ABSTRACT
Tricyclic antidepressants can, when taken in overdose, cause serious pulmonary failure such as the adult respiratory distress syndrome (ARDS). In this study we have examined the effects of some tricyclic antidepressants (amitriptyline, imipramine, nortriptyline and desipramine) on the viability and morphology of human endothelial and smooth muscle cells derived from umbilical cord. Effects of amitriptyline on endothelial cell fluidity, as well as permeability changes to an endothelial-smooth muscle cell bi-layer, were also studied. The tricyclic antidepressants induced acute, sub-lethal toxicity in both cell types above 100 microM as assessed by the MTT reduction assay. Morphological changes were also observed at these concentrations. Such changes were, however, absent at 33 microM and below. Amitriptyline did, however, cause a concentration-dependent fall in the electrical resistance of an endothelial-smooth muscle cell bi-layer, with significant effects already evident at 33 microM. All of these observed effects were fairly rapid and appeared within 5-15 min of exposure. The rapidity of these permeabilisation effects suggests potential membrane perturbations, since tricyclic antidepressants are lipophilic molecules with affinity for cell membranes. However, fluorescence anisotropy measurements showed no significant difference in membrane fluidity between amitriptyline-treated and control endothelial cells. Collectively, these data point to specific mechanisms of action of amitriptyline, and probably also the other tricyclic antidepressants studied, on endothelial permeability, which is a hallmark of ARDS. The data suggest that increased endothelial permeability could be due to impaired tight junction function.
Subject(s)
Amitriptyline/toxicity , Antidepressive Agents, Tricyclic/toxicity , Endothelium, Vascular/drug effects , Muscle, Smooth, Vascular/drug effects , Tight Junctions/drug effects , Cell Membrane Permeability/drug effects , Cell Survival/drug effects , Cells, Cultured , Coculture Techniques , Desipramine/toxicity , Electric Impedance , Endothelium, Vascular/pathology , Fluorescent Antibody Technique, Indirect , Formazans/metabolism , Humans , Imipramine/toxicity , Muscle, Smooth, Vascular/pathology , Nortriptyline/toxicity , Spectrometry, Fluorescence , Tetrazolium Salts/metabolism , Tight Junctions/physiology , Umbilical Cord/cytologyABSTRACT
We have previously shown that tricyclic antidepressants can induce vaso- and bronchoconstriction as well as oedema formation in isolated perfused lungs. This is an effect similar to that seen clinically in adult respiratory distress syndrome. In order to investigate whether endothelin can be a mediator of this reaction, isolated perfused rat lungs were exposed to 0.1 mM amitriptyline via the pulmonary circulation, perfusate was collected and endothelin-1 present in the perfusate and lavage fluids was determined by radioimmunoassay. A significant increase in perfusate concentration of endothelin-1 was noted, with the highest release seen within the first 10 min. of exposure. Histamine and thromboxane have also been proposed as mediators in induction of adult respiratory distress syndrome. However, no increased amounts of these mediators were detected in the perfusate. Experiments where lungs were exposed to exogenous endothelin-1(0.1-1 nmol), both via the perfusate and via intratracheal instillation were conducted. Similar effects as observed with amitriptyline (0.1 mM) on lung function and perfusion flow were detected. In conclusion, the detection of endothelin-1 release in our lung model proposes a role for endothelin-1 in amitriptyline-induced vaso- and bronchoconstriction and possibly in adult respiratory distress syndrome type reaction. Further studies with this model are interesting in order to elucidate mechanisms behind the complex issue of adult respiratory distress syndrome-induction.
Subject(s)
Amitriptyline/pharmacology , Antidepressive Agents, Tricyclic/pharmacology , Endothelin-1/metabolism , Lung/drug effects , Animals , Female , Histamine Release/drug effects , In Vitro Techniques , Lung/metabolism , Perfusion , Rats , Rats, Sprague-Dawley , Thromboxane B2/metabolismABSTRACT
Overdosing of several drugs, such as tricyclic antidepressants, salicylates, and opiates, is known to induce effects like those seen in patients with adult respiratory distress syndrome. By exposing isolated perfused and ventilated rat lungs via the perfusate to six different tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, mianserine, and maprotiline), we investigated possible effects on ventilation (conductance and dynamic compliance), lung perfusion flow, and edema formation. The effects of these substances were pronounced and appeared within 15 min after exposure. Amitriptyline was studied in greater detail and caused a dose-related (0.01-1.0 mM) reduction in ventilation and perfusion flow. At the highest drug concentration pronounced lung edema was observed. Morphological studies were conducted with a transmission electron microscope. The microscopic preparations showed dose-related edema (amitriptyline 0.1 and 1.0 mM). The effects noted in our experimental studies are similar to those described in patients who have taken an overdose of tricyclic antidepressants. This emphasizes the possibility of a noncardiogenic edema component in these patients.
