Thromboxane inhibition and monocrotaline-induced pulmonary hypertension in rats.
Monocrotaline (MCT)-induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY-046) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist (ONO-8809) on the development of MCT-induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY-046 or ONO-8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV + S) increased significantly in MCT-treated rats compared with the control rats. The %MT was attenuated by the administration of ONO-8809. Either OKY-046 or ONO-8809 attenuated the increase in RV/LV + S. In addition, both TXA2 inhibitors reduced urinary excretion of 11-dehydro-TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT-induced PH in rats, probably by inhibiting platelet aggregation.
Nagata
T
T
Second Department of Medicine, University of Tokyo, Japan.
Uehara
Y
Y
Hara
K
K
Igarashi
K
K
Hazama
H
H
Hisada
T
T
Kimura
K
K
Goto
A
A
Omata
M
M
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000652:urine; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D016686:Monocrotaline; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D015777:Eicosanoids; D005229:Fatty Acids, Monounsaturated; D008689:Methacrylates; D011448:Prostaglandin Antagonists; C067427:ONO 8809; D013928:Thromboxane A2; D016686:Monocrotaline; D013930:Thromboxane-A Synthase; C034364:ozagrel