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A Study Of Mechanisms Underlying Amitriptyline-induced Acute Lung Function Impairment.

K. Svens, Å. Ryrfeldt
Published 2001 · Chemistry, Medicine

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In this study possible mechanisms underlying the vaso- and bronchoconstriction caused by the tricyclic antidepressant drug amitriptyline in isolated rat lungs were investigated. Some features here are similar to those apparent in adult respiratory distress syndrome and acute lung injury. Amitriptyline exposure (50 and 100 microM) caused a dose-related, pronounced, and rapid vaso- (50 microM, 30 min, p < 0.001 and 100 microM, 30 min, p < 0.001) and bronchoconstriction (50 microM, 30 min, p = 0.01 and 100 microM, 30 min, p < 0.001). The maximal noted decrease in perfusion flow was 28 +/- 2.9% at 25 min and 80 +/- 4.5% at 30 min for 50 and 100 microM amitriptyline, respectively. The maximal noted decrease in airway conductance was 29 +/- 4.7% at 25 min and 68 +/- 5.0% at 30 min. To investigate mechanisms thought to be involved in amitriptyline-induced lung function impairment, lungs were treated with several different substances including antiinflammatory agents, antioxidants, inhibitors of enzymes involved in the arachidonic acid cascade, physiological antagonists, and neurogenic antagonists. A significant reduction of amitriptyline-induced vasoconstriction was observed when lungs were treated with the protein kinase inhibitor staurosporine (3 microM, 30 min, p < 0.001), the NO-donor S-nitrosoglutathione (100 microM, 30 min, p < 0.001) and the combined endothelin A/endothelin B receptor antagonist PD 145065. This latter inhibitor caused a significant attenuation of late vasoconstriction (1 microM, 60 min, p = 0.03). The amitriptyline-induced bronchoconstriction was attenuated by the beta(2)-agonist salbutamol (1 microM, 30 min, p = 0.03) and the platelet-activating factor antagonist WEB2086 (10 microM, 30 min, p = 0.03). Staurosporine had an initial protective effect on bronchoconstriction (3 microM, 5 min, p = 0.003), while PD145065 significantly decreased bronchoconstriction 60 min after start of amitriptyline exposure (1 microM, 30 min, p = 0.003). This indicates that endothelin as well as platelet activating factor and protein kinase activation are important in mediating amitriptyline-induced lung function impairment in our experimental model and perhaps also in acute lung injury.
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