Myocardial action potential and action of antiarrhythmic drugs

CARDIAC EXCITABILITY

Cardiac excitability refers to the ease with which cardiac cells undergo a series of events characterized by:

  • Sequential depolarization and repolarization
  • Communication with adjacent cells
  • Propagation of the electrical activity in a normal or abnormal manner

The heartbeat arises from organized flow of ionic currents through ion-specific channels in the cell membrane, through the myoplasm and gap junctions that connect cells, and through the extracellular space (figure 1) [1,2]. Mutations in genes encoding the subunits and associated proteins of these channels have been associated with familial arrhythmic syndromes and sudden cardiac death. Examples include the congenital long QT syndrome (sodium and potassium current), the Brugada syndrome (mainly sodium current), and congenital heart block (sodium current). (See "Genetics of congenital and acquired long QT syndrome" and "Brugada syndrome" and "Etiology of atrioventricular block", section on 'Familial disease'.)

Cardiac ion channels and currents — Ions (sodium, potassium, chloride and calcium) flow through the cardiac membrane in channels with pores formed by proteins encoded by specific genes [3]. The pore-forming protein is called the alpha subunit, which also contains the voltage dependent sensors and gates. The currents carry specific names based upon the permeant ion and distinguishing kinetics or pharmacology. In most cases, the gene and protein underlying each current has been described and each has a distinct name (figure 1). For example, the voltage dependent sodium current (INa) flows through the protein NaV1.5 encoded by the gene SCN5A and similarly for other ion channels. Ion channels also consist of multiple subunits (usually named beta, delta, gamma, and so on) and other accessory proteins forming a macromolecular complex that regulates the current. The sodium-potassium pump and the sodium-calcium exchanger are not considered channels because they require energy to drive ions across the membrane against their gradients, but they do generate currents.

The resting potential — The normal resting potential in most myocardial cells is between 80 and 95 mV, with the cell interior negative relative to the extracellular space. The resting potential of the cell is set by the balance of inward (sodium and calcium) and outward (potassium) currents and the corresponding equilibrium potentials of these currents. In turn, the equilibrium potential for a given ion is determined by the concentrations of that ion inside and outside the cell. Using these concentrations, the equilibrium potential is calculated by the Nernst equation. As an example, potassium ion concentrations are higher inside than outside the cell, and the potassium equilibrium potential is between -80 and -95 mV. When potassium channels open, potassium ions flow down their gradient as an outward current, carrying positive ions outside the cell and taking the cell toward more negative potentials.

         

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Literature review current through: Jul 2014. | This topic last updated: Sep 4, 2013.
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References
Top
  1. Arnsdorf MF. The cellular basis of cardiac arrhythmias. A matrical perspective. Ann N Y Acad Sci 1990; 601:263.
  2. Fozzard HA, Arnsdor MF. Cardiac electrophysiology. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.63.
  3. Grant AO. Cardiac Ion Channels. Circ Arrythm Electrophysiol 2009; 2:185.
  4. Catterall WA. Structure and function of voltage-sensitive ion channels. Science 1988; 242:50.
  5. Stühmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339:597.
  6. Fozzard HA, Danck DA. Sodium channels. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.1091.
  7. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991; 84:1831.
  8. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993; 72:671.
  9. Pelzer D, Pelzer S, McDonald TF. Calcium channels in heart. In: The Heart and Cardiovascular System,, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York1 991. p.1049.
  10. Snyders DJ, Hondeghem LM, Bennett PB. Mechanisms of drug-channel interaction. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.2165.
  11. Arnsdorf MF. Arnsdorf's paradox. J Cardiovasc Electrophysiol 1990; 1:42.
  12. Arnsdorf MF. Cardiac excitability, the electrophysiologic matrix and electrically induced ventricular arrhythmias: order and reproducibility in seeming electrophysiologic chaos. J Am Coll Cardiol 1991; 17:139.
  13. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24:387.
  14. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82:I103.
  15. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 2. Physiologic and metabolic effects. Am Heart J 1979; 97:797.
  16. Naccarelli GV, Lukas MA. Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005; 28:165.
  17. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686.