Effects of BQ-788 on amitriptyline-induced cardiovascular toxicity.
OBJECTIVE
We investigated both the effects of the endothelin type B (ETB) receptor antagonist, BQ-788, on amitriptyline-induced cardiotoxicity and the role of ETB receptors on amitriptyline-induced cardiovascular depression.


METHODS
Male Wistar rats were anaesthetized with urethane/chloralose. Mean arterial pressure (MAP), heart rate (HR) and QRS duration were recorded. Toxicity was induced by amitriptyline infusion (0.94 mg/kg per min) until the 50% inhibition of MAP. In the first protocol, 5% dextrose or BQ-788 bolus was administered to control or experimental group animals, respectively. In the second protocol, after incubation with BQ-788 or 5% dextrose, amitriptyline was infused.


RESULTS
Amitriptyline caused a significant decrease in MAP, prolonged QRS duration and decreased HR for both the groups. BQ-788 administration improved MAP (5, 10 and 15 min), shortened the prolonged QRS (5 and 10 minutes) and increased HR (5, 10 and 15 min) compared with dextrose group. While all the amitriptyline-infused rats survived in BQ-788 group, all the amitriptyline-infused rats died within 20 min in dextrose group. In the second protocol, BQ-788 incubation did not cause any statistically significant change in amitriptyline-induced cardiovascular depression.


CONCLUSIONS
BQ-788 may have beneficial effects in amitriptyline-induced cardiovascular changes via a physiologic antagonism. ETB receptor antagonists may be the promising antidotes for the cardiovascular toxicity with hypotension and bradycardia.
Department of Medical Pharmacology, Dokuz Eylul University School of Medicine, Izmir, Turkey. aylin.akgun@deu.edu.tr
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D000639:Amitriptyline; D000818:Animals; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use*; D062186:Arterial Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D065131:Endothelin B Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000931:Antidotes; D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D000639:Amitriptyline; C086539:BQ 788