title: Folic acid treatment normalizes NOS-dependence of vascular tone in the metabolic syndrome.
abstract: Obese subjects with the metabolic syndrome (MS+) are more prone to microvascular complications than obese subjects without the metabolic syndrome (MS-). Excessive vascular nitric oxide (NO) production has been demonstrated in MS+ compared to MS-, perhaps driven by increased inflammation or oxidative stress. We tested whether in MS+, folic acid (FA) treatment could normalize NO synthase (NOS)-dependence of vascular tone in the retina and kidney. MS+ (n = 49) and MS- (n = 26) subjects were included in a randomized, double-blind, crossover trial. After 4-weeks' treatment with placebo or FA (5 mg/day), several cytokines (C-reactive protein (CRP), interleukin-1β, adiponectin), and markers of oxidative stress (glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (TAC)) were determined. NOS-dependence of retinal and renal vascular tone was assessed by retinal scanning laser Doppler flowmetry and renal clearance technique, respectively. FA had no effect on cytokine levels, but increased GSH/GSSG ratio overall (36 ± 76 vs. 102 ± 200, P = 0.04), indicative of a reduction in oxidative stress. In MS+, treatment with FA reduced NOS-dependence of retinal and renal vascular tone compared to placebo (P = 0.03 and P = 0.04, respectively). FA had no effect in MS-. After treatment with FA, NOS-dependence of retinal and renal vascular tone was similar between MS+ and MS-. Retinal and renal vascular tone in MS+ subjects is characterized by increased dependence on NOS. NOS-dependence in MS+ could be corrected by FA treatment to levels not dissimilar in MS-, and this was associated with a reduction in oxidative stress. Future trials should test whether these effects translate into a reduction of microvascular complications.
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen, Nuremberg, Erlangen, Germany. m.schneider@clinmed.gla.ac.uk
authors.forename: Markus P
authors.initials: MP
authors.lastname: Schneider
authors.forename: Markus P
authors.initials: MP
authors.lastname: Schlaich
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Harazny
authors.forename: Ulrike
authors.initials: U
authors.lastname: Raff
authors.forename: Martin
authors.initials: M
authors.lastname: Ritt
authors.forename: Christian
authors.initials: C
authors.lastname: Ott
authors.forename: Roland E
authors.initials: RE
authors.lastname: Schmieder
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005492:Folic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000178:diet therapy* / Q000503:physiopathology; D018384:Oxidative Stress; D012160:Retina / Q000187:drug effects* / Q000503:physiopathology; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein; D005492:Folic Acid; D019001:Nitric Oxide Synthase