Effect of lowering tumour necrosis factor-α on vascular endothelial function in Type II diabetes

Abstract

Tumour necrosis factor-α (TNFα) is a mediator of reactive oxygen species, which are implicated in endothelial dysfunction and atherosclerosis. Type II diabetes is associated with endothelial dysfunction and elevated circulating TNFα. We hypothesized that reducing serum levels of TNFα, using pentoxifylline, would improve endothelial function. Thirteen subjects [age 58±2 (S.E.M.) years] with Type II diabetes (disease duration 74±13months) undertook a randomized, crossover study of 8weeks pentoxifylline and 8weeks placebo. Endothelium-dependent and-independent vasodilation in resistance arteries was assessed via bilateral forearm venous occlusion plethysmography during intra-brachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP) and NG-monomethyl-l-arginine (l-NMMA). High-resolution ultrasound of the brachial artery in response to ischaemia was used to determine endothelium-dependent conduit vessel flow-mediated dilation (FMD), and endothelium-independent conduit function was assessed by sublingual administration of glyceryl trinitrate (GTN). Serum concentrations of TNFα were also determined. Pentoxifylline lowered serum TNFα from 4.1±0.7 to 2.9±0.6 pg˙ml-1 (P = 0.001). Forearm blood flow (FBF) responses at each dose of ACh did not differ with treatment (P = 0.4). Similarly, FBF responses to SNP (P = 0.8) and l-NMMA (P = 0.2) did not differ. There was also no significant difference in brachial artery diameter during FMD (P = 0.2) or GTN administration (P = 0.06). Despite lowering serum TNFα concentration, pentoxifylline at a dose of 400mg three times a day for 8weeks did not improve vascular function in either conduit or resistance vessels in this group of Type II diabetic subjects.