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Polyamine synthesis blockade in monocrotaline-induced pneumotoxicity
J W Olson1, U Orlinska, M N Gillespie
1University of Kentucky College of Pharmacology, Division of Pharmacology and Toxicology, Lexington 40536-0082.
Biochemical Pharmacology
|September 1, 1989
Summary
Polyamines are crucial in developing monocrotaline-induced pulmonary hypertension. Blocking polyamine synthesis with alpha-difluoromethylornithine (DFMO) protects against this condition, but this effect can be reversed by adding ornithine.
Area of Science:
- Pulmonary Hypertension Research
- Vascular Biology
- Pharmacology
Background:
- Polyamines regulate cell growth and differentiation.
- Monocrotaline (MCT) induces pulmonary vascular disease.
- Alpha-difluoromethylornithine (DFMO) inhibits polyamine synthesis.
Purpose of the Study:
- To investigate the role of polyamines in MCT-induced pulmonary hypertension.
- To determine the timing of DFMO's protective effects.
- To assess if DFMO's protection can be reversed by exogenous polyamines.
Main Methods:
- Rats were treated with MCT to induce pulmonary hypertension.
- DFMO was administered orally to inhibit polyamine synthesis.
- Ornithine was supplemented to restore polyamine levels.
- Lung polyamine content and right ventricular hypertrophy were measured.
Main Results:
- MCT increased lung polyamine levels and caused right ventricular hypertrophy.
- DFMO treatment initiated 10 days post-MCT attenuated polyamine increases and hypertrophy.
- Ornithine supplementation reversed DFMO's protective effects.
- DFMO's benefits were not solely due to early intervention.
Conclusions:
- Polyamines play a central role in the delayed development of MCT-induced pulmonary hypertension.
- DFMO's protective mechanism involves sustained polyamine inhibition.
- Exogenous ornithine can reverse DFMO's therapeutic effects by restoring polyamine levels.