Long-Term Continuous Treatment with Sildenafil Ameliorates Aging-Related Erectile Dysfunction and the Underlying Corporal Fibrosis in the Rat1

Abstract

Aging-related erectile dysfunction is characterized by a loss of smooth muscle cells (SMCs) and fibrosis in the corpora cavernosa, and functionally by corporal veno-occlusive dysfunction (CVOD). Phosphodiesterase 5 (PDE5A) inhibitors, in part via upregulating inducible nitric oxide synthase (NOS2A), have antifibrotic properties in penile tissues. We aimed to determine whether in the aged rat the chronic long-term treatment with sildenafil ameliorates corporal SMC loss and fibrosis, stimulates NOS2A induction, and corrects the associated CVOD. Aged male rats (20 mo old) received sildenafil in their drinking water (20 mg/kg per day) or plain water for 45 days, and untreated young rats (5 mo old) served as controls (n = 8 per group). CVOD was assessed by dynamic infusion cavernosometry (DIC). Collagen:SMC (Masson trichrome) and collagen III:I (picrosirius red) ratios, SMC content (alpha-smooth muscle actin [ACTA2]), cell proliferation (proliferating nuclear antigen [PCNA]), apoptotic death (TUNEL), and NOS2A induction were measured by histochemistry and immunohistochemistry followed by quantitative image analysis. Collagen content was determined by hydroxyproline assay, and transforming growth factor beta-1 (TGFB1); xanthine oxidoreductase (XDH); ACTA2; NOS2A; and the Rho kinase inhibitor protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), and activator, VAV, were measured by quantitative Western blot. In the aged rats treated with sildenafil, the erectile response by DIC was normalized, and the corporal SMC:collagen ratio and SMC number were increased. In addition, sildenafil reduced the corporal collagen content without affecting the collagen III:I ratio, increased the PCNA:apoptosis ratio, and stimulated NOS2A induction, although there was no effect on XDH, TGFB1, PTPN11, or VAV levels. These data show that long-term PDE5A treatment corrected CVOD in the aged rat and partially reversed the aging-related fibrosis and loss of SMC in the corpora cavernosa without affecting TGFB1 or PTPN11 levels, which are markers of oxidative stress. It may be speculated that similar effects may be achieved with this paradigm in men.

Prediction of sexual function after radical prostatectomy

“…Chronic PDE5-I administration in cavernous nerve crush injury animal models increased the content of smooth muscle cells and decreased the deposition of collagen in the penile tissue compared with controls. 35,36 Moreover, chronic sildenafil use was associated with a significant reduction in the apoptotic indices and with a greater density of myelinized fibers in rats that underwent cavernous nerve injury. 37 Furthermore, chronic use of PDE5-I contributed to the enhanced expression of nitric oxide synthase in rat corpora cavernosa.…”

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

“…36 An antifibrotic effect by vardenafil and sildenafil was observed in the penile tunica albuginea in the rat model of Peyronie's disease, and in the case of sildenafil in the aged corpora smooth muscle. 37,38,12 In order to confirm and expand those findings by studying not only BCNR, but also unilateral cavernosal nerve resection (UCNR), and by using another PDE5 inhibitor, we have determined: (a) how a unilateral nerve injury compares to the more severe BCNR, and (b) whether sildenafil has similar anti-fibrotic properties as vardenafil and works via iNOS induction.…”

“…3,10 Several recent studies addressing CVOD in the aged or diabetic rat suggests that this form of erectile dysfunction is associated with the loss of SMC and excessive deposition of collagen fibers within the corpora, and that the long-term continuous administration of PDE5 inhibitors may counteract these processes. [11][12][13] It is likely that this occurs through the maintenance of high levels of cGMP, since this compound reduces collagen synthesis and the activation of the pro-fibrotic TGFb1 pathway and protects SMC from apoptosis, while stimulating the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2). [14][15][16][17][18][19][20][21][22][23] The expression of iNOS in certain non-immunological tissues is assumed to be a defense mechanism against fibrosis.…”

Erectile tissue molecular alterations with aging—differential activation of the p42/44 MAP Kinase pathway

“…Furthermore, it was reported that p42/44 kinase is a downstream effector of the transforming growth factor-beta 1 (TGF-b1) signaling pathway (He et al 2010). TGF-b1 expression is increased in aging trabecular fibroblasts and reported to be the main stimulator of collagen synthesis, inducing cavernosal fibrosis and promoting ED (Ferrini et al 2007;Ryu et al 2004). We hypothesize that increased p42/44 activation in aged ECM component may be a downstream event of the TGF-b1 pathway, adding a new piece in the complex puzzle of aging CC signaling events.…”

“…However, and regarding ED, only a study has reported that aged erectile tissue presents low percentage of proliferating cells (Ferrini et al 2007). Nonetheless, CC proliferation with age progression was never evaluated and quantified.…”