ADMA

1. ASYMMETRIC DIMETHYL ARGININE (ADMA) M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

2. INTRODUCTION • The endothelium play a crucial role in the regulation of vascular tone and structure and its dysfunction is or integral part of the processes leading to atherosclerosis • A symmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and an important cause of endothelial dysfunction

3. Basic semi-essential amino acid • Glucogenic • Sources : Exogenous sources – - Plant sources - Animal sources - Endogenous sources Arginine

4. Endogenous source of Arginine : Urea Cycle

5. ADMA SYNTHESIS • Is a metabolic by product of continual protein modification process is a naturally occurring chemical found in blood plasma • The guanidino nitrogen of arginineresiduces cretin protein are methylaled by a group of enzymes called protein arginine methyl transferases (PRMTS) yielding mono and di-methyl arginines.

6. PRMTS (Protein arginine methyl transferases) • Are two types • - Type 1 PRMTS • - Type 2 PRMTS • ADMA is the major product of type 1 PRMTS • Type1PRMTS: Found mainly in endothelial and smooth muscle cells in cytoplasm of all human cells • Type2 PRMTS : Central Nervous System

7. Synthesis of ADMA

8. CLEARANCE OF ADMA • Humans generate approximately 300 mol of ADMA/day. • A small amount of which (10%) is excreted unchanged into the urine • 90% is metabolized by the enzyme dimethyl arginine dimethyl amino hydrolase (DDAH) to yield citrulline and dimethlyamine. • DDAH • 2 Distinct Isoforms: • DDAH-1 DDAH-2

9. DDAH-1: Found mainly in tissues expressing neuronal nitric oxide synthase • Liver • Kidney cortex • Lung • DDAH-2: Found mainly in those tissue expressing-endothelial Nos (eNoS) • Inducible • In endothelium and smooth muscle cells of cardio vascular system • Also highly expressed in the kidney

10. INTERACTIONS BETWEEN OXIDATIVE STRESS, DIMETHYL ARGININE, DIMETHYL AMINO HYDROLASE (DDAH) AND A SYMMETRIC DIMETHYL ARGININE (ADMA) AND NITRIC OXIDE SYNTHASE (NOS).

11. CLINICAL ASSOCIATIONS ADMA is associated with cardiovascular risk factors • Hypercholesterolaemia • ADMA concentrations are increased approximately two fold in diet induced Hypercholesterolaemia • LDL cholesterol >4.1mmol/L was associated with reduced No synthesis

12. INSULIN • ADMA play role in insulin resistance and decreased NO availability help to drive insulin resistance. • Hyper glycerin impairs DDAH activity in human cells • Plasma ADMA concentration is increased in patients with type 2 diabetes mellitus.

13. Chronic kidney Disease (CKD) • Is a risk factor for cardio vascular disease. • Plasma ADMA concentration increase patient with end-stage renal failure (ESRF). • Hypertension • In essential hypertension, ADMA concentration is increased two fold and is associated with reduced levels of urinary NO metabolites

14. ADMA and Cardio Vascular Disease • ADMA concentration is associated with the presence and extent of atherosclerotic vascular disease. • Increased ADMA concentration can predict - -Acute coronary events - Myocardial infarction - Peripheral arterial disease - Chronic heart failure

15. ADMA in critical illness • ADMA concentration independently predicts mortality in critically ill patients in the intensive care unit (ICU) • ADMA contributes to the development of multiple organ failure in critical illness.

16. Evidence from prospective studies showing ADMA as prognostic marker

18. METHODS FOR MEASUREMENT OF ADMA

19. Thank you