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Intravenous lipid emulsion (ILE) is a lifesaving treatment of lipophilic drug intoxications. Not only does ILE have demonstrable efficacy as an antidote to local anesthetic toxicity, it is also effective in lipophilic drug intoxications. Our case series involved 10 patients with ingestion of different types of lipophilic drugs. Intravenous lipid emulsion treatment improved Glasgow Coma Scale or blood pressure and pulse rate or both according to the drug type. Complications were observed in 2 patients (minimal change pancreatitis and probable ILE treatment-related fat infiltration in lungs). In our case series, ILE was used for different lipophilic drug intoxications to improve cardiovascular and neurologic symptoms. According to the results, it was found that ILE treatment is a lifesaving agent in lipophilic drug intoxications and it can be used in unconscious patients who have cardiac and/or neurologic symptoms but no history of a specific drug ingestion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study explored a link between spinal 5-HT(7) and adenosine A(1) receptors in antinociception by systemic amitriptyline in normal and adenosine A(1) receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3mg/kg was blocked by intrathecal administration of the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A(1) receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A(1) receptor +/+ mice, the selective 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A(1) receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A(1) receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A(1) receptors secondarily to 5-HT(7) receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A(1) receptor +/+, but not -/- mice. Adenosine A(1) receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A(1) receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Since amitriptyline is a very frequently prescribed antidepressant drug, it is not surprising that amitriptyline toxicity is relatively common. Amitriptyline toxic systemic effects include cardiovascular, autonomous nervous, and central nervous systems. To understand the mechanisms of amitriptyline toxicity we studied the cytotoxic effects of amitriptyline treatment on cultured primary human fibroblasts and zebrafish embryos, and the protective role of coenzyme Q(10) and alpha-tocopherol, two membrane antioxidants. We found that amitriptyline treatment induced oxidative stress and mitochondrial dysfunction in primary human fibroblasts. Mitochondrial dysfunction in amitriptyline treatment was characterized by reduced expression levels of mitochondrial proteins and coenzyme Q(10), decreased NADH:cytochrome c reductase activity, and a drop in mitochondrial membrane potential. Moreover, and as a consequence of these toxic effects, amitriptyline treatment induced a significant increase in apoptotic cell death activating mitochondrial permeability transition. Coenzyme Q(10) and alpha-tocopherol supplementation attenuated ROS production, lipid peroxidation, mitochondrial dysfunction, and cell death, suggesting that oxidative stress affecting cell membrane components is involved in amitriptyline cytotoxicity. Furthermore, amitriptyline-dependent toxicity and antioxidant protection were also evaluated in zebrafish embryos, a well established vertebrate model to study developmental toxicity. Amitriptyline significantly increased embryonic cell death and apoptosis rate, and both antioxidants provided a significant protection against amitriptyline embryotoxicity.

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.

Potentiated antibodies to delta sleep-inducing peptide and S100 protein produced an antidepressant effect in Wistar rats. This effect was more pronounced after combined treatment with these antibodies. It can be assumed that these antibodies modulate neurobiological mechanisms of positive emotional reinforcement and, therefore, affect the resistance to depression associated with psychoemotional stress.

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.

Tricyclic antidepressants in overdose cause toxicity marked by prolongation of the QRS interval of the electrocardiogram. These drugs are bound to alpha(1)-acid glycoprotein (AAG) with high affinity in plasma. Animal studies have shown that the administration of AAG shortens the QRS prolongation induced by tricyclic antidepressants. In order to clarify the pharmacological mechanism involved and to obtain clinically relevant evidence at the cellular level, whole-cell patch clamp techniques were performed in single guinea-pig ventricular myocytes to elicit the time and voltage-dependent fast sodium currents using both normal and modified physiological solutions. Cells stayed viable for much longer when they were placed in normal physiological solutions, providing sufficient recording time for consistently reproducible, clinically relevant toxicological results to be obtained. Amitriptyline (AMI) produced a concentration-dependent blockade of sodium currents with an approximate IC(50) of 0.69 microM. AAG reversed this blockade in a concentration-dependent fashion at concentrations ranging from 3.2 to 12.8 microM. Using the same experimental conditions, AAG also reversed the blockade of sodium current by quinidine, a class I antiarrythmic drug. Albumin did not reverse the blockade of sodium channels by AMI. The results indicate that AAG is a potential antidote for tricyclic antidepressant overdose.

The effects of the dihydropyridine calcium channel blocker nimodipine on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box training and in previously trained mice of the DBA/2 strain. Nimodipine (0, 0.5, 1, 2.5, or 5 mg/kg) had no effect alone, but attenuated the avoidance impairment induced by 5 mg/kg amitriptyline on avoidance acquisition, as well as on a previously learned avoidance response. The avoidance improving action of the calcium channel blocker was less evident in mice receiving a larger dose (7.5 mg/kg) of the antidepressant drug. The effect of nimodipine did not appear to be specifically related to the avoidance impairment induced by amitriptyline, because the calcium antagonist also attenuated the avoidance impairing action of the neuroleptic chlorpromazine. The avoidance impairment induced by amitriptyline and chlorpromazine, and the related ameliorating action of nimodipine, seem imputable to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. The results suggest that, in the case of concomitant administration, nimodipine could alleviate adverse side effects of tricyclic antidepressant, i.e., psychomotor disturbances.

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

The effect of an antisense oligonucleotide to the K+ channel coding mKv1.1 mRNA on antinociception induced by the tricyclic antidepressants, clomipramine (20-35 mg kg(-1) s.c.) and amitriptyline (10-25 mg kg(-1) s.c.), was investigated in the mouse hot-plate test. Antisense oligonucleotide (0.5-1.0-2.0-3.0 nmol per i.c.v. injection) produced a dose-dependent inhibition of clomipramine and amitriptyline antinociception 72 h after the last i.c.v. injection. The sensitivity to both analgesic drugs returned 7 days after antisense oligonucleotide injection, indicating the absence of irreversible damage or toxicity. Treatment with a degenerated oligonucleotide did not modify the clomipramine- and amitriptyline-induced antinociception in comparison with that in naive (unpretreated controls), vector and saline i.c.v.-injected mice. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) study demonstrated a reduction in mRNA levels only in the antisense oligonucleotide treated group. Antisense oligonucleotide, degenerated oligonucleotide or vector pretreatment, in the range of doses used, did not produce any behavioural impairment as revealed by the mouse rotarod and hole-board tests. The present results indicate that modulation of the mKv1.1 K+ channel plays an important role in the central analgesia induced by the tricyclic antidepressants, clomipramine and amitriptyline.

The forced swimming test (FST) is a widely used behavioural model to predict potential antidepressant (AD) action of compounds in humans. It has been previously shown that pretreatment with lithium, quinine and clonidine had additive effects on AD drugs in the FST, an effect proposed to be a result of potassium channel blockade. It is possible that pretreatment with potassium channel openers may induce opposite effects to those seen following pretreatment with potassium channel blockers in the FST. Pretreatment with cromakalim (CROM) (1 mg/kg, intraperitoneally [i.p.]) antagonized the anti-immobility effect of the mixed noradrenaline (NA)/5-hydroxytryptamine (5-HT) reuptake inhibitors imipramine and amitriptyline (P < 0.05). CROM administration (0.06 and 1 mg/kg, i.p.) also blocked the AD-like effects of the specific NA reuptake inhibitor, desipramine, and the selective serotonin reuptake inhibitor, paroxetine (P < 0.05 and P < 0.01, respectively). Pretreatment with CROM via gavage (1 mg/kg) antagonized the AD-like effects of imipramine, amitiptyline, desipramine and paroxetine. CROM treatment (via i.p. route or gavage) did not have any significant effect on the anti-immobility activity of the atypical AD mianserin at any of the doses employed. Another potassium channel opener, minoxidil (MINOX), which does not cross the blood-brain barrier, was also tested to eliminate the possibility that CROM may be acting via peripheral/local mechanisms. MINOX (32 mg/kg) failed to antagonize anti-immobility effects of any of the AD tested. In conclusion, the results of the present study suggest that CROM is only acting on drugs involved with neurotransmitter uptake inhibition.

Regulations of the increase in intracellular Ca2+ concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) production by increasing intracellular cyclic AMP (cAMP) levels or activating protein kinase C (PKC) were studied in rat frontocortical cultured neurons. Amitriptyline (AMI; 1 mM), a tricyclic antidepressant, and bradykinin (BK; 1 microM) stimulated IP3 production and caused transient [Ca2+]i increases. Pretreatment with forskolin (100 microM, 15 min) decreased the AMI- and BK-induced [Ca2+]i increases by 33 and 48%, respectively. However, this treatment had no effect on the AMI- and BK-induced IP3 productions. Dibutyryl-cAMP (2 mM, 15 min) also decreased the AMI- and BK-induced [Ca2+]i increases by 23 and 47%, respectively. H-8 (30 microM), an inhibitor of protein kinase A (PKA), attenuated the ability of forskolin to inhibit the AMI- and BK-induced [Ca2+]i increases, suggesting that the activation of cAMP/PKA was involved in these inhibitory effects of forskolin. On the other hand, forskolin treatment had no effect on 20 mM caffeine-, 10 microM glutamate-, or 50 mM K(+)-induced [Ca2+]i increases. Pretreatment with phorbol 12-myristate 13-acetate (PMA; 100 nM, 90 min) decreased both the AMI-induced [Ca2+]i increases and the IP3 production by 31 and 25%, respectively. H-7 (200 microM), an inhibitor of PKC, inhibited the ability of PMA to attenuate the [Ca2+]i increases. PMA also inhibited the BK-induced IP3 production and the [Ca2+]i increases.(ABSTRACT TRUNCATED AT 250 WORDS)

This preliminary study evaluates the cardiac and neurological risks associated with the sudden antagonism of benzodiazepine (BZD)--induced sedation in dogs intoxicated with tricyclic anti-depressants (TCA). Twelve dogs were anesthetized with midazolam and ventilated with room air. EEG, ECG, and arterial pressure were continuously recorded. An infusion of amitriptyline (6 dogs) or clomipramine (6 dogs) 1 mg/kg. min was maintained until signs of cardiotoxicity (QRS prolongation, hypotension or arrhythmias) occurred. The effects of a bolus of flumazenil 0.2 mg/kg were then observed until 120 minutes. In amitriptyline poisoning, BZD reversal was associated with development of convulsions in 3 dogs, with severe arrhythmias in 4 and with one death. In clomipramine intoxication, 2 dogs developed sudden fatal arrhythmias. These results show that BZD reversal may unmask the convulsant properties and increase the severity of arrhythmias induced by TCA.

Bilateral injections of 1 microgram sulpiride in the rat nucleus accumbens antagonized the effect of a seven-day treatment with 20 mg kg-1 day-1 imipramine or amitriptyline in the swimming test. The data suggest that dopamine mechanisms in the limbic regions of the rat brain are involved in the effect of repeated treatment with imipramine and amitriptyline in that test.

The analgesic effect of several doses of amitriptyline was studied in rats. The lower doses of the tricyclic compound showed clear analgesic properties whereas the higher doses remained ineffective. Naloxone, deprived of effect when administered alone, reduced the antinociceptive action of amitriptyline. These results suggest that the analgesic properties of the tricyclic compound could involve endorphin central systems.

This study was designed to analyze the effects of carbocromene on circulatory and electrophysiologic failure in rats anesthetized with urethane. Amitriptyline was infused at 0.4 mg/kg/min (n = 12) until death of the animals at 30 +/- 6.7 min due to vascular collapse. Following initial heart rate increase and QRS prolongation, this was characterized by progressive hypotension, bradycardia, intraventricular conduction delay, S-T segment elevation and A-V block. In the initial 31 rats, carbocromene was administered i.v. with 4 mg/kg followed in two groups by 40 (n = 13) and 80 micrograms/kg/min (n = 18) i.v., respectively. The drug was effective in protecting the animals against the acute cardiovascular failure induced by amitriptyline. The preservation was associated with a diminution of the hypotension, negative chronotropic actions, S-T segment elevation and the incidence of A-V block produced by amitriptyline. Survival time of the rats increased to 46 +/- 5.3 min (p less than 0.05 vs. amitriptyline controls) and 63 +/- 6.5 min (p less than 0.01) with infusion of 40 and 80 micrograms/kg/min carbocromene, respectively. These results suggest that carbocromene is an effective treatment of amitriptyline-induced cardiotoxicity by massive overdose with beneficial effects largely due to hemodynamic and metabolic oxygen-sparing impact on the heart. Membrane stabilizing antiarrhythmic carbocromene effects may be contributory factors in its protective value in the treatment of acute amitriptyline poisoning.

1. The effect of amitriptyline on cardiovascular variables has been studied in anaesthetized dogs. 2. In small doses (0.25 mg/dg) amitryptyline caused small increases in heart rates, contractility, blood pressure, coronary blood flow and aortic flow. 3. Large doses produced initial depressant effects on myocardial reflex rises in these and rate and blood pressure, which were followed by secondary reflex rises in these measurements. 4. The depressant effects were dose-related and were accompanied by marked increases in coronary flow and smaller increases in ortic flow. 5. The secondary reflex rises in cardiac parameters were abolished by propranolol and that of the blood pressure was much reduced.

The effect of clonidine on amitriptyline-induced cardiotoxicity was investigated in an experimental rat mode. A continuous infusion of amitriptyline (30 mg/kg/h) was given until the animal died, usually within 2 hours. Fifteen minutes after starting the amitriptyline infusion, 50 micrograms/kg of clonidine was given intravenously over five minutes. This led to an increase in blood pressure and left ventricular end-diastolic pressure. There was no significant change in cardiac contractility. Heart rate decreased. These changes can be explained by an increase in afterload due to peripheral vasoconstriction. No signs of reduced sympathetic outflow were seen on the ECG. The peripheral effects of clonidine dominated over the central effects, which may be due to a competitive inhibition of amitriptyline at central noradrenergic sites. An increased afterload pushes the heart towards failure and increases mortality. In this model, clonidine did not reverse amitriptyline-induced cardiovascular toxicity. It may even be potentially harmful if used to treat tricyclic antidepressant poisoning.

Two cases of severe poisoning by tricyclic antidepressants (Amitriptylin, Imipramin) are reported. Both patients 3 and 11 years old children, developed a typical clinical picture with cardiovascular, neurological and atropine features. Beside a general supportive management, in one case physostigmin was used as antidote. Alternative treatments of enuresis in childhood are recommended.

Case reports have appeared describing a beneficial effect of phenytoin in reversing cardiac conduction abnormalities induced by tricyclic antidepressant (TCA) overdose. Controlled studies have not been published. The following questions were addressed using intravenous amitriptyline and phenytoin in a rabbit model: Can prophylaxis with phenytoin before amitriptyline poisoning forestall the onset of cardiac abnormalities? Would such prophylactic phenytoin administration allow a higher dose of amitriptyline before death occurs? Would phenytoin reverse the cardiotoxic effects of amitriptyline once in progress? Animals were used in repeated trials with one-week "washout" intervals and served as their own controls in all but the final trial. Prophylactic phenytoin did not change the potency of amitriptyline in inducing abnormal cardiac performance, nor did it allow the animals to be titrated to a higher dose of amitriptyline before death occurred. In 12 animals, phenytoin "rescue" at the point of a widened QRS or arrhythmia was attempted. Two showed improvement; the remainder did not. Because this portion of the experiment was neither blinded nor controlled, nor were respirations or blood pressure monitored, these results must be viewed cautiously. Although our results suggest that prophylactic phenytoin is not useful, its role in therapy of occasional cases requires further investigation.

Chronic treatment with amitriptyline produces dose-dependent super-sensitivity of a central muscarinic cholinergic mechanism involved in the regulation of core body temperature. The authors demonstrated that chronic treatment with lithium prevents the induction of this response. The potential clinical and theoretical significance of this finding is set forth.

The effect of amitriptyline that leads to ventricular tachycardia was evaluated by the repetitive extrasystole threshold (RET) technique in 18 dogs. The RET was 28.8 +/- 7.9 mamp before and 8.2 +/- 5.3 mamp after amitriptyline, p less than 0.001. Physostigmine, propranolol, sodium bicarbonate, and left stellate ganglionectomy reversed the effect of amitriptyline on RET. We conclude that amitriptyline overdose predisposes to sudden death by lowering the ventricular fibrillation threshold. This cardiotoxic effect is mediated partly through the central nervous system and can be inhibited by increased plasma binding (bicarbonate), cholinergic stimulation (physostigmine), beta adrenergic blockade (propranolol), and sympathetic denervation (left stellate ganglionectomy).

Factors that contribute to the lethality of amitriptyline overdosage were studied in cats. Amitriptyline (50 mg/kg) given i.p. to unanesthetized cats produced convulsions in all of the animals and death in five of six animals; pretreatment with diazepam (5 mg/kg) protected against the convulsions and death. Respiratory depression contributed to the mortality when amitriptyline was given i.v. in cats anesthetized with pentobarbital as indicated by the finding that artificial respiration delayed the time of death induced by a continuous i.v. infusion of the drug. The i.v. infusion of amitriptyline in pentobarbitalized cats under artificial respiration produced death due to cardiovascular collapse. The latter was characterized by hypotension, bradycardia, depression of myocardial contractile force, atrioventricular block, intraventricular conduction delay and cardiac arrhythmias. These effects appear to be due to a direct membrane (quindine-like) cardiotoxic action of amitriptyline. Dopamine and dobutamine were effective in protecting the animals against the acute cardiovascular collapse induced by amitriptyline. The protection was associated with a diminution of the hypotension, the negative inotropic and chronotropic actions and the incidence of atrioventricular block produced by the tricyclic antidepressant drug. The results suggest that the positive chronotropic, inotropic and dromotropic actions of the amines may all be contributory factors in their protection action. Isoproterenol and norepinephrine were less effective than the other two amines.