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 Rahme, M. M. Articles by Feld, G. K. Search for Related Content PubMed PubMed Citation Articles by Rahme, M. M. Articles by Feld, G. K. Related Collections Animal models of human disease Arrhythmias, clinical electrophysiology, drugs Receptor pharmacology

(Circulation. 1999;100:2010-2017.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Electrophysiological and Antiarrhythmic Effects of the Atrial Selective 5-HT₄ Receptor Antagonist RS-100302 in Experimental Atrial Flutter and Fibrillation

Marc M. Rahme, PhD; Bruno Cotter, MD; Elisabeth Leistad, MD; Manish K. Wadhwa, MD; Rajendra Mohabir, PhD; Anthony P. D. W. Ford, PhD; Richard M. Eglen, PhD; Gregory K. Feld, MD

From the Cardiac Electrophysiology Program, Division of Cardiology, Department of Medicine, University of California, San Diego (M.M.R., B.C., E.L., M.K.W., G.K.F.); Genentech, Inc, South San Francisco (R.M.); and Roche Bioscience, Inc, Palo Alto (A.P.D.W.F., R.M.E.), Calif.

Correspondence to Gregory K. Feld, MD, 200 W Arbor Dr, No. 8411, San Diego, CA 92103. E-mail gfeld{at}ucsd.edu

Background—Stimulation of 5-HT₄ receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT₄ receptors are present only in atrium. Therefore, the effects of a novel 5-HT₄ receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT₄ receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302.

Methods and Results—In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride. In the atrium, RS-100302 prolonged mean ERP (115±8 versus 146±7 ms, P<0.01) and wavelength (8.3±0.9 versus 9.9±0.8 cm, P<0.01), reduced dispersion of ERP (15±5 versus 8±1 ms, P<0.01), and minimally slowed conduction velocity (72±4 versus 67±5 cm/s, P<0.01). These effects were all partially reversed by cisapride. RS-100302 produced no ventricular electrophysiological effects. RS-100302 terminated atrial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals and prevented reinduction of sustained tachycardia in all animals.

Conclusions—The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.

Key Words: fibrillation • atrial flutter • serotonin • 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]

				D. Pau, A. J. Workman, K. A. Kane, and A. C. Rankin Electrophysiological Effects of Prucalopride, a Novel Enterokinetic Agent, on Isolated Atrial Myocytes from Patients Treated with {beta}-Adrenoceptor Antagonists J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 146 - 153. [Abstract] [Full Text] [PDF]

				E. Qvigstad, T. Brattelid, I. Sjaastad, K. W. Andressen, K. A. Krobert, J. A. Birkeland, O. M. Sejersted, A. J. Kaumann, T. Skomedal, J.-B. Osnes, et al. Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure Cardiovasc Res, March 1, 2005; 65(4): 869 - 878. [Abstract] [Full Text] [PDF]

				D. I. Leftheriotis, G. N. Theodorakis, D. Poulis, P. G. Flevari, E. G. Livanis, E. K. Iliodromitis, A. Papalois, and D. Th. Kremastinos The effects of 5-HT4 receptor blockade and stimulation, during six hours of atrial fibrillation Europace, January 1, 2005; 7(6): 560 - 568. [Abstract] [Full Text] [PDF]

				M. M. Rahme, G. Ungab, M. Wadhwa, F. Al-Kandari, B. Yao, A. Gupta, K. Lee, H.-Y. Kim, and G. K. Feld Electrophysiologic and Antiarrhythmic Effects of the New Class III Antiarrhythmic Drug KCB-328 in Experimental Canine Atrial Flutter Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2001; 6(3): 297 - 306. [Abstract] [PDF]

				M. R. Rosen Leaky Dikes and Fibrillating Swine Circulation, November 9, 1999; 100(19): 1942 - 1944. [Full Text] [PDF]