Lung N-methyl-D-aspartate receptors (NMDAR) may cause excitotoxic pulmonary edema if activated. Acute lung injury may be mediated by oxidative stress, frequently generated by local or remote ischemia and reperfusion (IR). This experimental study assessed the effects of intravenous dextromethorphan, an NMDAR antagonist, on reperfusion lung injury following superior mesenteric artery (SMA) clamping/unclamping. SMA of 48 (12 per group) anesthetized adult male Wistar rats was clamped for 90 min (IR); 48 additional rats underwent a sham laparotomy (control). The experimental timeframe was identical in all groups. Ten minutes before unclamping, three dextromethorphan doses were administered intravenously in three IR and three control groups, followed by 3 h of respiratory and hemodynamic assessment and postexperimental assessment of survival. Intravenous 10 and 20 mg/kg dextromethorphan attenuated an 85% increase in peak ventilatory pressure, a 45% reduction in PO(2)/FiO(2), 4-12-fold increase in bronchoalveolar lavage-retrieved volume, and polymorphonuclear leukocytes/bronchoalveolar cells ratio, all associated with SMA unclamping in the IR-nontreated and the IR-40 mg/kg dextromethorphan-treated rats. Lung tissue polymorphonuclear leukocyte count, total xanthine oxidase activity, reduced glutathione, and wet-to-dry weight ratio were all within normal ranges in the two lower-dose-treated groups. These effective regimens were also associated with longer postexperimental animal survival. Dextromethorphan was not associated with changes in three control groups. Thus, Intravenous dextromethorphan mitigates lung reperfusion injury following SMA clamping/unclamping in a dose-dependent manner. This is a novel potential use of dextromethorphan in vivo.