Polyamines and the development of monocrotaline-induced pulmonary hypertension

Previous work in our laboratory has shown that the development of monocrotaline-induced pulmonary vascular disease in rats is preceded by a prolonged activation of lung ornithine decarboxylase (ODC). We now report that significant increases in rat lung adenosylmethionine decarboxylase activity and levels of the diamine putrescine and the polyamines, spermidine and spermine, are produced by a single dose of monocrotaline (MCT). Lung putrescine levels were increased from days 7 through 21, and both spermidine and spermine were first elevated at day 10 following MCT administration. This sustained elevation of lung polyamine levels substantially preceded the development of right ventricular hypertrophy and pulmonary hypertension, which were first evident at days 14 and 16, respectively. Continuous treatment with alpha-difluoromethylornithine, a highly specific enzyme-activated, irreversible inhibitor of ODC activity, prevented the development of MCT-induced pulmonary toxicity. It thus appears that ODC and the polyamines may be important mediators of hypertensive pulmonary vascular disease that develops in response to monocrotaline administration.