Dysregulation of Dimethylarginine Dimethylaminohydrolase Causes Elevation of Asymmetric Dimethylarginine in a Rat Model of Vasculogenic Erectile Dysfunction / 대한비뇨기과학회지

ABSTRACT

PURPOSE: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and the major metabolic pathway of ADMA is enzymatic degradation via dimethylarginine dimethylaminohydrolasease (DDAH). In this study, we hypothesized that an elevated cavernosal ADMA level might result from poor DDAH activity in the corpus cavernosum. We examined whether ADMA was accumulated in our atherosclerotic rat model of vasculogenic erectile dysfunction (VED). MATERIALS AND METHODS: Twelve 12-wk-old Sprague-Dawley rats were grouped in either the atherosclerosis group (AS, n=6) or the control (n=6) group. The AS group received a 1% cholesterol diet for 6 weeks and the rats were also treated with NG-nitro-L-arginine methyl ester (3mg/ml) for the initial 2 weeks. The control group received a normal diet. Six weeks later, all the rats were anesthetized with urethane (1.6g/kg) and cavernous electrostimulation was done under continuous arterial and cavernosal pressure monitoring (6V, 0.5ms, 20Hz, 50sec). The methylarginine level in both the AS group and the control group was measured respectively. Also, the NOS activity and DDAH activity in the corpus cavernosum were evaluated. RESULTS: Upon cavernous electostimulation, the peak intracavernosal pressure (ICP) of the control group was 88.5+/-5.5mmHg (n=6). In contrast, the peak ICP level was markedly reduced in the atherosclerotic group to 54.2+/-4.8mmHg (n=6, p<0.001). The cavernosal level of ADMA in the control group was 320.5+/-23.6micrometer and it was 860.7+/-34.7micrometer in the AS group. The constitutive NOS activity in the rat corpus cavernosum of the AS group was markedly reduced compared to the control group. Also, the cavernosal DDAH activity was reduced in the AS rats and the activity showed significant negative correlation with the cavernosal ADMA level. CONCLUSIONS: In this study, we have demonstrated that the dysregulation of DDAH activity may be one of the causes of decreased NOS activity in atherosclerotic erectile dysfunction.