Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis.
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=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(-1) 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.
Park
K
K
Department of Urology, Korea Cancer Center Hospital, Seoul, Korea.
Lee
D G
DG
Kim
S W
SW
Paick
J-S
JS
D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications* / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D007172:Erectile Dysfunction / Q000201:enzymology* / Q000209:etiology*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C487735:dimethylarginine; D008315:Malondialdehyde; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase