Involvement of arachidonic acid metabolites in beta-adrenoceptor desensitization: functional and biochemical studies.
The prolonged in vitro perfusion of rat lung with isoproterenol (Iso) induced a desensitization of beta-adrenoceptors which was dose- and time-dependent. The decrease in functional responsiveness of rat lung parenchyma to the beta-agonist correlated well with the loss of [3H]dihydroalprenolol ([3H]DHA) binding sites and adenylate cyclase activity after the beta-adrenoceptor desensitization procedure. The cyclooxygenase inhibitor indomethacin prevented the beta-adrenoceptor desensitization as was shown by the restored isoproterenol-induced relaxation in rat lung parenchyma strips and adenylate cyclase activity after the milder desensitization procedure. Inhibition of the arachidonic acid cascade at different levels with different compounds such as BW 755C and betamethasone prevented the desensitization of beta-adrenoceptors. These findings suggest a role for arachidonic acid metabolites in beta-adrenoceptor desensitization. The possible sites of action of arachidonic acid metabolites are also discussed in relation to the inability of indomethacin to prevent the desensitization of beta-adrenoceptors that was induced by the higher Iso concentration used.
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / 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 / Q000502:physiology*
D001095:Arachidonic Acids; D011943:Receptors, Adrenergic, beta; D016718:Arachidonic Acid; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D007213:Indomethacin