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.