Serum copper concentration as an index of cardiopulmonary injury in monocrotaline-treated rats.
The pyrrolizidine alkaloid monocrotaline produces pulmonary inflammation, hemorrhage, fibrosis, and hypertension. In rats, monocrotaline pneumotoxicity can be ameliorated by cotreatment with inhibitors of angiotensin converting enzyme (ACE), such as CL242817. In the present study, serum and urine copper (Cu) concentrations were evaluated as indices of cardiopulmonary injury in rats sacrificed after six weeks of continuous administration of monocrotaline (0 to 3.6 mg per kg per day, in the drinking water) or CL242817 (60 mg per kg per day, in the feed), or both. Monocrotaline-treated rats exhibited dose-dependent increases in (1) pulmonary histopathology, (2) pulmonary endothelial dysfunction (decreased lung plasminogen activator activity, and increased prostacyclin and thromboxane production), (3) pulmonary hydroxyproline (collagen) content, and (4) cardiac right ventricular hypertrophy (an anatomic correlate of pulmonary hypertension). The severity of cardiopulmonary damage was accompanied by a dose-dependent elevation in serum Cu concentration. Serum iron concentration, in contrast, did not change. Urinary Cu concentration correlated roughly with that of serum, but the variability within groups was high. Cotreatment with the ACE inhibitor CL242817 not only ameliorated monocrotaline-induced right heart enlargement and lung hydroxyproline accumulation but also reduced the hypercupremia in monocrotaline-treated rats. Thus, serum copper concentration appears to be an accurate and minimally invasive index of monocrotaline pneumotoxicity in this model of pulmonary hypertension.
Molteni
A
A
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611.
Ward
W F
WF
Ts'ao
C H
CH
Fitzsimons
E J
EJ
D000818:Animals; D003300:Copper / Q000097:blood* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D008168:Lung / Q000187:drug effects*; D008297:Male; D016686:Monocrotaline; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D003300:Copper