Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease.
The pyrrolizidine alkaloid (PA) monocrotaline (MCT) is thought to be activated in the liver to monocrotaline pyrrole (MCTP) which is then transported to the lungs where it causes a pulmonary vascular syndrome characterized by elevated pulmonary artery pressure and right ventricular hypertrophy. We have found that, as opposed to Sprague-Dawley (SD) rats, Fischer 344 (F344) strain rats are resistant to the ventricular hypertrophy and pressure changes induced by MCT. To determine whether this strain difference might be related to differences in hepatic activation of MCT to MCTP, we compared the response of SD and F344 rats to treatment with MCT or MCTP. We determined right ventricular pressure and ventricular weight ratios with each treatment for each strain. We also compared subjective lesion scores of histopathologic changes characteristic of MCT pneumotoxicity. Sprague-Dawley rats treated with either MCT or MCTP had elevated right ventricular pressures (Control 13 +/- 1 mmH2O, MCTP 29 +/- 3 mmH2O, MCT 24 +/- 2 mmH2O) and increased right ventricular weight ratio (RV/LV + S) of 0.30 +/- 0.01 (Control), 0.44 +/- 0.05 (MCTP), 0.44 +/- 0.02 (MCT). Histopathologic evaluation demonstrated that significant alveolar septal fibrosis, edema and type II cell hypertrophy was induced by both PAs in both rat strains but that F344 rats had significantly less vascular medial hypertrophy and adventitial inflammation than SD rats. MCTP treated SD rats had similar vascular and parenchymal alterations as those treated with MCT but with a lesser inflammatory component. We conclude that the strain differences in cardiac and pulmonary vascular responses to MCT also occur with MCTP treatment. This, combined with the similarity in alveolar parenchymal response to both PAs in both strains, suggests that these differences are related to the pulmonary vascular response rather than differences in hepatic metabolism.
Pan
L C
LC
Department of Veterinary Pharmacology and Toxicology, University of California, Davis 95616.
Wilson
D W
DW
Segall
H J
HJ
D000818:Animals; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000031:analogs & derivatives / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D015430:Weight Gain / Q000187:drug effects
C014114:monocrotaline pyrrole; D016686:Monocrotaline