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      The role of prostaglandin and antioxidant availability in recovery from forearm ischemia–reperfusion injury in humans

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          Endothelial dysfunction, manifesting as attenuated flow-mediated dilation (FMD), is clinically important. Antioxidants may prevent this dysfunction; however, the acute effects of oral administration in humans are unknown. Low flow-mediated constriction (L-FMC), a further parameter of endothelial health, is largely unstudied and the mechanisms for this response unclear.


          Twelve healthy participants (five women and seven men) completed three test conditions: control; antioxidant cocktail (α-lipoic acid, vitamins C and E); and prostaglandin inhibitor ingestion (ibuprofen). Ultrasound measurements of brachial artery responses were assessed throughout 5 min of forearm ischemia and 3 min after. Subsequently, an ischemia–reperfusion injury was induced by a 20-min upper arm occlusion. Further, vascular function protocols were completed at 15, 30, and 45 min of recovery.


          Endothelial dysfunction was evident in all conditions. FMD was attenuated at 15 min after ischemia–reperfusion injury (Pre: 6.24 ± 0.58%; Post15: 0.24 ± 0.75%; mean ± SD, P< 0.05), but recovered by 45 min. Antioxidant administration did not preserve FMD compared with control ( P> 0.05). The magnitude of L-FMC was augmented at 15 min (Pre: 1.44 ± 0.27%; Post15: 3.75 ± 1.73%; P< 0.05) and recovered by 45 min. Ibuprofen administration produced the largest constrictive response (Pre: −1.13 ± 1.71%; Post15: −5.57 ± 3.82%; time × condition interaction: P< 0.05).


          Results demonstrate ischemia–reperfusion injury causes endothelial dysfunction and acute oral antioxidant supplementation fails to reduce its magnitude. Our results also suggest that a lack of shear stress during occlusion combined with suppression of prostaglandin synthesis magnifies L-FMC, possibly due to augmented endothelin-1 expression.

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          Most cited references 36

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          Ultrasound assessment of flow-mediated dilation.

          Developed in 1992, the flow-mediated dilation test is now the most commonly used noninvasive assessment of vascular endothelial function in humans. Since its inception, scientists have refined their understanding of the physiology, analysis, and interpretation of this measurement. Recently, a significant growth of knowledge has added to our understanding and implementation of this clinically relevant research methodology. Therefore, this tutorial provides timely insight into recent advances and practical information related to the ultrasonic assessment of vascular endothelial function in humans.
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            Retrograde flow and shear rate acutely impair endothelial function in humans.

            Changes in arterial shear stress induce functional and structural vasculature adaptations. Recent studies indicate that substantial retrograde flow and shear can occur through human conduit arteries. In animals, retrograde shear is associated with atherogenic effects. The aim of this study was to examine the impact of incremental levels of retrograde shear on endothelial function in vivo. On 3 separate days, we examined bilateral brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men (24+/-3 years) before and after a 30-minute intervention consisting of cuff inflation to 25, 50, or 75 mm Hg. Cuff inflations resulted in "dose"-dependent increases in retrograde shear rate, compared with the noncuffed arm, within subjects (P<0.001). Flow-mediated dilation in the cuffed arm did not change in response to the 25-mm Hg stimulus but decreased significantly after both the 50- and 75-mm Hg interventions (P<0.05). The decrease in flow-mediated dilation after the 75-mm Hg intervention was significantly larger than that observed after a 50-mm Hg intervention (P=0.03). In the noncuffed arm, no changes in shear rate or flow-mediated dilation were observed. These results demonstrate that an increase in retrograde shear rate induces a dose-dependent attenuation of endothelial function in humans. This finding contributes to our understanding regarding the possible detrimental effects of retrograde shear rate in vivo.
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              Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation.

              Our aim was to determine reproducibility of the flow-mediated dilation (FMD) response profile, and discriminatory ability of the components. Brachial FMD is widely used to study conduit artery endothelial function. Automated B-mode image edge detection (B-ED) provides a full response profile. Reproducibility and biological relevance of these additional components have not been fully explored. Forty-two healthy adults underwent FMD using B-ED repeated at fixed time intervals up to 3 months. The FMD profile was assessed for diameter changes, area under the curve, and time course. Measures were compared in 25 adults with hypercholesterolemia, 25 subjects with diabetes, and 50 matched control subjects. The maximum change in FMD was the most reproducible (coefficient of variation = 9.8%, 10.6%, 6.6%, and 9.2% at 4 to 6 h, 1 week, 1 month, and 3 months, respectively). Most of the variability occurred between subjects rather than within. All FMD measures except time course were significantly reduced in hypercholesterolemia and diabetes. Power curves were generated to indicate the appropriate number of subjects for parallel and crossover study designs. Maximum FMD percentage change from baseline is the most reproducible of the response curve measures and best identifies those with risk factors. Flow-mediated dilation measured by B-ED is robust and practical to assess the effect of interventions on endothelial function in clinical trials.

                Author and article information

                J Hypertens
                J. Hypertens
                Journal of Hypertension
                Lippincott Williams & Wilkins
                February 2014
                30 January 2014
                : 32
                : 2
                : 339-351
                [a ]Department of Biological Sciences, University of Essex, Colchester
                [b ]Comparative Biomedical Sciences, Royal Veterinary College, London
                [c ]Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, UK
                © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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