Based on the documented regulatory role of
polyamines in cell growth and differentiation, we have proposed that these organic
cations are involved with the development of
monocrotaline (MCT)-induced hypertensive pulmonary
vascular disease. Two lines of evidence support this hypothesis: (1) MCT causes progressive increases in lung
polyamine contents which are temporarily related to the development of cardiopulmonary abnormalities, and (2) blockade of
polyamine synthesis with the site-selective
enzyme-activated inhibitor,
alpha-difluoromethylornithine (DFMO), attenuates development of medial arterial thickening, increased pulmonary arterial pressure, and
right ventricular hypertrophy. To evaluate the mechanism of DFMO protection, the present study assessed when, during the course of MCT-induced pneumotoxicity, DFMO exerts its salutary effects, and determined if the protection afforded by DFMO could be reversed through supplementation with exogenous
polyamines. To address the first issue, rats were treated with 30 mg/kg MCT and, 10 days after administration when lung
polyamine contents were augmented and when
pulmonary edema was evident, DFMO treatment was initiated
as a 2%
solution in the
drinking water. In animals receiving MCT only, lung
polyamine contents were elevated and
right ventricular hypertrophy was evident at both 20 and 35 days
after treatment. DFMO treatment initiated at day 10 attenuated the increases in
putrescine and
spermidine but not
spermine and reduced the degree of
right ventricular hypertrophy at both the 20- and 35-day time points. To determine if the blockade by DFMO could be reversed by supplementation with exogenous
polyamines, animals were treated simultaneously with MCT and DFMO as described above and the immediate precursor to the
polyamines,
ornithine, was added to the
drinking water as a 2%
solution. Relative to animals receiving MCT and DFMO,
ornithine supplementation increased lung
polyamine contents to levels normally associated with MCT treatment only.
Ornithine also reversed the protection against
right ventricular hypertrophy normally afforded by DFMO. These observations indicate that the salutary effects of DFMO in MCT-induced
pulmonary hypertension cannot be ascribed solely to interference in the early events after MCT treatment and that restoration of lung
polyamine contents to high levels by supplementation with exogenous
ornithine reverses DFMO protection against sustained
pulmonary hypertension. It is concluded, therefore, that
polyamines play a central role in delayed responses of lung cells underlying the development of MCT-induced sustained
pulmonary hypertension.