Involvement of arachidonic acid metabolites in β-adrenoceptor desensitization: Functional and biochemical studies

Abstract

The prolonged in vitro perfusion of rat lung with isoproterenol (Iso) induced a desensitization of β-adrenoceptors which was dose- and time-dependent. The decrease in functional responsiveness of rat lung parenchyma to the β-agonist correlated well with the loss of [ 3H]dihydroalprenolol ([ 3H]DHA) binding sites and adenylate cyclase activity after the β-adrenoceptor desensitization procedure. The cyclooxygenase inhibitor indomethacin prevented the β-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 β-adrenoceptors. These findings suggest a role for arachidonic acid metabolites in β-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 β-adrenoceptors that was induced by the higher Iso concentration used.