Our previous studies showed that increased pulmonary artery elastolytic activity is associated with
monocrotaline-induced
pulmonary hypertension in rats, and the latter is reduced by the
elastase inhibitor
SC-39026. This agent, given orally, decreases
monocrotaline-induced muscularization of normally nonmuscular peripheral arteries but not medial
hypertrophy of muscular arteries. To establish whether constant infusion of an
elastase inhibitor would reduce both vascular lesions induced by
monocrotaline injection,
SC-37698 (an analogue of
SC-39026) was given intravenously by osmopump. To separately assess whether
SC-37698 would inhibit development of the vascular changes as well as their progression,
SC-37698 or vehicle was infused for the first 2 wk (2-wk study) or was delayed until 1 wk after
monocrotaline injection (3-wk study). Hemodynamic data were recorded from
indwelling catheters, and the lungs were evaluated morphologically. Saline-injected control rats given
SC-37698 or vehicle were similar at both time points.
Monocrotaline-injected rats given
SC-37698 compared with those given vehicle alone had lower pulmonary artery pressures, 17.9 +/- 0.5 vs. 23.7 +/- 0.8 mmHg (P less than 0.01) in the 2-wk study and 24.0 +/- 1.8 vs. 33.5 +/- 3.1 mmHg (P less than 0.05) in the 3-wk study. This was associated with significant decreases in muscularization of peripheral arteries and reductions in medial
hypertrophy of muscular arteries. In the hilar pulmonary arteries assessed at 3 wk only,
SC-37698 significantly decreased
monocrotaline-induced endothelial injury, subendothelial
edema, migration of smooth muscle cells into subendothelium, medial
hypertrophy,
collagen accumulation, and abnormal distribution of
elastin as interlamellar islands. Pulmonary artery elastolytic activity was reduced in SC-37698-treated compared with untreated
monocrotaline-injected rats (P less than 0.05). Thus infusion of
SC-37698 reduces
monocrotaline-induced
pulmonary hypertension when administered before or even after development of early vascular changes.