Pulmonary injury induced by the
plant alkaloid monocrotaline is partially prevented by the
angiotensin-converting enzyme (
ACE) inhibitor captopril.
CL242817 [(S-[R*,S*])-1-([3-acetylthio]-3-benzoyl-2-methyl-propionyl)-
L-proline] is a new orally active
ACE inhibitor under evaluation as an
antihypertensive agent. To determine whether
CL242817 also can modify
monocrotaline-induced
pulmonary injury, male rats were divided into four groups: control;
CL242817 (60 mg/kg/day, po);
monocrotaline (2.4 mg/kg/day, po); or
monocrotaline plus
CL242817, and were sacrificed after 6 weeks of continuous treatment. Rats receiving
monocrotaline alone exhibited occlusive medial thickening of the pulmonary arteries,
cardiomegaly, and
right ventricular hypertrophy. Electron micrographs of
monocrotaline-treated lung revealed degeneration of both endothelial and Type I epithelial cells, as well as marked interstitial hypercellularity and
fibrosis.
Hydroxyproline (
collagen) content of
monocrotaline-treated lung also increased significantly, confirming the
fibrosis observed in the electron micrographs. These structural changes were accompanied by decreased lung ACE and
plasminogen activator (PLA) activities, indicative of pulmonary endothelial dysfunction. Concomitant
CL242817 treatment ameliorated all anatomic manifestations of
monocrotaline injury, particularly the
right ventricular hypertrophy, pulmonary
arterial occlusion, epithelial degeneration, and interstitial
fibrosis.
CL242817 also significantly prevented the
monocrotaline-induced increase in lung
hydroxyproline content. In contrast, concomitant
CL242817 did not significantly influence the suppressed lung ACE and PLA activities in
monocrotaline-treated rats.
CL242817 alone produced retarded
weight gain, decreased heart weight relative to
body weight, decreased lung
hydroxyproline content and ACE activity, and increased serum ACE activity and plasma AII concentration. Thus
CL242817 resembles
captopril, both in its ability to ameliorate
monocrotaline-induced
pulmonary injury in rats, and in many of its side effects.