Measurement of action potential generation in isolated canine left ventricular midmyocardial myocytes

Curr Protoc Pharmacol. 2011 Dec;Chapter 10:Unit 10.14.1-23. doi: 10.1002/0471141755.ph1014s55.

Abstract

Proarrhythmic side effects are a major limitation during the drug development process for cardiac and non-cardiac compounds. Because changes in cardiac action potential (AP) are undesirable, the evaluation of the effects of test compounds on the AP is essential before advancing new compounds to clinical testing. However, an increase in repolarization duration alone is not always proarrhythmic, and newer surrogate markers have been suggested to better predict the occurrence of arrhythmia. Described in this unit is a protocol for assessing changes in AP duration in canine ventricular myocytes utilizing optical imaging techniques. This protocol can be used at an early stage of drug discovery due to its relatively fast throughput. Additionally, a protocol is presented for assessing the occurrence of after-depolarizations, as well as a novel parameter for proarrhythmic risk, beat-to-beat variability of repolarization. This protocol can be used at a later stage of the drug discovery process to assess proarrhythmic potential.

MeSH terms

  • Action Potentials / physiology*
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Cells, Cultured
  • Dimethyl Sulfoxide / pharmacology
  • Dogs
  • Female
  • Fluorescent Dyes
  • Heart Rate / drug effects*
  • Hydrogen-Ion Concentration
  • Isoproterenol / pharmacology
  • Isotonic Solutions / pharmacology
  • Myocytes, Cardiac / physiology*
  • Pyridinium Compounds
  • Reference Standards
  • Solvents / pharmacology
  • Ventricular Function, Left / physiology*

Substances

  • Adrenergic beta-Agonists
  • Anti-Arrhythmia Agents
  • Fluorescent Dyes
  • Isotonic Solutions
  • Pyridinium Compounds
  • Solvents
  • Tyrode's solution
  • 1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium betaine
  • Isoproterenol
  • Dimethyl Sulfoxide