Effect of ventilation pressure on alveolar fluid clearance and [beta]-agonist responses in mice

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 cm[H.sub.2]O P, but increased to 37.3% at 18 cm[H.sub.2]O P. AFC rate declined at 22 cm[H.sub.2]O P, which also induced lung damage. Increased AFC at 18 cm[H.sub.2]O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented [Na.sup.+] and [Cl.sup.-] absorption. PKA agonists and [beta]-agonists stimulated AFC at 10 cm[H.sub.2]O P by upregulating amiloride-sensitive Na+ transport. However, at 18 cm[H.sub.2]O P, PKA agonists and [beta]-agonists reduced AFC. At 15 cm[H.sub.2]O P, the AFC rate was intermediate (mean 26.6%), and forskolin and [beta]-agonists had no effect. Comparable P dependency of AFC and 13-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cm[H.sub.2]O was blocked by adenosine deaminase or an Azb-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cm[H.sub.2]O P. Modulation of adenosine signaling also resulted in altered responsiveness to [beta]-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to [beta]-agonists are impacted by ventilation pressure in an adenosine-dependent manner. tidal volume; epithelial sodium channel; adenosine doi: 10.1152/ajplung.00096.2009