alpha-Difluoromethylornithine attenuates monocrotaline-induced airway/lung dysfunction.
On the basis of the previous findings that alpha-difluoromethylornithine (DFMO, an inhibitor of ornithine decarboxylase, which is the rate-limiting enzyme in polyamine biosynthesis) treatment prevents monocrotaline-(MCT) induced pulmonary hypertension and that ventilatory dysfunction precedes pulmonary hypertension in MCT-treated rats, we hypothesize that MCT-induced changes in airway/lung function are polyamine dependent. To evaluate this hypothesis, in phase 1, 48 young Sprague-Dawley rats were evenly divided into four groups: control, DFMO, MCT, and DFMO + MCT. Each DFMO rat received DFMO in its drinking water (2%) for 11 days, with additional injections (400 mg/kg sc) on the 5th day. Each MCT rat received a single injection of MCT (60 mg/kg sc) 1 wk before the functional study. Each DFMO + MCT rat received the same DFMO and MCT treatments as above, and MCT was administered on the 5th day of the DFMO treatment. In the MCT group, there were marked rightward shifts in pressure-volume and maximal flow-static recoil (MFSR) curves and significant decreases in dynamic and quasi-static compliance, the maximal expiratory flow, slope of the MFSR curve, and the carbon monoxide diffusing capacity, as well as a significant increase in alveolar wall thickness. However, in rats treated with DFMO + MCT, most of MCT-induced changes were significantly attenuated. To evaluate whether MCT causes bronchoconstriction, a bronchodilator, terbutaline (0.2 mg/kg i.v.), was administered to control (n = 7) and MCT (n = 11) rats in phase 2. Terbutaline significantly reversed MCT-induced decreases in maximal expiratory flow and slope of the MFSR curve, whereas it did not alter these parameters in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhou
K R
KR
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington 40536.
Lai
Y L
YL
D000402:Airway Obstruction / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D000518:Eflornithine / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline / Q000037:antagonists & inhibitors* / Q000633:toxicity; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D016686:Monocrotaline; D013726:Terbutaline; D000518:Eflornithine