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(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

	Abstract

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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

	Introduction

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Atrial fibrillation (AF) is a common, frequently refractory arrhythmia associated with significant morbidity and mortality.¹ AF is a reentrant arrhythmia and is more likely to occur in the presence of an abnormally shortened atrial effective refractory period (ERP) and increased dispersion of ERP (ERP_disp).^{2 3 4 5} In addition, abnormally depressed conduction velocity (CV) and anatomic obstacles may play a role in the reentrant mechanism of AF.² Experimental studies have suggested that prolongation of atrial wavelength and a reduction in ERP_disp may be critical determinants of the efficacy of antiarrhythmic drugs in terminating and suppressing reentrant atrial arrhythmias.^{6 7 8 9} Both of these salutary electrophysiological effects are produced by class III antiarrhythmic drugs, such as sotalol, but not by class I antiarrhythmic drugs, such as quinidine.^{6 7} Despite their favorable electrophysiological profile, however, the class III drugs are not more effective than the class I drugs in suppressing AF in humans, with only 50% to 65% of patients in sinus rhythm after 6 months of therapy.^{10 11 12 13} In addition, the organ toxicity and potential life-threatening ventricular proarrhythmia associated with antiarrhythmic drugs further limit their use for treating AF.¹⁴

Because of the limited efficacy and potential adverse effects of antiarrhythmic drugs that modulate cardiac ion channels, new approaches to antiarrhythmic drug therapy must be developed. One possible approach is the modulation of membrane receptors that play a role in controlling normal cellular electrophysiology. One such receptor, which when stimulated causes increased heart rate in humans, is the 5-hydroxytryptamine, or 5-HT, receptor.^{15 16 17 18} Extensive research into the cardiac effects of 5-HT has revealed the existence of the 5-HT₄ receptor subtype in human atrium.^{19 20} Stimulation of the 5-HT₄ receptor produces positive chronotropic effects and increases cAMP levels, cAMP-dependent protein kinase activity and inotropic force, and onset of muscle relaxation.^{19 20} Furthermore, stimulation of 5-HT₄ receptors induces arrhythmic contractions in atrial myocardium that are inhibited by selective 5-HT₄ antagonists.^{21 22 23 24} Similar arrhythmic contractions have been demonstrated with stimulation of atrial ß₁- and ß₂-receptors.²⁵ However, it is unknown whether 5-HT₄ receptor stimulation, or conversely, its blockade, produces any other electrophysiological effect in the atrium.

Of particular importance is the observation that the 5-HT₄ receptor subtype is present in human atrium, but not in the ventricle.²⁶ The lack of 5-HT₄ receptors in human ventricle suggests that their pharmacological modulation may not cause ventricular proarrhythmia, provided that there is no direct electrophysiological effect of such a pharmacological agent. In contrast, ketanserin, a 5-HT₂ receptor subtype blocker, prolongs ventricular action potential duration and may cause ventricular proarrhythmia (ie, torsade de pointes), because this receptor is found in both atrium and ventricle.²⁷ Therefore, the electrophysiological and antiarrhythmic effects of the 5-HT₄ antagonist RS-100302²⁸ and the partial agonist cisapride were studied in pigs, which, like humans, have 5-HT₄ receptor activity confined to the atrium²⁹ during atrial flutter (AFL) (crush injury) or AF induced by rapid atrial pacing.^{6 7 8 30 31}

	Methods

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Seventeen juvenile pigs weighing 15 to 20 kg were studied after sedation with intramuscular ketamine and salazine and general anesthesia with intravenous pentobarbital 30 to 35 mg/kg bolus plus 0.05 mg · kg^-1 · min^-1 maintenance infusion. The pigs were intubated and ventilated mechanically with room air. A femoral vein and artery were cannulated via direct cutdown for intravenous drug administration and arterial pressure monitoring, respectively. Ringer’s lactate was infused continuously at 30 mL/h. The surface ECG was monitored continuously during the study. Body temperature was maintained by a warm-water–circulating pump. A median sternotomy was performed, and the heart was exposed by opening of the pericardium.

Induction of Arrhythmia
Bipolar hook electrodes (interelectrode spacing 2 mm) were attached to the right atrial appendage (Figure 1). Ten attempts were made to induce AF (Figure 2) by rapid atrial pacing for 60 seconds at a cycle length of 200 ms to atrial refractoriness, and if sustained >10 minutes, AF was studied.⁶ If sustained AF was not inducible, a crush injury was performed on the atrial free wall (Figure 1) as previously described.⁷ Attempts were then made to induce AFL (Figure 3) with rapid atrial pacing in a manner identical to that for AF, and if sustained >10 minutes, AFL was studied. Sustained AF or AFL was then terminated by pacing or DC cardioversion, and baseline electrophysiological measurements were performed (see below).

View larger version (15K): [in this window] [in a new window]   Figure 1. Schematic of right atrium showing location of epicardial mapping plaque on right atrial free wall (left) and approximate location of crush injury for AFL in animals without inducible AF (right). **Location of bipolar pacing electrode attached to atrial appendage. IVC indicates inferior vena cava; RAA, right atrial appendage; and SVC, superior vena cava. A1-A8 thru G1-G8 show 56 bipolar electrodes on mapping plaque

View larger version (44K): [in this window] [in a new window]   Figure 2. Epicardial electrograms from 1 column of electrodes on mapping plaque (A) and activation maps (3 beats in B, C, and D) during sustained AF at baseline. Note irregular, disorganized epicardial electrograms and varying direction of activation of multiple wave fronts traversing mapping plaque characteristic of AF. Abbreviations as in previous figures.

View larger version (28K): [in this window] [in a new window]   Figure 3. Epicardial electrograms from around crush injury (A) and activation map (B) during sustained AFL at baseline. Thick line on activation map represents location of right atrial crush injury. Note that in this case, reentry proceeds clockwise around crush injury (cycle length, 120 ms). TVA indicates tricuspid valve annulus. Other abbreviations as in Figure 1.

Electrophysiological Measurements and Mapping
A 56-electrode mapping plaque (Figure 1), measuring 3.5x2.5 cm with 3- to 5-mm interelectrode and 2-mm intraelectrode spacing, was sewn in place over the right atrial free wall.^{6 7} Pacing was performed from the mapping plaque for electrophysiological measurements. A 64-channel mapping system (Bard Electrophysiology, Inc) was used for activation mapping during AFL or AF. Activation maps were also obtained during atrial pacing from 4 electrodes, 1 at each corner of the mapping plaque, at cycle lengths of 200 and 150 ms to determine atrial CV. Right atrial ERP was determined at all 56 electrodes on the mapping plaque by decremental stimuli (S₁S₂) scanning diastole at 10-ms intervals at a drive cycle length (S₁S₁) of 200 ms. Right and left ventricular ERPs were similarly determined at drive cycle lengths of 400 and 300 ms via bipolar hook electrodes on the ventricular epicardium. Sinus cycle length (RR interval), QTc (QTc=QT/214 RR interval), and ventricular CV (estimated by measurement of QRS duration) were determined during sinus rhythm. After completion of baseline electrophysiological measurements, AFL or AF was reinduced and allowed to sustain for 10 minutes. Experimental study drugs were then administered.

Drug Studies
After completion of baseline electrophysiological measurements and induction of sustained AFL or AF, the 5-HT₄ receptor antagonist RS-100302 (Roche Bioscience, Inc) was administered in a dose of 30 µg/kg over 10 minutes. This dose of RS-100302 was previously determined to maximally inhibit 5-HT–induced tachycardia in pigs (unpublished data, Roche Bioscience, Inc). After completion of drug infusion, each animal was monitored for 20 minutes to observe arrhythmia response. If AFL or AF did not terminate spontaneously within 20 minutes after completion of drug infusion, sinus rhythm was restored by burst pacing or DC cardioversion, respectively. Electrophysiological measurements were then repeated as during control, and a venous blood sample was drawn for plasma levels of RS-100302. Attempts were then made to reinduce AFL or AF as performed at control. Reinduced arrhythmias were defined as sustained if lasting >10 minutes, nonsustained if lasting >30 seconds but <10 minutes, or none if lasting <30 seconds. Sustained arrhythmias were terminated after 10 minutes by burst pacing or DC cardioversion. Cisapride was then administered at a dose of 0.1 mg/kg over 10 minutes, after which electrophysiological measurements were repeated. Attempts were again made to reinduce AFL or AF, and the same definitions as those used after RS-100302 infusion regarding sustained, nonsustained, or no arrhythmias were applied. The study was then terminated, and animals were euthanized by an overdose of pentobarbital (150 mg/kg).

Data Analysis
All electrophysiological parameters, including RR; QTc and QRS intervals; minimum, maximum, and average atrial ERPs at all 56 electrodes; atrial CV; wavelength; ERP_disp and interelectrode dispersion (IE_disp); and AFL and AF cycle length (AFLCL and AFCL) are presented as mean±SD for all animals for control and drug conditions. ERP_disp was defined as the SD of the ERP determined at all 56 electrodes in each animal.^{7 8} IE_disp was defined as the number of electrode pairs on the mapping plaque with an ERP difference of 20 ms between adjacent electrodes.^{6 7} During pacing from each corner of the mapping plaque at 200- and 150-ms drive cycle length, an effective CV (cm/s) across the mapping plaque was calculated by dividing the length of the mapping plaque (3.5 cm) by the activation time (in seconds) across the mapping plaque.^{6 7} The average CV for each animal was then calculated from the effective CV measured in both directions along the upper and lower halves of the mapping plaque during pacing at each of these 4 electrodes. Wavelength was calculated by multiplying mean ERP by average CV in each animal. Mean AFLCL and AFCL were calculated for each animal by counting the number of local atrial activations during 8 seconds of rhythm at 1 electrode on the mapping plaque with discrete, nonfragmented electrograms. AFLCL and AFCL were determined at control and just before termination of sustained or nonsustained arrhythmia after both drug infusions.

Statistical Analysis
The statistical significances of differences in ERP, CV, wavelength, ERP_disp, IE_disp, AFCL, AFCL, sinus cycle length (RR), QRS, and QTc between baseline and after RS-100302 and cisapride administration were calculated by 1-way repeated-measures ANOVA with Bonferroni’s correction for pairwise multiple comparisons when the normality test failed or Student-Newman-Keuls correction when the normality test passed. For all tests, a value of P<0.05 was considered to be statistically significant.

	Results

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Atrial Electrophysiological Effects of RS-100302
RS-100302 significantly prolonged mean ERP from 115±8 to 146±7 ms (P<0.01), maximum ERP from 139±10 to 161±7 ms (P<0.01), and minimum ERP from 81±16 to 128±9 ms (P<0.01) (Table 1). Average CV at pacing cycle lengths of 200 and 150 ms decreased slightly, but significantly, after RS-100302 infusion, from 72±4 to 67±5 cm/s (P<0.01) and from 62±7 to 55±7 cm/s (P<0.01), respectively. RS-100302 prolonged atrial wavelength from 8.3±0.9 to 9.9±0.8 cm (P<0.01). RS-100302 reduced ERP_disp (Figure 4) from 15±5 to 8±1 ms (P<0.01) and IE_disp from 30±10 to 7±3 ms (P<0.01).

View this table: [in this window] [in a new window]   Table 1. Atrial Electrophysiological Effects of RS-100302 and Cisapride

View larger version (105K): [in this window] [in a new window]   Figure 4. 3D spatial representation of ERPdisp in 1 animal from 56-electrode mapping plaque at baseline (A), after infusion of RS-100302 (B), and after infusion of cisapride (C). Location of each column and row of electrodes is depicted on x and y axes and ERP on z axis. Note that there is significant atrial ERPdisp at baseline (A). After infusion of RS-100302, ERP is prolonged and dispersion reduced (B), effects of which are partially reversed by cisapride (C). Abbreviations as in previous figures.

Reversal of Atrial Electrophysiological Effects of RS-100302 by Cisapride
Cisapride shortened mean ERP from 146±7 to 130±5 ms (P<0.01), maximum ERP from 161±7 to 148±7 ms (P<0.01), and minimum ERP from 128±9 to 108±11 ms (P<0.01) (Table 1). Average CV at pacing cycle lengths of 200 and 150 ms increased slightly but significantly after cisapride infusion, from 67±5 to 70±5 cm/s (P<0.01) and from 55±7 to 59±7 cm/s (P<0.01), respectively. Cisapride shortened wavelength from 9.9±0.8 to 9.1±0.7 cm (P<0.01). Cisapride increased ERP_disp (Figure 4) from 8±1 to 11±3 ms (P<0.01) and IE_disp from 7±3 to 17±5 ms (P<0.01).

Effects of RS-100302 and Cisapride on ECG and Ventricular Electrophysiological Parameters
There were no significant effects of either RS-100302 or cisapride infusion on sinus cycle length, QRS duration, QTc, or left and right ventricular ERP at either 400- or 300-ms paced cycle lengths (Table 2). The systolic and diastolic blood pressure decreased slightly, but significantly, after infusion of cisapride but not RS-100302.

View this table: [in this window] [in a new window]   Table 2. ECG and Ventricular Electrophysiological Effects of RS-100302 and Cisapride

Effects of RS-100302 and Cisapride on AFL and AF
RS-100302 significantly increased AFLCL, from 134±15 to 161±22 ms (P<0.01) and AFCL, from 99±13 to 142±9 ms (P<0.01), respectively (Table 1). Cisapride partially reversed AFLCL, from 161±22 to 150±17 ms (P<0.01) and AFCL, from 142±9 to 129±9 ms (P<0.01), respectively.

At baseline, 8 pigs had inducible sustained AFL and 9 had AF (Table 3, Figures 2 and 3). During or after infusion of RS-100302, AFL terminated in 6 of 8 pigs, whereas AF terminated in 8 of 9 pigs. After infusion of RS-100302, AFL was no longer reinducible in 5 of 8 pigs, whereas nonsustained AFL was reinducible in 3. AF was no longer inducible in 6 of 9 pigs, whereas nonsustained AF was reinducible in 3. After infusion of cisapride, nonsustained AFL was reinducible in 6 of 8 pigs, and there was no AFL in 2 pigs. Nonsustained AF was reinducible in 6 of 9 pigs, and there was no AF in 3 pigs.

View this table: [in this window] [in a new window]   Table 3. Effects of RS-100302 and Cisapride on AFL and AF

	Discussion

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Electrophysiological and Antiarrhythmic Effects of RS-100302
The 5-HT₄ receptor antagonist RS-100302 produced significant electrophysiological and antiarrhythmic effects in pacing-induced AFL and AF in pigs. These electrophysiological and antiarrhythmic effects were comparable to those produced by class III antiarrhythmic drugs such as dofetilide and d-sotalol in similar arrhythmia models in the dog.^{6 7 8 9} For example, RS-100302 prolonged average ERP by 27%, whereas CV was slowed by only 7% at a pacing cycle length of 200 ms, thus producing a 19% increase in wavelength. RS-100302 also reduced ERP_disp by 47% and IE_disp by 77%. These electrophysiological effects resulted in termination of AFL in 75% of animals and AF in 89% of animals and prevented reinduction of sustained AFL or AF in all animals. However, RS-100302 had no effect on sinus or AV node function or any ventricular electrophysiological or hemodynamic effects. Cisapride, which is known to be a partial agonist of the 5-HT₄ receptor, incompletely reversed all of the electrophysiological effects of RS-100302, confirming the role of the 5-HT₄ receptor in mediating the action of RS-100302.

Possible Mechanism of the Electrophysiological Effects of RS-100302
Whereas the class III antiarrhythmic drugs produce significant electrophysiological effects by modulating potassium ion channels, such as I_Kr,³² RS-100302 produces electrophysiological effects via the novel mechanism of 5-HT₄ receptor blockade. The exact mechanism by which 5-HT₄ receptor modulation produces electrophysiological effects is unknown, but previous studies suggest 1 possibility. Stimulation of the 5-HT₄ receptor increases L-type Ca²⁺ channel current in human atrial myocytes via a cAMP-dependent protein kinase.³³ The resultant increase in intracellular Ca²⁺ may cause further release of Ca²⁺ from sarcoplasmic reticulum.^{34 35} In response to increased intracellular Ca²⁺, the delayed rectifier potassium current, I_K, may be augmented via a calmodulin-dependent pathway.³⁶ Thus, 5-HT₄ receptor stimulation could theoretically cause atrial arrhythmias, including delayed afterdepolarizations, as a result of increased intracellular Ca²⁺ concentration or even AF as a result of shortening of atrial refractory period due to increased delayed rectifier potassium current.^{33 34 35 36} Conversely, 5-HT₄ receptor blockade could have antiarrhythmic effects by decreasing intracellular Ca²⁺ concentration and delayed rectifier potassium current and prolonging atrial refractory period.^{33 34 35 36} Our data are consistent with such a mechanism, in that blockade of the 5-HT₄ receptor by RS-100302 was associated with prolongation of atrial ERP and atrial antiarrhythmic effects.

The observation that RS-100302 produced significant electrophysiological effects suggests that the 5-HT₄ receptor must have significant resting tone in vivo. The mechanism by which such resting tone might exist is unknown, but studies comparing atrial myocardium from patients with and without prolonged exposure to ß-blockers demonstrated that exposure to ß-blockers caused 5-HT₄ receptor–mediated hyperresponsiveness to 5-HT.^{24 37} This ß-blocker–induced hyperresponsiveness to 5-HT₄ receptor stimulation has been shown to increase both maximum inotropic force and cAMP levels in atrial myocardium.³⁷ These findings suggest that there may be intracellular cross talk between receptor populations within individual cells.²⁴ Although the pigs in this study did not receive ß-blockers, it is possible that sufficient resting 5-HT₄ receptor tone was present, as a result of stimulation by local or circulating levels of 5-HT, such that RS-100302 produced significant electrophysiological effects.

Potential Mechanisms of Antiarrhythmic Action of RS-100302
The electrophysiological determinants of termination and prevention of sustained AFL and AF by RS-100302 in the pig appear to be similar to those of the class III antiarrhythmic drugs dofetilide and sotalol in similar arrhythmia models in the dog.^{6 7 8 9} Specifically, the antiarrhythmic effects of RS-100302 were associated with prolongation of atrial ERP and wavelength and reduction in dispersion of refractoriness, electrophysiological effects that were partially reversed by cisapride. However, it is unknown whether the antiarrhythmic effects of RS-100302 were solely due to its class III–like electrophysiological effects or whether other effects of the compound played a role. For example, Ca²⁺ channel blockers have been shown to reduce the frequency of AF recurrence after cardioversion, possibly by preventing the shortening of atrial ERP or electrical remodeling that occurs during AFL or AF as a result of increased intracellular calcium concentration.³⁸ Thus, the antiarrhythmic effects of RS-100302 might be due in part to a reduction of intracellular Ca²⁺ loading during the rapid rates associated with AFL or fibrillation and in part to prolongation of atrial repolarization via an indirect effect on I_Kr.

Clinical Implications of the Study
The data from this study support previous speculation that 5-HT₄ receptors may play a role in atrial arrhythmogenesis and that 5-HT₄ receptor antagonists may have atrial antiarrhythmic effects without ventricular proarrhythmic effects.^{15 24 39}

Study Limitations
Several aspects of the methods may limit conclusions regarding the mechanisms of antiarrhythmic action of RS-100302. First, the mapping plaque did not cover all atrial surfaces. Thus, the electrophysiological characteristics in other areas of the atria were not determined, although the effects of RS-100302 and cisapride are not likely to have been different. Second, although epicardial measurement of CV has limitations owing to the 3D nature of the heart, this is not as problematic in the thin-walled atrium as in the ventricle. Last, thoracotomy and suturing of the mapping plaque to the atrium might have caused serotonin release and increased background 5-HT₄ receptor stimulation. This potentially could have shortened baseline atrial ERP and increased ERP_disp, such that infusion of a 5-HT₄ receptor blocker could then have produced a significant change compared with these baseline values. Whether a significant degree of resting tone of the 5-HT₄ receptor exists at baseline without such surgery, in pigs or humans, is unknown and may deserve further study.

	Acknowledgments

 
This research was supported by a grant from Roche Bioscience, Inc.

Received February 26, 1999; revision received June 18, 1999; accepted June 28, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med. 1982;306:1018–1022.[Abstract]
   
2. Wang J, Liu L, Feng J, Nattel S. Regional and functional factors determining induction and maintenance of atrial fibrillation in dogs. Am J Physiol. 1996;271:H148–H158.[Abstract/Free Full Text]
   
3. Daoud EG, Bogun F, Goyal R, Harvey M, Man KC, Strickberger SA, Morady F. Effect of atrial fibrillation on atrial refractoriness in humans. Circulation. 1996;94:1600–1606.[Abstract/Free Full Text]
   
4. Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. Circulation. 1995;92:1954–1968.[Abstract/Free Full Text]
   
5. Ramdat Misier AR, Opthof T, van Hemel NM, Defauw JJAM, de Bakker JMT, Janse MJ, van Capelle FJL. Increased dispersion of "refractoriness" in patients with idiopathic atrial fibrillation. J Am Coll Cardiol. 1992;19:1531–1535.[Abstract]
   
6. Feld GK, Cha Y. Electrophysiologic effects of the new class III antiarrhythmic drug dofetilide in an experimental canine model of pacing-induced atrial fibrillation. J Cardiovasc Pharmacol Ther. 1997;2:195–204.
   
7. Cha Y, Wales A, Wolf P, Shahrokni S, Sawhney N, Feld G. Electrophysiologic effects of the new class III antiarrhythmic drug dofetilide compared to the class IA antiarrhythmic drug quinidine in experimental canine atrial flutter. J Cardiovasc Electrophysiol. 1996;7:809–827.[Medline] [Order article via Infotrieve]
   
8. Feld GK, Venkatesh N, Singh B. Pharmacologic conversion and suppression of experimental atrial flutter: differing effects of d-sotalol, quinidine, and lidocaine and significance of changes in refractoriness and conduction. Circulation. 1986;74:197–204.[Abstract/Free Full Text]
   
9. Feld GK, Venkatesh N, Singh B. Effects of N-acetylprocainamide and recainam in the pharmacologic conversion and suppression of experimental atrial flutter: significance of changes in refractoriness and conduction. J Cardiovasc Pharmacol. 1988;11:573–580.[Medline] [Order article via Infotrieve]
   
10. Anderson JL, Gilbert EM, Alpert BL, Henthorn RW, Waldo AL, Bhandari AK, Hawkinson RW, Pritchett EL. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy: a multi-center, double-blind crossover study of flecainide and placebo with transtelephonic monitoring. Circulation. 1989;80:1557–1570.[Abstract/Free Full Text]
    
11. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation. 1990;82:1932–1939.[Abstract/Free Full Text]
    
12. Gosselink ATM, Crijns HJGM, Van Gelder IC, Hillage H, Wiesfeld AC, Lie KI. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA. 1992;267:3289–3293.[Abstract]
    
13. Blevins RD, Kerin NZ, Benaderat D, Frumin H, Faitel K, Jarandilla R, Rubenfire M. Amiodarone in the management of refractory atrial fibrillation. Arch Intern Med. 1987;147:1401–1404.[Abstract]
    
14. Feld GK. Atrial fibrillation: is there a safe and highly effective pharmacological treatment? Circulation. 1990;82:2248–2250.[Free Full Text]
    
15. Saxena PR. Serotonin receptors: subtypes, functional responses and therapeutic relevance. Pharmacol Ther. 1995;66:339–368.[Medline] [Order article via Infotrieve]
    
16. Hollander W, Michelson AL, Wilkins RW. Serotonin and antiserotonins: their circulatory, respiratory and renal effects in man. Circulation. 1957;16:246–255.[Medline] [Order article via Infotrieve]
    
17. Le Messurier DH, Schwartz CJ, Whelan RF. Cardiovascular effects of intravenous infusions of 5-HT in man. Br J Pharmacol. 1959;14:246–250.[Medline] [Order article via Infotrieve]
    
18. Kaumann AJ, Murray KJ, Brown AM, Frampton JE, Sanders L, Brown MJ. Heart 5-HT receptors: a novel 5-HT receptor in human atrium. In: Paoletti R, Vanhouette PM, Brunello N, Maggi FM, eds. Serotonin: From Cell Biology to Pharmacology and Therapeutics. Dordrecht, Netherlands: Kluwer Academic Publishers; 1989:347–354.
    
19. Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-HT receptor in human atrium. Br J Pharmacol. 1990;100:879–885.[Medline] [Order article via Infotrieve]
    
20. Bockaert J, Fozard JR, Dumuis A, Clarke DE. The 5-HT₄ receptor: a place in the sun. Trends Pharmacol Sci. 1992;13:141–145.[Medline] [Order article via Infotrieve]
    
21. Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-HT₄-like receptor in the human right atrium. Naunyn Schmiedebergs Arch Pharmacol. 1991;344:150–159.[Medline] [Order article via Infotrieve]
    
22. Villalon CM, den Boer MO, Heiligers J, Saxena PR. Mediation of 5-methoxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor. Br J Pharmacol. 1990;100:665–667.[Medline] [Order article via Infotrieve]
    
23. Villalon CM, den Boer MO, Heiligers JPC, Saxena P. Further characterization, by the use of tryptamine and benzamide derivatives, of the putative 5-HT₄ receptor mediating tachycardia in the pig. Br J Pharmacol. 1991;102:107–112.[Medline] [Order article via Infotrieve]
    
24. Kaumann AJ, Sanders L. 5-Hydroxytryptamine causes rate dependent arrhythmias through 5-HT₄ receptors in the human atrium: facilitation by chronic ß-adrenoreceptor blockade. Naunyn Schmiedebergs Arch Pharmacol. 1994;349:331–337.[Medline] [Order article via Infotrieve]
    
25. Kaumann AJ, Sanders L. Both ß₁- and ß₂-adrenoreceptors mediate catecholamine-evoked arrhythmias in isolated human right atrium. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:536–540.[Medline] [Order article via Infotrieve]
    
26. Jahnel U, Rupp J, Ertl R, Nawrath H. Positive inotropic response to 5-HT in human atrial but not in ventricular muscle. Naunyn Schmiedebergs Arch Pharmacol. 1992;346:482–485.[Medline] [Order article via Infotrieve]
    
27. Zhang ZH, Boutjdir M, El-Sherif N. Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes. Circ Res. 1994;75:711–721.[Abstract/Free Full Text]
    
28. Clark RD. Medicinal chemistry of 5-HT₄ receptor ligands. In: Englen RM, ed. 5-HT₄ Receptors in the Brain and Periphery. Georgetown, Tex: RG Landes; 1998:1–48.
    
29. Kaumann AJ. Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT-4-like receptors. Naunyn Schmiedebergs Arch Pharmacol. 1990;342:619–622.[Medline] [Order article via Infotrieve]
    
30. Feld GK, Shahandeh-Rad F. Activation patterns in experimental canine atrial flutter produced by right atrial crush injury. J Am Coll Cardiol. 1992;20:441–451.[Abstract]
    
31. Feld GK, Shahandeh-Rad F. Mechanism of double potentials recorded during sustained atrial flutter in the canine right atrial crush-injury model. Circulation. 1992;86:628–641.[Abstract/Free Full Text]
    
32. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their action on arrhythmogenic mechanisms. Circulation. 1991;84:1831–1851.[Abstract/Free Full Text]
    
33. Ouadid H, Seguin J, Dumuis A, Bockaert J, Nargeot J. Serotonin increases calcium current in human atrial myocytes via the newly described 5-HT receptors. Mol Pharmacol. 1991;41:346–351.[Abstract]
    
34. Berlin JR, Cannell MB, Lederer WS. Cellular origins of the transient inward current in cardiac myocytes: role of fluctuation and waves of elevated intracellular calcium. Circ Res. 1989;65:115–126.[Abstract/Free Full Text]
    
35. Lederer WS, Tsien RW. Transient inward current underlying arrhythmogenic effects of cardiotoxic steroids in Purkinje fibers. J Physiol. 1976;263:73–100.[Abstract/Free Full Text]
    
36. Nitta J, Furukawa T, Marumo F, Sawanobori T, Hiraoka M. Subcellular mechanism for Ca²⁺-dependent enhancement of delayed rectifier K⁺ current in isolated membrane patches of guinea pig ventricular myocytes. Circ Res. 1994;74:96–104.[Abstract/Free Full Text]
    
37. Sanders L, Lynham JA, Bond B, dal Monte F, Harding SE, Kaumann AJ. Sensitization of human 5-HT₄ receptors by chronic ß-blocker treatment. Circulation. 1995;92:2526–2539.[Abstract/Free Full Text]
    
38. Tieleman RG, Van Gelder IC, Crijns HJGM, DeKam PJ, van den Berg MP, Haaksma J, van der Woude HJ, Allessie MA. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation induced electrical remodeling of the atria? J Am Coll Cardiol. 1998;31:167–173.[Abstract/Free Full Text]
    
39. Kaumann AJ, Sanders L. 5-Hydroxytryptamine and human heart function: the role of 5-HT₄ receptors. In: Englen RM, ed. 5-HT₄ Receptors in the Brain and Periphery. Georgetown, Tex: RG Landes; 1998:127–148.
    

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