title: Beta1-adrenoceptor stimulation by high-dose terbutaline downregulates terbutaline-stimulated alveolar fluid clearance in ex vivo rat lung.
abstract: Because high-dose terbutaline and isoproterenol (10(-3) M), beta2-adrenergic agonists, failed to increase alveolar fluid clearance, the mechanisms responsible for this effect were examined in ex vivo rat lungs. An isosmolar 5% albumin solution with Evans blue dye was instilled into the distal airspaces in isolated rat lungs that were then inflated with 100% oxygen at an airway pressure of 8 cm H2O in a 37 degrees C incubator. Alveolar fluid clearance was measured by the progressive increase in dye concentrations over 1 hour. The results indicated that: (1) although 10(-5) M terbutaline or isoproterenol increased alveolar fluid clearance, 10(-3) M terbutaline or isoproterenol did not; (2) both concentrations of terbutaline (10(-5), 10(-3) M) increased intracellular adenosine 3',5'-cyclic monophosphate in cultured type II alveolar epithelial cells; (3) instillation of atenolol, a selective beta1-adrenergic antagonist, in the presence of either 10(-3) M terbutaline or isoproterenol was associated with an increase in alveolar fluid clearance. These results suggested that beta1-adrenoceptor stimulation prevented the normal response to a beta2-adrenergic agonist. To further test this hypothesis, a selective beta1-adrenergic agonist, denopamine, was administered; these results showed that (4) 10(-3) M denopamine, a selective beta1-adrenergic agonist, inhibited the increase in alveolar fluid clearance in the presence of 10(-5) M terbutaline; (5) hypoxia for 2 hours did not alter the effects of terbutaline on alveolar fluid clearance. The mechanism for the inability of the alveolar epithelium to respond to high-dose terbutaline or isoproterenol with the normal upregulation of alveolar fluid clearance in ex vivo rats lungs appears to be mediated by beta1-adrenoceptor stimulation that subsequently suppresses the beta2-adrenergic response.
authors.affiliation: Department of Thoracic Surgery, Kanazawa Medical University, Uchinade, Ishikawa, Japan. sakuma-t@kanazawa-med.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Sakuma
authors.forename: C
authors.initials: C
authors.lastname: Tuchihara
authors.forename: M
authors.initials: M
authors.lastname: Ishigaki
authors.forename: K
authors.initials: K
authors.lastname: Osanai
authors.forename: Y
authors.initials: Y
authors.lastname: Nambu
authors.forename: H
authors.initials: H
authors.lastname: Toga
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: N
authors.initials: N
authors.lastname: Ohya
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D015687:Cell Hypoxia; D004847:Epithelial Cells / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000378:metabolism; D013726:Terbutaline / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D007545:Isoproterenol; D013726:Terbutaline