Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA).
Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are found in various clinical settings, including renal failure, coronary heart disease, hypertension, diabetes and pre-eclampsia. In healthy people acute infusion of ADMA promotes vascular dysfunction, and in mice chronic infusion of ADMA promotes progression of atherosclerosis. Thus, ADMA may not only be a marker but also an active player in cardiovascular disease, which makes it a potential target for therapeutic interventions. This review provides a summary and critical discussion of the presently available data concerning the effects on plasma ADMA levels of cardiovascular drugs, hypoglycemic agents, hormone replacement therapy, antioxidants, and vitamin supplementation. We assess the evidence that the beneficial effects of drug therapies on vascular function can be attributed to modification of ADMA levels. To develop more specific ADMA-lowering therapies, mechanisms leading to elevation of plasma ADMA concentrations in cardiovascular disease need to be better understood. ADMA is formed endogenously by degradation of proteins containing arginine residues that have been methylated by S-adenosylmethionine-dependent methyltransferases (PRMTs). There are two major routes of elimination: renal excretion and enzymatic degradation by the dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). Oxidative stress causing upregulation of PRMT expression and/or attenuation of DDAH activity has been suggested as a mechanism and possible drug target in clinical conditions associated with elevation of ADMA. As impairment of DDAH activity or capacity is associated with substantial increases in plasma ADMA concentrations, DDAH is likely to emerge as a prime target for specific therapeutic interventions.
Maas
Renke
R
Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany. maas@uke.uni-hamburg.de
D000581:Amidohydrolases / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020138:Hyperhomocysteinemia / Q000097:blood / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase