Chronic treatment of DA-8159, a new phosphodiesterase type V inhibitor, attenuates endothelial dysfunction in stroke-prone spontaneously hypertensive rat.
This study examined the effects of chronic treatment of a new phosphodiesterase type 5 inhibitor, DA-8159, on endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHR-SP). Six-week-old male SHR-SP were divided into 4 groups; vehicle control, DA-8159 1, 3, and 10 mg/kg/day. During a 32-week experimental period, the animals were administered DA-8159 orally and fed a 4% NaCl-loaded diet. The systolic blood pressure was measured every two weeks throughout the experimental period using the tail-cuff method. At the end of experiments, the vascular function (acetylcholine-induced vasodilation) in the endothelium-intact aortic rings was investigated. In addition, the mortality, the left ventricular hypertrophy index, the plasma parameters and the incidence of a cerebral infarction were assessed. In the DA-8159 treated-rats, the vascular reactivity improved significantly in a dose-dependent manner. Although DA-8159 did not alter the elevation of the systolic blood pressure directly, the 3 and 10 mg/kg/day DA-8159 treatment delayed the early death caused by stroke. DA-8159 significantly reduced the left ventricular heart weight/body weight ratio compared with the vehicle control group. Furthermore, the DA-8159 treatment significantly increased the plasma nitric oxide, cGMP, and the total antioxidative status. The DA-8159 treatment also reduced the occurrence of stroke-associated cerebral damage. These results indicate that DA-8159 can ameliorate an endothelial dysfunction-related vascular injury. Therefore, pharmacological intervention aimed at attenuating an endothelial dysfunction is important and might be useful in both preventing and treating endothelial dysfunction-related complications.
Choi
Seul Min
SM
Research Laboratory, Dong-A Pharmaceutical Company, 47-5 Sanggal-Ri, Yongin, Kyunggi-Do 449-900, Korea.
Kim
Jee Eun
JE
Kang
Kyung Koo
KK
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D006352:Heart Ventricles / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides; D014664:Vasodilation / Q000187:drug effects; D000096926:Benzenesulfonamides
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011743:Pyrimidines; D013449:Sulfonamides; C517384:Pde5a protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides