The epithelial Na+ transport via an epithelial Na+ channel (ENaC) expressed in the lung epithelium would play a key role in recovery from lung edema at acute lung injury by removing the fluid in lung luminal space. The lung edema causes dysfunction of gas exchange, decreasing oxygen pressure level of artery (P-aO2). To study if ENaC plays a key role in recovering P-aO2 from a decreased level to a normal one in acute lung injury, we applied benzamil (20 muM, a specific blocker of ENaC) to the lung luminal space in acute lung injury treated with high frequency oscillation ventilation (HFOV) that is a lung-protective ventilation with a lower tidal volume and a smaller pressure swing than conventional mechanical ventilation (CMV). Benzamil facilitated the recovery of P-aO2 in acutely injured lung with HFOV but not CMV. The observation suggests that in acutely injured lung treated with HFOV an ENaC blocker, benzamil, can be applied as a therapeutic drug for acute lung injury combing with HFOV. (C) 2004 Elsevier Inc. All rights reserved.