In rats injected with the toxin
monocrotaline, altered synthesis and distribution of pulmonary artery
elastin suggest that increased
elastase activity may be important in the development of vascular changes and progressive
pulmonary hypertension. To test this hypothesis, male Sprague-Dawley rats (250-300 g) were given 40 mg/kg of the
elastase inhibitor
SC-39026 in a
carboxymethylcellulose vehicle or vehicle only by gavage, 12 hours before and twice daily for 8 days after a single
subcutaneous injection of either
monocrotaline (60 mg/kg) or saline. Thirteen days after injection, indwelling cardiovascular
catheters were inserted under
pentobarbital anesthesia, and at 15 days after injection, pulmonary and systemic hemodynamic measurements were recorded with the animals awake. At post-mortem examination, the lungs were perfused and morphometric techniques applied for light and electron microscopic evaluation. Saline-injected rats given either
SC-39026 or vehicle were similar in all features assessed. In contrast,
monocrotaline-injected rats given
SC-39026 had significantly lower mean pulmonary artery pressure than those given vehicle (21.0 +/- 1.6 vs. 27.5 +/- 0.8 mm Hg, p less than 0.05), and this correlated with a significant reduction in the number of abnormally muscularized arteries at alveolar wall level (r2 = 0.89, p less than 0.001).
SC-39026 did not significantly reduce
monocrotaline-induced medial
hypertrophy of muscular arteries, endothelial injury, and associated subendothelial
edema; nor was there a significant increase in the proportion of the medial
elastin, although a trend was apparent. Additional groups of
monocrotaline injected rats were followed 3 weeks after injection, but both
SC-39026 and vehicle-treated rats were similar at this point. Our data suggest that increased
serine elastase activity associated with endothelial injury may mediate early abnormal pulmonary vascular smooth muscle differentiation resulting in muscularization of normally nonmuscular peripheral arteries and
pulmonary hypertension induced in rats by injection of the toxin
monocrotaline. Lack of persistence of this protective effect suggests that there may be continued
elastase activity in this model. Failure to inhibit medial
hypertrophy with
SC-39026 suggests that a different mechanism or a different
elastase may be involved in this structural change.