Studies on the Mechanism of Decreased Angiotensin I Conversion in Rat Lungs Injured with Alpha-Naphthylthiourea

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Abstract
Lung endothelial cell injury may be an important early event in the pathogenesis of increased permeability pulmonary edema. Since angiotensin converting enzyme ACE) is located on the luminal surface of the endothelial cell membrane, we sought to determine whether the conversion of angiotensin I (AI) to angiotensin II is decreased after acute lung injury to rats, induced by alpha-naphthylthiourea (ANTU), and we investigated the mechanism of the decrease. We found that lungs isolated from rats treated 4 h earlier with ANTU at a dose of 15 mg/kg body weight (BW) had decreased AI conversion when perfused with Krebs-Henseleit at a constant flow rate of 30 ml/min/kg BW. When perfusate flow rate was increased from 30 to 50 ml/min/kg BW, lungs isolated from rats treated with 10 mg/kg BW ANTU also had decreased AI conversion when compared to controls treated with a vehicle, Tween 80. Investigating the mechanism of decreased AI conversion, there were no differences among experimental groups in pulmonary arterial pressures or effluent perfusate pH or p02. There was no correlation between lung wet/dry weight ratios and the extent of AI conversion among control rat lungs. Lung homogenate and serum ACE activity did not differ among control rats and rats pretreated with the two doses of ANTU. Ultrastructural studies revealed an increased percentage of capillaries with blebbing of endothelial cells in lungs injured with ANTU, as compared to controls, but no evidence of increased endothelial cell denudation in injured lungs. We conclude that angiotensin I conversion is decreased after ANTU lung injury and that the extent of decrease is related to the dose of ANTU and to perfusate flow rate. Although we cannot exclude decreased vascular surface area perfused as a cause of decreased conversion, we speculate that subtle changes in the luminal endothelial cell membrane may have caused decreased AI conversion after ANTU lung injury.