Adverse pulmonary vascular effects of high dose tricyclic antidepressants: acute and chronic animal studies.
Overdose of tricyclic antidepressants, which inhibit cellular serotonin (5-HT) uptake, sometimes causes acute respiratory syndrome-like symptoms. Their acute and chronic cardiopulmonary actions, which might be implicated, utilising both in vivo and ex vivo animal studies, were investigated in this study. Acute amitriptyline (AMI), iprindole and imipramine caused dose-dependent prolonged rises in pulmonary artery pressure and oedema in anaesthetised cats in vivo. Acute AMI, in isolated ex vivo blood-perfused rat lungs, also caused dose-dependent sustained vasoconstriction, which could be attenuated with either calcium channel inhibition or a nitric oxide donor. It was demonstrated that the pressor effects of AMI were not due to release of histamine, serotonin, noradrenaline, or the activities of cycloxygenase or lipoxygenase. After AMI, hypoxic pulmonary vasoconstriction and the pressor actions of 5-HT and noradrenaline were diminished, possibly due to uptake inhibition. Activities of the endothelial-based enzymes, nitric oxide synthase and endothelin-converting enzyme, were undiminished. Large acute doses of AMI caused oedema with rupture of capillaries and alveolar epithelium. Chronic iprindole raised pulmonary artery pressure and right ventricle (RV)/left ventricle (LV) + septal (S) weight. Chronic AMI led to attenuation of the pressor action of 5-HT, especially when associated with chronic hypoxic-induced pulmonary hypertension. RV/LV+S weight increased, attributable to LV decline. The acute and chronic effects observed might have relevance to clinical overdose, while the attenuation of acute effects offers possible therapeutic options.
Liu
X
X
Division of Clinical Sciences (S), University of Sheffield, UK.
Emery
C J
CJ
Laude
E
E
Herget
J
J
Gill
G
G
Cope
G
G
Barer
G R
GR
D000208:Acute Disease; D000639:Amitriptyline / Q000008:administration & dosage* / Q000633:toxicity*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage* / Q000633:toxicity*; D002415:Cats; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D007099:Imipramine / Q000008:administration & dosage* / Q000633:toxicity*; D007488:Iprindole / Q000008:administration & dosage* / Q000633:toxicity*; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D014652:Vascular Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D007488:Iprindole; D007099:Imipramine