title: Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus.
abstract: OBJECTIVE
  The development of microvascular complications in diabetes is a complex process in which endothelial dysfunction is important. Emerging evidence suggests that arginase is a key mediator of endothelial dysfunction in type 2 diabetes mellitus by reciprocally regulating nitric oxide bioavailability. The aim of this prospective intervention study was to test the hypothesis that arginase activity is increased and that arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction.
  
  
  METHODS
  Microvascular endothelium-dependent and -independent dilatation was determined in patients with type 2 diabetes (n = 12) and healthy age-matched control subjects (n = 12) with laser Doppler flowmetry during iontophoretic application of acetylcholine and sodium nitroprusside, respectively, before and after administration of the arginase inhibitor Nω-hydroxy-nor-L-arginine (120 min). Plasma ratios of amino acids involved in arginase and nitric oxide synthase activities were determined. The laser Doppler flowmetry data were the primary outcome variable.
  
  
  RESULTS
  Microvascular endothelium-dependent dilatation was impaired in subjects with type 2 diabetes (P < .05). After administration of Nω-hydroxy-nor-L-arginine, microvascular endothelial function improved significantly in patients with type 2 diabetes to the level observed in healthy controls. Endothelium-independent vasodilatation did not change significantly. Subjects with type 2 diabetes had higher levels of ornithine and higher ratios of ornithine/citrulline and ornithine/arginine (P < .05), suggesting increased arginase activity.
  
  
  CONCLUSIONS
  Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction. Arginase inhibition may represent a novel therapeutic strategy to improve microvascular endothelial function in patients with type 2 diabetes.
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Kövamees
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Checa
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östenson
authors.affiliation: Department of Medicine Unit of Cardiology (O.K., A.S., J.P.), Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, 17176 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics (A.C., C.E.W.), Division of Physiological Chemistry, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Physiology and Pharmacology (J.O.L.), Karolinska Institutet, 17176 Stockholm, Sweden; and Department of Molecular Medicine and Surgery Unit of Endocrinology (C.-G.Ö.), Karolinska Institutet, and Department of Endocrinology and Diabetology, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D009952:Ornithine / Q000097:blood; D016491:Peripheral Vascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012720:Severity of Illness Index; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; D014665:Vasodilator Agents; D009599:Nitroprusside; D001120:Arginine; D009952:Ornithine; D001119:Arginase; D000109:Acetylcholine