title: Vascular and metabolic effects of the haem oxygenase-1 inducer haem arginate in subjects with the metabolic syndrome: A translational cross-over study.
abstract: This translational randomized and vehicle-controlled cross-over study was performed to assess the impact of haem arginate treatment on haem oxygenase-1 induction, endothelial function and insulin sensitivity in subjects with the metabolic syndrome (n = 14). Both treatment periods consisted of 5 days. Haem arginate or vehicle (l-arginine) was administered intravenously on Days 1 and 3. Forearm blood flow in response to acetylcholine and nitroglycerine was measured by venous occlusion plethysmography (Day 3), insulin sensitivity by a hyperinsulinaemic clamp procedure (Day 5). Haem arginate did not improve endothelial function or insulin sensitivity but significantly reduced the vasodilator response to nitroglycerine (p < 0.01). These negative findings are in contrast to the preclinical data, which may be due to short duration of therapy and limited haem oxygenase-1 induction as well as interference by markedly elevated plasma haem levels observed after haem arginate treatment (p < 0.01). Future studies should pay attention to the delicate balance between sufficient dosing and timely normalization of plasma haem levels.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Douwe
authors.initials: D
authors.lastname: Dekker
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Intensive Care Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mirrin J
authors.initials: MJ
authors.lastname: Dorresteijn
authors.affiliation: Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Wilbert Hm
authors.initials: WH
authors.lastname: Peters
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Bilos
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sebastiaan W C
authors.initials: SW
authors.lastname: Pennings
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands frank.wagener@radboudumc.nl.
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001120:Arginine / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D018592:Cross-Over Studies; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005293:Ferritins / Q000187:drug effects / Q000378:metabolism; D015309:Glucose Clamp Technique; D006418:Heme / Q000378:metabolism / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology*; D008875:Middle Aged; D005996:Nitroglycerin / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D057170:Translational Research, Biomedical; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D014665:Vasodilator Agents; D006418:Heme; D005293:Ferritins; D001120:Arginine; D051547:Heme Oxygenase-1; D005996:Nitroglycerin; D000109:Acetylcholine; C048849:heme arginate; D001663:Bilirubin
keywords: Translational medical research; endothelial function; haem arginate; haem oxygenase; insulin resistance; metabolic syndrome