Effect of ventilation pressure on alveolar fluid clearance and {beta}-agonist responses in mice

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio Submitted 23 March 2009 ; accepted in final form 7 August 2009 High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cmH 2 O P, but increased to 37.3% at 18 cmH 2 O P. AFC rate declined at 22 cmH 2 O P, which also induced lung damage. Increased AFC at 18 cmH 2 O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented Na + and Cl – absorption. PKA agonists and β-agonists stimulated AFC at 10 cmH 2 O P by upregulating amiloride-sensitive Na + transport. However, at 18 cmH 2 O P, PKA agonists and β-agonists reduced AFC. At 15 cmH 2 O P, the AFC rate was intermediate (mean 26.6%), and forskolin and β-agonists had no effect. Comparable P dependency of AFC and β-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cmH 2 O was blocked by adenosine deaminase or an A 2b -adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cmH 2 O P. Modulation of adenosine signaling also resulted in altered responsiveness to β-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to β-agonists are impacted by ventilation pressure in an adenosine-dependent manner. tidal volume; epithelial sodium channel; adenosine Address for reprint requests and other correspondence: I. C. Davis, Dept. of Veterinary Biosciences, The Ohio State Univ., 331 Goss Lab, 1925 Coffey Road, Columbus, OH 43210 (e-mail: davis.2448{at}osu.edu ).