The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction

Abstract

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.

Acute Effects of Hypercholesterolemic Diet on Erectile Responses in Rats

“…Synthesis of NO and the consequences of NO binding to soluble guanylyl cyclase is essential for the erectile process and several cardiovascular risk factors affect the NO/cGMP pathway [17] . Our findings are similar to those of previous studies in which erectile function was evaluated in diabetic and hypercholesterolemic rats [15,18] . In these studies it was shown that the detumescence time was prolonged in diabetic and hypercholesterolemic rats with the use of phosphodiesterase type 5 inhibitors.…”

“…The maximum relaxation capacity of these erectile structures differs depending on the NO content. Hypercholesterolemia-induced ED has been shown in previous experimental models with longterm and/or high content of L -NAME, a NO inhibitor, added to cholesterol diet in rats [8,15] . Gholami et al [8] established that the development of ED was due to neurogenic and vascular changes in rats fed a 2% cholesterolemic diet for a period of 6 months.…”

“…However, in their study Park et al [14] showed that a 1% cholesterol only diet for 6 weeks affects erectile function and internal pudendal artery intimal media thickness in male rats. Additionally, Kang et al [15] showed that a 2% cholesterol only diet for 5 months affects erectile and endothelial functions of the thoracic aorta in rats. As seen in these studies, several concentrations of HCD were given for different time durations, and additive hyperlipidemic agents, including choline, cholic acid and L -NAME, were used in previous studies.…”

Anti-atherogenic Effects of a New Thienylacylhydrazone Derivative, LASSBio-788, in Rats Fed a Hypercholesterolemic Diet

“…However, when the endothelial function is impaired, the ability to maintain the vascular tone is impaired, which leads to a decrease in the endothelium-dependent vasodilator responses, a decrease in the ROS production, disruption of the eNOS, and a decrease in NO bioavailability (27). Furthermore, studies have shown that ingestion of a high fat diet provokes endothelial dysfunction, leading to the impairment of vascular relaxing responses and an increased response to vasoconstrictor agonists in experimental animals (26,28). Thus, both the pharmacologic reduction of plasma lipid levels and the antioxidant therapy have been associated with an improvement of the endothelial function.…”

Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study

“…Another possible explanation may be dependent on the inhibitory effect of tadalafil on cyclic 3 0 ,5 0 guanosine monophophate degradation at the endothelial level with consequent increase in insulin secretion, as previously reported by other authors'. 21 At present, the effect of PDE5 inhibition on endothelial function remains controversial; animal studies in hypercholesterolemic 22 and diabetic 23 rat models suggest that this class of drugs may be effective in improving the degree of induced endothelial dysfunction; on the other hand, studies in humans suggest that this does not improve peripheral endothelium dependent vasomotor or fibrinolytic function in patients with coronary heart disease. 24 The results of this study have important clinical implications for patients with impaired endothelial function regardless of the presence of clinical cardiovascular disease, 25 and for this reason our study population included tadalafil responders only, no matter their ED etiology so that we did not perform a complete diagnostic workup before entering into the study.…”