The Role of the Adenosine Receptors and Endogenous Adenosine in the Cardiovascular Toxic Effects Induced by the Citalopram Overdose In Rats.

Objective: The antidepressant drugs are one of the most common causes of poisonings all over the world. In our country, the selective serotonin re-uptake inhibitors (SSRI) are the second most frequent reasons of the antidepressant toxicity. It was reported that citalopram is the only SSRI which requires routine cardiac monitoring in overdose. Serotonine syndrome, neurotoxicity and cardiac toxicities (bradycardia, hypotension, QT and QRS prolongations) can be seen with the citalopram overdose. Adenosine shows its well known cardiovascular effects by A1, A2a and A2b receptors. Activation of A1 receptors depresses the heart by negative inotropic, chronotropic and dromotropic effects. The aim of this study is to clarify the role of adenosine receptors and/or endogenous adenosine in the mechanism of the cardiovascular toxic effects induced by citalopram overdose.Materials & Methods: This study consists of two protocols. In the first protocol, the cardiovascular toxic dose of the citalopram was found as 4 mg/kg/min (n=18). The rats were randomized into four groups. After the stabilization period, sodium cromoglycate (A3 receptor antagonist, 20 mg/kg, i.v) was administered to all groups. 5% dextrose was administered to the first group (n=7), DPCPX (8-Cyclopentyl-1,3-Dipropylxanthine; selective adenosine A1 receptor antagonist, 20 ? g/kg/dk, n=7) was administered to the second group, CSC (8-(3-chlorostyryl) caffeine; selective adenosine A2a receptor antagonist, 24 ?g/kg/min, n=7) was administered to the third group and 10% DMSO (n=3) was administered to the fourth group for 20 minutes. Following the infusions, we administered 4 mg/kg/min citalopram for 60 minutes. In the second protocol, the rats were randomized into three groups. 5% dextrose was administered intraperitoneally (i.p) 1 hour before the beginning of the citalopram infusion (4 mg/kg/min, for 60 minutes, n=8). EHNA (Erythro-9-(2-hydroxy-3-nonyl) adenine, 10 mg/kg, i.p) and NBTI (S-(4-nitrobenzyl)-6-thioinosine,1mg/kg, i.p) were administered 1 hour before the drug infusions. After the stabilization period, 5% dextrose and citalopram was administered for 60 minutes to the second and the third group, respectively. We collected blood from the rats before and after the experiment to measure the basal plasma adenosine levels by HPLC. Mean arterial pressure (MAP), heart rate (HR), QT and QRS durations and survival times were recorded during the experiments for both protocols. Statistical analysis of data within groups was evaluated by repeated measures ANOVA followed by Tukey?s multiple comparison tests. To analyze the differences among the groups, ANOVA and Tukey?s multiple comparison tests were performed. Duration of survival was compared using survival analysis based on the Kaplan Meier procedure. For all studies, p values of < 0.05 were considered to be statistically significant.Results: In the first protocol, the citalopram infusion in the dextrose group, caused a significant decrease in the MAP and HR after the 20th minute (in MAP p<0.001 for all, in HR p<0.01, p<0.001, p<0.001, p<0.001, p<0.001; 20th, 30th, 40th, 50th and 60th minutes, respectively) and caused a significant prolongation in the QRS and QT durations after the 30th minute (for QRS duration p<0.05, p<0.01, p<0.001 and p<0.001, 30th, 40th, 50th and 60th minutes respectively; for QT duration p<0.01, p<0.001, p<0.001, p<0.001, 30th, 40th, 50th and 60th minutes, respectively). The citalopram infusion in the DPCPX group, caused a significant decrease in the MAP after 20th minute (p<0.001 for all) and caused a significant decrease in the HR after the 30th minute (p<0.01, p<0.001, p<0.001, p<0.001, 30th, 40th, 50th and 60th minutes respectively). It caused also a significant prolongation in the QRS duration at the 60th minute (p<0.05). But it did not cause any significant difference in the QT duration (p>0.05). It was determined that DPCPX infusion significantly prevented the prolongation of the QT duration induced by citalopram after 20th minute when compared to the control group (p<0.05, p<0.05, p<0.01, p<0.01, p<0.01; 20th, 30th, 40th, 50th and 60th minutes, respectively). In the CSC and DMSO groups, there was not any significant change in the decrease of MAP and HR and in the prolongation of the QT and QRS durations induced by citalopram infusion when compared to the dextrose group (p>0.05). All rats completed the experiment alive. In the second protocol, plasma adenosine concentrations did not change significantly after citalopram infusion (p>0.05). In the other two groups pretreated with EHNA/NBTI, plasma adenosine concentrations showed a significant increase at the end of the experiment. (p<0.01, p<0.05 in group 2 and 3, respectively). Citalopram infusion caused a significant decrease in the MAP and HR and caused a significant prolongation in QT and QRS durations after 10th minute (p<0.001, for all). In the second group there was a significant decrease in the MAP and HR after 30. minute (for MAP p<0.01, p<0.001, p<0.001, p<0.001, 30th, 40th, 50th and 60th minutes respectively; for HR p<0.05, p<0.001, p<0.001, p<0.001, 30th, 40th, 50th and 60th minutes respectively) and there was a significant prolongation in the QRS duration only at 50th minute (p<0.05). In the EHNA/NBTI administered group followed by citalopram infusion, the decrease in MAP and HR (for MAP p<0.05, p<0.05, p<0.01, 10th, 20th and 30th minutes respectively; for HR p<0.001, p<0.01, p<0.001, p<0.001, 20th, 30th, 40th and 60th minutes respectively) and the prolongation in the QRS and QT durations (for QRS p<0.05 after 20th minute; for QT p<0.01, p<0.05, 10th and 20th minutes, respectively) were more significant than the EHNA/NBTI administered group followed by dextrose infusion. There was no significant difference in survival rates among the groups (p>0.05).Conclusion: In the first protocol, the prolongation of the QT duration induced by citalopram was prevented by DPCPX (selective adenosine A1 receptor antagonist) infusion significantly. According to this result, it can be suggested that the endogenous adenosine and/or adenosine A1 receptor stimulation may be responsible for the QT prolongation induced by citalopram. In the second protocol, the citalopram in overdose did not increase the plasma adenosine concentrations. Citalopram in overdose potentialized the cardiovascular effects induced by the increased endogenous adenosine concentrations after EHNA/NBTI administration. It can be suggested according to these results, adenosine and citalopram use the similar mechanisms in the cardiovascular effects. As a result, citalopram in overdose without any increase in the adenosine plasma concentrations, may cause to cardiovascular toxic effects by increasing the sensitivity to endogenous adenosine and/or direct stimulation of the adenosine A1 receptors,Keywords: Adenosine, adenosine receptor antagonists, citalopram toxicity, QT prolongation, QRS prolongation and hypotension.