title: Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C.
abstract: Endothelial dysfunction has been reported in obese subjects, but its mechanism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependent vasodilation and 2) whether oxidative stress participates in endothelial dysfunction. We recruited 76 healthy subjects (50 men and 26 women aged 21-45 years) and measured their BMI (kg/m2), WHR, and insulin resistance (IR) estimated by the homeostasis model assessment (HOMA). Endothelium-dependent and -independent vasodilation were assessed by increasing doses of acetylcholine (ACh) (7.5, 15, and 30 pg x ml(-1) x min(-1)) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)) during saline and vitamin C coinfusion (24 mg/min). The effects of cyclooxygenase activity were evaluated by a dose-response curve to intrabrachial coinfusion of ACh and indomethacin (500 microg/min). Three different groups have been identified according to their BMI: group A (BMI <25), consisting of 10 men and 5 women; group B (BMI between 25 and 29), consisting of 16 men and 8 women; and group C (BMI > or =30), consisting of 24 men and 13 women. Obese subjects had significantly lower forearm blood flow (FBF) during ACh infusions (means +/- SD): 19.8 +/- 2.8, 10.8 +/- 2.7, and 6.5 +/- 1.8 ml x 100 ml(-1) tissue x min(-1) (P < 0.0001) for groups A, B, and C, respectively. SNP caused comparable increments in FBF in all groups. Regression analysis revealed a significant negative correlation between BMI (r = -0.676, P < 0.0001), WHR (r = -0.631, P < 0.0001), fasting insulin (r = -0.695, P < 0.0001), HOMA-IR (r = -0.633, P < 0.0001), and percent peak increase in FBF during ACh infusion. In obese subjects, both vitamin C and indomethacin increased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation is blunted, and the increase in FBF is inversely related to BMI, WHR, fasting insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction in human obesity.
authors.affiliation: Department of Experimental and Clinical Medicine G. Salvatore, University of Catanzaro Magna Graecia, Italy. perticone@unicz.it
authors.forename: F
authors.initials: F
authors.lastname: Perticone
authors.forename: R
authors.initials: R
authors.lastname: Ceravolo
authors.forename: M
authors.initials: M
authors.lastname: Candigliota
authors.forename: G
authors.initials: G
authors.lastname: Ventura
authors.forename: S
authors.initials: S
authors.lastname: Iacopino
authors.forename: F
authors.initials: F
authors.lastname: Sinopoli
authors.forename: P L
authors.initials: PL
authors.lastname: Mattioli
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D018384:Oxidative Stress; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D004338:Drug Combinations; D014665:Vasodilator Agents; D009599:Nitroprusside; D000109:Acetylcholine; D001205:Ascorbic Acid; D007213:Indomethacin