MONOCROTALINE PYRROLE-INDUCED CHANGES IN ANGIOTENSIN-CONVERTING ENZYME-ACTIVITY OF CULTURED PULMONARY-ARTERY ENDOTHELIAL-CELLS

1 Changes in the structural and functional integrity of endothelium have been recognized as relatively early features of delayed and progressive pulmonary vascular injury caused by the pyrrolizidine alkaloid, monocrotaline (MCT). Although a number of investigators have evaluated angiotensin-converting enzyme (ACE) activity in the lungs of rats treated with MCT, the exact nature of changes in activity of this enzyme and the role they may play in MCT pneumotoxicity remain controversial. 2 We examined the direct effects of monocrotaline pyrrole (MCTP), a toxic metabolite of MCT, on cultured endothelial cell ACE activity. Post-confluent monolayers of porcine or bovine pulmonary artery endothelial cells (PECs or BECs, respectively) were treated with a single administration of MCTP at time 0; then they were examined for their ability to degrade the synthetic peptide, [H-3]-benzoyl-Phe-Ala-Pro. 3 In PECs, which are relatively insensitive to the direct cytolytic effects of MCTP, monolayer ACE activity was unchanged initially but gradually decreased within 4 days after treatment with a high concentration of MCTP (150 muM). This decrease was transient, and PEC monolayer ACE activity returned to the control value by 10 days post treatment. 4 BEC monolayer ACE activity was also unchanged initially but rapidly declined within 4 days after MCTP treatment and remained depressed throughout the post treatment period. BECs were quite sensitive to the cytolytic effects of MCTP and the decline in ACE activity occurred coincident with the decrease in monolayer cellularity and appearance of marked cytotoxicity. 5 We conclude that high concentrations of MCTP decrease endothelial ACE activity. The decline in ACE activity is delayed and the magnitude and duration of the decrease corresponds to the degree of MCTP-induced cytotoxicity. This suggests that altered endothelial ACE activity is unlikely to be a direct effect of MCTP on the enzyme but may reflect the delayed cell injury which results from exposure to this compound.