* Conflict of interest: Ketil Haugan was a full-time employee at Zealand Pharma A/S during the time of the study.
Rotigaptide (ZP123) Improves Atrial Conduction Slowing in Chronic Volume Overload-Induced Dilated Atria
Article first published online: 7 JUL 2006
Basic & Clinical Pharmacology & Toxicology
Volume 99, Issue 1, pages 71–79, July 2006
How to Cite
Haugan, K., Miyamoto, T., Takeishi, Y., Kubota, I., Nakayama, J., Shimojo, H. and Hirose, M. (2006), Rotigaptide (ZP123) Improves Atrial Conduction Slowing in Chronic Volume Overload-Induced Dilated Atria. Basic & Clinical Pharmacology & Toxicology, 99: 71–79. doi: 10.1111/j.1742-7843.2006.pto_432.x
- Issue published online: 7 JUL 2006
- Article first published online: 7 JUL 2006
- (Received December 23, 2005; Accepted February 2, 2006)
Abstract: Chronic atrial dilation is associated with atrial conduction velocity slowing and an increased risk of developing atrial tachyarrhythmias. Rotigaptide (ZP123) is a selective gap junction modifier that increases cardiac gap junctional intercellular communication. We hypothesised that rotigaptide treatment would increase atrial conduction velocity and reduce the inducibility to atrial tachyarrhythmias in a model of chronic volume overload induced chronic atrial dilatation characterized by atrial conduction velocity slowing. Chronic volume overload was created in Japanese white rabbits by arterio-venous shunt formation. Atrial conduction velocity and atrial tachyarrhythmias inducibility were examined in Langendorff-perfused chronic volume overload hearts (n=12) using high-resolution optical mapping before and after treatment with rotigaptide. Moreover, expression levels of atrial gap junction proteins (connexin40 and connexin43) were examined in chronic volume overload hearts (n=6) and compared to sham-operated controls (n=6). Rotigaptide treatment significantly increased atrial conduction velocity in chronic volume overload hearts, however, rotigaptide did not decrease susceptibility to the induction of atrial tachyarrhythmias. Protein expressions of Cx40 and Cx43 were decreased by 32% and 72% (P<0.01), respectively, in chromic volume overload atria compared to control. To conclude, rotigaptide increased atrial conduction velocity in a rabbit model of chromic volume overload induced atrial conduction velocity slowing. The demonstrated effect of rotigaptide on atrial conduction velocity did not prevent atrial tachyarrhythmias inducibility. Whether rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.
A decade ago, modification of cardiac gap junction intercellular communication was proposed as a new treatment strategy for the treatment of cardiac arrhythmias (Dhein & Tudyka 1995). Cardiac gap junctions are transmembrane channels that transmit electrical impulses between neighbouring cells. Cardiac gap junctions are responsible for the synchronized propagation of the action potential from cell to cell and are a major determinant of cardiac conduction velocity (Rohr et al. 1998). Several clinical and experimental studies have shown that abnormal atrial conduction and impaired gap junction intercellular communication are important in the pathogenesis of atrial fibrillation (AF) (Sato et al. 1992; Verheule et al. 1999; Anyukhovsky et al. 2002; Hayashi et al. 2002; Ohara et al. 2002; Sinno et al. 2003; Rosiak et al. 2003; Budeus et al. 2005).
Recently, a selective gap junction modifier, named rotigaptide (formerly known as ZP123), has been developed (Kjølbye et al. 2003). Rotigaptide is a stable analogue of the naturally occurring antiarrhythmic peptide first described in 1980 (Aonuma et al. 1980). Rotigaptide increases gap junction intercellular communication in pairs of ventricular cardiomyocytes (Xing et al. 2003), prevents ventricular conduction slowing (Eloff et al. 2003), and prevents and reverts atrial conduction slowing (Haugan et al. 2005a & 2005b). Moreover, rotigaptide treatment reduces the incidence of ischaemia-induced reentrant ventricular tachycardia (Xing et al. 2003) and ischaemia-reperfusion-induced ventricular tachycardia (Hennan et al. 2005). Thus, gap junction modification with rotigaptide has been proven efficacious in two different experimental models of ventricular arrhythmias, and clinical trials examining the effect of rotigaptide in the treatment of ventricular arrhythmias are currently ongoing. However, the effect of rotigaptide on atrial tachyarrhythmia inducibility has not been investigated previously.
In the present study we examined the effect of rotigaptide on atrial conduction and atrial tachyarrhythmia inducibility in a rabbit model of chronic atrial dilatation characterized by slowed atrial conduction (Hirose et al. 2005). Several clinical and experimental studies have shown that chronic atrial dilation is associated with atrial conduction slowing and an increased risk of developing atrial fibrillation (Keren et al. 1987; Benjamin et al. 1994; Verheule et al. 2004; Hirose et al. 2005; Neuberger et al. 2005). We hypothesized that rotigaptide would increase atrial conduction velocity and thereby reduce the inducibility of atrial tachyarrhythmia in the chronically dilated atria.
Materials and Methods
Surgical procedures. The experimental protocol was approved by the institutional animal experiments committee and it complied with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication 85-23, revised 1996). Chronic atrial dilation was created in 18 Japanese white rabbits (2.0–2.5 kg) using chronic volume overload for 8 weeks induced by arterio-venous shunt formation (carotid-jugular shunt) as previously described (Takahashi et al. 2000). As a control, 6 rabbits only underwent an incision at the neck. The rabbits were housed individually in cages with light on between 9:00 a.m. and 9:00 p.m. and were provided water and the usual stock diet (120 g/day, Labo-R-Grower, Nihon Nosan Kogyo Ltd., Tokyo, Japan).
Echocardiography. Echocardiography was performed eight weeks after shunt surgery to quantify the degree of atrial dilatation. Briefly, rabbits were lightly anesthetized with an intravenous injection of sodium pentobarbital (10 mg/kg) and placed in the left lateral decubitus position. Two-dimensional and M-mode echocardiograms were recorded with a 7.5 MHz transducer, using commercially available equipment (SSA260A; Toshiba Co., Ltd., Tochigi, Japan). Left atrial diameter was measured by the leading-edge method at long axis view. Data from three successful measurements were averaged and used for later analysis.
Electrophysiological study. Eight weeks after shunt surgery the rabbits were treated with sodium heparin (500 units/kg, intravenously) and anaesthetized with sodium pentobarbital (30 mg/kg intravenously). After a midline sternal incision, hearts including myocardial sleeves in the pulmonary veins were quickly excised and connected to a modified Langendorff apparatus. Each preparation was perfused with oxygenated (95% oxygen, 5% CO2) Tyrode's solution containing in mM: NaCl, 128.0; KCl, 4.7; CaCl2, 1.3; NaHCO3, 25.0; MgCl2, 0.5; NaH2PO4, 1.2; dextrose, 11.0 and 2,3-butanedione monoxime (BDM), 5 (pH of 7.4 at 36±1 °). Perfusion pressure was measured with a pressure transducer (Nihon Kohden Co, Tokyo, Japan) and maintained within a pressure range (50–60 mmHg) by adjusting flow. Preparations were stained with 200 ml of the voltage sensitive dye, di-4-ANEPPS (Molecular Probes, Eugene, OR, USA) dissolved in 0.19 ml of ethanol at a final concentration of 7.5 μM by direct coronary perfusion for 5 to 7 min. Cardiac rhythm was monitored using 3 silver disk electrodes fixed to the chamberin positions corresponding to ECG limb leads I, II, and III. The ECG signals were filtered (0.3 to 300 Hz), amplified (1000×), and displayed on a digital recorder. Perfusion pressure and flow were continuously monitored during each experiment. The optical mapping system used in this study has been described in detail elsewhere (Laurita et al. 1996; Laurita & Rosenbaum 2000; Hirose et al. 2005). Briefly, excitation light (514 nm) obtained from a 250 W quartz tungsten halogen lamp (Oriel Co. Stratford, CT, USA) was directed to the heart using a liquid light guide. Fluorescent light from the heart was collected by a tandem lens assembly and directed to a long pass filter (>630 nm) that passes light of longer wavelengths to a 16×16 element photodiode array. Signals recorded from each photodiode and ECG signals were multiplexed and digitized with 12-bit precision at a sampling rate of 1000 Hz per channel (Microstar Laboratories Inc., Bellevue, WA, USA). An optical magnification of 0.81× was used, corresponding to a mapping field of 2.1 cm×2.1 cm and 0.13 cm spatial resolution between recording pixels. To view, digitize, and store anatomical features, a mirror was temporarily inserted between the lenses of the tandem lens assembly to direct reflected light to a digital video camera (DCR-PC120 Sony Co. Tokyo, Japan).
Two polyterafluoroethylene-coated silver bipolar electrodes with 1-mm interelectrode spacing were used to stimulate the epicardial surface of the right atrial appendage at twice a diastolic threshold current with duration of 1 msec. First, to measure atrial conduction velocity, optical action potentials were recorded for 5 sec. from right atrial free walls at a basic cycle length of 300, 200 and 100 msec. before and after vehicle (vehicle treated group, n=5) or rotigaptide (10 nM) treatment (rotigaptide-treated group, n=7). Secondly, to induce atrial tachyarrhythmia, rapid atrial pacing was performed for approximately 10 sec. from the right atrium after vehicle or rotigaptide treatment. The pacing cycle length was decreased from 100 to 50 msec. by 10 msec. decrements until atrial tachyarrhythmia occurred. Atrial tachyarrhythmia was defined as a rapid (cycle length<180 msec.) regular or irregular rhythm persisting longer than 1 min. Each experiment ended after rapid pacing was performed ten times or when rapid pacing induced atrial tachyarrhythmia. One minute after atrial tachyarrhythmia induction, optical action potentials were recorded sequentially from the epicardial surface of three areas in both atria for 5 sec. as described previously (Hirose et al. 2005).
Western blot analysis of atrial Cx40 and Cx43 expression. Changed expression levels of atrial gap junction proteins have been described in several experimental models of atrial fibrillation (Elvan et al. 1997; van der Velden et al. 2000). To determine the expression of the major atrial gap junction proteins, connexin40 and connexin43 were measured in chronic volume overload atria (n=6) and in control (n=6). In this study, rabbits were anaesthetized with sodium pentobarbital (30 mg/kg intravenously) and their atrial tissue was isolated and homogenized in ice-cold lysis buffer containing (mM) NaCl 50, NaF 100, Tris-HCl 25, (%) sodium deoxycholate 0.5, NP-40 2.0, SDS 0.2 and sodium vanadate 200 μM at pH 7.4, along with 10 μg/ml leupeptin, 10 μg/ml aprotinin, 100 μg/ml PMSF as previously reported (Takeishi et al. 1999). Equal amounts of protein (confirmed by Ponceau S staining) were subjected to electrophoresis on 8–14% SDS-polyacrylamide gels and transferred to polyvinylidene fluoride (PVDF) membranes (Hybond P, Amersham Pharmacia Biotech, Inc., NJ, USA). After blocking, membranes were incubated with primary antibodies specific to connexin40 (Chemicon International, CA, USA) and connexin43 (BD Transduction Laboratories, CA, USA). After washing, membranes were then incubated with horseradish peroxidase-conjugated secondary antibody (Santa Cruz Biotechnology, Inc., CA, USA). Immunoreactive bands were visualized by the enhanced chemiluminescence detection method (Amersham Pharmacia Biotech, Inc., NJ, USA), normalized to the protein expression of GAPDH, and quantified using a densitometer with an imaging system.
Data analysis. In all experiments, automated algorithms were used to determine depolarization time relative to a single fiducial point (i.e., the stimulus). Depolarization time was defined as the point of maximum positive derivative in the action potential upstroke (dV/dtmax). Depolarization contour maps were computed for the entire mapping field (see fig. 1). The method of Bayly et al. (1998) was modified for optically recorded action potential maps to accurately quantify the direction and magnitude of conduction velocity at each recording site. Mean conduction velocity was calculated as previously described (Hirose et al. 2005). To analyse the activation pattern during atrial tachyarrhythmia, spectral analysis was performed using the Fast Fourier transforms (FFTs) on single-pixel optical recordings. The relative amplitude of peaks in the FFT was compared to determine the dominant frequency of each optical signal at 256 sites.
Statistics. Two-way analysis of variance (ANOVA) followed by Fisher's least significant difference test was used for the statistical analysis of conduction velocity data before and after treatment with vehicle or rotigaptide. Inducibility of atrial tachyarrhythmia was analyzed using Fishers' exact test (Chi-square test). Differences in connexin expression, left atrial diameter and heart weight were compared using Student's t-test for unpaired data. For all analyses, P<0.05 was considered statistically significant. All data are shown as mean±S.E.M.
Drugs. Rotigaptide (proposed INN name for the drug formerly known as ZP123) (Ac-D-Tyr-D-Pro-D-4-Hyp-Gly-D-Ala-Gly-NH2; purity 97%) was synthesized at Bachem AG (Bubendorf, Switzerland) for Zealand Pharma A/S and dissolved in isotonic saline.
Atrial diameter and heart weight.
The left atrial diameter was similar between rotigaptide and vehicle treated group (vehicle: 15.0±0.9 mm versus rotigaptide: 16.9±0.7 mm, P=0.12). Moreover, there were no differences in heart weight between the two groups (vehicle: 15.6±0.9 g versus rotigaptide: 16.2±0.3 g, P=0.49).
Rotigaptide increased atrial conduction velocity in chronic volume overload hearts.
The perfusion pressure was stable during the optical mapping experiments and there were no differences in the pressure between the two groups (data not shown).
Fig. 1 shows representative examples of isochrone maps during steady-state pacing from right atrial appendage at a basic cycle length of 100 msec. before and after treatment with rotigaptide and vehicle. Before treatment with rotigaptide and vehicle, large areas with marked atrial conduction slowing was present in both hearts (illustrated by relative crowding of isochrones). After treatment with rotigaptide, atrial conduction was markedly increased (illustrated by less crowding of isochrones). In contrast to the rotigaptide treated heart, the activation pattern was unchanged in the vehicle treated heart.
Fig. 2 shows the atrial conduction velocity at three different pacing cycle lengths before and after treatment with rotigaptide and vehicle. There were no differences in atrial conduction velocity at baseline (i.e. prior to treatment) between the rotigaptide and vehicle treated group (conduction velocity at pacing cycle length 300, 200, and 100 msec.; vehicle: 0.68±0.04, 0.66±0.04, 0.58±0.06 m/sec. versus rotigaptide: 0.66±0.03, 0.63±0.03, 0.52±0.05 m/sec., P=0.5). Treatment with vehicle had no effect on atrial conduction velocity, indicating that the cardiac preparation was stable for the entire duration of the experiment. In contrast, treatment with rotigaptide (10 nM) resulted in a significant increase in atrial conduction velocity relative to baseline (P<0.05, two-way ANOVA).
Rotigaptide had no effect on atrial tachyarrhythmia inducibility.
In vehicle treated-hearts, reentrant atrial tachyarrhythmia was induced in 3 out of 5 hearts following rapid pacing. This was not different from the atrial tachyarrhythmia inducibility that has been reported by us previously (Hirose et al. 2005). Reentrant atrial tachyarrhythmia was induced in 3 out of 7 rotigaptide-treated hearts after rapid pacing. Furthermore, in one rotigaptide-treated heart, a supraventricular tachyarrhythmia that resembled AV nodal reentrant tachycardia (AVNRT) was induced. Thus, rotigaptide had no overall effect on atrial tachyarrhythmia inducibility (qui-square: P=0.45).
Fig. 3 shows the effects of rotigaptide on atrial conduction velocity in hearts in which atrial tachyarrhythmia was induced as well as in hearts in which atrial tachyarrhythmia was not induced. Rotigaptide increased atrial conduction velocity in all hearts regardless of atrial tachyarrhythmia induction. This suggests that the lack of antiarrhythmic effect of rotigaptide was not due to a lack of effect on atrial conduction velocity in the atrial tachyarrhythmia-induced hearts.
Fig. 4 shows a representative example of an episode of reentrant atrial tachyarrhythmia in a rotigaptide treated chronic volume overload heart. The activation maps were recorded sequentially from the left (panel B, left) and the right atrium (panel B, right) during atrial tachyarrhythmia. The position of the recording areas and the pacing site in the right atrial appendage is shown in the diagram in fig. 4 (panel A). The activation map from the right atrium shows an incomplete macroreentrant circuit rotating counterclockwise persisting for the entire length of the recording time (5 sec.). The sequentially recorded activation maps from the left atrium (fig. 4, panel B, left) showed propagation of daughter waves from the reentrant circuit in the right atrium. FFTs of the optical action potentials recorded from the left atrium showed a single peak at a frequency of 10.7 Hz (fig. 4, panel C, right) identical to that of the reentrant circuit in the right atrium (fig. 4, panel C, right) indicating that the activity emanating from the rotor (daughter waves) propagated in a 1:1 fashion. The optical signals from both areas were regular and the FFTs showed the same dominant frequency, suggesting that the mechanism of atrial tachyarrhythmia was atrial flutter.
Chronic volume overload-induced atrial dilatation was associated with a reduced atrial Cx40 and Cx43 expression.
A separate study was performed to examine the atrial connexin expression levels in the rabbit chronic volume overload model. Fig. 5A and 5B shows that the relative expression levels of atrial Cx40 and Cx43 proteins were significantly lower in chronic volume overload hearts compared to control hearts (i.e. from rabbits subjected to sham surgery). In the connexin study left atrial diameter was increased in the chronic volume overload hearts (16.8±0.3 mm, n=6) compared to control hearts (11.4±0.6 mm, n=6). Importantly, there was no difference in the degree of atrial dilatation between chronic volume overload hearts used for measurements of connexin expression and those used for electrophysiological measurements.
The major finding in this study is that the gap junction modifier rotigaptide improves atrial conduction slowing in a model of chronic atrial dilatation due to chronic volume overload. However, the effect of rotigaptide on atrial conduction was not sufficient to prevent atrial tachyarrhythmia induction in this model. Rotigaptide has previously been shown to have significant effects on cardiac conduction velocity in vitro (Eloff et al. 2003; Haugan et al. 2005b) and cardiac arrhythmias in vivo (Kjølbye et al. 2003; Xing et al. 2003). In the present study, rotigaptide produced a significant increase in atrial conduction velocity in hearts from rabbits with chronic atrial dilatation. The use of a vehicle-treated control group (in which atrial conduction velocity was stable over time) allows us to conclude that the increase in atrial conduction velocity in the rotigaptide-treated group was caused by the drug. We used a concentration of rotigaptide (10 nM) which has been reported to increase gap junction intercellular communication in pairs of ventricular cardiomyocytes (Xing et al. 2003), to prevent stress- and acidosis-induced cardiac conduction slowing (Eloff et al. 2003; Haugan et al. 2005b), to prevent ischaemia-induced re-entry ventricular tachycardia (Xing et al. 2003), and to revert established cardiac conduction slowing (Haugan et al. 2005a).
While previous studies with rotigaptide were performed in animals without chronic heart disease, this is the first study to examine the effects of rotigaptide in chronically remodelled hearts. Thus, our data provides evidence that rotigaptide can increase atrial conduction velocity in chronically remodelled hearts.
Interestingly, the atrial tachyarrhythmia inducibility in rotigaptide-treated hearts was similar to that in vehicle-treated hearts. As illustrated in fig. 3, rotigaptide increased atrial conduction velocity in the atrial tachyarrhythmia-induced hearts as well as in the atrial tachyarrhythmia non-induced hearts. This suggests that the lack of antiarrhythmic effect of rotigaptide was not due to a lack of effect on atrial conduction velocity in the atrial tachyarrhythmia-induced hearts. In the atrial tachyarrhythmia-induced hearts, however the atrial conduction velocity was similar between rotigaptide-treated hearts and vehicle-treated hearts (fig. 3). This could indicate that the atrial conduction velocity did not reach a certain threshold to prevent atrial tachyarrhythmia in these animals. However, in the vehicle-treated hearts, there were no differences in the absolute conduction velocity between the atrial tachyarrhythmia induced and non-induced atria. Taken together, this indicates that factors other than atrial conduction slowing play a role in the pathogenesis of the arrhythmia inducibility in the setting of chronic atrial dilatation in the rabbit.
It is well recognized that the expression levels of atrial gap junction proteins are altered in experimental models of atrial fibrillation as well as in patients with atrial fibrillation compared to those in normal sinus rhythm (Nao et al. 2003; Wetzel et al. 2005). In order to investigate on which background rotigaptide was exerting its effect on atrial conduction velocity in the present study, we examined the expression levels of the two major atrial gap junction protein, connexin40 (Cx40) and connexn43 (Cx43) in a separate series of experiments. We found a significant down regulation of both Cx40 and Cx43 in the chronically dilated atria compared to control. Taken together, this suggests that rotigaptide can increase atrial conduction velocity even in the presence of a significant gap junction down regulation.
Rotigaptide increases gap junction intercellular communication in ventricular cardiomyocytes (Xing et al. 2003) as well as in the atria-derived cell line HL-1 (Clarke et al. 2006), however the molecular target through which rotigaptide exerts its effect is not yet discovered. Theoretically, rotigaptide could increase gap junction intercellular communication by affecting connexin gating, connexin expression, and connexin distribution. Rotigaptide increases the activity of protein kinase C and increases the phosphorylation of CX43 (Dhein et al. 2003). Furthermore, rotigaptide site-specifically suppresses dephosphorylation of serine residues in the C-terminal tail of Cx43 in rat hearts subjected to ischaemia (Axelsen et al. 2005). Phosphorylation of the C-terminal tail of Cx43 is an important regulator of connexin gating (Lampe & Lau 2004) and the data from Dhein et al. (2003) and Axelsen et al. (2005) suggest that the effect of rotigaptide could have been mediated through an effect on connexin gating. However, connexin phosphorylation not only affects gap junction channel gating but also affects connexin expression and connexin turnover rate as reviewed recently (Herve & Sarrouilhe 2002). Thus, it cannot be ruled out that the effect of rotigaptide could have been mediated through an effect on connexin expression too. In a recent study, 1–5 hr rotigaptide treatment had no effect on Cx43 expression in neonatal cardiomycoytes or Hela cells (Clarke et al. 2006). However, in another study it was recently demonstrated that 24 hr rotigaptide-treatment increased Cx43 expression in cultured rat neonatal cardiomyocytes (Stahlhut et al. 2006). The increased Cx43 expression level was associated with an increased formation of gap junctions determined using fluorescence microscopy. Taken together these in vitro data suggest that rotigaptide may affect both connexin gating and connexin expression, however the study by Clarke et al. (2006) and Stahlhut et al. (2006) suggest that the effect on connexin expression is not occurring very acutely. In our study we used a rotigaptide wash-in period of 20 min. between the pre- and post-drug studies. Even though we cannot exclude that rotigaptide may have affected connexin expression during this short timeframe, the Cx43 turnover rate of 1.5–2 hr (Beardslee et al. 1998) and the lack of effect of rotigaptide on Cx expression within 1–5 hr makes it less likely that an increase in Cx expression was the mechanism whereby rotigaptide increased conduction velocity in the present study.
We hypothesized that rotigaptide would increase conduction velocity and thereby reduce the inducibility of atrial tachyarrhythmia in the chronically dilated atria. Rotigaptide increased atrial conduction velocity as hypothesized, but in contrast to our hypotheses the effect of rotigaptide on atrial conduction velocity was not associated with an antiarrhythmic effect. Whether higher concentrations of rotigaptide would have had any effect on atrial tachyarrhythmia inducibility is unknown. A methodological problem using the excitation-contraction uncoupler BDM is that BDM has been reported to reduce gap junction conductance in primary cultures of ventricular cardiomyocytes at doses from 1–15 mmol/l (Verrecchia & Herve 1997; Duthe et al. 2000). However, in a concentration range from 5–20 mmol/l, BDM was reported to have no significant effect on epicardial ventricular conduction velocity in isolated sheep and guinea pig hearts (Liu et al. 1993). In addition, BDM had no significant effect on intra-atrial conduction velocity in the rabbit heart at a concentration of 5 mM (Cheng et al. 1997). In order to minimize any potentially confounding influences from BDM on the epicardial conduction velocity measurements we used a lower concentration of BDM (5 mM) than most other investigators have used. Therefore, the concentration of BDM used in our studies should not affect gap junction intercellular communication (Liu et al. 1993) and thereby reduce atrial conduction velocity. In addition to the lack of significant effects of 5 mM BDM on atrial conduction, our previous study using the same chronic volume overload model also demonstrated no effect of BDM on atrial tachyarrhythmia inducibility at a concentration of 5 mM (Hirose et al. 2005). Whereas we have no reason to believe that BDM affected atrial conduction velocity and atrial tachyarrhythmia inducibility, we cannot exclude the possibility that BDM may have interacted with rotigaptide's effect on atrial conduction velocity. As we used a low concentration of BDM, motion artifacts during repolarization were not suppressed and therefore we were unable to evaluate dispersion of action potential duration. Action potential duration dispersion is considered an important substrate of reentrant arrhythmias and rotigaptide has been reported to reduce ventricular action potential duration dispersion by several investigators (Dhein et al. 2003; Eloff et al. 2003; Kjølbye et al. 2003). Whether the dose of rotigaptide used in this study was sufficient to suppress atrial action potential duration dispersion in this model is unknown.
To conclude, rotigaptide increased atrial conduction velocity in isolated hearts from rabbits with chronic volume overload induced atrial dilatation. The effect of rotigaptide on atrial conduction velocity was not associated with an effect on atrial tachyarrhythmia inducibility. Whether rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.
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