title: Rosiglitazone causes endothelial dysfunction in humans.
abstract: OBJECTIVE
  We explored the impact of rosiglitazone on endothelial function in normal volunteers and its interaction with glyceryl trinitrate (GTN)-induced abnormalities in endothelial function. We hypothesized that rosiglitazone would have a neutral effect on endothelial function in normal volunteers and would favorably modify endothelial dysfunction induced by GTN.
  
  
  METHODS
  In this double-blind, randomized, placebo-controlled study, 44 participants were randomized to placebo, rosiglitazone (4 mg twice daily), transdermal GTN (0.6 mg/h), or both GTN and rosiglitazone. After 7 days of treatment, participants underwent measures of forearm blood flow during brachial artery infusion of acetylcholine (Ach). Serum glucose concentrations and insulin sensitivity were assessed.
  
  
  RESULTS
  Unexpectedly, rosiglitazone-treated participants experienced blunted responses to endothelium-dependent responses to Ach (P < .05 vs placebo). Sustained GTN administration caused similar abnormalities in endothelial function (P < .05 vs placebo) and rosiglitazone + GTN (P < .05 vs placebo; P = ns vs rosiglitazone). Interestingly, co-infusion of the antioxidant vitamin C improved endothelial responses in those randomized to rosiglitazone and GTN alone (P = not significant [ns] compared with placebo), but it did not improve endothelial function in those treated with rosiglitazone + GTN. Neither rosiglitazone nor GTN treatment modified the measures of glucose metabolism.
  
  
  CONCLUSIONS
  Unexpectedly, therapy with rosiglitazone caused abnormalities in endothelial function in normal volunteers. These findings have important implications with respect to drug development and surveillance.
authors: Division of Cardiology, Department of Medicine, University of Health Network and Mount Sinai Hospitals, University of Toronto, Toronto, Ontario, Canada.
authors: Kumar
authors: K
authors: Perampaladas
authors: Tommaso
authors: T
authors: Gori
authors: John D
authors: JD
authors: Parker
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001205:Ascorbic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D005996:Nitroglycerin; D000109:Acetylcholine; D001205:Ascorbic Acid