Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.

Abstract

OBJECTIVE:

To determine whether clinically relevant airspace concentrations of beta2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta2 agonist therapy decreased pulmonary edema in experimental acute lung injury.

DESIGN:

Prospective randomized laboratory investigation.

SETTING:

University-affiliated laboratory.

SUBJECTS:

Sprague Dawley rats.

INTERVENTIONS:

Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury.

MEASUREMENTS AND MAIN RESULTS:

Basal alveolar fluid clearance was 7.6 +/- 2.2 %/hr. Maximal cAMP-dependent alveolar fluid clearance rate was 32.9 +/- 10.9 %/hr (p <.05). Racemic albuterol 10(-5) M, salmeterol 10(-6) M, and isoproterenol 10(-6) M each stimulated alveolar fluid clearance to a level comparable to maximal cAMP-dependent alveolar fluid clearance. Compared with basal rates, alveolar fluid clearance was increased by both racemic albuterol 10(-6) M (14.5 +/- 3.0%, p <.05) and R-enantiomer 10(-6) M (15.0 +/- 4.6%, p <.05), but there was no difference between the two groups. Intra-alveolar salmeterol 10 (-6) M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 +/- 30 microL with salmeterol treatment, compared with 296 +/- 65 microL in saline-treated rats 4 hrs after acid injury (p <.05). This decrease in lung water was accompanied by a 2.4-fold increase in the rate of alveolar fluid clearance at 4 hrs in the salmeterol-treated group. Lung endothelial permeability, expressed as extravascular plasma equivalents, was reduced to 64 +/- 9 microL with salmeterol compared with 119 +/- 51 microL in saline-treated rats 4 hrs after acid injury (p <.05).

CONCLUSIONS:

Clinically relevant airspace concentrations of beta2-adrenergic agonists a) stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and b) reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability. Clinical studies are required to determine whether beta2-adrenergic agonists improve outcome in patients with acute lung injury.

• Authors: Daniel F McAuley, James A Frank, Xiaohui Fang, Michael A Matthay
• Journal: Critical care medicine (Crit Care Med) Vol. 32 Issue 7 Pg. 1470-6 (Jul 2004) ISSN: 0090-3493 [Print] United States
• PMID: 15241090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Agonists
• Adenosine Monophosphate
• Salmeterol Xinafoate
• Albuterol

Topics

• Adenosine Monophosphate (metabolism)
• Adrenergic beta-Agonists (therapeutic use)
• Albuterol (analogs & derivatives, therapeutic use)
• Animals
• Extravascular Lung Water (drug effects)
• Pulmonary Alveoli (drug effects, metabolism)
• Pulmonary Edema (drug therapy)
• Pulmonary Gas Exchange (drug effects)
• Rats
• Rats, Sprague-Dawley
• Respiratory Distress Syndrome (drug therapy)
• Salmeterol Xinafoate
• Stereoisomerism