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). 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.     

The effect of the nitric oxide synthesis inhibitor L-NAME on amitriptyline-induced hypotension in rats

OBJECTIVE: Hypotension induced by tricyclic antidepressants is multifactorial. Previous animal experiments suggest a contribution from nitric oxide production. Our study aimed to evaluate the role of nitric oxide in amitriptyline-induced hypotension using N-nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, and 3-morpholino sydnonimine, a nitric oxide donor, in anesthetized rats. METHODS: Amitriptyline intoxication was induced by the continuous infusion of amitriptyline 0.625 mg/kg/min throughout the experiment in anesthetized rats. Fifteen and 25 minutes after amitriptyline infusion began, two bolus doses of 10 mg/kg of N-nitro-L-arginine methyl ester (n = 8) or an equivalent volume of 5% dextrose solution (n = 8) was administered to each rat (Protocol 1). To investigate whether the effect of N-nitro-L-arginine methyl ester on blood pressure is counteracted by 3-morpholino sydnonimine, after the same protocol of amitriptyline infusion and 5 minutes after an N-nitro-L-arginine methyl ester bolus, a bolus of 3000 nmol/kg of 3-morpholino sydnonimine was administered (n = 8) to each rat (Protocol 2). To investigate the effect of N-nitro-L-arginine methyl ester on 3-morpholino sydnonimine induced hypotension, a group of rats received a continuous infusion of 0.54 mg/kg/h of 3-morpholino sydnonimine until 50% reduction was observed in mean arterial blood pressure followed by a bolus dose of 10 mg/kg of N-nitro-L-arginine methyl ester (n = 6) or 5% dextrose solution (n = 6) (Protocol 3). Outcome measures included mean arterial blood pressure, heart rate, and QRS duration in electrocardiogram. Student's t test and survival analysis were used for selected comparisons. RESULTS: For all parameters, the treatment groups were similar at baseline and at postamitriptyline periods before therapy was rendered. Amitriptyline infusion significantly reduced mean arterial blood pressure by 50.8 +/- 2.2% and prolonged QRS by 23.9 +/- 7.2% after 15 minutes. In Protocol 1, N-nitro-L-arginine methyl ester significantly increased mean arterial blood pressure compared to dextrose-treated control animals within 30 minutes (77.9 +/- 8.5% vs. 49.7 +/- 5.0% mmHg, p < 0.01, 95% CI 57.1-98.7%). QRS duration progressively increased during the amitriptyline infusion; however, there was no significant difference in QRS width between N-nitro-L-arginine methyl ester and control groups at any time point. N-nitro-L-arginine methyl ester increased survival time compared to controls (33.4 +/- 4.1 vs. 19.9 +/- 2.7 minutes, p < 0.01, 95% CI 25.4-41.3) but did not affect mortality. In Protocol 2 of continuous infusion of amitriptyline, 3-morpholino sydnonimine counteracted the N-nitro-L-arginine methyl ester-induced increase in mean arterial blood pressure. In both protocols, heart rate decreased significantly during amitriptyline infusion but there was no difference between treatment and control groups. In Protocol 3, N-nitro-L-arginine methyl ester bolus reversed 3-morpholino sydnonimine-induced hypotension compared to dextrose bolus. (83.8 +/- 5.7% vs. 54.6 +/- 4.8%, p < 0.01, 95% CI 69.2-98.4). CONCLUSION: N-nitro-L-arginine methyl ester is found to be effective in temporarily improving hypotension and prolonging survival time but does not affect overall mortality. Because this effect was antagonized by 3-morpholino sydnonimine, nitric oxide production appears to contribute to the pathophysiology of amitriptyline-induced hypotension.     

Do adenosine receptors play a role in amitriptyline-induced cardiovascular toxicity in rats?

OBJECTIVE: The aim of the our study was to investigate the role of adenosine receptors on cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant agent. Therefore, the hypothesis of this study was that adenosine receptor antagonists would improve and/or prevent amitriptyline-induced hypotension and conduction abnormalities in an anesthetized rat model of amitriptyline intoxication. METHODS: Two separate experimental protocols were performed. Amitriptyline intoxication was induced by the infusion of amitriptyline 0.94 mg/kg/min until 40-45% reduction of mean arterial pressure (MAP). Sodium cromoglycate (10 mg/kg) was injected i.v. to inhibit the A3 receptor-mediated activation of mast cells. In protocol 1, after amitriptyline infusion, while control animals (n=8) were given dextrose solution, treatment groups received a selective adenosine A1 antagonist DPCPX (8-cyclopentyl-1,3-Dipropylxanthine, 20 microg/kg/min, n=8) or a selective A2a antagonist CSC (8-(3-chlorostyryl) caffeine, 24 microg/kg/min, n=8) for 60 minutes. In protocol 2, after the sodium cromoglycate, while control group of rats (n=8) recevied a dextrose solution, treatment groups of rats were administered DPCPX (20 microg/kg/min, n=8) or CSC (24 microg/kg/min, n=8) infusion to block adenosine A1 and A2a receptors for 20 minutes before amitriptyline infusion. After pretreatment with adenosine antagonists, all rats were given a dose of 0.94 mg/kg/min of amitriptyline infusion during 60 minutes. Outcome measures were mean arterial pressure (MAP), heart rate (HR), QRS duration and survival rate. RESULTS: In protocol 1, amitriptyline infusion significantly reduced MAP and prolonged QRS within 15 minutes. HR was not changed significantly during the experiments. While dextrose did not improve MAP and QRS prolongation, DPCPX or CSC administration developed a significant improvement in MAP compared to the dextrose group within 10 min (88.5 +/- 2.8%, 75.6 +/- 4.7% and 50.1 +/- 14.7%, p<0.01, p<0.05, respectively). Both DPCPX and CSC decreased QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.00001). In protocol 2, pretreatment with DPCPX or CSC prevented the reduction in MAP due to amitriptyline toxicity compared to rats administered dextrose infusion (99.5 +/- 2.6%, 102.4 +/- 2.6%, 81.8 +/- 5.4, p<0.01 at 30 min; 98.0 +/- 2.9%, 93.5 +/- 6.0%, 64.9 +/- 4.7, p<0.001, p<0.01 at 40 min, respectively). Pretreatment with DPCPX or CSC also prevented the QRS prolongation (p<0.05) and increased median survival time significantly (log-rank test, p<0.0001). CONCLUSION: Adenosine antagonists were found to be effective in improving hypotension, QRS prolongation and survival time in our rat model of amitriptyline toxicity. Additionally, amitriptyline-induced cardiotoxicity was abolished by pretreatment with adenosine receptor antagonists. These results suggest that adenosine receptors may have a role in the pathophysiology of amitriptyline-induced cardiovascular toxicity. Adenosine A1 and A2a receptor antagonists may be promising agents for reversing amitriptyline-induced cardiovascular toxicity.     

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.     

Does adenosine A1 receptor stimulation causes QRS prolongation by blocking beta adrenergic receptors in amitriptyline poisoning?

Aims

To investigate the role of beta receptor blockade via adenosine A₁ receptor stimulation on amitriptyline-induced QRS prolongation.

Methods

Isolated rat hearts were randomized into three groups (n = 8 for each group). After pretreatment with 5% dextrose (control) or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or propranolol + DPCPX, amitriptyline infusion was given to all groups. Intact beta adrenergic receptor response was verified with a bolus dose of isoproteranol (3 × 10⁻⁵ M).

Results

Amitriptyline (5.5 × 10⁻⁵ M) infusion following pretreatment with 5% dextrose or 10⁻⁴ M DPCPX prolonged QRS by 40–110% and 30–75%, respectively. After the beta receptor blockade with 10⁻² M propranolol bolus, amitriptyline infusion following pretreatment with DPCPX prolonged QRS by 40–130%. Amitriptyline infusion following pretreatment with DPCPX (10⁻⁴ M) shortened the QRS at 40, 50 and 60  min significantly when compared to propranolol + DPCPX group (168.8 ± 4.9%, p < 0.05; 170.8 ± 6.9%, p < 0.01; 174.0 ± 6.9%, p < 0.01, respectively). Amitriptyline infusion following pretreatment with 5% dextrose prolonged QRS duration significantly at 50th minutes (209.5 ± 6.1%, p < 0.05) compared to DPCPX pretreatment group.

Conclusion

DPCPX pretreatment shortened amitriptyline-induced QRS prolongation. Beta adrenergic receptor blockade enhanced QRS prolongation shortened by DPCPX pretreatment. Adenosine A₁ receptor stimulation related to beta adrenergic receptor blockade may play a role in amitriptyline-induced QRS prolongation in isolated rat hearts.     

The effect of sodium bicarbonate on propranolol-induced cardiovascular toxicity in a canine model

STUDY OBJECTIVE: To evaluate the potential utility of sodium bicarbonate in an established model of acute propranolol toxicity. METHODS: Two minutes after the completion of a propranolol infusion (10 mg/kg), a bolus of 1.5 mEq/kg of sodium bicarbonate solution (1 mEq/mL) followed by an infusion of 1.5 mEq/kg over the next 26 minutes (n = 6) or an equivalent timing and volume of 5% dextrose solution (n = 6) was administered in each dog. Targeted cardiovascular parameters included heart rate, mean arterial pressure, left ventricular dP/dtmax, and QRS interval. RESULTS: Propranolol infusion significantly depressed heart rate (p < 0.0001), mean arterial pressure (p < 0.0001), dP/dtmax (p < 0.0001) and prolonged the QRS interval (p < 0.0001). Sodium bicarbonate failed to significantly improve these targeted parameters when compared to control animals. CONCLUSION: In this canine model of propranolol toxicity, intravenous sodium bicarbonate appears to be an ineffective single therapy. Furthermore, these results may suggest a different mechanism of sodium channel blockade for propanolol than that of type IA antiarrhythmic agents.     

Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning

We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.     

Effects of naloxone and verapamil in experimental amitriptyline poisoning in rats

The effects of verapamil and naloxone as potential antidotes for amitriptyline-induced cardiotoxicity were investigated in an experimental rat model. Amitriptyline was infused continuously at a dose of 37.5 mg/kg/h. After 15 minutes, the animals were given either naloxone (2 mg/kg + 3 mg/kg/h), verapamil (0.08 mg/kg + 0.08 mg/kg/h), or physiological saline. In the group given naloxone, a significant decrease in heart rate was seen. Although MAP and max dP/dT increased, there was no significant difference from controls. Naloxone did not decrease mortality. When the bolus dose of verapamil was given, a significant decrease in MAP and max dP/dT was obtained. Although the mean blood pressure was significantly higher in those animals treated with verapamil who survived 60 minutes, verapamil did not change the course of the amitriptyline poisoning. In conclusion, our findings indicate that naloxone lacks significant positive effects and that verapamil has an additional negative inotropic effect. Neither drug can be recommended for the treatment of amitriptyline poisoning.     

Hemodynamic and electrocardiographic effects of fluoxetine and its major metabolite, norfluoxetine, in anesthetized dogs

The cardiovascular effects of the selective serotonin uptake inhibitor, fluoxetine, and its N-desmethyl metabolite, norfluoxetine, were studied in anesthetized dogs during constant iv infusion of supratherapeutic doses (0.1 mg/kg/min for 50 min). Fluoxetine and norfluoxetine did not significantly affect mean blood pressure, pulmonary artery wedge pressure, or heart rate compared to a corresponding vehicle group. Cardiac output fell 15 to 20% during fluoxetine infusion due to nonsignificant decreases in both heart rate (10%) and stroke volume (5 to 10%). In contrast, the tricyclic antidepressant agent, amitriptyline, infused at the same dose, decreased both mean pressure and systemic vascular resistance (20%) and increased heart rate (20%). Pulmonary wedge pressure rose by 35%, and stroke volume fell by 20% suggesting impaired ventricular contractility. Both intramyocardial and infranodal conduction was slowed during amitriptyline infusion as indicated by increases in the QRS duration, and the PQ and HV interval. Fluoxetine and norfluoxetine had no influence on cardiac impulse conduction velocity as assessed by either surface or intracardiac conduction indices. Plasma concentrations of fluoxetine, norfluoxetine, and amitriptyline reached during infusion ranged from 1.0 to 2.5 micrograms/ml. Platelet [3H]serotonin uptake was inhibited by 95% during infusion of fluoxetine and about 75% during infusion of norfluoxetine or amitriptyline. These observations indicate that large iv doses of fluoxetine or norfluoxetine lack prominent cardiodepressant effects in dogs, suggesting a greater margin of safety for fluoxetine compared to tricyclic antidepressant drugs.     

BB-882 is a Potent Antagonist of the Haemodynamic Changes Induced by Platelet-Activating Factor in Pigs

Abstract: The effects of bolus doses (0.2-2 μg) of platelet-activating factor (PAF) on systemic and pulmonary arterial pressures were tested in five juvenile pigs, and were demonstrated to have a biphasic effect. There was an initial drop in the mean systemic arterial pressure within seconds, followed by an increase within 1-2 min., whereas mean pulmonary arterial pressure only rose. The response was dose-related and did not include tachyphylaxis. The pressures returned to baseline within 10 min. After confirming these results a novel specific PAF receptor antagonist (BB-882) was given as a 1 mg/kg bolus followed by a continous infusion of 2 mg/kg/hr, and a third dose response curve was repeated with ten-fold higher PAF doses (2-20 μg). BB-882 effectively counteracted these effects. Six pigs were given a continous infusion of BB-882 33 mg/kg/hr for 5 hr and were compared with another group of five pigs given vehicle only. In this high dose BB-882 did not affect the intravascular pressures. These results indicate that BB-882 is a potent PAF receptor antagonist in juvenile pigs.     

Continuous i.v. infusion versus multiple bolus doses of metoclopramide for prevention of cisplatin-induced emesis

Continuous infusion of metoclopramide was compared with bolus dosing in a randomized, double-blind study in 27 patients receiving cisplatin therapy. Hospitalized patients receiving their first course of cisplatin (120 mg/sq m administered i.v. over four hours) were randomized to receive either bolus doses or a continuous infusion of metoclopramide. In the infusion group (14 patients), a loading dose of metoclopramide 3 mg/kg (total body weight) as the hydrochloride salt was infused over one hour immediately before the administration of cisplatin, followed by a continuous infusion of metoclopramide 0.5 mg/kg/hr (as the hydrochloride salt) for 12 hours. Each patient received a total metoclopramide dose of 9 mg/kg over 13 hours. These patients also received five bolus doses of 5% dextrose injection (as placebo) over 15 minutes, with the first dose given one hour before the cisplatin and four more doses at two-hour intervals. In the bolus-dose group (13 patients), metoclopramide 2 mg/kg as the hydrochloride salt was added to each of the bolus doses, while the continuous infusion was a placebo of 5% dextrose injection. All patients also received dexamethasone 10 mg i.v. and diphenhydramine hydrochloride 50 mg i.v. Patients were monitored for 24 hours after initiation of metoclopramide administration for number of emesis episodes and for adverse effects. In the infusion group, 11 of 14 (79%) patients had two or fewer episodes of emesis. In the bolus group, 10 of 13 (77%) had two or fewer vomiting episodes. Mild sedation occurred in both the infusion (79%) and bolus-dose (77%) groups. Despite the use of diphenhydramine, extrapyramidal reactions were seen in one bolus-dose patient and two infusion patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous Lipid Emulsion Entraps Amitriptyline into Plasma and Can Lower its Brain Concentration – An Experimental Intoxication Study in Pigs

Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well‐perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid^® (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid‐rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.     

Angiotensin II facilitates tricyclic antidepressant-induced changes in QRS-duration in the rat.

Experimental evidence indicates that angiotensin II can modulate sodium channel and gap junction function. This raises the possibility that variations in angiotensin II could alter the effect of drugs that act on these mechanisms. In this study, the influence of changing salt status and angiotensin II activity has been investigated by evaluating the QRS prolonging effects of the sodium channel blocking drug, desmethylimipramine. In control rats with a normal salt intake, intravenous infusion of desmethylimipramine (0.8 mg/kg/min) over 60 min increased QRS duration over time to 150% of control by 60 min; mean arterial blood pressure and pulse rate were decreased. In salt-deplete rats, the response to desmethylimipramine was similar to controls for 30 min. Thereafter, QRS duration increased more rapidly than controls. In rats on a high salt diet, the same desmethylimipramine infusion produced no change in QRS duration for 30 min, despite equivalent reductions in mean arterial blood pressure. Thereafter, QRS duration increased, reaching values similar to control by 60 min. In rats on a normal salt diet pretreated with captopril, there was a similar blunting of the QRS response to desmethylimipramine to that observed in salt-loaded rats. The QRS response to desmethylimipramine and salt-loaded rats on normal salt diets receiving captopril returned to the control pattern after a subpressor infusion of angiotensin II (3 ng/min), while a higher rate of angiotensin II (10 ng/min) further enhanced the QRS prolonging effect of desmethylimipramine. These data demonstrate that endogenous angiotensin II contributes to the regulation of the cardiac electro-physiological response to DMI.     

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; A_2a 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.KEY WORDS: Adenosine receptor, citalopram toxicity, endogenous adenosine, QT prolongation, rat     

The effect of ethanol on arterial blood pressure, central venous pressure and ECG in rabbits treated with the single or multiple dose of amitriptyline or imipramine

Amitriptyline and imipramine given in the single dose insignificantly depressed the arterial blood pressure but significantly elevated the central venous pressure, prolonged the PQ interval and widened the QRS complex. After a prolonged daily treatment, the subsequent 21st dose of either antidepressant significantly depressed the arterial blood pressure; amitriptyline also depressed the central venous pressure. When given chronically, amitriptyline induced rhythm disturbances and the flattening of T-wave, while imipramine caused the widening of the QRS complex, block of the left bundle branch, changes in the T-wave amplitude, elevation in the ST interval. An intravenous infusion of ethanol potentiated those changes. The impairment of atrioventricular conduction occurred more frequently after administration of ethanol jointly with amitriptyline than with imipramine. Physostigmine salicylate elevated the depressed arterial blood pressure, aggravated the impairment of conduction and potentiated rhythm disturbances caused by the interaction of ethanol with antidepressants. In the above interactions with ethanol imipramine was less toxic than amitriptyline.     

Experimental amitriptyline intoxication: electrophysiologic manifestations and management

Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.     

Ranolazine, a novel anti-anginal agent, does not alter isosorbide dinitrate- or sildenafil-induced changes in blood pressure in conscious dogs

Effects of ranolazine on isosorbide dinitrate- and on sildenafil-induced changes in mean arterial pressure and heart rate were assessed in conscious dogs. Dogs (n = 7) were chronically instrumented for measurements of mean arterial pressure and heart rate. Bolus intravenous injections of either isosorbide dinitrate (0.2 mg/kg) or sildenafil (0.5 mg/kg) caused biphasic changes in mean arterial pressure and heart rate: a transient (approximately 20 s) decrease in mean arterial pressure and an increase in heart rate, followed by prolonged (10-15 min) decreases in mean arterial pressure by 11 +/- 1.6 and 11 +/- 2.2 mm Hg, respectively. Infusion of ranolazine alone (plasma concentrations = 4 or 8 microM) for 10 min did not significantly affect mean arterial pressure and heart rate. The transient hypotension and tachycardia caused by isosorbide dinitrate were not altered by ranolazine. The sildenafil-induced transient tachycardia (Delta change: 114 +/- 10 beats/min) was significantly (P < 0.05) blunted by either 4 (Delta change: 71 +/- 8 beats/min) or 8 (Delta change: 66 +/- 9 beats/min) microM ranolazine. However, the sildenafil-induced transient decrease in mean arterial pressure was not altered by ranolazine. During ranolazine infusion (4-5 or 8-10 microM), isosorbide dinitrate and sildenafil caused prolonged decreases in mean arterial pressure. These results indicate that except for a blunting of the transient tachycardia caused by sildenafil, ranolazine at concentrations up to 10 microM does not alter changes in mean arterial pressure and heart rate induced by either isosorbide dinitrate or sildenafil in conscious dogs.     

No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline

Abstract: Intravenous lipid emulsion has been used in the resuscitative treatment of intoxications caused by local anaesthetics and tricyclic antidepressants with seemingly beneficial results. We studied the effect of intravenous lipid emulsion on the plasma concentration of amitriptyline and haemodynamic recovery in a pig model of amitriptyline intoxication. Twenty pigs were anaesthetized (1% isoflurane in 21% O₂) and given amitriptyline 15 mg/kg intravenously for 15 min. In random fashion immediately thereafter, either 20% lipid emulsion (ClinOleic^®, Lipid group) or Ringer’s acetate (Control group) was infused for 30 min.; first 1.5 ml/kg for 1 min., followed by 0.25 ml/kg/min. for 29 min. The amitriptyline concentration in total and lipid‐poor plasma and haemodynamic parameters were measured until 30 min. after the infusions. Lipid infusion prevented the decrease in plasma total amitriptyline concentration, resulting in a 90% higher (p < 0.001) total concentration and significantly (p = 0.014) lower free fraction of plasma amitriptyline in the Lipid group (1.1%) compared with the Control group (3.0%) at 30 min. Haemodynamic recovery from the intoxication as measured by heart rate, arterial pressure or cardiac output was similar in both groups. However, five pigs in the Lipid group and two pigs in the Control group died. In conclusion, a marked entrapment of amitriptyline by intravenous lipid emulsion was observed but this did not improve the pigs’ haemodynamic recovery from severe amitriptyline intoxication. Care should be exercised in the antidotal use of lipid emulsion until controlled human studies indicate its efficacy and safety.     

D-myo-inositol-1,2,6-trisphosphate is a selective antagonist of neuropeptide Y-induced pressor responses in the pithed rat.

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1,2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2 micrograms/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8 microgram/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i.v. bolus injection of the alpha 1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.     

Effect of ketanserin on phenylephrine-dependent changes in splanchnic hemodynamics and systemic blood pressure in healthy subjects

We studied the effect of ketanserin on basal status and phenylephrine-dependent changes in arterial blood pressure and splanchnic hemodynamics in seven healthy subjects. The drug was administered as an intravenous bolus of 10 mg followed by infusion of 4 mg/h. After a basal period of saline or ketanserin infusion, phenylephrine was infused at a constant rate in a fixed dose sequence of 1, 2, and 3 micrograms/kg/min. Blood pressure was measured intraarterially. Splanchnic blood flow, mean wedged hepatic blood pressure, and splanchnic vascular resistance were assessed by means of the hepatic venous catheter technique using indocyanine green dye. At steady-state plasma concentrations, basal arterial pressure and heart rate were not altered in this small group of normal subjects, whereas mean wedged hepatic venous pressure was lowered by ketanserin. During saline infusion, phenylephrine provoked a dose-dependent rise in arterial and wedged hepatic blood pressure; these effects were attenuated by ketanserin. Phenylephrine induced a significant, but not dose-dependent, decrease in estimated splanchnic blood flow. Ketanserin did not relevantly influence basal or phenylephrine-dependent splanchnic blood flow. We suggest that the hypotensive action of ketanserin is in part related to an interaction at alpha 1-adrenoceptors. Moreover, a dissociation of effects on vascular alpha-receptors seems to exist in the splanchnic and systemic circulations.