Denopamine, a β₁-adrenergic agonist, increases alveolar fluid clearance in ex vivo rat and guinea pig lungs

Abstract

The effect of denopamine, a selective beta(1)-adrenergic agonist, on alveolar fluid clearance was determined in both ex vivo rat and guinea pig lungs. Alveolar fluid clearance was measured by the progressive increase in the concentration of Evans blue-labeled albumin over 1 h at 37 degrees C. Denopamine (10(-6) to 10(-3) M) increased alveolar fluid clearance in a dose-dependent manner in ex vivo rat lungs. Denopamine also stimulated alveolar fluid clearance in guinea pig lungs. Atenolol, a selective beta(1)-adrenergic antagonist, and amiloride, a sodium channel inhibitor, inhibited denopamine-stimulated alveolar fluid clearance. The potency of denopamine was similar to that of similar doses of isoproterenol or terbutaline. Short-term hypoxia (100% nitrogen for 1-2 h) did not alter the stimulatory effect of denopamine. Denopamine (10(-4), 10(-3) M) increased intracellular adenosine 3',5'-cyclic monophosphate levels in cultured rat alveolar type II cells. In summary, denopamine, a selective beta(1)-adrenergic agonist, stimulates alveolar fluid clearance in both ex vivo rat and guinea pig lungs.

Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

“…Experimental and clinical studies have shown that the cAMP-mediated stimulation of CFTR-dependent alveolar fluid clearance by endogenous or exogenous ␤ 2 AR agonists is one of the major mechanisms that prevent the flooding of the airspaces after onset of ALI (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)23). However, despite the massive release of catecholamines associated with several condi- B, prolonged exposure (6 h) to TGF-␤1 inhibits the epinephrine-dependent PKA activation in polarized rat primary ATII cells.…”

“…Although significant efforts have been made to pharmacologically up-regulate alveolar fluid clearance to reverse the progression of lung injury, these approaches have not been successful (4). ␤ 2 -Adrenergic receptor (␤ 2 AR) agonists have been shown to enhance alveolar epithelial fluid transport via a cAMP-dependent mechanism under physiological conditions (5)(6)(7)(8)(9)(10)(11) and in various experimental models of ALI (12)(13)(14) as well as in one small prospective study in ALI patients (15). However, one of the main limitations of this therapeutic approach is that ␤-adrenergic agonist hyporesponsiveness has been reported in some experimental models of ALI (16,17), although none of the critical mediators of ALI have yet been shown to inhibit the ␤-adrenergic-stimulated fluid transport of the distal lung epithelium.…”

Beta1-Adrenergic Agonist Is a Potent Stimulator of Alveolar Fluid Clearance in Hyperoxic Rat Lungs

“…Measurement of alveolar fluid clearance: As previously reported (9,15,19), we isolated rat lungs and measured alveolar fluid clearance in the absence of either pulmonary perfusion or ventilation. Briefly, rats were anesthetized by an intraperitoneal administration of pentobarbital sodium (50 mg/ kg body wt).…”

“…Alveolar fluid clearance was estimated by measuring the progressive increase in the concentrations of alveolar Evans blue labeled albumin (9,15,19). Alveolar fluid clearance (AFC) was calculated as follows: Measurement of extravascular lung water: The water content of the left lung was measured by drying the lungs to a constant weight at 70°C for 48 h. Lung water-to-dry lung weight ratio (LW/ DL) was calculated as LW /DL = (wet lung weight -dry lung weight) / (dry lung weight).…”

“…Interestingly, isoproterenol increased alveolar fluid clearance via b 1-adrenoceptors in guinea pig lungs (13), whereas isoproterenol increased alveolar fluid clearance via b 2-adrenoceptors in rat lungs (14). Recently, we reported that denopamine, a selective b1-adrenergic agonist, increased alveolar fluid clearance in normal rat and guinea pig lungs (15).…”