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Oh, Park, and Paick: Dysregulation of Dimethylarginine Dimethylaminohydrolase Causes Elevation of Asymmetric Dimethylarginine in a Rat Model of Vasculogenic Erectile Dysfunction
Original Article
Korean Journal of Urology

Korean Journal of Urology 2006; 47(10): 1079-1085.

Published online: 31 October 2006

DOI: https://doi.org/10.4111/kju.2006.47.10.1079

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

Jin Gyu Oh, Kwan Jin Park1, Jae Seung Paick

Department of Urology, Seoul National University College of Medicine, Seoul, Korea.

1Department of Urology, Korea Cancer Center Hospital, Seoul, Korea.

Corresponding author (jspaick@snu.ac.kr)

Received 15 May 2006       Accepted 7 July 2006

Copyright © 2006 The Korean Urological Association

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±23.6µM and it was 860.7±34.7µM 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.

Keywords: Erectile dysfunction, Dimethylarginine dimethylaminohydrolase, Asymmetric dimethylarginine, Rats

Figures and Tables

Fig. 1
Expression of endothelial NOS and DDAH 2 in the rat penile tissue of the control group and the AS group. The DDAH 2 expression is more prominent in the AS group than that in the control group. M: marker, Con: control group, AS: atherosclerosis group, POS: postive control, NOS: nitric oxide synthase, eNOS: endothelial NOS, DDAH: dimethylarginine dimethylaminohydrolasease.
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Fig. 2
Densitometry of endothelial NOS and DDAH 2 in the rat penile tissue of the control group and the AS group. The DDAH expression is significantly increased in the AS group. AS: atherosclerosis group, Con: control, eNOS: endothelial NOS, NOS: nitric oxide synthase, DDAH: dimethylarginine dimethylaminohydrolasease. *significantly different from corresponding value in the control at p<0.05.
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Fig. 3
NOS activity in the rat corpus cavernosum between the control group and the AS group. Though there is no significant difference for iNOS between the two groups, the activity in the AS group is more prominently increased than that in the control group. AS: atherosclerosis group, NOS: nitric oxide synthase, cNOS: constitutive NOS, iNOS: inducible NOS. *significantly different from corresponding value in the control at p<0.01
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Fig. 4
Cavernosal DDAH activity between the control group and the AS group. As shown, the DDAH activity in the AS group is significantly decreased (p<0.05). AS: atherosclerosis group, *denotes statistical significance (p<0.05). DDAH: dimethylarginine dimethylaminohydrolasease.
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Fig. 5
Correlation between cavernosal DDAH activity and the ADMA level. As shown, the DDAH activity is inversely correlated with the cavernosal ADMA level. DDAH: dimethylarginine dimethylaminohydrolaserolase, ADMA: asymmetrical dimethylarginine.
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Table 1
The results of cavernous stimulation
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ICP: intracavernosal pressure, AUC: area under curve, MAP: mean arterial pressure

Table 2
Chromatographic analysis of a standard mixture of methylarginine derivatives, cavernosal extract from the control and cavernosal extract from the atherosclerosis group (mean±SD)
kju-47-1079-i002

L-NMMA: NG-monomethyl-L-arginine, ADMA: asymmetric NG,NG-dimethyl-L-arginine, SDMA: symmetric NG,NG-dimethyl-L-arginine, *significantly different from control.

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