The Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and its Vasculature

Marlieke Visser; Walter J. Paulus; Mechteld A.R. Vermeulen; Milan C. Richir; Mariska Davids; Willem Wisselink; Bas A.J.M. de Mol; Paul A.M. van Leeuwen

Disclosures

Eur J Heart Fail. 2010;12(12):1274-1281. 

In This Article

Abstract and Introduction

Abstract

Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability.

Introduction

Nitric oxide (NO) is a prominent compound in the heart and its vasculature and plays an intriguing role in the physiology of this organ.[1] In the coronary vasculature, NO is involved in vasodilatation, down regulation of cellular adhesion molecules, inhibition of platelet aggregation, vascular proliferation, and angiogenesis. In cardiomyocytes, the actions of NO are more complex as it can induce different, and sometimes opposing effects on cardiac functioning such as triggering apoptosis and improving left ventricular function.

Nitric oxide is formed from the amino acid arginine by the enzyme nitric oxide synthase (NOS), simultaneously with citrulline. Three different isoforms of NOS are known: neuronal NOS (nNOS or NOS1), endothelial NOS (eNOS or NOS3), and inducible NOS (iNOS or NOS2). Arginine is a semi-essential amino acid, meaning that under healthy conditions, endogenous arginine production is adequate for metabolic needs, but under stress conditions, when arginine is excessively catabolized by the enzyme arginase, dietary intake of this amino acid is required.

The production of NO can be disturbed by NOS inhibitors, such as asymmetric dimethylarginine (ADMA).[2] As a consequence, ADMA has been indicated as a new marker of cardiovascular risk. Asymmetric dimethylarginine can either be excreted by the kidneys or metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Since ADMA inhibits NO production by competing with arginine for NOS binding, the net amount of NO production might be indicated by the ratio between substrate and inhibitor: the arginine/ADMA ratio. Therefore, the detrimental effect of ADMA might be inhibited by increasing the concentration of arginine or the concentration of its precursors, citrulline and glutamine, which would increase the arginine/ADMA ratio and thereby might reverse the competitive inhibition of NOS by ADMA. In this review, we focus on the role of ADMA and arginine in the failing heart and its vasculature. Furthermore, we will discuss therapies to reduce the deleterious effects of ADMA, especially that of arginine and its precursor's citrulline and glutamine.

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