title: Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms.
abstract: The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N(epsilon)-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre- and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.
authors.affiliation: Institute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan. t-miyata@is.icc.u-tokai.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Kohji
authors.initials: K
authors.lastname: Ichimori
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onogi
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kurokawa
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000068557:Olmesartan Medoxomil; D010084:Oxidation-Reduction / Q000187:drug effects; D011498:Protein Precursors / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002614:Chelating Agents; D017127:Glycation End Products, Advanced; D007093:Imidazoles; D011498:Protein Precursors; D013777:Tetrazoles; D013841:Thiazepines; C069156:temocaprilat; D000068557:Olmesartan Medoxomil