The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats

Abstract

The aim of this study was to assess the effect of phosphodiesterase 5 inhibitor, DA-8159, on erectile function throughout the quantitative analysis of vascular endothelial cell, smooth muscle (SM), TGF-beta1 expression in rat corpus cavernosum and measurement of intracavernous pressure (ICP) in diabetic rats. DA-8159 (0, 5, 10, 20 mg/kg) was administered orally once a day to diabetic rats. After 8 weeks, immunohistochemistry and computerized image analysis were performed to quantify the percent area within the Corpora Cavernosa occupied by the endothelial cells, SM cells and fibrotic tissues. ICP/mean arterial pressure (MAP) was also measured by electrostimulation of the cavernous nerve. Diabetic rats showed a significant decrease in the SM and endothelial cell content, and an increase in the TGF-beta1 expression level within the cavernosa areas compared to the normal rats. The mean cavernous SM, endothelial cell content and TGF-beta1 expression level were 9.7+/-0.7, 4.5+/-0.7 and 17.9+/-2.1%, respectively. DA-8159 prevented reduction of SM (12.3+/-0.4% (5 mg/kg), 13.8+/-0.4% (20 mg/kg)) and endothelial cell content (5.6+/-0.5% (5 mg/kg), 6.3+/-0.6% (20 mg/kg)). Immunoreactivity of TGF-beta1 and intracorporal fibrosis were also significantly lower in DA-8159-treated groups (11.8+/-1.2% (5 mg/kg), 9.5+/-1.1% (20 mg/kg)). Electrostimulation of the cavernous nerve induced significant increase in maximum ICP (62.2+/-13.6 mmHg in 10 mg/kg vs 37.5+/-17.5 mmHg in diabetic group) and area under the curve of the ratio of ICP/MAP (8891.09+/-1957 in 10 mg/kg vs 6315.87+/-2272 in diabetic group). These results suggest that subchronic treatment of DA-8159 can prevent the development of erectile dysfunction (ED), and provides a rationale for the use of DA-8159 as treatment of diabetic ED.

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

“…27 Furthermore, a chronic treatment of DA-8159 partially prevented the development of ED in the diabetic rats by increasing the smooth muscle and endothelial cell content, decreasing the level of TGF-b1 overexpression, and eventually increasing the ICP. 28 Based on these results and references, it is believed that DA-8159 might protect the development of ED by preserving the endothelial function and morphological changes in the penile tissue, while the histomorphological changes were not examined in this study. Further investigation is required to determine how DA-8159 treatment preserves the erectile function.…”

Endothelial dysfunction in diabetic erectile dysfunction

“…Derangements in growth factors and cytokines such as VEGF, [109][110][111] basic fibroblast growth factor, 112 insulin-like growth factor-1 and its binding proteins, 113 and transforming growth factor-b 114 may induce endothelial dysfunction and ED in the setting of diabetes. Endocrine disorders such as low testosterone and changes in hormone receptors may also be associated with diabetes-associated ED.…”

Vascular endothelial growth factor (VEGF) gene therapy using a nonviral gene delivery system improves erectile function in a diabetic rat model

“…Further, it has been clearly demonstrated that a common histological endpoint of decreased smooth muscle and increased collagen deposition exists in animal models of diabetic ED leading to venous insufficiency. 19 With this information, many proteins have been targeted by several investigators as potential treatments for this disease including VEGF, endothelial nitric oxide synthase and inducible nitric oxide synthase. However, based on several recently published series, VEGF appears to have the most impressive results.…”