Previously in rats injected with the toxin
monocrotaline and administered
SC-39026, a
serine elastase inhibitor,
pulmonary hypertension was decreased in association with reduced muscularization of peripheral pulmonary arteries. To determine whether inhibition of elastolytic activity might prevent this vascular change in other conditions producing
pulmonary hypertension, we administered
SC-39026 to rats during a 10-day exposure to chronic hypobaric
hypoxia. We also measured elastolytic activity in the central pulmonary arteries of rats using [3H]
elastin substrate and determined whether there was an increase in activity either as early
as 2 days or at completion of the hypoxic exposure, which could be inhibited by
SC-39026. to further determine whether the mechanism of muscularization of peripheral arteries is modulated by degradation of
elastin or other
elastase-susceptible
extracellular matrix proteins, we assessed
desmosine excretion and ultrastructural alterations in
elastin as well as in
type IV collagen,
fibronectin, and
laminin.
SC-39026 reduced the number of muscularized arteries and the level of pulmonary arterial pressure during exposure to chronic
hypoxia. Elastolytic activity was fourfold higher in central pulmonary arteries 2 days after
hypoxia when compared with values in control vessels, and the activity was inhibited by
SC-39026. In small peripheral pulmonary arteries there were no significant changes with
hypoxia reflected in desmosines or in the immunocytochemistry of
elastase-susceptible
glycoproteins, with the exception of decreased
laminin. This feature was not inhibited by
SC-39026. To further assess whether the protective effect of
SC-39026 was related to its inhibition of
elastase, an extended study was carried out using a different
elastase inhibitor, alpha 1-proteinase inhibitor. An even greater reduction in
hypoxia-induced
pulmonary hypertension and vascular changes was observed with this
elastase inhibitor and the latter included medial
hypertrophy.