Suppression of polyamine biosynthesis prevents monocrotaline-induced pulmonary edema and arterial medial thickening.
Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.
D000818:Animals; D001711:Biotransformation; D000518:Eflornithine; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D011763:Pyrrolizidine Alkaloids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D009952:Ornithine; D000518:Eflornithine