The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction.
This study examined the effects of a new phosphodiesterase type 5 inhibitor, DA-8159, on erectile function associated with hypercholesterolemia. First of all, in order to investigate whether chronic administration of DA-8159 prevents the development of erectile dysfunction associated with hypercholesterolemia, male SD rats were divided into four groups (normal control, hypercholesterolemic control, DA-8159 5 or 20 mg/kg/day). Over a 5-month period, the animals were fed a 2% cholesterol diet and administered DA-8159 orally once a day. After 5 months, the electrostimulation-induced penile erection and the vascular function using acetylcholine-induced vasodilation with endothelium-intact aortic rings were examined. Furthermore, the plasma lipid profiles, endothelin and N(G),N(G)-dimethylarginine (asymmetrical dimethylarginine, ADMA) concentrations were measured. In order to investigate the acute treatment effect of DA-8159 on the erectile function in an established hypercholesterolemic model, additional animals were given a 2% cholesterol diet for 5 months without DA-8159. At the end of 5 months, the rats were divided into three groups (hypercholesterolemic control, DA-8159 0.3 or 1 mg/kg). DA-8159 was administered intravenously 1 min prior to the intracavernous pressure (ICP) measurement. In a chronic treatment study, while the hypercholesterolemic control showed a significantly lower erectile function, vascular reactivity, and increased plasma cholesterol, endothelin and ADMA concentration, the chronic DA-8159 treatment clearly restored the erectile responses by electric stimulation, preserved the potential of thoracic aortic relaxation in a dose-dependent manner, and significantly decreased the plasma endothelin and ADMA concentrations. In an acute treatment study, DA-8159 induced a dose- and frequency-dependent increase in ICP. The ICP/BP ratio and the corresponding AUC values, and the detumescence time were also significantly increased compared to the hypercholesterolemic control. These results suggest that DA-8159 is beneficial for erectile dysfunction in a rat hypercholesterolemic model and provided a rationale for the potential use of DA-8159 for treating erectile dysfunction secondary to hypercholesterolemia.
Kang
K K
KK
Research Laboratories of Dong-A Pharmaceutical Company, Preclinical Division, Sangal, Kiheung, Youngin, Kyunggi, Republic of Korea. kangkk@donga.co.kr
Yu
J Y
JY
Yoo
M
M
Kwon
J W
JW
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000097:blood; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D006937:Hypercholesterolemia / Q000150:complications*; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011312:Pressure; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000109:Acetylcholine; D001120:Arginine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D016232:Endothelins; D008055:Lipids; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C487735:dimethylarginine; C517384:Pde5a protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides