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.

Triiodo-l-thyronine Rapidly Stimulates Alveolar Fluid Clearance in Normal and Hyperoxia-injured Lungs

“…Decreases in AFC occur in acute lung injury/acute respiratory distress syndrome (38), cardiogenic pulmonary edema (39), reperfusion injury after lung transplantation (40), and other less common forms of pulmonary edema. Stimulation of AFC by b-adrenergic agonists in normal and injured lungs is well described (16,19,41,42), but critical illness is associated with high endogenous catecholamine levels and there may be desensitized and/or down-regulated b-adrenergic receptors in the alveolar epithelium (19). There is a potential major benefit to identifying other agents that could be applied directly to the distal lung either individually or in combination with b-adrenergic agonists to increase AFC.…”

“…Airspace T 3 rapidly restores the decreased alveolar fluid clearance in rat lungs with hyperoxia-induced lung injury. 19) by instilling an isosmolar 5% bovine serum albumin solution with fluorescein-labeled albumin tracer and measuring the change in fluorescein isothiocyanate-albumin concentration over time. AFC measurement was performed using a ventilated lung model for (1) control unmanipulated rats, (2) rats receiving intraperitoneal injections of either saline or 30 mg of T 3 , 24 hours apart for 3 consecutive days, and (3) rats with airspace instillation of T 3 as described below.…”

“…On the basis of our in vitro data (7,8), 10 26 M T 3 or reverse T 3 (rT 3 ) was included in the instillate to determine the effects of airspace instillation of T 3 . Because a number of extrapulmonary changes could affect AFC, for all subsequent experiments AFC was measured in ex vivo rat lungs as described previously (19), with some modifications. The direct effect of airspace instillation of T 3 was studied in both normal lung and injured lungs, with and without 10 26 M T 3 in the instillate.…”

Inactivation of sodium-transporting proteins in the kidney

“…A second mouse is engineered containing Cre recombinase under control of a tissue or cell-specific (here: nephron segment-specific) promoter. Mating results in mice in which the floxed gene of interest is only deleted in tissues or cells in which the Cre transgene is expressed transgenic mice expressing Flp recombinase to obtain offspring without the neo gene or, in vitro, in targeted ES cells by transient expression of eukaryotic FLPe expression vector [34,35,36]. The remaining frt site and the two loxP sites in the targeted allele normally do not interfere with gene expression and the resulting floxed allele can be used for further conditional knock-out experiments.…”

A Prostacyclin Analogue, OP-41483a-CD, Restores the Ability of a � 2 -Adrenergic Agonist to Stimulate Alveolar Fluid Clearance in Rats

“…1,5 It was recently reported that high-dose terbutaline (10 Ϫ3 M) did not stimulate alveolar fluid clearance in rats, but atenolol, a 1 -adrenergic antagonist, restored the stimulant effect of high-dose terbutaline on alveolar fluid clearance. 6 The inhalation of a stable prostacyclin analogue, iloprost, has offered a new therapeutic option to improve hemodynamics and physical function in patients with pulmonary hypertension and progressive rightheart failure. 7 An admixture of prostaglandin I (PGI) 2 and PGE 1 prostanoids is routinely used for the flush perfusion of pulmonary grafts in many medical centers.…”