Restoration of Normal Adult Penile Erectile Response in Aged Rats by Long-Term Treatment with Androgens1

Abstract

In order to determine whether the aging-related impairment of penile erection can be corrected by exogenous androgens, 20-mo-old ("old") rats received implants of Silastic tubing containing either testosterone (T) or dihydrotestosterone (DHT). Untreated aged-matched rats were used as reference controls, and values were compared with those obtained previously for 5-mo old ("adult") rats. After 45 days, groups of six rats were submitted to electrical field stimulation of the cavernosal nerve (EFS), and the intracavernosal pressure and mean arterial pressure (MAP) were recorded. Compared to the untreated old rats, the old animals receiving either T or DHT showed a similar and significant (p < 0.01) increase (56%) in the maximal intracavernosal pressure (MIP) to a level slightly above that of the untreated adult rats. The response was sensitive to the nitric oxide synthase (NOS) inhibitor Nw-nitro-L-arginine methyl ester (L-NAME). The MIP:MAP ratio in the treated animals was nearly double that found in the old untreated controls. Penile NOS activity was measured by the [3H]L-arginine-citrulline conversion, and neuronal NOS (nNOS) levels were estimated by a semiquantitative Western blot assay with antibodies against human nNOS. No significant variations were observed in either NOS levels or NOS activity between the treated and untreated old rats. These results suggest that aging-related erectile dysfunction in the intact rat may be responsive to androgen therapy and that this correction is not associated with an increase in the basal levels of penile NOS, in contrast to what occurs in castrated rats.

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…There is evidence for involvement of the NO/cGMP system. Thus, Garban et al (1995) found that the soluble NOS activity decreased significantly in penile tissue from senescent rats. Lower NOS mRNA expression was found in old rats than in young rats (Dahiya et al, 1997).…”

Smooth muscle pathology and erectile dysfunction

“…29 In adult rats, the decrease in NOS activity that followed castration is restored with androgen replacement, whereas no additional NOS activity is observed when intact animals were given additional androgens. 30 In dogs, castration leads to a decline in the ratio of intracavernosal pressure to peak systolic pressure and there is also evidence of higher outflow rates in the castrate animals. 31 A decline in the magnitude of the induced intracavernosal pressure rise during erection is observed but the investigators attributed the lower intracavernosal pressure to be accompanying reduction in mean arterial pressure.…”

Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis

“…Clinical and animal studies provided evidence that androgens protect cavernous SM, promoting cell proliferation and maintaining functional integrity (Andersson and Wagner 1995;Aversa et al 2000Aversa et al , 2003Garban et al 1995;Huang et al 2008;Lue and Dahiya 1997;Mills et al 1992;Shabsigh 1997). It was also demonstrated that androgen deficiency contributes to endothelial damage in a castrated rat model (Lu et al 2007).…”