DA-8159, a potent cGMP phosphodiesterase inhibitor, attenuates monocrotaline-induced pulmonary hypertension in rats.
In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.
Kang
Kyung Koo
KK
Research Laboratories, Dong-A Pharm. Co. Ltd., 47-5, Sanggal, Kiheung, Yongin, Kyunggi 449-905, Korea. kangkk@donga.co.kr
Ahn
Gook Jun
GJ
Sohn
Yong Sung
YS
Ahn
Byoung Ok
BO
Kim
Won Bae
WB
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; D016686:Monocrotaline; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C419664:udenafil; D000096926:Benzenesulfonamides