Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

Protective effects of wheat germ oil against erectile and endothelial dysfunction in streptozotocin-induced diabetic rats.

Our aim was to investigate the protective effect of wheat germ oil (WGO) at different doses on diabetes mellitus (DM)-induced erectile and endothelial dysfunction. Twenty-four male Wistar rats weighing 250-300 g were divided into four groups as; control group treated with saline, DM group, DM group treated with 3 ml/kg WGO (DM + 3WGO group), DM group treated with 6 ml/kg WGO. Type 1 DM was induced by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). STZ-induced diabetic rats received saline, 3 ml/kg WGO, and 6 ml/kg WGO via oral gavage daily for 5 weeks. The density of WGO used was 0.92 g/ml. The protective effect of WGO was evaluated by (i) in vitro vascular function, (ii) in vivo erectile function, and (iii) oxidative stress parameters in both aorta and penile tissue. Acetylcholine-mediated relaxation in the aorta and erectile functions decreased significantly in the DM group (p = 0.018 and p = 0.005). WGO (3 and 6 ml/kg) improved vascular functions in the DM groups (p = 0.001 and p = 0.014). The beneficial effect of WGO on erectile function appeared at higher doses of WGO. However, a higher dose of WGO substantially increased the oxidative stress parameters in both aorta and penile tissue. These findings suggest that the improvement in vascular or erectile function by WGO was not related to antioxidant effects, and new studies are needed to clarify the mechanism.

Antivenom use in bite and sting cases presenting to a public hospital.

BACKGROUND: To evaluate the distribution of bite and sting cases presenting to a district public hospital and the use of antivenom in scorpion sting and snake bite cases. METHODS: The demographic characteristics of patients with bites/stings reporting to a public hospital in 2014, the agent involved, the season of reporting, severity of clinical findings during presentation, and use of antivenom in scorpion sting and snake bite cases were evaluated retrospectively. χ2 test was used for statistical analysis. RESULTS: Bite and sting cases comprised 0.5% of all the patients reporting to the hospital's emergency department, with scorpion sting cases comprising almost half (54.2%) of these hospital presentations, followed by Hymenoptera (bee and wasp) sting (30.8%) and snake bite (5.5%) cases. Unnecessary antihistamine administration was found to be significantly high in asymptomatic patients (p=0.00006). Furthermore, antivenom use was found to be significantly high in patients with scorpion sting and snake bite despite the absence of systemic or local indications (p<0.0001, χ2=80.595). CONCLUSION: The study results showed that antivenom was used in scorpion sting and snake bite cases even when it was not indicated. Therefore, primary practitioners should be provided training for management of envenomation cases and should be made aware of the updated guidelines and references to raise their knowledge levels.

The Effects of the Adenosine Receptor Antagonists on the Reverse of Cardiovascular Toxic Effects Induced by Citalopram In-Vivo Rat Model of Poisoning.

BACKGROUND: Citalopram is a selective serotonin reuptake inhibitor that requires routine cardiac monitoring to prevent a toxic dose. Prolongation of the QT interval has been observed in acute citalopram poisoning. Our previous experimental study showed that citalopram may be lead to QT prolongation by stimulating adenosine A1 receptors without affecting the release of adenosine. AIMS: We examined the effects of adenosine receptor antagonists in reversing the cardiovascular toxic effects induced by citalopram in rats. STUDY DESIGN: Animal experimentation. METHODS: Rats were divided into three groups randomly (n=7 for each group). Sodium cromoglycate (20 mg/kg) was administered to all rats to inhibit adenosine A3 receptor mast cell activation. Citalopram toxicity was achieved by citalopram infusion (4 mg/kg/min) for 20 minutes. After citalopram infusion, in the control group (Group 1), rats were given an infusion of dextrose solution for 60 minutes. In treatment groups, the selective adenosine A1 antagonist DPCPX (Group 2, 8-cyclopentyl-1,3-dipropylxanthine, 20 µg/kg/min) or the selective A2a antagonist CSC (Group 3, 8-(3-chlorostyryl)caffeine, 24 µg/kg/min) was infused for 60 minutes. Mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval measurements were followed during the experiment period. Statistical analysis was performed by ANOVA followed by Tukey's multiple comparison tests. RESULTS: Citalopram infusion reduced MAP and HR and prolonged the QT interval. It did not cause any significant difference in QRS duration in any group. When compared to the control group, DPCPX after citalopram infusion shortened the prolongation of the QT interval after 40, 50 and 60 minutes (p<0.01). DPCPX infusion shortened the prolongation of the QT interval at 60 minutes compared with the CSC group (p<0.05). CSC infusion shortened the prolongation of the QT at 60 minutes compared with the control group (p<0.05). CONCLUSION: DPCPX improved QT interval prolongation in citalopram toxicity. The results of this study show that mechanism of cardiovascular toxicity induced by citalopram may be related adenosine A1 receptor stimulation. Adenosine A1 receptor antagonists may be used for the treatment of citalopram toxicity.

The role of adenosine receptors and endogenous adenosine in citalopram-induced cardiovascular toxicity.

AIM: We investigated the role of adenosine in citalopram-induced cardiotoxicity. MATERIALS AND METHODS: Protocol 1: Rats were randomized into four groups. Sodium cromoglycate was administered to rats. Citalopram was infused after the 5% dextrose, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 receptor antagonist), 8-(-3-chlorostyryl)-caffeine (CSC; A2a receptor antagonist), or dimethyl sulfoxide (DMSO) administrations. Protocol 2: First group received 5% dextrose intraperitoneally 1 hour prior to citalopram. Other rats were pretreated with erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; inhibitor of adenosine deaminase) and S-(4-Nitrobenzyl)-6-thioinosine (NBTI; inhibitor of facilitated adenosine transport). After pretreatment, group 2 received 5% dextrose and group 3 received citalopram. Adenosine concentrations, mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval were evaluated. RESULTS: In the dextrose group, citalopram infusion caused a significant decrease in MAP and HR and caused a significant prolongation in QRS and QT. DPCPX infusion significantly prevented the prolongation of the QT interval when compared to control. In the second protocol, citalopram infusion did not cause a significant change in plasma adenosine concentrations, but a significant increase observed in EHNA/NBTI groups. In EHNA/NBTI groups, citalopram-induced MAP and HR reductions, QRS and QT prolongations were more significant than the dextrose group. CONCLUSIONS: Citalopram may lead to QT prolongation by stimulating adenosine A1 receptors without affecting the release of adenosine.

Could decitabine treatment impair memory functions in humans?

The role of epigenetic mechanisms in cognitive functions and neurological/psychiatric disorders has been studied in a number of studies recently. One of these mechanisms is DNA methylation, for which DNA methyltransferases (DNMT) are responsible. Decitabine, or 5-aza-2'-deoxycytidine, is a cytosine-analog DNMT inhibitor and is used in the treatment of certain myelodysplastic syndromes (MDS) subsets. Several studies address the role of DNA methylation and negative effects of decitabine on memory formation and consolidation in animals. We, therefore, hypothesize that standard decitabine treatment for MDS in patients without dementia might cause learning and memory deficits. A clinical trial is proposed to test the hypothesis which could support the role of DNA methylation in cognitive abilities of humans.

Adenosine-mediated cardiovascular toxicity in amitriptyline-poisoned rats.

We investigated the contribution of endogenous adenosine to amitriptyline-induced cardiovascular toxicity in rats. A control group of rats was pretreated with intraperitoneal (i.p.) 5% dextrose and received intravenous 0.94 mg/kg/min of amitriptyline for 60 minutes. The second and third groups of rats pretreated with i.p. 10 mg/kg of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, and i.p. 1 mg/kg of S-(4-nitrobenzyl)-6-thioinosine (NBTI), a facilitated adenosine transport inhibitor, received 5% dextrose and amitriptyline infusion, respectively. Outcome parameters were mean arterial pressure (MAP), heart rate (HR), QT and QRS durations, and plasma adenosine concentrations. Plasma adenosine concentrations were increased in all groups. In the control group, amitriptyline decreased MAP and HR and prolonged QT and QRS durations after 10 minutes of infusion. In EHNA/NBTI-pretreated rats, amitriptyline prolonged QRS duration at 10 and 20 minutes. In EHNA/NBTI pretreated rats, amitriptyline-induced MAP, HR reductions, and QRS prolongations were more significant than that of dextrose-infusion-induced changes. Our results indicate that amitriptyline augmented the cardiovascular effects of endogen adenosine by increasing plasma levels of adenosine in rats.

An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline.

We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P < 0.05, respectively). There was no statistically significant difference in the results of arterial blood-gas analyses among the groups (P > 0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.

Effects of adenosine receptor antagonists on survival in amitriptyline-poisoned mice.

OBJECTIVE: We investigated the effects of adenosine receptor antagonists on survival rates in a mouse model of amitriptyline poisoning. MATERIALS AND METHODS: In the preliminary study, amitriptyline was given at doses of 75, 100, and 125 mg/ kg to mice intraperitoneally (i.p.; n = 20 for each dose) to determine the lethal dose at 50% (LD(50)). Different doses (1, 3, and 5 mg/kg) of DPCPX (selective adenosine A(1) antagonists, n = 10 for each dose, total n = 30) or CSC (selective adenosine A(2a) antagonists, n = 10 for each dose, total n = 30) were given i.p. to find the nonlethal dose. After the administration of the LD(50) dose of amitriptyline (125 mg/kg), mice were treated with DPCPX (3 mg/kg), CSC (3 mg/kg), saline, or DMSO (dimethyl sulfoxide) (n = 25 for each group). Mice were observed during a 24-hour period. RESULTS: Kaplan-Meier estimates of the 24-hour survival rate was 52% (13/25) for saline and 68% (17/25), 52% (13/25), and 40% (10/25) for the DPCPX, CSC, and DMSO groups, respectively. There was no statistically significant difference in survival rates among the groups (P > 0.05). CONCLUSIONS: Adenosine antagonists failed to increase the survival rates of amitriptyline-poisoned mice. Further studies are needed with repeated doses of adenosine antagonists.

Protective effect of an adenosine A1 receptor agonist against metamidophos-induced toxicity and brain oxidative stress.

The aim of this study was to evaluate the effects of different doses of an adenosine A(1) selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD(50) dose of metamidophos (20 mg/kg body weight, p.o.) was followed by 1 mL/kg body weight of 0.9% NaCl or 1 mg/kg, 2 mg/kg, 3 mg/kg, or 5 mg/kg body weight PIA ip. Incidence of clinical signs including chewing, salivation, convulsion, and respiratory distress did not show any significant difference among all treatment groups (p > 0.05). PIA was found to be effective to reverse the necrotic changes in diaphragm muscle induced by metamidophos significantly in all groups. Brain Thiobarbituric Acid Reactive Substance (TBARS) levels were significantly increased after the metamidophos poisoning. Administration of 2 to 5 mg/kg body weight PIA decreased brain TBARS levels compared to 0.9% NaCl treated rats. The results indicate that, although different doses of PIA reduced the OP-induced oxidative stress and diaphragm necrosis, a single dose of PIA was not able to recover cholinergic signs and symptoms of metamidophos poisoning.

Effects of adenosine receptor antagonists on amitriptyline-induced QRS prolongation in isolated rat hearts.

OBJECTIVE: We investigated the effects of adenosine receptor antagonists on amitriptyline-induced cardiotoxicity in isolated rat hearts. METHODS: The amitriptyline concentrations that prolonged the QRS duration more than 150% (10(-4) M) and 50-75% (5.5 x 10(-5) M) were accepted as the control groups for two experimental protocols, respectively. In the first protocol, amitriptyline (10(-4) M) was infused following pretreatment with a selective adenosine A(1) receptor antagonist, DPCPX (8-cyclopentyl-1,3-Dipropylxanthine,10(-4) to 10(-6) M) or a selective adenosine A(2a) receptor antagonist, CSC (8-3-chlorostyryl-caffeine,10(-4) to 10(-6) M). In the second protocol, amitriptyline (5.5 x 10(-5) M) was infused following pretreatment with DPCPX (10(-4) M) or CSC (10(-5) M). Left ventricular developed pressure (LVDP), dp/dt(max), QRS duration and heart rate (HR) were measured. RESULTS: In the first protocol, 10(-4) M DPCPX pretreatment shortened QRS duration at 50 minutes when compared to the control group (p < 0.05). In the second protocol, pretreatment with 10(-4) M DPCPX shortened the QRS duration at 40, 50, and 60 minutes after amitriptyline infusion when compared to the control group (p < 0.05, p < 0.01 and p < 0.05, respectively). Pretreatment with 10(-5) M CSC prolonged QRS duration at 20, 30, and 60 minutes (p < 0.05). Amitriptyline infusion following pretreatment with DPCPX or CSC did not change LVDP, dp/dt(max), or HR when compared to control in both protocols (p > 0.05). CONCLUSION: While 10(-4) M DPCPX shortened QRS prolongation, 10(-5) M CSC prolonged QRS duration in the isolated rat hearts with prolonged QRS duration induced by 5.5 x 10(-5)M amitriptyline. An adenosine A(1) receptor antagonist, DPCPX, might shorten amitriptyline-induced QRS prolongation by activating beta adrenergic receptors.

Effects of adenosine receptor antagonists on amitriptyline-induced vasodilation in rat isolated aorta.

BACKGROUND: Although we have previously demonstrated the beneficial effects of adenosine receptor antagonists in preventing cardiovascular toxicity of amitriptyline in rats, it is not clear whether adenosine receptors in heart or in vasculature are dominant. The aim of the current study was to investigate the role of adenosine A(2a) receptors on amitriptyline-induced vasodilation in rat isolated aorta. METHODS: After determining EC(80) of noradrenalin (NA) (the concentration of noradrenalin that produces 80% of maximal contractile response) as 10(-5)M, the IC(50) value of amitriptyline was measured in rat isolated aorta (the drug concentration causing a half- maximal inhibition of contractile responses to NA); IC(50) of amitriptyline was then compared in the presence of the DPCPX (a selective adenosine A(1) antagonist), CSC (a selective A(2a) antagonist) or DMSO (a solvent for adenosine antagonists). Statistical analysis was done using the Student t test. RESULTS: Amitriptyline-inhibited 49.9 +/- 3.7 % contractile response to NA on aorta segments at 1.8 x 10(-5)M (IC(50)). While DPCPX increased amitriptyline-induced inhibition on contractile response to NA dose dependently, CSC decreased the contractile response to NA only at 10(-5)M. DMSO did not change amitriptyline-induced IC(50). CONCLUSION: Adenosine A(2a) receptor stimulation seems to be responsible partly for amitriptyline-induced vasodilation and hypotension since the adenosine A(1) antagonist, DPCPX, increased amitriptyline-induced vasodilation in rat isolated aorta.