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Cellular ADMA: regulation and action.

Tom Teerlink¹, Zaiming Luo, Fredrik Palm

¹Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.

Pharmacological Research

|August 18, 2009

Summary

Asymmetric dimethylarginine (ADMA) regulates endothelial function by inhibiting nitric oxide synthase (NOS). Cellular ADMA levels, influenced by production, degradation, and transport, are key to understanding NOS activity in cardiovascular and kidney diseases.

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Area of Science:

Biochemistry and Molecular Biology
Cardiovascular Physiology
Renal Physiology

Background:

Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is a molecule found in plasma and cells.
ADMA inhibits nitric oxide synthase (NOS) and cationic amino acid transporters (CATs), impacting nitric oxide (NO) production and substrate supply.
Endothelial dysfunction, linked to ADMA, is implicated in hypertension, chronic kidney disease (CKD), and cardiovascular disease (CVD).

Purpose of the Study:

To review the mechanisms regulating intracellular ADMA levels.
To explore the role of cellular ADMA in modulating nitric oxide synthase (NOS) activity.
To understand the balance between ADMA and its substrate, l-arginine, within cells.

Main Methods:

Review of existing literature on ADMA metabolism and transport.
Analysis of the interplay between ADMA production (PRMT), degradation (DDAH), and transport (CAT).
Examination of ADMA's impact on NOS activity in various pathophysiological contexts.

Main Results:

Plasma ADMA levels may be insufficient to inhibit NOS, but cellular ADMA can be 5- to 20-fold higher.
Cellular ADMA levels are determined by a balance of production, degradation, and transport.
Intracellular ADMA concentrations can reach levels sufficient for tonic inhibition of NOS.

Conclusions:

Cellular ADMA plays a critical role in regulating NOS activity and endothelial function.
The balance of protein arginine methyltransferase (PRMT), N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH), and cationic amino acid transporters (CATs) dictates intracellular ADMA levels.
Understanding these regulatory processes is crucial for comprehending the l-arginine:ADMA ratio and its impact on cardiovascular and renal health.