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Abstract

We investigated the role of adenosine receptors in amitriptyline-induced cardiac action potential (AP) changes in isolated rat atria. In the first group, APs were recorded after cumulative addition of amitriptyline (1 μM, 10 μM and 50 μM). In other groups, each atrium was incubated with selective adenosine A₁ antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 10⁻⁴ M) or selective adenosine A_2a receptor antagonist (8-(3-chlorostyryl) caffeine, 10⁻⁵ M) before amitriptyline administration. Resting membrane potential, AP amplitude (APA), AP duration at 50% and 80% of repolarization (APD₅₀ and APD₈₀, respectively), and the maximum rise and decay slopes of AP were recorded. Amitriptyline (50 μM) prolonged the APD₅₀ and APD₈₀ (p < 0.001) and the maximum rise slope of AP was reduced by amitriptyline (p < 0.0001). Amitriptyline reduced maximum decay slope of AP only at 50 μM (p < 0.01). DPCPX significantly decreased the 50-μM amitriptyline-induced APD₅₀ and APD₈₀ prolongation (p < 0.001). DPCPX significantly prevented the effects of amitriptyline (1 μM and 50 μM) on maximum rise slope of AP (p < 0.05). DPCPX significantly prevented the amitriptyline-induced (50 μM) reduction in maximum decay slope of AP (p < 0.001). The selective adenosine A₁ receptor antagonist prevented the electrophysiological effects of amitriptyline on atrial AP. A₁ receptor stimulation may be responsible for the cardiovascular toxic effects produced by amitriptyline.

Keywords

Amitriptyline adenosine receptor antagonists cardiac action potential

Introduction

The manifestations of tricyclic antidepressant (TCA) toxicity are mainly of cardiovascular origin including cardiac conduction abnormalities, dysrhythmias and hypotension. Cardiovascular toxicity is primarily responsible for the morbidity and mortality attributed to TCAs. Sinus tachycardia is the most common dysrhythmia associated with TCA toxicity and usually does not cause hemodynamic compromise. Ventricular tachycardia is the most common lethal ventricular dysrhythmia. Clinical observational data concerning QRS (>100 msec) and QT (>450 msec) prolongation suggest that the ventricular tachyarrhythmias are induced by TCAs. The blockade of cardiac Na⁺ and K⁺ channels is the primary mechanism responsible for arrhythmias.¹

Opipramol and amitriptyline are the most common agents of TCA poisonings in Turkey.² In our previous study, we demonstrated that amitriptyline-induced QRS prolongation and hypotension were reversed by the blockade of adenosine A₁ and A_2a receptors with specific antagonists like 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; selective A₁ receptor antagonist) and 8-(3-chlorostyryl) caffeine (CSC; selective A_2a receptor antagonist). Furthermore, pretreatment with these antagonists also prevented the development of amitriptyline-induced QRS prolongation and hypotension.³ Additionally, the adenosine A₁ receptor antagonist, DPCPX, was found to shorten the QRS prolongation induced by amitriptyline in an isolated rat heart model.^4,5 These results showed that adenosine A₁ receptor stimulation and/or endogenous adenosine may have a role in amitriptyline-induced QRS prolongation.

Adenosine is a potent extracellular messenger in cardiac tissue, where it induces negative inotropic and chronotropic effects, reduces conduction in the sinoatrial and atrioventricular (AV) nodes and modulates response to beta adrenergic stimulation through adenosine receptors. The regulatory actions of adenosine are mediated via four subtypes of the receptor described as A₁, A_2a, A_2b and A₃. The heart contains predominantly A₁ adenosine receptors. Adenosine A₁ receptor-mediated actions in heart are either cyclic adenosine monophosphate (cAMP)-independent (direct effects) or c-AMP-dependent (indirect or anti-adrenergic effects).^6,7

In the present study, we investigated the role of adenosine receptors in amitriptyline-induced electrophysiological changes in isolated rat atria.

Materials and methods

Animals

Adult male Wistar rats, weighing 250–280 g, were obtained from the animal facility of Hacettepe University and were housed under environmentally controlled conditions at 21 ± 2°C with 12 h dark/12 h light illumination sequence (the lights were on between 07:00 and 19:00) with food and water ad libitum. The Guiding Principles in the Care and Use of Laboratory Animals together with The Recommendations from the Declaration of Helsinki were strictly adhered during execution of all procedures. This project was approved by the Animal Care and Use Committee of Dokuz Eylul University, School of Medicine, Izmir, Turkey (Protocol number: 55/2007). Experiments were performed at Hacettepe University, Faculty of Medicine, Department of Pharmacology.

Chemicals

Amitriptyline was obtained from Merck Chemical Company (Darmstadt, Germany), DPCPX (a selective A₁ receptor antagonist) and CSC (a selective A_2a receptor antagonist) were purchased from Sigma Chemical Company (St Louis, Missouri, USA). Dimethyl sulfoxide (DMSO) was obtained from Aldrich Chemical (St Louis, Missouri, USA). Amitriptyline was dissolved in distilled water (stock concentration of 0.01 M). Both DPCPX and CSC were dissolved in DMSO. All adenosine antagonists were prepared at stock concentrations of 10⁻² M (in 10% DMSO).

Recording of cardiac APs

Rats were anesthetized with diethyl ether and then their hearts were quickly removed. Atrial action potentials (APs) were recorded by conventional microelectrode tecnique. Right and left atria were carefully dissected and immediately mounted in a 10-ml perfusion chamber. The superfusing Tyrode solution (5 mL/min) was oxygenated with a gas mixture of 5% CO₂ and 95% O₂ and kept at 37°C by a temperature-controlled circulator. The composition of the Tyrode solution was (in millimoles per liter) given as follows: NaCl: 137 mM/L, KCl: 4 mM/L, CaCl₂: 1.8 mM/L, MgCl₂: 0.5 mM/L, Na₂HPO₄: 1 mM/L, NaHCO₃: 12 mM/L and glucose: 5.0 mM/L at pH 7.4. Borosilicate glass micropipettes were prepared using a vertical pipette puller (Model 700C, David Kopf Instruments, USA). The tip resistances of pipettes were 30–50 MΩ when filled with 3 M KCl. The atria were electrically driven using a pair of platinum electrodes placed under the tissue. A 2-ms duration and 1-Hz frequency square-wave pulses were delivered from a stimulator (Grass S88, Grass Instruments, Missouri, USA).⁸ AP signals were amplified by Axoclamp-2A (Axon Instruments, Foster City, California, USA) and displayed on a digitized oscilloscope (Tektronix, Wilsonville, Oregon, USA). Data were recorded by PowerLab and analyzed by Scope 3.7 software (ADI Instruments, Sydney, Australia). The variables measured were resting membrane potential (RMP), AP amplitude (APA), AP duration at 50% and 80% of repolarization (APD₅₀ and APD₈₀, respectively) levels and maximum rise and decay slopes of AP.

RMP: During resting, membrane potential is mainly determined by the K⁺ equilibrium potential.

APA: AP amplitude is related with voltage-dependent Na⁺ channel activity.

Prolongation of APD₅₀ or APD₈₀ is due to the reduced K⁺ channel activity and shortens when the K⁺ channel activity is increased.

Maximum rise of AP is a measure of voltage-dependent Na⁺ recruitment. Decay slope of AP is correlated with delayed rectifier K⁺ channel activity.

Each atrium was used once for testing a single drug. We used the average of AP values recorded from 12 cells for each atrium. The ‘n’ is the number of atrium and also is the number of rats. The baseline values of AP were recorded from each atrium at the beginning of the experimental protocol. In all rats, initial values of AP were pooled to be used as the control value.

Drug administration

Rats were randomly allocated into the following three groups.

Group 1 (three animals, 12 cells for each dose)

In this group, we evaluated the electrophysiological effects of amitriptyline in rat atria. Cumulative concentration–response curves were obtained by stepwise increased concentrations of amitriptyline (1 μM, 10 μM and 50 μM). The effect of amitriptyline on RMP, APA, APD₅₀ and APD₈₀ levels and the maximum rise and decay slopes of AP were recorded.

Group 2 (three animals, 12 cells for each dose)

Atria were incubated with DPCPX (a selective adenosine A₁ antagonist, 100 μM) for 20 min before the administration of amitriptyline.⁴ Following the incubation period, amitriptyline (1 μM, 10 μM and 50 μM) was administered. The effect of amitriptyline on RMP, APA, APD₅₀ and APD₈₀ levels and the maximum rise and decay slopes of AP were compared with the effects in the presence of DPCPX.

Group 3 (three animals, 12 cells for each dose)

Atria were incubated with CSC (a selective A_2a antagonist, 10 μM) for 20 min before the administration of amitriptyline.⁴ Following the incubation period, amitriptyline (1 μM, 10 μM and 50 μM) was administered. The effect of amitriptyline on RMP, APA, APD₅₀ and APD₈₀ levels and the maximum rise and decay slopes of AP were compared with the effects in the presence of CSC.

We did not test the effect of DMSO (solvent of adenosine receptor antagonists). The final concentration of DMSO were 0.1% and 1% in groups 2 and 3, respectively. In our previously studies, we tested the effects of 10% DMSO. It did not cause any change in the cardiovascular parameters.^3
–5

Statistical analysis

Changes in the same group were evaluated by Student’s t test for paired data. To analyze the differences among groups, analysis of variance and for multiple comparison Tukey’s post hoc test were performed (GraphPad Instat, GraphPad Software, La Jolla, California, USA). All data were expressed as mean ± SEM. p < 0.05 was considered statistically significant.

Results

The electrophysiological effects of amitriptyline on rat atrium

Amitriptyline did not alter RMP and APA in the rat atria; however, 50 μM amitriptyline significantly prolonged the APD₅₀ and APD₈₀ when compared with control values (from 11.78 ± 0.92 ms to 33.21 ± 1.81 ms, p < 0.001; from 21.50 ± 1.79 ms to 62.28 ± 2.49 ms, p < 0.0001, respectively; Table 1). The maximum rise slope of AP was reduced in a dose-dependent manner with all three concentrations of amitriptyline (from 9.25 ± 0.47 V/s to 4.89 ± 0.65 V/s, 2.67 ± 0.29 V/s and 1.48 ± 0.27 V/s, p < 0.0001, p < 0.0001 and p < 0.0001, respectively; Table 1). Amitriptyline produced a significant reduction on the maximum decay slope of AP only at the highest (50 μM) concentration (from −0.53 ± 0.03 V/s to −0.11 ± 0.01 V/s, p < 0.01; Table 1).

Table 1.

Atrial action potential characteristics after amitriptyline administration with or without selective adenosine receptor antagonists

Groups	RMP (mV)	APA (mV)	APD₅₀ (ms)	APD₈₀ (ms)	Maximum rise slope of AP (V/s)	Maximum decay slope of AP (V/s)
Control	−75.96 ± 0.54	85.12 ± 0.59	11.78 ± 0.92	21.50 ± 1.79	9.25 ± 0.47	−0.53 ± 0.03
Amitriptyline
Amit 1 μM	−77.75 ± 1.17	85.80 ± 1.22	10.98 ± 1. 01	22.98 ± 2.20	4.89 ± 0.65^a	−0.37 ± 0.03
Amit 10 μM	−77.46 ± 1.79	85. 01± 1.86	13.52 ± 1.23	26.20 ± 2.78	2.67 ± 0.29^a	−0.35 ± 0.04
Amit 50 μM	−78.22 ± 2.06	85.38 ± 2.19	33.21 ± 1.81^b	62.28 ± 2.49^a	1.48 ± 0.27^a	−0.11 ± 0.01^c
100 μM DPCPX + Amit
DPCPX	−74.64 ± 0.83	83.76 ± 0.94	11.93 ± 1.51	21.10 ± 2.62	9.29 ± 0.67	−0.54 ± 0.05
DPCPX + Amit 1 μM	− 76.92 ± 0.93	85.96 ± 1.02	11.56 ± 0.98	22.06 ± 1.86	7.62 ± 0.84	−0.47 ± 0.04
DPCPX + Amit 10 μM	−76.91 ± 0.63	85.42 ± 0.67	15.08 ± 1.39	30.89 ± 2.56	4.00 ± 0.49^a	−0.29 ± 0.02^d
DPCPX + Amit 50 μM	−78.43 ± 1.59	86.40 ± 1.61	16.65 ± 1.75	32.76 ± 3.11	3.28 ± 0.46^a	−0.29 ± 0.03^d
10 μM CSC + Amit
CSC	−75.46 ± 0.90	84.58 ± 0.99	14.17 ± 1.23	26.43 ± 3.16	8.35 ± 0.97	−0.41 ± 0.05
CSC + Amit 1 μM	−76.13 ± 0.73	84.76 ± 0.79	11.97 ± 0.68	21.91 ± 1.59	5.65 ± 0.68	−0.41 ± 0.02
CSC + Amit 10 μM	−74.67 ± 1.10^d	83.14 ± 1.25^d	14.40 ± 1.29	32.69 ± 3.33	5.56 ± 0.68^c	−0.29 ± 0.04
CSC + Amit 50 μM	−74.61 ± 1.92	82.61 ± 1.97	22.11 ± 1.13^c	52.00 ± 3.31	1.69 ± 0.09^d	−0.13 ± 0.01

Amit: amitriptyline; DPCPX: 8-cyclopentyl-1,3-dipropylxanthine, selective adenosine A₁ antagonist; CSC: 8-(3-chlorostyryl) caffeine, selective A_2a antagonist; RMP: resting membrane potential; APA: action potential (AP) amplitude; APD₅₀ and APD₈₀: action potential duration at 50 and 80% of repolarization levels.

^a p < 0.0001 versus control.

^b p < 0.001 versus control.

^c p < 0.01 versus control.

^d p < 0.05 versus control.

The electrophysiological effects of amitriptyline on rat atrium after DPCPX (10⁻ ⁴ M) incubation

After 20-min incubation with DPCPX, amitriptyline had no effect on the RMP, APA, APD₅₀ or APD₈₀. When compared with control values, amitriptyline produced a dose-dependent reduction in both the maximum rise and decay slopes of AP at 10 μM and 50 μM, but there was no significant effect at 1 μM (from 9.25 ± 0.47 V/s to 4.00 ± 0.49 V/s and 3.28 ± 0.46 V/s, p < 0.0001 and p < 0.0001, respectively, from −0.53 ± 0. 03 V/s to −0.29 ± 0.02 V/s and −0.29 ± 0.03 V/s, p < 0.05 and p < 0.05, respectively; Table 1).

The electrophysiological effects of amitriptyline on rat atrium after CSC (10⁻ ⁵ M) incubation

After 20-min incubation with CSC, amitriptyline produced a minor reduction in the RMP and APA at 10 μM (from −75.96 ± 0.54 mV to −74.67 ± 1.10 mV, p < 0.05; from 85.12 ± 0.59 mV to 83.14 ± 1.25 mV, p < 0.05, respectively; Table 1). The amitriptyline (50 μM) significantly prolonged the APD₅₀ when compared with control values (from 11.78 ± 0.92 ms to 22.11 ± 1.13 ms, p < 0.01; Table 1). When compared with control values, amitriptyline (10 μM and 50 μM) produced a significant reduction in the maximum rise slope of AP (from 9.25 ± 0.47 V/s to 5.56 ± 0.68 V/s and 1.69 ± 0.09 V/s, p < 0.01 and p < 0.05, respectively; Table 1).

When the difference was compared between the groups, DPCPX significantly decreased the amitriptyline (50 μM)-induced prolongation of APD₅₀ and APD₈₀ (from 33.21 ± 1.81 ms to 16.65 ± 1.75 ms, p < 0.001; from 62.28 ± 2.49 ms to 32.76 ± 3.11 ms, p < 0.001, respectively; Figures 1 and 2). DPCPX significantly prevented the effects of amitriptyline (1 μM and 50 μM) on the maximum rise slope of AP (p < 0.05 and p < 0.05, Figure 3). DPCPX significantly prevented the amitriptyline (50 μM)-induced reduction in the maximum decay slope of AP (p < 0.001, Figure 4). After CSC pretreatment, amitriptyline (10 μM)-induced reduction in the maximum rise slope of AP abolished (p < 0.01, Figure 3).

Figure 1.

The effects of amitriptyline administration on the action potential duration at 50% of repolarization (APD₅₀) with or without selective adenosine receptor (three animals, 12 cells for each dose). DPCPX: 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A₁ antagonist (100 μM); CSC: 8-(3-chlorostyryl) caffeine, a selective A_2a antagonist (10 μM). ^### p < 0.001 versus control; ***p < 0.001 versus amitriptyline (50 μM).

Figure 2.

The effects of amitriptyline administration on the action potential duration at 80% of repolarization (APD₈₀) with or without selective adenosine receptor antagonists (three animals, 12 cells for each dose). DPCPX: 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A₁ antagonist (100 μM); CSC: 8-(3-chlorostyryl) caffeine, a selective A_2a antagonist (10 μM). ^#### p < 0.0001 versus control; ***p < 0.001 versus amitriptyline (50 μM).

Figure 3.

The effects of amitriptyline administration on the maximum rise slope of action potential with or without selective adenosine receptor antagonists (three animals, 12 cells for each dose). DPCPX: 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A₁ antagonist (100 μM); CSC: 8-(3-chlorostyryl) caffeine, a selective A_2a antagonist (10 μM). ^### ^# p < 0.0001 versus control; ^† p < 0.05 versus amitriptyline (1 μM); **p < 0.01 versus amitriptyline (10 μM); ^δ p < 0.05 versus amitriptyline (50 μM).

Figure 4.

The effects of amitriptyline administration on the maximum decay slope of action potential with or without selective adenosine receptor antagonists (three animals, 12 cells for each dose). DPCPX: 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A₁ antagonist (100 μM); CSC: 8-(3-chlorostyryl) caffeine, a selective A_2a antagonist (10 μM). ^## p < 0.01 versus control. ***p < 0.001 versus amitriptyline (50 μM).

Discussion

Our study revealed the role of the adenosine receptors in cardiac conduction abnormalities induced by amitriptyline in isolated rat atria. Our major findings are as follows: (1) Amitriptyline (50 μM) administration prolonged APD₅₀ and APD₈₀ without altering RMP, APA. The maximum rise slope of AP was reduced in a concentration-dependent manner by amitriptyline. Amitriptyline produced a reduction in the maximum decay slope of AP only at 50 μM concentration. (2) DPCPX (a selective adenosine A₁ receptor antagonist) significantly decreased the amitriptyline (50 μM)-induced APD₅₀ and APD₈₀ prolongation. DPCPX significantly prevented the effects of amitriptyline (1 μM and 50 μM) on the maximum rise slope of AP. DPCPX also blocked the amitriptyline (50 μM)-induced reduction on the maximum decay slope of AP. CSC (a selective adenosine A_2a receptor antagonist) significantly prevented the amitriptyline (10 μM)-induced reduction in the maximum rise slope of AP.

In our study, amitriptyline administration reduced the maximum rise slope of AP without altering RMP and APA. The reduction in the maxium rate of rise slope of AP supports the concept of potent sodium channel blockade by amitriptyline in rat atria. Some studies demonstrated that amitriptyline inhibited sodium channels.^9

–14 In electrophysiological studies, tricylic antidepressants such as imipramine, clomipramine, amitriptyline, desipramine, dibenzepin, lofepramine and amoxapine were demonstrated to reduce the maximum velocity of depolarization (V _max) of the AP, an indirect index of the fast inward sodium current, (I _Na).¹⁵ Sasyniuk et al. reported that amitriptyline significantly depressed APA and APD as well as V _max.⁹

In our study, amitriptyline (50 μM) prolonged the APD₅₀ and APD₈₀ levels and produced a significant reduction in the maximum decay slope of AP. These findings imply that amitriptyline may also have potassium channel blocking actions. The transient outward K⁺ current I _to is responsible for the initial rapid phase of AP repolarization. Several antidepressants with different chemical structures such as imipramine, amitriptyline, mianserine, maprotiline and trazodone block I _to.^14,16 Thus, the reduction in I _to could explain the prolongation of the APD. Jo et al. showed that amitriptyline blocked HERG (human ether a-go-go-related gene), the molecular equivalent of rapidly activating delayed rectifier K⁺ current (I _Kr), which is one of the most important K⁺ current in the repolarization of cardiac AP. However, amitriptyline blocked I _Kr rather than I _to in their experimental conditions. It has been suggested that amitriptyline may prolong APD primarily by blocking I _Kr rather than blocking I _to.¹⁷ Kobayashi et al. demonstrated that all of the tricylic antidepressants tested that desipramine, imipramine, amitriptyline, nortriptyline and clomipramine inhibited G protein-activated inwardly rectifying K⁺ channels at micromolar concentrations.¹⁸

In our study, the amitriptyline-induced electrophysiological changes were prevented by DPCPX in isolated rat atria. DPCPX decreased the amitriptyline (50 μM)-induced prolongation of APD₅₀ and APD₈₀ and prevented the effects of amitriptyline (1 μM and 50 μM) on the maximum rate of rise slope of AP. DPCPX significantly prevented the amitriptyline (50 μM)-induced reduction in the maximum decay slope of AP. These results suggest that adenosine A₁ receptor stimulation may contribute to electrophysiological effects of amitriptyline. The results of our study are comparable with our previous studies.³ Kalkan et al. showed that hypotension and QRS prolongation by amitriptyline poisoning in rats were reverted by selective adenosine A₁ and A_2a receptor antagonists (DPCPX and CSC, respectively).^3
–5 Furthermore, in another study, it was found that the QRS prolongation developed by amitriptyline was diminished by specific adenosine A₁ receptor antagonist (DPCPX).⁴ In an isolated rat heart study, Akgun Arici et al. suggested that adenosine A₁ receptor stimulation that causes β-adrenergic receptor (β-AR) blockade may have a role in amitriptyline-induced QRS prolongation. An adenosine A₁ receptor antagonist, DPCPX, might prevent the inhibition of β-AR-mediated sodium current enhancement that results in shortening of QRS duration.⁵

Adenosine A₁ receptors, located in atrial and ventricular myocardium and sinoatrial and AV node, inhibit the activity of adenylyl cyclase enzyme.^19
–21 Adenosine A₁ receptor-mediated actions in the heart are both cAMP-independent (direct effects) and cAMP-dependent (indirect or anti-adrenergic effects).^6,21 Adenosine produces a negative inotropic effect in atrial myocardium.^7,21 Two distinct mechanisms account for this effect. Under basal conditions, adenosine shortens the duration of AP and decreases contractility.⁷ This action is mediated by the adenosine-activated potasium acetylcholine (K_ACh) channel effector system.^{7

–22} With enhanced adrenergic activity, adenosine attenuates both catecholamine-activated outward I _K and inward I _Ca, presumably by inhibition of phosphorylation of these channels, because adenosine inhibits adenylate cyclase activity and decrease the generation of cAMP.⁷ Adenosine presents antiadrenergic efficiency over delayed rectifier potassium (I _K) and chloride (I _Cl) currents and cAMP-dependent mechanism with l-type Ca⁺² channel current (I _CaL) in both supraventricular and ventricular tissues. While shortening is observed in ventricular AP by inhibition of I _CaL current-dependent catecholamine, prolongation is realized in AP with inhibition of I _K and I _Cl currents related to catecholamine.^6,23 The cardiac sodium channels and the delayed outward potassium channels are also regulated by intracellular cAMP-dependent protein kinase.⁷ Similar antagonistic regulation by adenosine may also exist for these channels.

Amitriptyline-induced cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and noradrenaline accumulation in the synapses by blockade of the noradrenaline transporter.^1,24 In our study, the selective adenosine A₁ receptor antagonist prevented the electrophysiological effects of amitriptyline on atrial AP. A₁ receptor stimulation may be responsible for the cardiovascular toxic effects such as prolongation of QRS duration and QT interval produced by amitriptyline. The results of this study suggest that a cAMP-dependent (indirect or antiadrenergic effect) pathways via A₁ receptor may play a role on the mechanisms underlying electrophysiological changes induced by amitriptyline.

Footnotes

Authors’ Note

This study was presented as poster at Turkish Pharmacology Society, 21th National Congress of Pharmacology, 5th Clinical Pharmacology Symposium and 4th Clinical Toxicology Symposium, Eskisehir, Turkey, October 19–22, 2011.

Funding

This study was supported by a grant from The Scientific and Technological Research Council of Turkey (TUBITAK, Grant Number: 107S251) and by the Turkish Academy of Sciences, in the framework of the Young Scientist Award Program (EA-TUBA-GEBIP/2001-2-11; to A.B.I.).

Conflict of interest

The authors declared no conflict of interest.

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The role of adenosine receptors on amitriptyline-induced electrophysiological changes on rat atrium

Abstract

Keywords

Introduction

Materials and methods

Animals

Chemicals

Recording of cardiac APs

Drug administration

Group 1 (three animals, 12 cells for each dose)

Group 2 (three animals, 12 cells for each dose)

Group 3 (three animals, 12 cells for each dose)

Statistical analysis

Results

The electrophysiological effects of amitriptyline on rat atrium

The electrophysiological effects of amitriptyline on rat atrium after DPCPX (10− 4 M) incubation

The electrophysiological effects of amitriptyline on rat atrium after CSC (10− 5 M) incubation

Discussion

Footnotes

Authors’ Note

Funding

Conflict of interest

References

The electrophysiological effects of amitriptyline on rat atrium after DPCPX (10⁻ ⁴ M) incubation

The electrophysiological effects of amitriptyline on rat atrium after CSC (10⁻ ⁵ M) incubation