Electrocardiographic Toxicity in the Guinea Pig

Pierre Lacroix1

1 Porsolt and Partners Pharmacology, Boulogne Billancourt
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.29
DOI:  10.1002/0471141755.ph0529s18
Online Posting Date:  November, 2002
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Abnormalities of cardiac rhythm are one of the most common clinical problems in cardiology and arise as the result of either disorders of cardiac impulse formation or conduction, or a combination of both. It has been established that some classes of drugs, such as tricyclic antidepressants (e.g., imipramine), cardiac glycosides (e.g., digoxin), and Class I or Class III antiarrhythmic drugs (e.g., quinidine or amiodarone) can produce electrocardiographic toxicity in humans. It is therefore highly advisable to assess the effect of any new compound in this respect, during the early phases of drug development. This unit presents a protocol to detect the electrocardiographic toxicity of compounds in the anesthetized guinea pig.

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Table of Contents

  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1:

  • Male Duncan‐Hartley albino guinea pigs weighing 280 to 320 g at the beginning of the experiment
  • Urethane (Sigma)
  • 5000 IU/ml heparine Choay (Sanofi Winthrop Pharmaceuticals) in physiological saline
  • Test compound(s)
  • Animal balance accurate to 1 g (e.g., Sartorius type 1401.001.2)
  • 5‐ml Terumo syringes, type B5‐05S, and 25‐G needles for intraperitoneal administration of anesthetic solution and to infuse the test compound
  • Heating table (e.g., Harvard Apparatus)
  • Polyethylene catheters (0.58‐mm i.d. and 0.96‐mm o.d. for jugular vein; 1.67‐mm i.d. and 2.42‐mm o.d. for trachea)
  • Ventilator (e.g., Harvard model for small animals)
  • Electrocardiograph (Burdik model; Siemens)
  • Adhesive strips
  • Programmable multiple‐syringe low‐flow infusion pump (e.g., Harvard Apparatus model PH 2000)
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Literature Cited

Literature Cited
   Boissier, J.R., Simon, P., and Witchitz, S. 1965. Etude chez le cobaye de la toxicitè cardiaque de l'imipramine, de l'amitriptyline et de leurs derives monodesmethylés. Thérapie 20:67‐75.
   Carmeliet, E. 1998. Effects of citerizine on the delayed K+ currents in cardiac cells:comparison with terfenadine. Br. J. Pahrmacol. 124:663‐668.
   Daleau, P., Lessard, E., Groleau, M.F., and Turgeon, J. 1995. Erythromycin blocks the rapid component of the delayed rectifier current and lengthens repolarization of guinea pig ventricular myocytes. Circulation 91:3010‐3016.
   Deharo, J.C., Durand, A., Macaluzo, G., Malaterre, H., Le Tallec, L., Panagides, D., Bory, M., and Djiane, P. 1997. Clinical electrophysiologic effect of a single high oral dose of amiodarone. Fund. Clin. Pharmacol. 11:275‐280.
   De Ponti, F., Poluzzi, E., and Montanaro, N. 2000. QT‐interval prolongation by non‐cardiac drugs: Lessons to be learned from recent experience. Eur. J. Clin. Pharmacol. 56:1‐18.
   Fowler, N.O., McCall, D., Chou, T.C., Holmes, J.C., and Hanenson, I.B. 1976. Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am. J. Cardiol. 37:223‐230.
   Keren, A., Tzigono, D., Gottlieb, S., Benhorin, J., and Stern, S. 1982. A typical ventricular tachycardia (torsade de pointe) induced by amiodarone: Arrhythmia previously induced by quinidine and disopyramide. Chest 81:384‐386.
   Knaffl‐Lenz, E. 1926 The physiological assay of preparation of digitalis. J. Pharmacol. Exp. Ther. 29:407‐425.
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   Moe, G.K. and Mendezm, R. 1951. The action of several cardiac glycosides on conduction velocity and ventricular excitability in the dog heart. Circulation 4:729‐734.
   Neuvonen, P.J., Elonen, E., Vuorenmaa, T., and Laakso, M. 1981. Prolonged QT interval and severe tachyarrhythmias, common features of sotalol intoxication. Eur. J. Clin. Pharmacol. 20:85‐89.
   Rampe, D., Murawsky, M.K., Grau, J., and Lewis, E.W. 1998. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J. Phar. Exp. Ther. 286:788‐793.
   Sekiya, A. and Vaughan Williams, E.M. 1963. The effect of pronethalol, dichloroisoprenaline and disopyramide on the toxicity to the heart of ouabain and anesthetics. Brit. J. Pharmacol. 21:462‐472.
   Zhou, M.S., Gong, Q., and January, C.T. 1997. Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am. J. Physiol. 273:H2534‐H2538.
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