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. 1987 Sep;92(1):97–103. doi: 10.1111/j.1476-5381.1987.tb11300.x

Resting, and rate-dependent depression of Vmax of guinea-pig ventricular action potentials by amiodarone and desethylamiodarone.

R T Pallandi 1, T J Campbell 1
PMCID: PMC1853634  PMID: 3664094

Abstract

1 The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea-pig ventricular myocardium by use of standard microelectrode techniques. 2 Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations. 3 The Class I effects were rate-dependent, with small (0-16%) falls in maximum depolarization rate in the absence of stimulation ('resting block') and progressively larger effects at decreasing interstimulus intervals (range 1200-300 ms). 4 The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class Ib agents). 5 It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.

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Selected References

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  1. Campbell T. J. Importance of physico-chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea-pig ventricle. Br J Pharmacol. 1983 Sep;80(1):33–40. doi: 10.1111/j.1476-5381.1983.tb11046.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Campbell T. J. Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res. 1983 Jun;17(6):344–352. doi: 10.1093/cvr/17.6.344. [DOI] [PubMed] [Google Scholar]
  3. Campbell T. J. Voltage- and time-dependent depression of maximum rate of depolarization of guinea-pig ventricular action potentials by two steroidal antiarrhythmic drugs, CCI 22277 and ORG 6001. Br J Pharmacol. 1982 Nov;77(3):541–548. doi: 10.1111/j.1476-5381.1982.tb09329.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Courtney K. R. Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol. 1980 Nov;12(11):1273–1286. doi: 10.1016/0022-2828(80)90071-1. [DOI] [PubMed] [Google Scholar]
  5. Courtney K. R. Structure-activity relations for frequency-dependent sodium channel block in nerve by local anesthetics. J Pharmacol Exp Ther. 1980 Apr;213(1):114–119. [PubMed] [Google Scholar]
  6. Finerman W. B., Jr, Hamer A., Peter T., Weiss D., Mandel W. J. Electrophysiologic effects of chronic amiodarone therapy in patients with ventricular arrhythmias. Am Heart J. 1982 Nov;104(5 Pt 1):987–996. doi: 10.1016/0002-8703(82)90430-6. [DOI] [PubMed] [Google Scholar]
  7. Grant A. O., Starmer C. F., Strauss H. C. Antiarrhythmic drug action. Blockade of the inward sodium current. Circ Res. 1984 Oct;55(4):427–439. doi: 10.1161/01.res.55.4.427. [DOI] [PubMed] [Google Scholar]
  8. Grant A. O., Trantham J. L., Brown K. K., Strauss H. C. PH-Dependent effects of quinidine on the kinetics of dV/dtmax in guinea pig ventricular myocardium. Circ Res. 1982 Feb;50(2):210–217. doi: 10.1161/01.res.50.2.210. [DOI] [PubMed] [Google Scholar]
  9. Harris L., McKenna W. J., Rowland E., Holt D. W., Storey G. C., Krikler D. M. Side effects of long-term amiodarone therapy. Circulation. 1983 Jan;67(1):45–51. doi: 10.1161/01.cir.67.1.45. [DOI] [PubMed] [Google Scholar]
  10. Holt D. W., Tucker G. T., Jackson P. R., Storey G. C. Amiodarone pharmacokinetics. Am Heart J. 1983 Oct;106(4 Pt 2):840–847. doi: 10.1016/0002-8703(83)90006-6. [DOI] [PubMed] [Google Scholar]
  11. Hondeghem L. M., Cotner C. L. Measurement of Vmax of the cardiac action potential with a sample/hold peak detector. Am J Physiol. 1978 Mar;234(3):H312–H314. doi: 10.1152/ajpheart.1978.234.3.H312. [DOI] [PubMed] [Google Scholar]
  12. Hondeghem L. M., Katzung B. G. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol. 1984;24:387–423. doi: 10.1146/annurev.pa.24.040184.002131. [DOI] [PubMed] [Google Scholar]
  13. Hondeghem L. M., Katzung B. G. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. doi: 10.1016/0304-4157(77)90003-x. [DOI] [PubMed] [Google Scholar]
  14. Hondeghem L., Katzung B. G. Test of a model of antiarrhythmic drug action. Effects of quinidine and lidocaine on myocardial conduction. Circulation. 1980 Jun;61(6):1217–1224. doi: 10.1161/01.cir.61.6.1217. [DOI] [PubMed] [Google Scholar]
  15. Latini R., Tognoni G., Kates R. E. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet. 1984 Mar-Apr;9(2):136–156. doi: 10.2165/00003088-198409020-00002. [DOI] [PubMed] [Google Scholar]
  16. Mason J. W., Hondeghem L. M., Katzung B. G. Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch. 1983 Jan;396(1):79–81. doi: 10.1007/BF00584702. [DOI] [PubMed] [Google Scholar]
  17. Mason J. W., Hondeghem L. M., Katzung B. G. Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone. Circ Res. 1984 Sep;55(3):278–285. doi: 10.1161/01.res.55.3.278. [DOI] [PubMed] [Google Scholar]
  18. Nademanee K., Hendrickson J., Kannan R., Singh B. N. Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythmias: potent suppression of spontaneously occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia. Am Heart J. 1982 Jun;103(6):950–959. doi: 10.1016/0002-8703(82)90556-7. [DOI] [PubMed] [Google Scholar]
  19. Polster P., Broekhuysen J. The adrenergic antagonism of amiodarone. Biochem Pharmacol. 1976 Jan 15;25(2):131–134. doi: 10.1016/0006-2952(76)90279-3. [DOI] [PubMed] [Google Scholar]
  20. Raeder E. A., Podrid P. J., Lown B. Side effects and complications of amiodarone therapy. Am Heart J. 1985 May;109(5 Pt 1):975–983. doi: 10.1016/0002-8703(85)90238-8. [DOI] [PubMed] [Google Scholar]
  21. Sada H., Ban T. Time-independent effects on cardiac action potential upstroke velocity (resting block) and lipid solubility of beta adrenergic blockers. Experientia. 1981 Feb 15;37(2):171–172. doi: 10.1007/BF01963214. [DOI] [PubMed] [Google Scholar]
  22. Singh B. N., Vaughan Williams E. M. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol. 1970 Aug;39(4):657–667. doi: 10.1111/j.1476-5381.1970.tb09891.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Storey G. C., Adams P. C., Campbell R. W., Holt D. W. High-performance liquid chromatographic measurement of amiodarone and desethylamiodarone in small tissue samples after enzymatic digestion. J Clin Pathol. 1983 Jul;36(7):785–789. doi: 10.1136/jcp.36.7.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Varro A., Nakaya Y., Elharrar V., Surawicz B. Use-dependent effects of amiodarone on Vmax in cardiac Purkinje and ventricular muscle fibers. Eur J Pharmacol. 1985 Jun 19;112(3):419–422. doi: 10.1016/0014-2999(85)90791-5. [DOI] [PubMed] [Google Scholar]
  25. Vaughan Williams E. M. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol. 1984 Apr;24(4):129–147. doi: 10.1002/j.1552-4604.1984.tb01822.x. [DOI] [PubMed] [Google Scholar]
  26. Walton M., Fozzard H. A. The relation of Vmax to INa, GNa, and h infinity in a model of the cardiac Purkinje fiber. Biophys J. 1979 Mar;25(3):407–420. doi: 10.1016/S0006-3495(79)85312-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Williams E. M. Mexiletine in isolated tissue models. Postgrad Med J. 1977;53 (Suppl 1):30–34. [PubMed] [Google Scholar]
  28. Yabek S. M., Kato R., Singh B. N. Effects of amiodarone and its metabolite, desethylamiodarone, on the electrophysiologic properties of isolated cardiac muscle. J Cardiovasc Pharmacol. 1986 Jan-Feb;8(1):197–207. doi: 10.1097/00005344-198601000-00029. [DOI] [PubMed] [Google Scholar]
  29. Zipes D. P., Prystowsky E. N., Heger J. J. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects. J Am Coll Cardiol. 1984 Apr;3(4):1059–1071. doi: 10.1016/s0735-1097(84)80367-8. [DOI] [PubMed] [Google Scholar]

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