Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis.
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
Paloma Lluch, Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain.
Paloma
P
Lluch
Paloma Lluch, Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain.
Gloria
G
Segarra
Paloma Lluch, Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain.
Pascual
P
Medina
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism* / Q000503:physiopathology
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase
Dimethylarginine dimethylaminohydrolase; Dimethylarginines; Endothelial function; Liver diseases; Nitric oxide