Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate ( P <0.005) and flow-mediated dilation percentage ( P <0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 ( P <0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb ( P <0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans.

Flow-mediated dilation (FMD) is a noninvasive index of endothelial function and vascular health in humans. Studies examining the role of nitric oxide (NO) are not conclusive. In this article, we quantified the contribution of NO in FMD of conduit arteries and explored the effect of the protocol (ie, distal cuff, ≈5-minute ischemia) and method of analysis (ie, automated and continuous edge detection) on the NO dependency of this test. A systematic review and 3-stage meta-analysis of published crossover studies that measured FMD under local infusion of saline or the NO synthase blocker N ^G monomethyl-L-arginine (L-NMMA) was undertaken. Twenty studies met the inclusion criteria for stage 1 (374 individual comparisons). The meta-analyzed outcome was the difference in FMD between infusion of saline (ie, FMD _saline ) and NO synthase blocker (ie, FMD _L-NMMA ). Overall, FMD _saline was 8.2% (95% confidence interval [CI], 6.8%–9.6%) compared with FMD _L-NMMA of 3.7% (95% CI, 3.1%–4.3%; P <0.001). Stage 2 analysis focused on studies that used the most commonly adopted approach in healthy volunteers (ie, distal cuff placement, ≈5-minute occlusion), which similarly revealed a significant NO contribution to FMD (FMD _saline , 6.5% [95% CI, 5.7%–7.3%]; FMD _L-NMMA , 0.9% [95% CI, 0.5%–1.3%]; P <0.001). Stage 3 meta-analyzed the studies that adopted the commonly adopted approach and automated, continuous method of analysis, which also revealed a significant contribution of NO to the FMD (FMD _saline , 6.9% [95% CI, 6.0%–7.8%]; FMD _L-NMMA , 2.4% [95% CI, 1.1%–3.7%]; P <0.001). This comprehensive analysis demonstrates that FMD of conduit arteries in humans is, at least in part, mediated by NO.

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P <0.001, no interaction between interventions; P =0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P <0.001, no interaction; P =0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions ( P <0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P <0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation 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.

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O₂ delivery and uptake. Here, we examined whether the uptake of O₂ and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O₂ delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 ± 10 W; mean ±s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 ± 0.2 versus 7.5 ± 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial–internal jugular venous differences (a‐v diff) for O₂ and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA V_mean) and cardiac output increased by ∼22 and ∼115%, respectively. Thereafter, brain extraction of O₂, glucose and lactate increased by ∼45, ∼55 and ∼95%, respectively, while frontal cortex tissue oxygenation, MCA V_mean and cardiac output declined ∼40, ∼15 and ∼10%, respectively. At exhaustion in both trials, systemic declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O₂, glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O₂ delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O₂ and substrates.