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Changes in electrical activity of heart during ischemic–reperfusion injury modified by the administration of antidepressants

Changes in electrical activity of heart during ischemic–reperfusion injury modified by the... Keywords Kúcové slová: INTRODUCTION It is well known that drugs such as antidepressants can affect the function of heart. According to WHO, ischemic heart disease was world's leading cause of death in 2012, so it is important to find out how the antidepressants modify hearts function during I-R injury. Some authors (Ma-Li et al., 2008, Waring et al., Leonard et al., 2011) described the increased risk of myocardial infarction and sudden death within the initial days of antidepressant therapy. Until now, the experimental data about the effects of drugs on heart function after the administration of single dose of antidepressant were missing. In our experiments, the effects of single dose (30 mg/kg) of representatives from main antidepressants groups (TCA, SSRI and SNRI) were tested. Pretreatment of animals with drugs was followed by heart function analysis under conditions of spontaneously beating perfused hearts isolated 24 h after * E-mail: matej.vicen@gmail.com © European Pharmaceutical Journal rats premedication. The purpose of this study is to detect the changes in electrical activity of the hearts modified by antidepressants under conditions without or with ischemic­ reperfusion myocardial injury. MATERIAL AND METHODS The experiments were carried out on male Wistar rats with body weight of 220­270g fed on standard pellet diet and water ad libitum with light period of 12 h from 8 a.m. Rats were divided into four groups: animals that received only vehicle s.c., ischemic­reperfusion injury (control, I-R) group (n = 12), and animals pretreated with selected antidepressants: amitriptyline (Ami) group (n = 6), citalopram (Cit) group (n = 6) and venlafaxine (Ven) group (n = 6). Substances of Eur. Pharm. J. LXIII, 2016 (1): 5-8. Changes in electrical activity of heart during ischemic­reperfusion injury modified by the ... Table 1. Incidence and duration of dysrhythmias during ischemic­reperfusion injury of spontaneously beating hearts isolated from the rats pretreated with single dose 30 mg/kg s.c. of selected antidepressants 24 h before heart isolation I-R Incidence per heart Duration of episodes (s) VPB forms life-threatening life-threatening 123.4 ± 47.7 1.6 ± 0.9 25.2 ± 13.2 Amitriptyline 356.2 ± 79.7* 15.6 ± 5.1 296.6 ± 73.5* Citalopram 238.8 ± 61.1 8.7 ± 4.0 66.3 ± 39.8 Venlafaxine 214.0 ± 53.9 9.2 ± 3.1* 157.0 ± 82.0 Incidence of VPB forms (ventricular premature beat + bigeminy + trigeminy + salvos) expressed as mean ± SEM per heart, incidence and duration of life-threatening (ventricular tachycardia + ventricular fibrillation + bradycardia) dysrhythmias expressed as mean ± SEM per heart in group of animals without pretreatment with antidepressant (I-R), or with pretreatment with amitriptyline, citalopram or venlafaxine. *p 0.05, pretreated group versus I-R group antidepressants were solubilised in aqua pro injectione and applied s.c. in a single dose of 30 mg/kg. Rats were anesthetised after 24 hours using thiopental i.p. (VUAB pharma, Czech republic, 45 mg/kg). Chest was opened and anticoagulant heparin (0.2 ml, 1000IU Lachema, Czech republic) was applied into inferior vena cava. Heart was isolated into the ice cold K-H solution (NaCl (118 mmol/l), KCl (4.7 mmol/l), MgSO4 × 7H2O (2.39 mmol/l), KH2PO4 (2.35 mmol/l), CaCl × 2 H2O (9.73 mmol/l), NaHCO3 (25 mmol/l) in distilled water). Subsequently, the heart was positioned into Langendorff apparatus and perfused under constant pressure 7.5 kPa using K-H solution gassed by pneumoxide at a pH of 7.4 and temperature (t) of 36­37°C. Electrical activity of isolated spontaneously beating hearts was recorded during 20-min stabilisation, 35-min ischemia and 45-min reperfusion. Electrical activity was recorded by the needle electrodes (MLA1213 Needle Electrodes) inserted into the free wall of left ventricle and connected to the module PowerLab 8/30 (all the equipments were from ADInstruments, Spechbach, Germany) by the amplifier (FE136 Animal Bio Amplifier). Obtained data were stored in computer (HP, Palo Ato, USA). Data analyses were carried out by using the LabChart 7 Pro version 7.3.7. software (ADInstruments, Spechbach, Germany). Statistical comparison between the groups was done by using oneway ANOVA with the Bonferroni test, and the difference was considered statistically significant at a level p 0.05. citalopram the least. Venlafaxine significantly increased heart rate during ischemia and also prolonged QTc interval at the beginning of reperfusion, followed by serious dysrhythmias. Incidence of different forms of ventricular premature beats decreased in the order Ami > Cit > Ven > I-R. Duration of life-threatening dysrhythmias ventricular tachycardia (VT), ventricular fibrillation (VF) and bradycardia decreased in the order Ami > Ven > Cit > I-R (Table 1). DISCUSSION AND CONCLUSION The highest incidence and duration of life-threatening dysrhythmias was in amitriptyline group. At the beginning of reperfusion, there were typical VT and VF, during reperfusion bradycardia episodes. Citalopram caused the lowest amount of dysrhythmias, which suggests that this antidepressant is safer than amitriptyline and venlafaxine. After venlafaxine premedication were present typical episodes of VT, which are also in clinical practice biggest problem during therapy (Abozguia et al., 2006). Some drugs induce arrhythmias directly by affecting the conduction system of heart. Other drugs act on the heart indirectly, through their effect on the sympathetic or parasympathetic nervous system or by causing other physiological changes, such as hypotension, changes in metabolism or electrolyte disorders. Amitriptyline predominantly inhibit inward currents, such as INa and ICa, and also inhibits outward current, IKr. Citalopram inhibits predominantly outward current, IKr (Sicouri et al., 2008). After venlafaxine premedication, minor blocade of ion currents was also observed (Pacher et al., 2004). The effects of amitriptyline on heart function are well known (Nezafati et al., 2015, Ueterecker et al., 2015, Noordam et al., 2015, Vicen et al., 2015). This is the reason why we decided to use this antidepressant as a reference drug and compare its effects with those of venlafaxine and citalopram on heart. Amitriptyline increased heart frequency and prolonged the duration of QTc interval. This effect was the most intensive in reperfusion. Citalopram decreased heart frequency during reperfusion of I-R experiment. Some studies suggest that this effect of citalopram may positively affect patients' quality RESULTS Amitriptyline prolonged both QRS complex and QTc interval duration during I-R injury; citalopram and venlafaxine prolonged only QTc interval duration. Differences in the duration of QRS complex were significant according to the Bonferroni test between amitriptyline and control groups and amitriptyline and venlafaxine groups (p 0.05) (Fig. 1b). Differences in the duration of QTc interval after the administration of antidepressant in a single dose was statistically significant after the administration of all antidepressants compared to control group (p 0.05) (Fig. 1c). Amitriptyline worked most proarrhythmogenic, Vicen M. et al. (a) (b) (c) Figure 1. (a) Changes in heart rate during I-R experiment.(b) Changes in QRS complex duration during I-R experiment. (c) Changes in QTc interval duration during I-R experiment of life (Thase et al., 2013, Hanash et al., 2012). Interesting is the increase in heart frequency in phase of ischemia after venlafaxine pretreatment, which is followed by prolongation of QTc interval at the beginning of reperfusion and increase in the amount of dysrhythmias. This might be caused by energy depletion of the heart (Wang et al., 2005). The results suggest that single dose of antidepressants is enough to induce significant changes in electrical activity of heart. ACKNOWLEDGEMENT This work was supported by grants VEGA, SR 1/1342/12 and UK/430/2015. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Changes in electrical activity of heart during ischemic–reperfusion injury modified by the administration of antidepressants

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de Gruyter
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Copyright © 2016 by the
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2453-6725
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2453-6725
DOI
10.1515/afpuc-2016-0006
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Abstract

Keywords Kúcové slová: INTRODUCTION It is well known that drugs such as antidepressants can affect the function of heart. According to WHO, ischemic heart disease was world's leading cause of death in 2012, so it is important to find out how the antidepressants modify hearts function during I-R injury. Some authors (Ma-Li et al., 2008, Waring et al., Leonard et al., 2011) described the increased risk of myocardial infarction and sudden death within the initial days of antidepressant therapy. Until now, the experimental data about the effects of drugs on heart function after the administration of single dose of antidepressant were missing. In our experiments, the effects of single dose (30 mg/kg) of representatives from main antidepressants groups (TCA, SSRI and SNRI) were tested. Pretreatment of animals with drugs was followed by heart function analysis under conditions of spontaneously beating perfused hearts isolated 24 h after * E-mail: matej.vicen@gmail.com © European Pharmaceutical Journal rats premedication. The purpose of this study is to detect the changes in electrical activity of the hearts modified by antidepressants under conditions without or with ischemic­ reperfusion myocardial injury. MATERIAL AND METHODS The experiments were carried out on male Wistar rats with body weight of 220­270g fed on standard pellet diet and water ad libitum with light period of 12 h from 8 a.m. Rats were divided into four groups: animals that received only vehicle s.c., ischemic­reperfusion injury (control, I-R) group (n = 12), and animals pretreated with selected antidepressants: amitriptyline (Ami) group (n = 6), citalopram (Cit) group (n = 6) and venlafaxine (Ven) group (n = 6). Substances of Eur. Pharm. J. LXIII, 2016 (1): 5-8. Changes in electrical activity of heart during ischemic­reperfusion injury modified by the ... Table 1. Incidence and duration of dysrhythmias during ischemic­reperfusion injury of spontaneously beating hearts isolated from the rats pretreated with single dose 30 mg/kg s.c. of selected antidepressants 24 h before heart isolation I-R Incidence per heart Duration of episodes (s) VPB forms life-threatening life-threatening 123.4 ± 47.7 1.6 ± 0.9 25.2 ± 13.2 Amitriptyline 356.2 ± 79.7* 15.6 ± 5.1 296.6 ± 73.5* Citalopram 238.8 ± 61.1 8.7 ± 4.0 66.3 ± 39.8 Venlafaxine 214.0 ± 53.9 9.2 ± 3.1* 157.0 ± 82.0 Incidence of VPB forms (ventricular premature beat + bigeminy + trigeminy + salvos) expressed as mean ± SEM per heart, incidence and duration of life-threatening (ventricular tachycardia + ventricular fibrillation + bradycardia) dysrhythmias expressed as mean ± SEM per heart in group of animals without pretreatment with antidepressant (I-R), or with pretreatment with amitriptyline, citalopram or venlafaxine. *p 0.05, pretreated group versus I-R group antidepressants were solubilised in aqua pro injectione and applied s.c. in a single dose of 30 mg/kg. Rats were anesthetised after 24 hours using thiopental i.p. (VUAB pharma, Czech republic, 45 mg/kg). Chest was opened and anticoagulant heparin (0.2 ml, 1000IU Lachema, Czech republic) was applied into inferior vena cava. Heart was isolated into the ice cold K-H solution (NaCl (118 mmol/l), KCl (4.7 mmol/l), MgSO4 × 7H2O (2.39 mmol/l), KH2PO4 (2.35 mmol/l), CaCl × 2 H2O (9.73 mmol/l), NaHCO3 (25 mmol/l) in distilled water). Subsequently, the heart was positioned into Langendorff apparatus and perfused under constant pressure 7.5 kPa using K-H solution gassed by pneumoxide at a pH of 7.4 and temperature (t) of 36­37°C. Electrical activity of isolated spontaneously beating hearts was recorded during 20-min stabilisation, 35-min ischemia and 45-min reperfusion. Electrical activity was recorded by the needle electrodes (MLA1213 Needle Electrodes) inserted into the free wall of left ventricle and connected to the module PowerLab 8/30 (all the equipments were from ADInstruments, Spechbach, Germany) by the amplifier (FE136 Animal Bio Amplifier). Obtained data were stored in computer (HP, Palo Ato, USA). Data analyses were carried out by using the LabChart 7 Pro version 7.3.7. software (ADInstruments, Spechbach, Germany). Statistical comparison between the groups was done by using oneway ANOVA with the Bonferroni test, and the difference was considered statistically significant at a level p 0.05. citalopram the least. Venlafaxine significantly increased heart rate during ischemia and also prolonged QTc interval at the beginning of reperfusion, followed by serious dysrhythmias. Incidence of different forms of ventricular premature beats decreased in the order Ami > Cit > Ven > I-R. Duration of life-threatening dysrhythmias ventricular tachycardia (VT), ventricular fibrillation (VF) and bradycardia decreased in the order Ami > Ven > Cit > I-R (Table 1). DISCUSSION AND CONCLUSION The highest incidence and duration of life-threatening dysrhythmias was in amitriptyline group. At the beginning of reperfusion, there were typical VT and VF, during reperfusion bradycardia episodes. Citalopram caused the lowest amount of dysrhythmias, which suggests that this antidepressant is safer than amitriptyline and venlafaxine. After venlafaxine premedication were present typical episodes of VT, which are also in clinical practice biggest problem during therapy (Abozguia et al., 2006). Some drugs induce arrhythmias directly by affecting the conduction system of heart. Other drugs act on the heart indirectly, through their effect on the sympathetic or parasympathetic nervous system or by causing other physiological changes, such as hypotension, changes in metabolism or electrolyte disorders. Amitriptyline predominantly inhibit inward currents, such as INa and ICa, and also inhibits outward current, IKr. Citalopram inhibits predominantly outward current, IKr (Sicouri et al., 2008). After venlafaxine premedication, minor blocade of ion currents was also observed (Pacher et al., 2004). The effects of amitriptyline on heart function are well known (Nezafati et al., 2015, Ueterecker et al., 2015, Noordam et al., 2015, Vicen et al., 2015). This is the reason why we decided to use this antidepressant as a reference drug and compare its effects with those of venlafaxine and citalopram on heart. Amitriptyline increased heart frequency and prolonged the duration of QTc interval. This effect was the most intensive in reperfusion. Citalopram decreased heart frequency during reperfusion of I-R experiment. Some studies suggest that this effect of citalopram may positively affect patients' quality RESULTS Amitriptyline prolonged both QRS complex and QTc interval duration during I-R injury; citalopram and venlafaxine prolonged only QTc interval duration. Differences in the duration of QRS complex were significant according to the Bonferroni test between amitriptyline and control groups and amitriptyline and venlafaxine groups (p 0.05) (Fig. 1b). Differences in the duration of QTc interval after the administration of antidepressant in a single dose was statistically significant after the administration of all antidepressants compared to control group (p 0.05) (Fig. 1c). Amitriptyline worked most proarrhythmogenic, Vicen M. et al. (a) (b) (c) Figure 1. (a) Changes in heart rate during I-R experiment.(b) Changes in QRS complex duration during I-R experiment. (c) Changes in QTc interval duration during I-R experiment of life (Thase et al., 2013, Hanash et al., 2012). Interesting is the increase in heart frequency in phase of ischemia after venlafaxine pretreatment, which is followed by prolongation of QTc interval at the beginning of reperfusion and increase in the amount of dysrhythmias. This might be caused by energy depletion of the heart (Wang et al., 2005). The results suggest that single dose of antidepressants is enough to induce significant changes in electrical activity of heart. ACKNOWLEDGEMENT This work was supported by grants VEGA, SR 1/1342/12 and UK/430/2015.

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Sep 1, 2016

References