. A., et al. (1992) Ischemic but not reperfusion arrhythmias depend upon serum potassium concentration. J. Mol. Cell Cardiol. 24, 701–709.

    PubMed  CAS  Google Scholar 

  101. Naudrehaug, J. E. and Von der Lippe, G., (1983) Hyperkalaemia and ventricular fibrillation in acute myocardial infarction. Br. Heart J. 50, 525–529.

    Google Scholar 

  102. Priori, S. and Schwartz, P. J. (1989) Catecholamine-dependent cardiac arrhythmias: mechanisms and implication, in Adrenergic System and Ventricular Arrhythmias in Myocardial Infarction (Brachman, J. and Schömig, A., eds). Springer-Verlag, Heidelberg, pp. 239–247.

    Google Scholar 

  103. Culling, W., Penny, W. J., Lewis, M. J., et al. (1984) Effects of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias during ischaemia and reperfusion Cardiovasc. Res. 18, 675–682.

    PubMed  CAS  Google Scholar 

  104. Schömig, A., Dart, A. M., Dietz, R., et al. (1984) Release of endogenous catecholamines in the ischemic myocardium of the rat. Part, A. Locally mediated release. Circ. Res. 55, 689–701.

    PubMed  Google Scholar 

  105. Lameris, T. W., de Zeeuw, W., Alberts, G., et al. (2000) Time course and mechanism of myocardial catecholamine release during transient ischemia in vivo. Circulation 101, 2645–2650.

    PubMed  CAS  Google Scholar 

  106. Botting, J. H., Johnson, K. M., MacLeod, B. A., and Walker, M. J. A. (1983) The effect of modification of sympathetic activity on responses to the ligation of a coronary artery in the conscious rat. Br. J. Pharmacol. 79, 269–271.

    Google Scholar 

  107. Daugherty, A., Frayne, K. N., Refern, W. S., and Woodward, B. (1986) The role of catecholamines in the production of ischemia-induced ventricular arrhythmias in the rat in vivo and in vitro. Br. J. Pharmacol. 87, 265–278.

    PubMed  CAS  Google Scholar 

  108. Curtis, M. J., MacLeod, B. A., and Walker, M. J. A. (1985) The effects of ablations in the central nervous system on arrythmias induced by coronary occlusion. Br. J. Pharmacol. 86, 663–670.

    PubMed  CAS  Google Scholar 

  109. Curtis, M. J., Botting, J. H., Hearse, D. J., and Walker, M. J. A. (1989) The sympathetic nervous system, catecholamines and ischaemia-induced arrhythmias: Dependence on serum potassium concentration, in Adrenergic System and Ventricular Arrhythmias in Myocardial Infarction (Brachman, J. and Schömig, A., eds). Springer-Verlag, Heidelberg, pp. 205–219.

    Google Scholar 

  110. Paletta, M., Abraham, S., Beatch, G. N., and Walker, M. J. A. (1989) Mechanisms underlying the antiarrhythmic properties of beta adrenoceptor blockade against ischemia-induced arrhythmias in acutely prepared rats. Br. J. Pharmacol. 98, 87–94.

    PubMed  CAS  Google Scholar 

  111. Guo, P., Pugsley, M. K., Yong, S. L., and Walker, M. J. A. (1999) Cardiac transplantation does not effect ischaemia-induced arrhythmias. Cardiovasc. Res. 43, 930–938.

    PubMed  CAS  Google Scholar 

  112. Chess-Williams, R. and Milton, R. (2001) Arrhythmogenesis in isolated hearts with enhanced alpha-adrenoceptor mediated responsiveness. J. Auto. Pharamacol. 21, 39–45.

    CAS  Google Scholar 

  113. Strasser, R. H., Marquetant, R., and Kubler, W. (1989) Sensitization of the adrenergic system in early myocardial ischemia: independent regulation of β-adrenergic receptors and adenylate cyclase, in Adrenergic System and Ventricular Arrhythmias in Myocardial Infarction (Brachman, J. and Schömig, A., eds). Springer-Verlag, Heidelberg, pp. 298–111.

    Google Scholar 

  114. Podzuweit, T., Binz, K. H., Nennsteil, P., and Flaig, W. (1989) The antiarrhythmic effects of myocardial ischemia. Relation to reperfusion arrhythmias? Cardiovasc. Res. 23, 81–90.

    PubMed  CAS  Google Scholar 

  115. Saman, S., Coetzee, W. A., and Opie, L. H. (1988) inhibition by simulated ischemia or hypoxia of delayed afterdepolarizations provoked by cyclic AMP: Significance to ischemia and reperfusion arrhythmia. J. Mol. Cell Cardiol. 20, 91–95.

    PubMed  CAS  Google Scholar 

  116. Zeigelhoffer, A., Krause, E. G., Fedelesova, M., et al. (1976) Changes of cyclic AMP levels in the non-ischaemic and ischaemic myocardium after coronary artery ligation. Seventh European Congress of Cardiology, p. 691.

    Google Scholar 

  117. Kane, K. A., Moricillo-Sanchez, E. J., Parratt, J. R., et al. (1985) The relationship between coronary artery occlusion-induced arrhythmias and myocardial cyclic nucleotide levels in the anesthetized rat. Br. J. Pharmacol. 84, 139–145.

    PubMed  CAS  Google Scholar 

  118. Morganroth, J. and Goin, J. E. (1991) Quinidine-related mortality in the short-to-medium-term treatment of ventricular arrhythmias. A meta-analysis. Circulation 84, 1977–1983.

    PubMed  CAS  Google Scholar 

  119. Hine, L. K., Laird N, Hewitt P, et al. (1989) Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch. Intern. Med. 149, 2694–2698.

    PubMed  CAS  Google Scholar 

  120. Akiyama, T., Pawitan, Y., Greenberg, H., et al. (1991) Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial. CAST Investigators. Am. J. Cardiol. 68, 1551–1555.

    PubMed  CAS  Google Scholar 

  121. Coromilas, J., Saltman, A. E., Waldecker, B., et al. (1995) Electrophysiological effects of flecainide on anisotropic conduction and reentry in infarcted canine hearts. Circulation 91, 2245–2263.

    PubMed  CAS  Google Scholar 

  122. Krishnan, S. C. and Antzelevitch, C. (1993) Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 87, 562–572.

    PubMed  CAS  Google Scholar 

  123. Lukas, A. and Antzelevitch, C. (1996) Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. Cardiovasc. Res. 32, 593–603.

    PubMed  CAS  Google Scholar 

  124. Dominguez, G. and Fozzard, H. A. (1970) Influence of extracellular K+ concentration on cable properties and excitability of sheep cardiac Purkinje fibers. Circ. Res. 26, 565–574.

    PubMed  CAS  Google Scholar 

  125. Lue, W. M. and Boyden, P. A. (1992) Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current. Circulation 85, 1175–1188.

    PubMed  CAS  Google Scholar 

  126. Janse, M. J. and Wit, A. L. (1989) Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol. Rev. 69, 1049–1169.

    PubMed  CAS  Google Scholar 

  127. Carmeliet, E. (1982) Induction and removal of inward-going rectification in sheep cardiac Purkinje fibres. J. Physiol. (Lond.) 327, 285–308.

    CAS  Google Scholar 

  128. Scamps, F. and Carmeliet, E. (1989) Effect of external K+ on the delayed K+ current in single rabbit Purkinje cells. Pflugers Arch. 414(Suppl), S169–S170.

    PubMed  Google Scholar 

  129. Lie, K. I., Wellens, H. J., van Capelle, F. J., et al. (1974) Lidocaine in the prevention of primary ventricular fibrillation. A double-blind, randomized study of 212 consecutive patients. N. Engl. J. Med. 291, 1324–1326.

    PubMed  CAS  Google Scholar 

  130. Woosley, R. L., Siddoway, L. A., Duff, H. J., et al. (1984) Flecainide dose-response relations in stable ventricular arrhythmias. Am. J. Cardiol. 53, 59B–65B.

    PubMed  CAS  Google Scholar 

  131. Dinh, H. A., Murphy, M. L., Baker, B. J., et al. (1985) Efficacy of propafenone compared with quinidine in chronic ventricular arrhythmias. Am. J. Cardiol. 55, 1520–1524.

    PubMed  CAS  Google Scholar 

  132. Antman, E. M., Lau, J., Kupelnick, B., et al. (1992) A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA 268, 240–248.

    PubMed  CAS  Google Scholar 

  133. Teo, K. K., Yusuf, S., and Furberg, C. D. (1993) Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. JAMA 270, 1589–1595.

    PubMed  CAS  Google Scholar 

  134. Pugsley, M. K., Walker, M. J. A., and Yong, S. L. (1999) Are arrhythmias due to myocardial ischaemia and infarction dependent upon the sympathetic system? Cardiovasc. Res. 43, 830–831.

    PubMed  CAS  Google Scholar 

  135. Curtis, M. J., MacLeod, B. A., and Walker, M. J.A. (1987) Models for the study of arrhythmias in myocardial ischaemia and infarction: the use of the rat. J. Mol. Cell. Cardiol. 19, 399–419.

    PubMed  CAS  Google Scholar 

  136. Schömig, A. (1990) Catecholamines in myocardial ischemia. Systemic and cardiac release. Circulation 82(3 Suppl II), 13–22.

    Google Scholar 

  137. Andrews, T. C., Reimold, S. C., Berlin, J. A., and Antman, E. M. (1991) Prevention of supraventricular arrhythmias after coronary artery bypass surgery. A meta-analysis of randomized control trials. Circulation 84(5 Suppl. III), 236–244.

    Google Scholar 

  138. Kowey, P. R., Taylor, J. E., Rials, S. J., and Marinchak, R. A. (1992) Meta-analysis of the effectiveness of prophylactic drug therapy in preventing supraventricular arrhythmia early after coronary artery bypass grafting. Am. J. Cardiol. 69, 963–965.

    PubMed  CAS  Google Scholar 

  139. Veldkamp, M. W., van Ginneken, A. C., Opthof, T., and Bouman, L. N. (1995) Delayed rectifier channels in human ventricular myocytes. Circulation 92, 3497–3504.

    PubMed  CAS  Google Scholar 

  140. Bauer, A., Becker, R., Karle, C., et al. (2002) Effects of IKr-blocking agent dofetilide and of the Iks-blocking agent chromanol 293b on regional disparity of left ventricular repolarization in the intact canine heart. J. Cardiovasc. Pharmacol. 39, 460–467.

    PubMed  CAS  Google Scholar 

  141. Yang, T. and Roden, D. M. (1996) Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use dependence. Circulation 93, 407–411.

    PubMed  CAS  Google Scholar 

  142. Zhibo, L., Kamiya, K., Tobias, O, et al. (2001) Density and Kinetics of IKr and Iks in guinea pig and rabbit ventricular myocytes explain different efficacy of IKs blockade at high heart rate in guinea pig and rabbit. Circulation 104, 951–956.

    Google Scholar 

  143. Shimoni, Y., Clark, R. B., and. Giles, W. R. (1992) Role of an inwardly rectifying potassium current in rabbit ventricular action potential. J. Physiol. (Lond.) 448, 709–727.

    CAS  Google Scholar 

  144. Rees, S. A. and Curtis, M. J. (1993) Specific IK1 blockade: A new antiarrhythmic mechanism? Effect of RP58866 on ventricular arrhythmias in rat, rabbit, and primate. Circulation 87, 1979–1989.

    PubMed  CAS  Google Scholar 

  145. Pugsley, M. K., Ries, C. R., Guppy, L. J., et al. (1995) Effects of anipamil, a long acting analog of verapamil, in pigs subjected to myocardial ischemia. Life Sci. 57, 1219–1231.

    PubMed  CAS  Google Scholar 

  146. Curtis, M. J. and Walker, M. J. A. (1986) The mechanism of action of the optical isomers of verapamil against ischaemia-induced arrhythmias in the conscious rat. Br. J. Pharmacol. 89, 137–147.

    PubMed  CAS  Google Scholar 

  147. Mauritson, D. R., Winniford, M. D., Walker, W. S., et al. (1982) Oral verapamil for paroxysmal supraventricular tachycardia: A long-term, double-blind randomized trial. Ann. Intern. Med. 96, 409–412.

    PubMed  CAS  Google Scholar 

  148. Farkas, A., Qureshi, A., and Curtis, M. J. (1999) Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart. Br. J. Pharmacol. 128, 41–50.

    PubMed  CAS  Google Scholar 

  149. Curruthers, S. G., Hoffman, B. B., Melmon, K. L., and Nierenberg, D. W., eds. (2000) Melmon and Morrelli’s Clinical Pharmacology, 4th Edition, McGraw-Hill, Medical Publishing Division, New York.

    Google Scholar 

  150. Florent, B., Boissel, J-P., Connolly, S. J., et al. (1999) Amiodarone interaction with β-blockers: Analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. Circulation 99, 2268–2275.

    Google Scholar 

  151. Connolly, S. J. (1999) Meta-analysis of antiarrhythmic drug trials. Am. J. Cardiol. 84, 90R–93R.

    PubMed  CAS  Google Scholar 

  152. Raatikainen, M. J., Napolitano, C. A., Druzgala, P., and Dennis, D. M. (1996). Electrophysiological effects of a novel, short-acting and potent ester derivative of amiodarone, ATI-2001, in guinea pig isolated heart. J. Pharmacol. Exp. Ther. 277, 1454–1463.

    PubMed  CAS  Google Scholar 

  153. Sun, W, Sarma, J. S., and Singh, B. N. (1999) Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart: Comparison with amiodarone. Circulation 100, 2276–2281.

    PubMed  CAS  Google Scholar 

  154. Domanovits, H., Schillinger, M., Lercher, P., et al. (2000) E 047/1: A new class III anti-arrhythmic agent. J. Cardiovasc. Pharmacol. 35, 716–722.

    PubMed  CAS  Google Scholar 

  155. Kimura, J, Kawahara, M, Sakai, E., et al. (1999) Effects of a novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes. Jpn. J. Pharmacol. 79, 275–281.

    PubMed  CAS  Google Scholar 

  156. Baczko, I., El-Reyani, N. E., Farkas, A., et al. (2000) Antiarrhythmic and electrophysiological effects of GYKI-16638, a novel N-(phenoxyalkyl)-N-phenylalkylamine, in rabbits. Eur. J. Pharmacol. 404, 181–190.

    PubMed  CAS  Google Scholar 

  157. Nakaya, H., Furusawa, Y., Ogura, T., et al. (2000) Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. Br. J. Pharmacol. 131, 1363–1372.

    PubMed  CAS  Google Scholar 

  158. Nattel, S., De Blasio, E., Beatch, G. N., and Wang, W. Q. (2001) RSD1235: A novel antiarrhythmic agent with a unique electrophysiological profile that terminates AF in dogs [abstract]. Eur. Heart J. 22, 448.

    Google Scholar 

  159. Van Wagoner, D. R., Pond, A. L., Mccarthy, P. M., et al. (1997) Outward KC current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ. Res. 80, 772–781.

    PubMed  Google Scholar 

  160. Heisler, B. E. and Ferrier, G. R. (1996) Proarrhythmic actions of flecainide in an isolated tissue model of ischemia reperfusion. J. Pharmacol. Exp. Ther. 279, 317–324.

    PubMed  CAS  Google Scholar 

  161. Xu, R., Abraham, S., McLarnon, J. G., and Walker, M. J. (1997) KC8851, a tedisamil analogue with mixed channel blockade, exhibits antiarrhythmic properties against ischemia-and electrically-induced arrhythmias. Life Sci. 61, 237–248.

    PubMed  CAS  Google Scholar 

  162. Knopf, H., McDonald, F. M., Bischoff, A., et al. (1988) Effect of propranolol on early postischemia arrhythmiasand noradrenaline and potassium release of ischemic myocardium in anesthetized pigs. J. Cardiovasc. Pharmacol. 12 (Suppl), S41–S47.

    PubMed  CAS  Google Scholar 

  163. Smith, W. T., Fleet, W. F., Johnson, T. A., et al. (1995) The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Circulation 92, 3051–3060.

    PubMed  Google Scholar 

  164. McArthur, K. E., Jensen, R. T., and Gardener, J. D. (1986) Treatment of acid-peptic disease by inhibition of gastric H+, K+-ATPase. Annu. Rev. Med. 37, 97–105.

    PubMed  CAS  Google Scholar 

  165. Maton, P. N., Vinayek, R., Frucht, H., et al. (1989) Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: A prospective study. Gastroenterology 97, 827–836.

    PubMed  CAS  Google Scholar 

  166. Gintant, G. A., Hoffman, B. F., and Naylor, R. E. (1983) The influence of molecular form of local anesthetic-type antiarrhythmic agents on reduction of the maximum upstroke velocity of canine cardiac Purkinje fibers. Circ. Res. 52, 735–746.

    PubMed  CAS  Google Scholar 

  167. Beatch, G. N., Barrett, T. D., Plouvier, B., et al. (2002) ventricular fibrillation, an uncontrolled arrhythmia seeking new targets. Drug Dev. Res. 55, 45–52.

    CAS  Google Scholar 

  168. Abraham, S., Beatch, G. N., MacLeod, B. A., and Walker, M. J. A. (1989) Antiarrythmic properties of tetrodotoxin against occlusion-induced arrhythmias in the rat: A novel approach to the study of the antiarrhythmic effects of ventricular sodium channel blockade. J. Pharmacol. Exp. Ther. 251, 1166–1173.

    PubMed  CAS  Google Scholar 

  169. Pugsley, M. K., Saint, D. A., Hayes, E., et al. (1995) The cardiac electrophysiological effects of sparteine and its analogue BRB-1—28 in the rat. Eur. J. Pharmacol. 294, 319–327.

    PubMed  CAS  Google Scholar 

  170. Pugsley, M. K., Saint, D. A., Penz, W. P., and Walker, M. J. A. (1993) Electrophysiological and antiarrhythmic actions of the kappa agonist PD 129290 and its R,R (+) enantiomer, PD 129289. Br. J. Pharmacol. 110, 1579–1585.

    PubMed  CAS  Google Scholar 

  171. Wat, J. Y. K., Groom, A. J., and Walker, M. J. A. (1994) Effects of arylbenzacetamides on neuromuscular preparations. Proc. West. Pharmacol. Soc. Abstract no. 54—II.

    Google Scholar 

  172. Walker, M. L., Wall, R. A., and Walker, M. J. A. (1996) Determination of an arylacetamide antiarrhythmic in rat blood and tissue using reversed-phase high-performance liquid chromatography. J. Chromatogr. Biomed. Appl. 675, 257–263.

    CAS  Google Scholar 

  173. Bain, A. I., Barrett, T. D., Beatch, G. N., et al. (1997) Better antiarrhythmics? Development of antiarrhythmic drugs selective for ischaemia-dependent arrhythmias. Drug. Dev. Res. 42, 198–210.

    CAS  Google Scholar 

  174. Yong, S. L., Xu, R., McLarnon, J. G., et al. (1999) RSD1000: A novel antiarrhythmic agent with increased potency under acidic and high potassium conditions. J. Pharmacol. Exp. Ther. 289, 236–244.

    PubMed  CAS  Google Scholar 

  175. Franciosi, S. and McLarnon, J. G. (2001) pH-dependent blocking actions of three novel antiarrhythmic compounds on K+ and Na+ currents in rat ventricular myocytes. Eur. J. Pharmacol. 425, 95–107.

    PubMed  CAS  Google Scholar 

  176. Cheung, P. H., Pugsley, M. K., and Walker, M. J. A. (1993) Arrhythmia models in rats. J. Pharmacol. Methods 29, 179–184.

    CAS  Google Scholar 

  177. Barrett, T. D. and Walker, M. J. A. (1997) In vivo and in vitro cardiac preparations used in antiarrhythmic assays, in Measurement of Cardiac Function (McNeill, J. H., ed.), CRC Press, Boca Raton.

    Google Scholar 

  178. Barrett, T. D., MacLeod, B. A., and Walker, M. J. A. (1997) A model of myocardial ischemia for the simultaneous assessment of electrophysiological changes and arrhythmias in intact rabbits. J. Pharmacol. Toxicol. Methods 37, 27–36.

    PubMed  CAS  Google Scholar 

  179. Walker, M. J. A., Curtis, M. J., Hearse, D. J., et al. (1988) The Lambeth Conventions: Guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc. Res. 22, 447–455.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

    Michael J. A. Walker & Leon J. Guppy

Authors
  1. Michael J. A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leon J. Guppy
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacology, Forest Research Institute, Jersey City, NJ

    Michael K. Pugsley

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Humana Press Inc., Totowa, NJ

About this protocol

Cite this protocol

Walker, M.J.A., Guppy, L.J. (2003). Targeting Ischemic Ventricular Arrhythmias. In: Pugsley, M.K. (eds) Cardiac Drug Development Guide. Methods in Pharmacology and Toxicology. Humana Press. https://doi.org/10.1385/1-59259-404-2:175

Download citation

  • DOI: https://doi.org/10.1385/1-59259-404-2:175

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-097-7

  • Online ISBN: 978-1-59259-404-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation