Chronic administration of phosphodiesterase 5 inhibitor improves erectile and endothelial function in a rat model of diabetes.
This study was conducted to determine if the long-term administration of the phosphodiesterase type 5 (PDE 5) inhibitor, DA-8159, to diabetic rats can ameliorate the development of erectile dysfunction (ED) and endothelial dysfunction. After inducing diabetes with streptozotocin, DA-8159 was orally administered at a dose of 3 mg/kg or 10 mg/kg for 8 weeks. To examine the effect on erectile response, electrostimulation of the cavernous nerve with the parameters of 3 V, 5 ms, 5 Hz or 10 Hz, was performed to measure the intracavernous pressure (ICP) and mean arterial pressure (MAP). Thoracic aorta relaxation in vitro was evaluated by adding acetylcholine (Ach) cumulatively to the bathing medium. In addition, the plasma endothelin-1 (ET-1) levels were measured in order to investigate the effect of DA-8159 on endothelial dysfunction. The area under the curve (AUC) from the ICP/MAP ratio in the 10 Hz stimulation showed a significantly increased AUC after the 10 mg/kg treatment compared with the diabetic group (8891 +/- 619 vs. 6316 +/- 1016, respectively, p < 0.05). At the 5 Hz frequency, DA-8159 10 mg/kg also induced a significant increase in the AUC compared with the diabetic control. The maximum ICP/MAP ratio (%) of the 10 mg/kg treatment group was significantly higher in both the 10 Hz and 5 Hz frequency groups (p < 0.05). A treatment of 3 mg/kg tended to increase the AUC and peak ICP/MAP but was not statistically significant. The Ach EC50 value of the diabetic group was significantly higher than in the normal control (120.50 +/- 22.90 nm vs. 86.80 +/- 9.30 nm, respectively), and 10 mg/kg treatment group showed a significantly lower EC(50) value (88.38 +/- 19.7 nm). The ET-1 level was lower in groups treated with DA-8159, 3 mg/kg and 10 mg/kg treatment induced a statistical difference compared with the diabetic control (1.15 +/- 0.34 fmol/mL vs. 2.51 +/- 0.55 fmol/mL, respectively, p < 0.05). These results demonstrate that chronic administration of DA-8159 could attenuate the development of the ED in diabetes and its effect is associated with an improvement in the endothelial function.
Ahn
Gook Jun
GJ
Research Institutes, Dong-A Pharmaceutical Company, 47-5 Sanggal, Kiheung, Youngin, Kyunggi 449-905, Korea. ahnsnu2@donga.co.kr
Yu
Jae Young
JY
Choi
Seul Min
SM
Kang
Kyung Koo
KK
Ahn
Byoung Ok
BO
Kwon
Jong Won
JW
Kang
Sung Keun
SK
Lee
Byeong Chun
BC
Hwang
Woo Suk
WS
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; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010410:Penile Erection / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D014664:Vasodilation / Q000187:drug effects; D000096926:Benzenesulfonamides
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D019332:Endothelin-1; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011743:Pyrimidines; D013449:Sulfonamides; C517384:Pde5a protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides