Chronic Vardenafil Treatment Improves Erectile Function via Structural Maintenance of Penile Corpora Cavernosa in Rats with Acute Arteriogenic Erectile Dysfunction

Abstract

Introduction Chronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown. Aim The aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats. Methods Eight-week-old male Wistar-ST rats were divided into four groups: sham-operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low-dose (0.4 mg/kg/day; VL group) or high-dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature. Main Outcome Measures Erectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)-β1, vascular endothelial growth factor-A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real-time PCR. Western blotting for TGF-β1 protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery. Results In the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF-β1 mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05). Conclusions Chronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats.

Effects of Chronic Vardenafil Treatment Persist after End of Treatment in Rats with Acute Arteriogenic Erectile Dysfunction

“…Our previous study found that in rats with acute arteriogenic ED model induced by ligation of bilateral internal iliac arteries, daily vardenafil treatment for 3 weeks significantly improved erectile function when compared with vehicle treatment soon after the end of the treatment. This improvement appeared to be caused by maintenance of penile CC via downregulation of TGF‐β 1 [7].…”

A Novel Method to Establish a Rat ED Model Using Internal Iliac Artery Ligation Combined with Hyperlipidemia

“…For example, Bakircioglu reported that 4 months were necessary to establish a hyperlipidemia-induced ED model in rats, and Metze had reported severe sexual dysfunction after major pelvic trauma [11], [21]. Lee successfully developed a traumatic arteriogenic ED rat model, but ED may occur only in the acute phase and erectile function may show autocompensation at 6 weeks after surgery [12], [16]. Although no direct evidence, such as collateral circulation building or regrowth of new blood vessels, has demonstrated autocompensation occurred in the BIIAL, HFD and BCH groups at 12 weeks, the erectile function of these three groups decreased immediately after injuring according to previous report [12].…”

“…However, the disadvantages of establishing arteriogenic ED models are the long duration of high-fat diet feeding and the auto-compensation observed 3 or more months after injury [11]–[13]. Another disadvantage is the high price of the special rats required for arteriogenic ED models, such as testosterone-supplemented spontaneously hypertensive rats, transgenic rats even though the period in ED developing was shorter, and rats with injuries made in the acute phase [14]–[16]. These disadvantages have slowed the study of the mechanisms of normal erection and the investigation of pathophysiological factors associated with ED.…”

Fibrotic Protein Expression Profiles in Penile Tissue of Patients With Erectile Dysfunction

“…Age, a known risk factor for ED, was also found to be related to an increased expression of collagen and decreased expression of smooth muscle in human cavernosal tissue 19 . Arteriogenic ED is related to an increased expression of TGFβ1 mRNA, and correlates with a reduced smooth muscle to collagen ratio in cavernosal tissue from rats with bilateral internal iliac artery ligation 20 . TGFβ1 expression was also shown to be increased in cavernosal tissue of the rat penis after CN injury, leading to collagen synthesis and tissue fibrosis 21 .…”