title: Long-term hemodynamic and molecular effects persist after discontinued renin-angiotensin system blockade in patients with type 1 diabetes mellitus.
abstract: Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.
authors.affiliation: Division of Nephrology, Toronto General Hospital and Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David Z I
authors.initials: DZ
authors.lastname: Cherney
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Christopher R J
authors.initials: CR
authors.lastname: Kennedy
authors.forename: Rahim
authors.initials: R
authors.lastname: Moineddin
authors.forename: Vesta
authors.initials: V
authors.lastname: Lai
authors.forename: Stuart
authors.initials: S
authors.lastname: Yang
authors.forename: Judith A
authors.initials: JA
authors.lastname: Miller
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
authors.forename: Heather N
authors.initials: HN
authors.lastname: Reich
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D018925:Chemokines / Q000652:urine; D016207:Cytokines / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004656:Enalapril / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009864:Ontario; D018384:Oxidative Stress / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D016896:Treatment Outcome; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D018925:Chemokines; D016207:Cytokines; D004656:Enalapril; D019808:Losartan