This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nattel, S. Articles by Yue, L. Search for Related Content PubMed PubMed Citation Articles by Nattel, S. Articles by Yue, L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 4-AMINOPYRIDINE Related Collections Animal models of human disease Arrythmias-basic studies Ion channels/membrane transport Arrhythmias, clinical electrophysiology, drugs

(Circulation. 2000;101:1179.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Dose-Dependence of 4-Aminopyridine Plasma Concentrations and Electrophysiological Effects in Dogs

Potential Relevance to Ionic Mechanisms In Vivo

Stanley Nattel, MD; Carol Matthews, RT; Emma De Blasio, MSc; Wei Han, MSc; Danshi Li, MD, PhD; Lixia Yue, PhD

From the Research Center and Department of Medicine, Montreal Heart Institute (S.N., E.D.B., W.H., D.L., L.Y.); Department of Medicine, University of Montreal (S.N.); and Department of Pharmacology, McGill University (S.N., C.M., L.Y.), Montreal, Quebec, Canada.

Correspondence to Dr Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail nattel{at}icm.umontreal.ca

Background—Previous investigators have administered 4-aminopyridine (4AP) to dogs to evaluate the role of transient outward current (I_to) in vivo; however, plasma concentrations of 4AP were not measured, and it is therefore uncertain which cardiac ion channels were blocked at the concentrations achieved.

Methods and Results—We applied high-performance liquid chromatography to measure 4AP concentrations produced by intravenous 4AP administration to dogs. A previously described dose regimen produced plasma concentrations that increased during the maintenance infusion but never exceeded 250 µmol/L and caused significant mortality. Whole-cell patch-clamp experiments on isolated canine myocytes showed that even the maximum 4AP concentrations achieved in vivo failed to alter ventricular I_to and had very small effects on atrial I_to; however, concentrations achieved in vivo had a strong inhibitory effect on the dog ultrarapid delayed rectifier (I_Kur.d), present only in atrial cells. We designed a loading and maintenance infusion regimen to produce stable 4AP plasma concentrations. At concentrations in the range of 25 and 50 µmol/L, 4AP had no effect on ventricular refractory period but increased atrial refractoriness significantly, consistent with the results of voltage clamp studies.

Conclusions—The interpretation of previous studies using intravenous 4AP administration to inhibit I_to in dogs in vivo needs to be reevaluated in light of the fact that the infusion regimens used produce plasma concentrations that are inadequate to affect ventricular I_to. Our findings also support the concept that selective inhibition of ultrarapid delayed rectifier current can prolong atrial refractory periods without affecting ventricular refractoriness.

Key Words: ion channels • antiarrhythmic agents • electrophysiology • action potentials • heart diseases

This article has been cited by other articles:

				K. Tsujimae, S. Murakami, and Y. Kurachi In silico study on the effects of IKur block kinetics on prolongation of human action potential after atrial fibrillation-induced electrical remodeling Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H793 - H800. [Abstract] [Full Text] [PDF]

				A. Burashnikov, J. M. Di Diego, A. C. Zygmunt, L. Belardinelli, and C. Antzelevitch Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation: Differences in Sodium Channel Inactivation Between Atria and Ventricles and the Role of Ranolazine Circulation, September 25, 2007; 116(13): 1449 - 1457. [Abstract] [Full Text] [PDF]

				N. Gaborit, S. Le Bouter, V. Szuts, A. Varro, D. Escande, S. Nattel, and S. Demolombe Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart J. Physiol., July 15, 2007; 582(2): 675 - 693. [Abstract] [Full Text] [PDF]

				Y. Blaauw, H. Gogelein, R.G. Tieleman, A. van Hunnik, U. Schotten, and M.A. Allessie "Early" Class III Drugs for the Treatment of Atrial Fibrillation: Efficacy and Atrial Selectivity of AVE0118 in Remodeled Atria of the Goat Circulation, September 28, 2004; 110(13): 1717 - 1724. [Abstract] [Full Text] [PDF]

				A. Burashnikov, S. Mannava, and C. Antzelevitch Transmembrane action potential heterogeneity in the canine isolated arterially perfused right atrium: effect of IKr and IKur/Ito block Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2393 - H2400. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]