Preventive effects of raloxifene, a selective estrogen receptor modulator, on monocrotaline-induced pulmonary hypertension in intact and ovariectomized female rats.
We investigated whether the chronic treatment with raloxifene, a selective estrogen receptor modulator, prevents the development of monocrotaline-induced pulmonary hypertension in ovary-intact and ovariectomized female rats. Four weeks after a single subcutaneous injection of monocrotaline (60 mg/kg), right ventricular systolic pressure, right ventricle-to-left ventricle plus septal weight ratio, pulmonary arterial medial thickening and endothelin-1 levels in right ventricular tissue increased significantly in both female rats, compared with saline-treated control rats. These monocrotaline-induced alterations were much greater in ovariectomized rats than the changes in intact females. Daily oral administration of raloxifene (10 mg/kg/day for 4 weeks) significantly attenuated the increase in right ventricular systolic pressure to the same levels in both groups of animals, but raloxifene suppressed the increases in right ventricle-to-left ventricle plus septal weight ratio and pulmonary arterial medial thickness more efficiently in ovariectomized females than the case with intact females. In addition, raloxifene completely suppressed the increase in right ventricular endothelin-1 levels in ovariectomized rats, but not in intact females. These data suggest that chronic treatment with raloxifene effectively prevents the development of monocrotaline-induced pulmonary hypertension in ovariectomized female rats than in intact females, at least in part, by suppressing right ventricular endothelin-1 overproduction.
Nishida
Masahiro
M
Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
Hasegawa
Youichi
Y
Tanida
Izumi
I
Nakagawa
Erika
E
Inaji
Haruka
H
Ohkita
Mamoru
M
Matsumura
Yasuo
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016686:Monocrotaline / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D020849:Raloxifene Hydrochloride / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors; D018497:Ventricular Dysfunction, Right / Q000150:complications / Q000378:metabolism / Q000503:physiopathology
D019332:Endothelin-1; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride; D016686:Monocrotaline