1. The mechanisms involved in the human skin blood flow responses to iontophoretic application of acetylcholine (ACh; delivered using an anodal charge) or sodium nitroprusside (SNP; administered with a cathodal charge) are unclear. The aims of this study were to investigate possible contributions of prostaglandin production to the increase in skin blood flow induced following the iontophoresis of ACh and to investigate possible contributions from local sensory nerves to the perfusion responses induced by ACh, SNP and their vehicles. 2. The contribution of prostaglandins to the ACh response was determined in a randomized double-blind study of eight healthy subjects, who were studied on two occasions. Basal responses to ACh were measured before the oral administration of 600 mg soluble aspirin in diluted orange juice (1 occasion) or orange juice (1 occasion) and again 30 min after the drink. The contribution of local sensory nerve activation to the responses to ACh and ACh vehicle (8 subjects) and and to SNP and SNP vehicle (7 subjects) was assessed. EMLA (5%) (a eutectic mixture of lignocaine and prilocaine) and placebo cream were applied to two separate areas on the forearm in a double-blind randomized manner 2 h before drug responses were measured. In all studies the skin microcirculation responses to iontophoretically applied drug vehicle (1 site) and drug (2 sites) were recorded by laser Doppler perfusion imaging. 3 The increase in forearm skin perfusion (P < 0 001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different following placebo or aspirin administration. The increase in forearm skin red blood cell flux (P < 0 001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different at the placebo-compared with the EMLA-treated site. The small increase in perfusion (P < 0 01) in response to the iontophoresis of ACh vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0 05). The marked increase in perfusion (P < 0 001) in response to the iontophoresis of SNP vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0 01). 4. These data suggest that in healthy volunteers: (1) mechanisms other than prostaglandin production and local sensory nerve activation may be involved in the increase in skin perfusion observed following the iontophoretic application of ACh; and (2) stimulation of local sensory nerves may be responsible for the increase in tissue perfusion observed following the iontophoretic application of either ACh vehicle or SNP vehicle.

SummaryBackground-Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.

Conclusion:Antioxidant consumption can acutely restore endothelial dysfunction in elderly patients.Summary: Endothelial dysfunction likely contributes to atherosclerosis through a reduction in bioavailability of nitrite oxide (NO). There is also an age-related increase in plasma free radical concentration that contributes to a decrease in the bioavailability of NO. The authors investigated whether acute antioxidant treatment would result in a reversal of the decrease in endothelial function in elderly patients. As markers of endothelial function, the authors used flow-mediated vasodilatation and reactive hyperemia, which were evaluated after the individual consumed placebo or an oral antioxidant cocktail consisting of 1000 mg of vitamin C, 600 IU of vitamin E, and 600 mg of ␣-lipoic acid. This study was performed in 87 healthy volunteers, pairing 42 younger volunteers (25 Ϯ 1 years) with 45 older volunteers (71 Ϯ 1 years). This was a double-blind, crossover, designed study. Blood velocity and brachial artery diameter, as measured with ultrasound imaging, were assessed before and after 5 minutes of forearm circulatory arrest. Serum markers of lipid peroxidation, total antioxidant capacity, endogenous antioxidant activity, vitamin C, plasma nitrite, nitrate, and 3-nitrotyrosine were also determined. With placebo, there was an agerelated reduction of brachial artery vasodilatation in young (7.4% Ϯ 0.6%) vs older (5.2% Ϯ 0.4%) patients. Antioxidant consumption improved flowmediated vasodilatation in older participants (placebo, 5.2% Ϯ 0.4%; antioxidant, 8.2% Ϯ 0.6%). Flow-mediated vasodilatation declined after antioxidant therapy in younger participants (placebo, 7.4% Ϯ 0.6%; antioxidant, 5.8% Ϯ 0.6%). Age was associated with a reduction in reactive hyperemia, but antioxidants did not alter the response in the younger or older groups.Comment: The data demonstrate that antioxidant consumption can acutely restore some elements of endothelial function in older patients. Antioxidants, however, apparently disrupt normal endothelial-dependent vasodilatation in younger individuals. The data must be rectified with clinical trials that have failed to demonstrate a beneficial effect of long-term antioxidant administration on cardiovascular health (Kris-Etherton PM et al, Circulation 2004;110:637-41). There are, however, certainly marked differences in study design between short-term interventional studies, such as in this report, and longer-term clinical trials of antioxidant therapy on cardiovascular health. The current study suggests some link between endothelial dysfunction and oxidative stress in older patients. The authors note the assay used in this study reflects peroxynitrite and that peroxynitrite may originate from multiple sources. The data cannot therefore be directly translated to imply potential benefits of long-term antioxidant therapy. Additional background work will be required before consideration of designing clinical trials evaluating the oral antioxidant cocktail used in this report.

Diets rich in green, leafy vegetables have been shown to lower BP and reduce the risk of cardiovascular disease. Green, leafy vegetables and beetroots are particularly rich in inorganic nitrate. Dietary nitrate supplementation, via sequential reduction to nitrite and NO, has previously been shown to lower BP and improve endothelial function in healthy humans.We sought to determine if supplementing dietary nitrate with beetroot juice, a rich source of nitrate, will lower BP, improve endothelial function and insulin sensitivity in individuals with type 2 diabetes (T2DM). Twenty-seven patients, age 67.2 +/-4.9 years, (18 male) were recruited for a double blind, randomised, placebo-controlled crossover trial. Participants were randomised to begin in either order a 2 week period of supplementation with 250 ml beetroot juice daily (active) or 250 ml nitratedepleted beetroot juice (placebo). At the conclusion of each intervention period 24 hour ambulatory blood pressure monitoring, tests of macro and microvascular endothelial function and a hyperinsulinaemic isoglycaemic clamp were performed. After two weeks administration of beetroot juice mean ambulatory systolic BP was unchanged: 134.6 ± 8.4 mmHg versus 135.1 ± 7.8 mmHg (mean ± SD) placebo vs. active -mean difference of -0.5 mmHg (placebo-active), p=0.737 (95% CI -3.9 to 2.8). There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity. Supplementation of the diet with 7.5 mmoles of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration, but did not lower BP, improve endothelial function or insulin sensitivity in individuals with T2DM.3