title: The role of L-arginine/L-homoarginine/nitric oxide pathway for aortic distensibility and intima-media thickness in stroke patients.
abstract: Asymmetric dimethylarginine (ADMA) and L-homoarginine (hArg) are L-arginine (Arg) metabolites derived from different pathways. Protein arginine N-methyltransferase (PRMT) and subsequent proteolysis of proteins containing methylarginine residues release ADMA. Arginine:glycine amidinotransferase (AGAT) converts Arg to hArg and guanidinoacetate (GAA). While high concentrations of ADMA and low concentrations of hArg in the blood have been established as cardiovascular risk markers, the cardiovascular relevance of GAA is still unexplored. Arg and hArg are substrates and ADMA is an inhibitor of nitric oxide (NO) synthase (NOS). The cardiovascular effects of ADMA and hArg have been related to NO, a potent endogenous vasodilator. ADMA and hArg are considered to exert additional, not yet explored, presumably NO-unrelated effects and to act antagonistically in the renal and cardiovascular systems. Although the physiological role of Arg, ADMA, hArg and NO for endothelial function in small- and medium-sized arteries has been intensively studied in the past, the clinical relevance of aortic wall remodeling still remains unclear. Here, we evaluated potential relation between aortic distensibility (AD) or aortic intima-media thickness (aIMT) and circulating ADMA, hArg, GAA, and the NO metabolites nitrite and nitrate in the plasma of 78 patients (24 females, 54 males; aged 59 ± 14 years) with recent ischemic stroke or transient ischemic attack (TIA). All biochemical parameters were determined by stable-isotope dilution gas chromatography-mass spectrometry. AD and aIMT were measured by transesophageal echocardiography. Arg, hArg, ADMA and GAA median plasma concentrations (µM) were determined to be 61, 1.43, 0.50 and 2.16, respectively. hArg, ADMA and GAA correlated closely with Arg. Nitrite, nitrate and creatinine median plasma concentrations (µM) were 2.49, 48.7, and 84.1, respectively. Neither AD (2.61 vs. 1.85 10-6× cm2× dyn-1, P = 0.064) nor aIMT (1.25 vs. 1.13 mm, P = 0.596) differed between females and males. The hArg/ADMA molar ratio (r = -0.351, P = 0.009), nitrate (r = 0.364, P = 0.007) and nitrite (r = 0.329, P = 0.015) correlated with aIMT but not with AD. Arg, hArg, ADMA and GAA correlated with aIMT but not with AD. The results demonstrate a strong relation between the Arg/NO pathway and aortic atherosclerosis but not with AD suggesting different mechanisms underlying the two aspects of aortic wall remodeling.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.|Department of Cardiology, Charité Universitätsmedizin Berlin (Campus Benjamin Franklin), Berlin, Germany.
authors.forename: Arash
authors.initials: A
authors.lastname: Haghikia
authors.affiliation: Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
authors.forename: Georgi Radoslavov
authors.initials: GR
authors.lastname: Yanchev
authors.affiliation: Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
authors.forename: Arslan Arinc
authors.initials: AA
authors.lastname: Kayacelebi
authors.affiliation: Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Hanff
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Bledau
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.|Department of Cardiology, Heart Center Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Widera
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sonnenschein
authors.affiliation: Department of Neurology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Aiden
authors.initials: A
authors.lastname: Haghikia
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Weissenborn
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
authors.affiliation: Centre of Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany. tsikas.dimitros@mh-hannover.de.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
mesh_terms: D001011:Aorta / Q000000981:diagnostic imaging / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000000981:diagnostic imaging; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006709:Homoarginine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood*; D020521:Stroke / Q000097:blood / Q000000981:diagnostic imaging; D014463:Ultrasonography; D066253:Vascular Remodeling
chemical_list: D006709:Homoarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine
keywords: AGAT; Aortic atherosclerosis and distensibility; Cardiovascular disease; GC–MS; Guanidino amino acids; Nitric oxide; Plasma