Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model

Abstract

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n ¼ 5). Group IFcontrol animals received peanut oil, group IIFvitamin E 20 IU/day, group IIIFsildenafil 5 mg/kg/day and group IVFvitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle a-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.

Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

“…Indeed, a dose-response study in rats showed that 5 mg/kg per day i.p. was the optimal erectogenic dose of sildenafil (34).…”

“…The use of sildenafil is particularly appealing because this drug has been thoroughly studied in terms of its pharmacological effectiveness and safety (34,47). At least 21 genes encode PDE proteins in mammals, each containing several distinct transcriptional units, bringing the number of PDE proteins to Ͼ50.…”

Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

“…Although the efficacy of sildenafil in general population has been reported as 74 --97%, it is only 50 --56% among diabetic individuals. 7,8 As mentioned before, the effect of both AGE inhibitors and cross-link breakers has already been shown in various experimental studies. 4 --6 On the other hand, the potential impact of combining AGE cross-link breaker namely ALT-711 and sildenafil to treat diabetes-related ED remains to be determined.…”

“…The authors concluded that vitamin E enhanced the therapeutic effect of sildenafil, which indicated a potential means of salvaging erectile function among men who are refractory to sildenafil. 8 Similarly, Bivalacqua et al 12 reported the effect of combination of sildenafil and NO synthase gene therapy on erectile function in STZ diabetic rats. The authors clearly showed that overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats.…”

“…Recently, De Young et al 8 have assessed the effect of sildenafil combined with free oxygen radical scavenger namely vitamin E on erectile function in a diabetic rat model. The results of that study suggested that significant increases in ICP were measured in the animals receiving combined vitamin E plus sildenafil treatment when compared with animals either treated with vitamin E or sildenafil alone.…”