Monocrotaline pyrrole (
MCTP), a putative toxic metabolite of the
pyrrolizidine alkaloid,
monocrotaline, causes pulmonary vascular thrombi that are associated with
vascular remodeling,
pulmonary hypertension, and right cardioventricular
hypertrophy in rats. It is possible that such thrombi contribute to the
lung injury and
pulmonary hypertension in this model. A previous study indicated that rats treated with
MCTP did not have excessive procoagulant activity in the peripheral blood. Since
thrombosis may also result from insufficient fibrinolytic activity in the systemic circulation, we evaluated the fibrinolytic system of rats given
MCTP. Male Sprague-Dawley rats were given a single injection of
MCTP (3.5 mg/kg) or an equal volume of
N,N-dimethylformamide vehicle in the tail vein and were killed at 1, 3, 5, 8, 11, or 14 days after toxin administration. Several markers of
lung injury and fibrinolysis were measured.
Lung injury was evident 3 days after administration of
MCTP and became more pronounced with time. In
MCTP-treated rats, right
heart hypertrophy was observed at 11 days and became more pronounced at 14 days. There was no change in the
plasminogen concentration or in the activities of
tissue plasminogen activator or alpha 2-antiplasmin in blood throughout the time course. Beginning at Day 8 and continuing through Day 14, there was an increase in the activity of
plasminogen activator inhibitor in blood of rats that received
MCTP. In addition, we evaluated the fibrinolytic activity of lung tissue slices. Rats treated with
MCTP had a significant decrease in fibrinolytic activity of lung tissue at Day 3. A more pronounced decrease was evident by Day 8, and this continued through Day 14. In summary,
MCTP treatment of rats decreases the fibrinolytic activity of lung tissue relatively early after exposure to the toxicant and before the onset of
pulmonary hypertension. The change is reflected slightly later in plasma. These alterations in fibrinolytic activity may explain why
fibrin thrombi form in the lungs of rats treated with
MCTP.