© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
The effects of 5-HT4 receptor blockade and stimulation, during six hours of atrial fibrillation
2nd Department of Cardiology, Onassis Cardiac Surgery Center 356 Syngrou Avenue, 17674 Athens, Greece
Manuscript submitted 9 November 2004. Accepted after revision 30 June 2005.
*Corresponding author. Tel.: +30 210 9493372/3000, +30 6944785025 (mobile); fax: +30 10 9493 373. dionle1{at}otenet.gr
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Abstract |
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AIMS: Stimulation of atrial 5-HT4 receptors is associated with arrhythmias. Their blockade prolongs atrial effective refractory period (ERP), following short runs of atrial fibrillation (AF). The role of 5-HT4 receptors during longer periods of AF is unknown. In this study, we investigated the effects of the selective 5-HT4 receptor stimulation and blockade on porcine atria, during 6 h of AF.
METHODS: Atrial ERP, monophasic action potential (MAP) duration, time to sinus rhythm restoration (TSRR) and ERP/MAP ratio were assessed in 27 pigs, at baseline and every hour, during 6 h of AF, induced by rapid atrial pacing. Ten animals were used as controls, 10 were administered the selective 5-HT4 antagonist SB203186 and seven were administered the selective 5-HT4 agonist RS67333.
RESULTS: During the first few hours of fibrillation, ERP, MAP and TSRR were preserved in SB203186-treated pigs, while they were shortened in controls and RS67333-treated animals. After 6 h of arrhythmia, ERP and MAP were shortened in all three groups, but the decrease was less in SB203186-treated pigs. ERP/MAP ratio increased in controls and RS67333-treated animals, while it remained unchanged in SB203186-treated pigs. Towards the end of the AF period, four of the SB203186-treated pigs developed sustained atrial tachycardia.
CONCLUSION: Following short periods of AF, 5-HT4 receptors' blockade protects the porcine atria against ERP and MAP shortening, while their stimulation has the opposite result. This beneficial effect, though, is gradually diminished following longer periods of AF and atrial tachycardia may develop.
Key Words: atrial fibrillation, serotonin (5-HT)
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Introduction |
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There is evidence suggesting that 5-HT4 receptors are present in the porcine and human atria and their stimulation may elicit sinoatrial tachycardia in pigs, an effect that can be prevented or reversed by the blockade of porcine 5-HT4 receptors[1–
3]. The increased human atrial contractility and experimental arrhythmias induced by serotonin in humans [4–9] are also prevented or abolished by selective 5-HT4 receptor-antagonists [3,7,8,10,11]. Furthermore, it has been reported that 5-HT4 receptor blockade prevents shortening of the effective refractory period (ERP) in pigs, following a brief period of rapid right atrial pacing[12], and this might imply protection against electrical remodelling. However, the question whether the blockade of atrial 5-HT4 receptors has any antiarrhythmic effect and protects the atrium following longer periods of atrial fibrillation (AF) has not yet been answered. In this study, we investigated the influence of (a) the selective 5-HT4 blockade and (b) the selective 5-HT4 stimulation on the porcine atrium, during a 6 h period of AF. |
Methods |
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Experimental preparation
Thirty-three juvenile male pigs (mean weight 23 ± 1.5 kg) were included in the study, divided into three groups of 11 each. They were sedated by intramuscular administration of midazolam (0.5 mg/kg) and ketamine (15 mg/kg) and then anaesthetized by intravenous infusion of propofol (3 mg/kg bolus plus 0.15 mg/kg/min maintenance infusion), fentanyl (10 µg/kg bolus and then 250 µg/h) and pancuronium bromide (4 mg bolus plus 2 mg every 20 min). All pigs were intubated and ventilated mechanically with room air (15 ml/kg, 16–18 breaths per minute). Then, in a closed-chest procedure, both jugular veins and right carotid artery were cannulated via direct cutdown, for the insertion of electrodes and for blood pressure monitoring. A monophasic action potential recording electrode (MAP), with pacing poles (Franz catheter, EP Technologies, Sunnyvole, California, USA), was advanced to the right atrial free wall and positioned in a place where a satisfactory atrial monophasic action potential was recorded and a good pacing threshold was achieved. MAP recordings were obtained with two nonpolarizable silver chloride electrodes, one at the tip of the catheter and the other located 5 mm proximal to the tip. Pacing was performed with two platinum electrodes mounted opposite to each other at 2 mm distance from the catheter tip. This allowed us to obtain reliable MAP recordings and measure the ERP of the atrial tissue at the same location. MAP signals were amplified via a custom-made amplifier that allowed fine tuning of stimulus output strength in a range < 1 mA. ECG (derivation II) was continuously recorded. Blood pressure was monitored continuously during the study.
A quadripolar electrode was also introduced in the right atrium for atrial pacing, fibrillation induction, and intracardiac atrial activity recording. All recordings were performed by a Nihon Kohden recording system (Polygraph Systems RM-6000).
Electrophysiological study
Heart rate in sinus rhythm (HR), systolic and diastolic blood pressure (SBP and DBP, respectively), P–R interval and QTc (QT corrected by Bazzet's formula) were measured in all animals. Basic measures of MAP and ERP in sinus rhythm and with driving cycles of 400 and 300 ms were also obtained. MAP was continuously recorded throughout the experiment. Every time the duration of the MAP had to be measured, the stability of MAP configuration was confirmed. Then the mean of five sequential stable MAPs was considered as the MAP duration at that time. ERP was measured by extrastimulus (S2) introduced following eight sensed (in sinus rhythm) or paced (S1) cycles. Pacing output was twice atrial threshold. S1–S2 coupling intervals were decreased during diastole in steps of 10 ms, until the extrastimulus began to encroach into the repolarization phase of the S1 response. At this point, the coupling interval was decreased in 5 ms steps, until capture was lost. The longest coupling interval between the basic S1 MAP and the extrastimulus artifact that failed to produce atrial response was defined as ERP. MAP was measured at the level of 90% repolarization at the stimulation site.
Six of the 33 pigs were excluded, because, in four cases, no stable MAP recordings were achieved throughout the study, and in the other two cases, ventricular tachycardia developed during catheter manipulation.
Following these initial measurements, 100 ml of normal saline, infused over 10 min, and 100 ml more of normal saline continuously infused for 6 h, were administered in 10 of the remaining 27 animals (control group). In another 10 pigs, the selective 5-HT4 receptor-antagonist SB203186, diluted in 100 ml of normal saline, was intravenously infused over 10 min, at a dose of 1.5 mg/kg (SB203186-treated group). A second identical dose of SB203186 was continuously administered throughout the study. The dose-related 5-HT4 antagonism of serotonin-induced tachycardia by SB203186 has been previously reported[3,7]. The remaining seven pigs of the third group, were intravenously administered the selective 5-HT4 receptor agonist RS67333 at a dose of 300 µg/kg bolus, as previously described (RS67333-treated group)[13,14]. A continuous administration of another dose of RS67333 300 µg/kg was delivered throughout the study.
Following the initial infusion of normal saline, SB203186, or RS67333, we reevaluated all the above-mentioned parameters in the three groups, and we assessed their changes in comparison with the initial values. Then, rapid atrial pacing was performed by a pacing device delivering extrastimuli at a rate of 50 HZ and 0.1 mA. Atrial fibrillation was induced in all 27 animals. Every hour, rapid atrial pacing was interrupted and the time to sinus rhythm restoration (TSRR) was assessed. If AF did not terminate within 10 min, DC cardioversion was performed. HR, SBP, DBP, PR interval, QTc, ERP, MAP duration and ERP/MAP ratio at drive cycle lengths of 400 and 300 ms were assessed again. After this, pacing was started again and all variables were reassessed up to the full 6 h of AF. Heparin (1000 iu/h) was intravenously infused, following electrode introduction and every hour during the 6 h period of AF.
The protocol of the study was approved by Animal Care Committee, according to the Declaration of Helsinki, the European Union Act and the Greek Law for Experimentation.
Statistical analysis
Comparisons of absolute values of the evaluated variables among the three groups were analyzed using the One way Analysis of Variance model. Paired multiple comparisons were performed using the Scheffe test.
One factor repeated measures ANOVA was used for the comparison of each variable separately during the 6 h of AF (baseline to 6 h after the drug infusion). Paired multiple comparisons were performed using the method of Turkey critical difference.
In order to indicate the trend of the assessed parameter in each group from baseline (after the drug administration), the mean percentage changes for each time point and their standard errors of the mean were evaluated. All changes from baseline values were compared among the three groups by means of One way Analysis of Variance model. Paired multiple comparisons were performed using the Scheffe test.
The Mann–Whitney U test was used to compare time to sinus rhythm restoration and the incidence of atrial tachycardia between groups. For all tests, a P value <0.05 was considered to be statistically significant.
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Results |
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ECG and blood pressure measures
In all the three groups, following SB203186, RS67333 or normal saline infusion, no significant changes were observed in HR, QTc and PR interval compared with baseline measures (Table 1). During the 6 h of AF, HR in sinus rhythm, QTc and PR interval also remained stable in all groups. Similarly, SBP and DBP did not change following SB203186, RS67333 or normal saline administration and they remained unaltered during the 6 h of AF in all the three groups, as shown in Table 1.
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ERP measures
Following the intubation of the pigs and the insertion of the electrodes, ERP values in sinus rhythm and at pacing cycle length of 400 and 300 ms were comparable between the three groups.
Before AF induction, placebo administration was not followed by any change in ERP during sinus rhythm and at each of the pacing cycle lengths. SB203186 infusion was associated with a prolongation of atrial ERP in sinus rhythm and at pacing cycle lengths of 400 and 300 ms: 152 ± 29 ms vs 140 ± 30 ms, 156 ± 29 ms vs 141 ± 30 ms, and 146 ± 29 ms vs 135 ± 29 ms, respectively (P < 0.05 for each comparison). On the contrary, RS67333 infusion was associated with a shortening in atrial ERP in sinus rhythm and at both drive cycle lengths (400 and 300 ms): 125 ± 13 ms vs 135 ± 14 ms (P < 0.01), 135 ± 42 ms vs 145 ± 47 ms (P < 0.01), and 122 ± 35 ms vs 132 ± 44 ms (P < 0.05), respectively.
During the 6 h of AF, a significant decrease in ERP was observed in all the three groups (controls, SB203186-treated and RS67333-treated), compared with baseline values. However, at each hour of AF the ERP shortening in the SB203186-treated pigs was less than in the RS67333-treated and the control group, during sinus rhythm, at 400 ms pacing cycle length, and at pacing cycle of 300 ms. On the contrary, in the RS67333-treated group, ERP values were shorter than in the control group, especially during the first 4 h of AF. The proportional ERP changes are shown in Fig. 1.
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MAP duration
Baseline MAP duration was comparable in the three groups (controls, RS203186-treated and RS67333-treated) in sinus rhythm and at each pacing cycle length.
Before AF induction, placebo administration did not cause any change in the MAP duration, while SB203186 infusion prolonged MAP and RS67333 shortened MAP during sinus rhythm, at 400 ms pacing cycle length and at 300 ms pacing cycle length. SB203186 infusion was associated with a prolongation of the plateau of the MAP (phase 2), as shown in Fig. 2. On the contrary, RS67333 shortened the plateau and was associated with a steeper slope of MAP during phase 3.
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During the 6 h of AF, MAP was shortened in all the three groups, as shown in Fig. 3. This shortening was significantly less in the SB203186-treated group than in the other two groups during the 6 h of AF. At each hour of AF, MAP duration in sinus rhythm, and at pacing cycle length of 400 and 300 ms was longer in the SB203186-treated group than in the control and the RS67333-treated groups (P < 0.05). The opposite was observed in RS67333-treated pigs: in this group, MAP was significantly shorter than in the control group during the first 4 h of the arrhythmia, although this difference was not always statistically significant.
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ERP/MAP ratio evaluation
The ERP/MAP ratio remained unaltered following SB203186 or RS67333 infusion, compared with the initial values.
During the 6 h of AF, no significant changes in ERP/MAP ratio were observed in the SB203186-treated group, compared with baseline measures. In contrast, a statistically significant increase was observed in the ERP/MAP ratio in the RS67333-treated and the control group. As shown in Fig. 4, the increase in ERP/MAP ratio, observed in the control and RS67333-treated groups, started after the second hour of AF and became gradually larger by the end of the 6-h AF period.
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Time to sinus node restoration and atrial tachycardia
As shown in Table 2, following 1 and 2 h of AF, the time to sinus rhythm restoration was significantly shorter in the SB203186-treated group than in the control group and the RS67333-treated animals. Following 3, 4, 5 and 6 h of AF, time to sinus node restoration was not significantly different between the three groups.
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Following 4 h of AF, one of the SB203186-treated pigs developed a sustained atrial tachycardia, immediately after the termination of AF. This tachycardia lasted 2 min and was self-terminated. Following 5 and 6 h of AF, the number of pigs, among the SB203186-treated animals, that developed a sustained atrial tachycardia increased to four (P < 0.05 compared with RS67333-treated and the control groups). In two of them, this tachycardia was terminated by external cardiovertion, 10 min after its development. In the remaining two pigs, the tachycardia was self-terminated after 5 and 8.5 min.
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Discussion |
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The effects of atrial 5-HT4 receptor blockade, following a relatively long period of AF have not so far been investigated. To our knowledge, this is the first study concerning the effects of atrial 5-HT4 stimulation and blockade after 6 h of arrhythmia. Our main findings are the following: (a) SB203186 seems to protect the porcine atrium against the ERP and MAP shortening during the first few hours of AF, although this beneficial effect is limited towards the end of the AF period. On the contrary, RS67333 hastens the shortening of ERP and MAP. (b) The ERP/MAP ratio remained stable in the SB203186-treated group, while it increased in RS67333-treated animals and in the control group. (c) SB203186 infusion was associated with shorter time to sinus rhythm restoration than that observed in the RS67333-treated group and the control group, following 1 and 2 h of AF. However, SB203186 did not protect the porcine atrium against arrhythmias; on the contrary, it increased the incidence and duration of atrial tachycardias following 5 and 6 h of AF, compared with RS67333-treated pigs and the control group.
Activation of 5-HT4 receptors in human isolated atrial strips causes a positive inotropic and arrhythmic response [3,8,9]. The selective location of 5-HT4 receptors in human atrial tissue has led to the suggestion that their activation may play a role in the pathogenesis of atrial arrhythmias, including AF. It has been proposed that serotonin release and 5-HT4 receptor activation cause an increase in atrial cAMP levels and cAMP-dependent protein kinase activity and thus the phosphorylation of L-type Ca2+ channels, leading to increased atrial cytoplasmic Ca2+. Arrhythmia may be induced due to calcium overload that leads to oscillations at repolarization and triggered activity [4,7,11].
Another mechanism possibly responsible for the 5-HT4 receptor mediated arrhythmogenesis is that suggested by Pino et al., regarding the effect of serotonin on the hyperpolarization-activated current If in human atrial myocytes[15]. The voltage of half- maximal activation for If in human atrial cells is approximately –90 mV, whereas the maximal diastolic potential is less negative[16,17]. In Pino's study, it has been demonstrated that serotonin causes a shift of the activation voltage of If to less negative potentials and the resultant inward current may lead to spontaneous diastolic depolarization and arrhythmic activity[15].
Blockade of 5-HT4 receptors reduces the arrhythmogenic effect of serotonin on atrial myocytes[7,8]. The mechanisms of this antiarrhythmic activity are not clear. Recently, Rahme et al. carried out in vivo experiments in pigs and have shown that the selective 5-HT4 antagonist RS100302 prolonged the atrial ERP and prevented reinduction of atrial flutter or fibrillation, when administered following a short period of rapid atrial pacing[12]. Our observations are in agreement with Rahme's findings, in regard to the changes in atrial ERP following SB203186 infusion. Furthermore, investigating the atrial electrical remodelling during a longer period of AF, we have observed that ERP shortening was significantly less in the SB203186-treated group. In addition, the selective 5-HT4-receptor blockade was associated with protection against MAP shortening (Fig. 3). The adverse result was observed following 5-HT4 stimulation by the selective agonist RS67333. When the morphology of MAP before and following the AF period was compared between groups (Fig. 2), a remarkable shortening of the plateau was observed in the control group, without any prominent change in the slope of phase 3. In the RS67333-treated group, an almost total disappearance of the plateau was observed, accompanied by a steeper slope of the MAP during phase 3. On the contrary, in the SB203186-treated group, the plateau was diminished but still distinguishable, while a smoother slope was observed in MAP during phase 3. The effects of 5-HT4 blockade on the atrial ERP and MAP could be attributed to the protection against the fibrillation-induced ICaL reduction. Additionally, there are indications that the potassium currents IK1, IKACh may also be involved, although this hypothesis has yet to be proven [17–24].
The time to sinus rhythm restoration, following the first 2 h of AF, was shorter in the SB203186-treated group than in the control and the RS67333-treated groups and this might imply a protective effect of serotonin antagonism against atrial electrical remodelling. However, following 3 h of AF, this effect was not observed any more and no difference in time to sinus rhythm restoration was found between the three groups. Additionally, a sustained atrial tachycardia developed in some SB203186-treated animals. Interestingly, the ERP/MAP ratio was significantly lower in this group compared with the control group and RS67333-treated pigs, following 6 h of AF. The precise mechanism of this tachycardia is not known, but it might be associated with the low ERP/MAP ratio which is considered to be arrhythmogenic. Previous studies have shown that the increase in ERP/MAP ratio is an index of the efficacy of antiarrhythmic drugs[25,26]. The low ERP/MAP ratio indicates an ERP which is shorter than MAP. Consequently, there is a vulnerable to excitation period between the end of ERP and the end of MAP; during this period, the triggering of a tachycardia due to afterdepolarizations may be facilitated[2,22]. Recently, it has been reported that conditions of increased atrial wall stress predisposing to AF are also associated with a decrease in ERP/MAP ratio[27].
The waning protective effect of SB203186 on the porcine atrium following the first few hours of fibrillation could be attributed to the relatively rapid desensitization of 5-HT4 receptors[28–31]. Another speculative explanation is that Ca2+ channels and 5-HT4 receptors may have a critical role during the first hours of AF, but not after longer periods of the arrhythmia. The underlying mechanisms may be analogous to those of verapamil, which has been reported to protect the atrium during short-term AF, but not after long periods of atrial pacing[32,33]. Finally, the conditions of prolonged anaesthesia may have contributed to the gradually decreased effect of 5-HT4 agonism and antagonism.
According to our observations, R–R, QT and QTc intervals remained unaltered during the AF period. This might be an indirect indication that ventricular MAP and refractoriness were not modified by SB203186 and RS67333 administration[34].
In the present study, the selective effect of the 5-HT4 antagonist SB203186 and 5-HT4 agonist RS67333 have been studied in two groups of pigs and compared with a placebo-group. Although a simultaneous administration of the two agents would have shown that the effect of each is reversed by the other, our observations point out that the 5-HT4 antagonist and agonist have the opposite effect on the 5-HT4 receptors.
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Conclusion |
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Our study shows that selective 5-HT4 blockade might protect the porcine atrium against electrical remodelling, following short periods of AF. This beneficial effect seems to be gradually diminished following longer periods of AF. However, further studies are required to investigate whether the selective antagonism of 5-HT4 receptors has any clinical implication in human patients with paroxysmal AF.
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References |
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