Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is mainly metabolized by N G ,N G -dimethylarginine dimethylaminohydrolase (DDAH). We investigated whether altered cavernosal ADMA-DDAH metabolism might cause impairment of erection in rat model of atherosclerosis (AS). Male Sprague-Dawley rats (3 months old) were divided into an AS group and a normal control (Con) group (n ¼ 20 in each group). The AS rats received AS-prone treatment (6 weeks of 1% cholesterol diet plus early 2 weeks of N G -nitro-L-arginine methyl ester (3 mg ml À1 per day) treatment). After 6 weeks, rats underwent cavernosometry measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios as a surrogate marker of erectile function. The amount of cavernosal ADMA was assessed by immunoblot analysis and correlated with the ICP/MAP. Isoform-specific DDAH expression was compared by immunohistochemistry. Cavernosal DDAH and NOS activity were measured. Cavernosal malondialdehyde levels were assayed to determine the degree of lipid peroxidation. Compared to the controls, the AS rats had signs of impaired erectile function. Higher cavernosal ADMA was observed in the AS rats. The cavernosal ADMA had a moderately negative correlation with the ICP/MAP. Immunohistochemistry revealed the expression of both isoforms was not affected by the presence of AS. However, significantly diminished DDAH as well as NOS activity was observed in the AS group. In addition, elevated cavernosal malondialdehyde levels were noted in the AS rats. Our study showed that decreased cavernosal DDAH activity is the cause of cavernosal ADMA accumulation leading to reduced cavernosal NOS activity and impairment of erectile function.

Herbal Viagra and nitric oxide: how hard is the evidence?

“…Cavernosal ADMA was negatively correlated with the intra-cavernosal pressure [67]. These findings may explain the observations of others, supporting the use of supplemental L-arginine for erectile function.…”

“…In a model of atherosclerosis in Sprague-Dawley rats, Park and colleagues found that by comparison to control animals, cavernosal ADMA was increased in association with a decline in DDAH activity, and an impairment in NO synthesis [67]. Cavernosal ADMA was negatively correlated with the intra-cavernosal pressure [67].…”

Is It Possible to Recover Erectile Function Spontaneously after Cavernous Nerve Injury? Time-Dependent Structural and Functional Changes in Corpus Cavernosum Following Cavernous Nerve Injury in Rats

“…13,14 After CN identification, a platinum bipolar electrode was placed around the CN, just distal to the MPG, but proximal to the location of the nerve injury. Stimulation parameters were a square wave of 0.2 ms pulse duration at 3 V and 20 Hz for 30 s. After completion of the functional studies, the entire penis was removed.…”

Epigallocatechin-3-gallate ameliorates erectile function in aged rats via regulation of PRMT1/DDAH/ADMA/NOS metabolism pathway

“…found that decreased cavernosal DDAH activity results in cavernosal ADMA accumulation, which leads to reduced cavernosal NOS activity and impairment of erectile function in a rat model of atherosclerosis. Moreover, they suggested that the decreased DDAH activity was associated with the NOS activity showing a functional correlate of erectile function 20. Imamura et al .…”

“…In the corpus cavernosum tissue homogenates, the DDAH activity was estimated using the colorimetric method and is expressed per gram of protein as previously described 20. This method is based on the L-citrulline production rate.…”