Arachidonic acid metabolites induce beta-adrenoceptor desensitization in rat lung in vitro.
The possible involvement of arachidonic acid (AA) or its metabolites in beta-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 X 10(-5)M 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 beta-agonist. Moreover, AA treatment reduced the capacity of ISO to stimulate adenylate-cyclase activity, whereas the number of beta-receptor binding sites was not significantly modified. Inhibition of cyclo-oxygenase pathway by indomethacin (INDO) (1.5 X 10(-5)M) 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 beta-adrenoceptor desensitization, changes of endogenous free AA levels have also been studied in lung homogenates. Perfusion of rat lung with ISO (10(-6)M for 20 min) decreased by about 50% the levels of free AA and the pretreatment with BW755C (9 X 10(-5)M), 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 beta-adrenoceptor desensitization in lung tissues with a possible interference at the site beyond the drug-receptor interaction.
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D004082:Dihydroalprenolol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D001095:Arachidonic Acids; D011943:Receptors, Adrenergic, beta; D016718:Arachidonic Acid; D004082:Dihydroalprenolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D007213:Indomethacin