The possible involvement of arachidonic acid (AA) or its metabolites in β-adrenoceptor desensitization has been studied in rat lung parenchyma both from a functional and a biochemical point of view. In vitro perfusion of rat lungs with AA (3×10-5M for 20 min) reduced the relaxant effect of isoproterenol (ISO) on lung parenchymal strips, shown by a shift to the right of ISO dose-response curve, similar to that obtained using desensitizing concentration of specific β-agonist. Moreover, AA treatment reduced the capacity of ISO to stimulate adenylate-cyclase activity, whereas the number of β-receptor binding sites was not significantly modified. Inhibition of cyclo-oxygenase pathway by indomethacin (INDO) (1.5 × 10-5M) prevented both the loss of ISO-relaxing capacity and the decrease of adenylate-cyclase activity induced by AA treatment. In order to support the role of eicosanoids in β-adrenoceptor desensitization, changes of endogenous free AA levels have also been studied in lung homogenates. Perfusion of rat lung with ISO (10-6M for 20 min) decreased by about 50% the levels of free AA and the pretreatment with BW755C (9×10-5M), a lipo- and cyclo-oxygenase inhibitor, prevented this phenomenon. On the basis of these results, we suggest that the activation of AA cascade is actually involved in β-adrenoceptor desensitization in lung tissues with a possible interference at the site beyond the drug-receptor interaction.
|Titolo:||ARACHIDONIC-ACID METABOLITES INDUCE BETA-ADRENOCEPTOR DESENSITIZATION IN RAT LUNG IN VITRO|
ABBRACCHIO, MARIA PIA (Secondo)
CATTABENI, FLAMINIO NICOLA (Penultimo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1985|
|Digital Object Identifier (DOI):||10.1016/0090-6980(85)90008-5|
|Appare nelle tipologie:||01 - Articolo su periodico|