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 N G -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.

We have demonstrated previously that inhibition of angiotensin-converting enzyme (ACE) with enalapril and angiotensin II blockade with losartan improve acetylcholine-dependent endothelial function in resistance vessels of patients with Type II diabetes. It was therefore of interest to examine the effect of losartan on conduit vessel function in this group. The influence of losartan (50 mg daily for 4 weeks) on endothelium-dependent and -independent vasodilator function was determined in 12 subjects with Type II diabetes using a randomized, double-blind, placebo-controlled crossover protocol. Conduit vessel endothelial function was assessed using high-resolution ultrasound and the brachial artery response to reactive hyperaemia (flow-mediated dilation; FMD); glyceryl trinitrate (GTN) was used as a non-endothelium-dependent dilator. Losartan administration significantly increased the FMD response from 5.2±0.7% (mean±S.E.M.) to 7.4±0.6% of vessel diameter ( P < 0.05; paired t -test). There was no effect of losartan on the endothelium-independent responses to GTN (17.8±1.8% to 17.6±1.2%). Consistent with our previous findings in resistance vessels, administration of 50 mg of losartan daily improves NO-mediated dilation in the conduit vessels of subjects with Type II diabetes. Together with the findings that both ACE inhibition and angiotensin II blockade improve resistance vessel function in this group, it is likely that at least some of the beneficial effect is mediated through the angiotensin II/type 1 receptor pathway. A type 1 receptor antagonist seems a reasonable alternative to an ACE inhibitor to maintain conduit vessel endothelial function in Type II diabetic subjects.

1. Vitamin E administration improves endothelial function in hypercholesterolaemic animals but, generally, has not been found to do so in man. The aim of this study was to determine whether vitamin E administration improves basal or stimulated function of the nitric oxide (·NO) dilator system in patients with hypercholesterolaemia. 2. Seven subjects aged 47±3 (±S.E.M.) years with moderately elevated serum cholesterol concentrations (6.0±0.1 ;mmol/l) were given 4 weeks of placebo therapy followed by 500 i.u. of vitamin E twice daily for 4 weeks. Endothelium-dependent and -independent vasodilatation were assessed by intrabrachial infusion of acetylcholine and sodium nitroprusside, and forearm blood flow was measured by strain-gauge plethysmography. Basal ·NO function was assessed by infusion of N G -monomethyl- l -arginine. 3. Plasma α-tocopherol concentration was enhanced after administration of vitamin E (34.6±1.8 to 86.9±9.6 ; μ mol/l; P < 0.001). In addition, vitamin E administration significantly increased acetylcholine-mediated vasodilatation whether the results were expressed in terms of changes in absolute forearm blood flow ( P < 0.01), forearm vascular resistance ( P < 0.05) or forearm blood flow ratios ( P < 0.001). Similarly, absolute forearm blood flow ( P < 0.05), forearm vascular resistance ( P < 0.01) and forearm blood flow ratio ( P < 0.01) responses to N G -monomethyl- l -arginine were augmented by vitamin E therapy. Sodium nitroprusside responses were unaltered. 4. These results indicate that 4 weeks therapy with 1000 i.u. of vitamin E daily improves basal and stimulated ·NO-related endothelial function in subjects with hypercholesterolaemia.

1. Using venous occlusion plethysmography, we have investigated the forearm blood flow response in healthy subjects to the acute plasma volume expansion caused by a rapid intravenous infusion of saline. The contribution made to this response by nitric oxide has been investigated using local intra-arterial infusions of the nitric oxide synthase inhibitor N G -monomethyl- l -arginine. 2. The infusion of 1000 ml of saline over 25 min caused plasma volume to increase by about 7%, and resulted in a rise in forearm blood flow, with no change in arterial blood pressure. The onset of the blood flow response occurred within 10 min and blood flow remained elevated above baseline 20 mm after the end of the saline infusion. 3. Local intra-arterial infusion of N G -monomethyl- l -arginine alone caused a reduction in forearm blood flow which was maximal at the end of the infusion and gradually recovered to baseline levels over 40 min. 4. When local intra-arterial infusion of N G -monomethyl- l -arginine was followed by plasma volume expansion, the calculated effect of N G -monomethyl- l -arginine was such as to abolish the vasodilator response to saline. 5. The effect of local intra-arterial infusion of N G -monomethyl- l -arginine on forearm blood flow was greater when the drug was given after volume expansion had occurred, than when it was given before the administration of saline. However, in control experiments the vasoconstrictor response to noradrenaline was also enhanced after the administration of the volume load in comparison with the response to noradrenaline given alone. 6. These results are consistent with the possibility that increased local synthesis of nitric oxide contributes to the vasodilator response to volume expansion.