THE EFFECTS OF MONOCROTALINE PYRROLE ON CULTURED BOVINE PULMONARY-ARTERY ENDOTHELIAL AND SMOOTH-MUSCLE CELLS

Monocrotaline pyrrole (MCTP), a reactive electrophile, induces delayed and progressive pulmonary edema, vascular remodeling, and pulmonary hypertension after a single intravenous administration to rats. The effects of a single exposure of cultured bovine pulmonary artery endothelial cells (BEC) and bovine pulmonary artery smooth muscle cells (BSMC) to MCTP were examined. Monocrotaline pyrrole caused a dose-dependent, delayed, and progressive cell detachment and release of lactate dehydrogenase activity from monolayers of BECs but not BSMCs. Monolayers of BECs also released increased concentrations of 6-keto-prostaglandin F1-alpha, the stable metabolite of prostacyclin, as the post-treatment interval increased. Progressive and marked endothelial cell hypertrophy occurred after exposure to a nominal concentration of 5 or 50-mu-g/ml of MCTP but not after 0.5-mu-g/ml. Morphologic changes in monolayers of BSMCs were minimal, even up to 2 weeks after exposure. Ultrastructurally the hypertrophic, MCTP-treated BECs had enlarged cell profiles with enlarged nuclei. The nucleoli were prominent, occasionally multiple, and had separation of granular and fibrillar components. Cytoplasmic microtubules and perinuclear intermediate filaments were prominent in some cells, as were the golgi apparatus and endoplasmic reticulum. Degenerative changes were not prominent in cells that remained in the monolayer. Monocrotaline pyrrole inhibited proliferation of both cell types at concentrations (0.5-mu-g/ml) that were not cytotoxic. These findings indicate that MCTP induces direct, dose-dependent injury to cells in culture that is delayed and progressive, and the expression of this injury depends, in part, on the cell type.