Published Online
on August 19, 2002

A more recent version of this article appeared on September 10, 2002

This Article Full Text (PDF) All Versions of this Article: 106/11/1410    most recent 01.CIR.0000028587.85711.F6v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal 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 Miyata, A. Articles by Rubart, M. Search for Related Content PubMed Articles by Miyata, A. Articles by Rubart, M. Related Collections Arrythmias-basic studies

Submitted on April 10, 2002
Revised on June 5, 2002
Accepted on June 11, 2002

KB-R7943 Prevents Acute, Atrial FibrillationInduced Shortening of Atrial Refractoriness in Anesthetized Dogs

Akira Miyata MD, Douglas P. Zipes MD, Stephen Hall PhD, and Michael Rubart MD^*

From the Krannert Institute of Cardiology (A.M., D.P.Z., M.R.) and Department of Medicine, Division of Clinical Pharmacology (S.H.), Wishard Memorial Hospital, Indianapolis, Ind.

^* To whom correspondence should be addressed. E-mail: mrubartv{at}iupui.edu.

Background—To test the hypothesis that Ca²⁺ influx via Na⁺/Ca²⁺ exchange (NCX) underlies atrial fibrillation (AF)induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca²⁺-influx mode NCX, to attenuate this effect.

Methods and Results—Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean±SEM) 4.4±0.4% (1 mg/kg) to 14.8±2.6% (5 mg/kg; ED₅₀=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacinginduced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9±2.1% after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg · kg^-1 · min^-1) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86±3.26 nmol/L; n=4 dogs) and declined to 0.56±0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged 40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca²⁺ influx in isolated canine right atrial myocytes by 60%, but had no significant effect on NCX-dependent Ca²⁺ extrusion.

Conclusion—NCX-mediated Ca²⁺ influx plays an important role in acute, AF-induced AERP shortening.

Key words: atrium • fibrillation • electrophysiology

This article has been cited by other articles:

				I. Savelieva and J. Camm Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches Europace, June 1, 2008; 10(6): 647 - 665. [Abstract] [Full Text] [PDF]

				C. P. Regan, L. Kiss, G. L. Stump, C. J. McIntyre, D. C. Beshore, N. J. Liverton, C. J. Dinsmore, and J. J. Lynch Jr. Atrial Antifibrillatory Effects of Structurally Distinct IKur Blockers 3-[(Dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one and 2-Phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in Dogs with Underlying Heart Failure J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 322 - 330. [Abstract] [Full Text] [PDF]

				W. Wongcharoen, Y.-C. Chen, Y.-J. Chen, C.-M. Chang, H.-I Yeh, C.-I Lin, and S.-A. Chen Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity Cardiovasc Res, June 1, 2006; 70(3): 497 - 508. [Abstract] [Full Text] [PDF]

				G. L. Stump, A. A. Wallace, C. P. Regan, and J. J. Lynch Jr. In Vivo Antiarrhythmic and Cardiac Electrophysiologic Effects of a Novel Diphenylphosphine Oxide IKur Blocker (2-Isopropyl-5-methylcyclohexyl) Diphenylphosphine Oxide J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1362 - 1367. [Abstract] [Full Text] [PDF]

				J. G. Akar, T. H. Everett, R. Ho, J. Craft, D. E. Haines, A. P. Somlyo, and A. V. Somlyo Intracellular Chloride Accumulation and Subcellular Elemental Distribution During Atrial Fibrillation Circulation, April 8, 2003; 107(13): 1810 - 1815. [Abstract] [Full Text] [PDF]

				M. Rubart and D. P. Zipes NO Hope for Patients With Atrial Fibrillation Circulation, November 26, 2002; 106(22): 2764 - 2766. [Full Text] [PDF]