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Angiotensin converting enzyme (ACE), a glycoprotein, is found in high concentration in pulmonary capillary endothelial cells. Several investigators have studied the relationship between various direct and indirect pulmonary insults and ACE activity and in some cases have found conflict. In an attempt to clarify this relationship we have examined the effect of endotoxin on rat plasma ACE activity in vitro and in vivo. We used the synthetic ACE substrate 3H-BPAP and the assay described by Catravas and Gillis [J Pharmacol Exp Ther 217:263-270, 1981]. In vitro, a statistically significant concentration-dependent reduction in ACE activity was demonstrated (p less than .005). In vivo an intravenous dose of endotoxin (20 mg/kg) alone resulted in no significant change in plasma ACE activity. However, the combination of intravenous endotoxin (20mg/kg) and mild hemorrhage (5-10% of blood volume) caused a statistically significant reduction in plasma ACE activity by 15 min as compared to control rats with hemorrhage only (39% vs. 66%, p less than .005). This reduction persisted at 30 and 60 min. However, by 180 min ACE activity was no longer statistically different from control values. We have demonstrated an acute reduction of plasma ACE activity in the endotoxemic rat that appears to be dependent on the amount of circulating endotoxin and the presence of mild blood loss.