Mechanism of isoprenaline induced desensitization of rabbit aortic smooth muscle beta-adrenoceptor responses.

The effects of short term (1 h) as well as prolonged (16 h) activation of beta-adrenoceptors by isoprenaline on the functioning of the beta-adrenoceptor linked adenylate cyclase system of rabbit aortic smooth muscle cells in the contractile phenotype in primary culture was examined. Smooth muscle cells responded to 50 mumol/l isoprenaline with a rapid increase in intracellular cAMP. Continued exposure of these cells to this concentration of isoprenaline results in a rapid time dependent reduction in maximum beta-adrenoceptor responsiveness. In vitro analyses of adenylate cyclase activities, phosphodiesterase activity and 125I-iodocyanopindolol specific (beta-adrenoceptor) binding sites suggest that the decrease in the cells' ability to increase intracellular cAMP may be due to a reduction in beta-adrenoceptor binding sites. The loss in cell receptor responsiveness and membrane receptor concentration was only very slowly reversible. These results suggest that following prolonged exposure of vascular smooth muscle cells to beta-adrenoceptor agonists, beta-adrenoceptors are rapidly internalized and degraded. This mechanism may account for the haemodynamic tolerance observed to chronic therapy with beta-adrenoceptor agonists.