Beta(1)-adrenoceptor stimulation by high-dose terbutaline downregulates terbutaline-stimulated alveolar fluid clearance in ex vivo rat lung

Because high-order terbutaline and isoproterenol (10(-3) M), beta (2)-adren ergic agonists, failed to increase alveolar fluid clearance, the mechanisms , responsible for this effect were examined in ex vivo rat lungs. An isosmo lar 5% albumin solution with Evans blue dye was instilled into the distal a irspaces in isolated rat lungs that were then inflated with 100% oxygen at an airway pressure of 8 cm H2O in a 37 degreesC incubator. Alveolar fluid c learance was measured by the progressive increase in dye concentrations ove r 1 hour. The results indicated that: (1) although 10(-5) M terbutaline or isoproterenol increased alveolar fluid clearance, 10(-3) M terbutaline or i soproterenol did not; (2) both concentrations of terbutaline (10(-5), 10(-3 ) M) increased intracellular adenosine 3 ', 5 ' -cyclic monophosphate in cu ltured type II alveolar epithelial cells; (3) instillation of atenolol, a s elective beta (1)-adrenergic antagonist, in the presence of either 10(-3) M terbutaline or isoproterenol was associated with an increase in alveolar f luid clearance. These results suggested that beta (1)-adrenoceptor stimulat ion prevented the normal response to a beta (2)-adrenergic agonist. To furt her test this hypothesis, a selective beta (1)-adrenergic agonist, denopami ne, was administered; these results showed that (4) 10(-3) M denopamine, a selective beta (1)-adrenergic agonist, inhibited the increase in alveolar f luid clearance in the presence of 10(-5) M terbutaline; (5) hypoxia for 2 h ours did not alter the effects of terbutaline on alveolar fluid clearance. The mechanism, for the inability of the alveolar epithelium to respond to h igh-dose terbutaline or isoproterenol with the normal upregulation of alveo lar fluid clearance in ex vivo rats lungs appears to be mediated by beta (1 )-adrenoceptor stimulation that subsequently suppresses the beta (2)-adrene rgic response.