Development of monocrotaline-induced pulmonary hypertension is attenuated by a serotonin receptor antagonist.
The significance of serotonin in the pathogenesis of monocrotaline-induced pulmonary hypertension (MCT-PH) in rats, plasma serotonin concentrations, and the effect of a serotonin receptor antagonist administration in association with the number of proliferative cells were investigated. The thickness of the media of the small pulmonary arteries and the weight ratio of the RV to that of LV + S (RV/[LV + S] weight ratio) were used as indices of the severity of PH. Plasma serotonin concentrations were measured by high-performance liquid chromatography. Histopathologic analysis of the lung tissue was performed by hematoxylin-eosin and elastin van Gieson staining. Immunohistopathologic staining for proliferating cell nuclear antigen (PCNA) was performed to identify proliferative cells. The severity of PH as determined by the medial thickness of the small pulmonary arteries and RV/(LV + S) weight ratio in rats with MCT-PH was significantly reduced after treatment with MCI-9042 (p < 0.01 and p < 0.05, respectively). The serotonin concentration was significantly greater in MCT-PH rats than in normal control rats (p < 0.05). The scores for histopathologic changes, such as thickening of the alveolar walls and interstitial inflammatory cell infiltration in MCT-PH rats, were significantly reduced after treatment with MCI-9042 (p < 0.05 and p < 0.01, respectively). The number of PCNA-positive cells was significantly greater in MCT-PH rats than in normal control rats (p < 0.0001) and was reduced after treatment with MCI-9042 (p < 0.0001). Treatment with MCI-9042 significantly inhibited the development of MCT-PH along with a decrease in the number of PCNA-positive cells, suggesting a pivotal role of serotonin in the development of PH induced by MCT.
Miyata
M
M
Department of Internal Medicine II, Fukushima Medical University School of Medicine, 1 st. Hikarigaoka, Fukushima-City, Fukushima, 960-1295, Japan.
Ito
M
M
Sasajima
T
T
Ohira
H
H
Sato
Y
Y
Kasukawa
R
R
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013386:Succinates / Q000494:pharmacology*
D018809:Proliferating Cell Nuclear Antigen; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; D016686:Monocrotaline