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The coupling between skeletal muscle blood flow and metabolic demand is largely attributed to feedback regulation of oxygen delivery. However, the relative importance of feedforward mechanisms in increasing blood flow in proportion to contractile work is unknown. We hypothesized that the change in blood flow following initiation of exercise is preserved independent of the level of baseline oxygen delivery, and that reciprocal reductions in oxygen extraction occur during elevations in resting blood flow. In 6 young healthy adults (4M/2F, 22±1 y) we quantified forearm blood flow (FBF; Doppler ultrasound), oxygen extraction (O2 extraction; based on venous O2 content), and forearm oxygen consumption (mVO2; Fick equation). Measurements were taken at rest and during 5 minutes of rhythmic handgrip exercise under control conditions and during intra‐arterial infusion of the vasodilator sodium nitroprusside (SNP) to pharmacologically manipulate oxygen delivery (O2D) prior to initiation of contractions. We elevated resting blood flow to levels that matched (MAT) and exceeded (EXC) steady‐state hyperemia during control (CON) exercise trials. Steady‐state FBF and O2D during dynamic forearm contractions at an intensity equivalent to 10% of participants maximal voluntary contraction under CON conditions were 159 ± 24 ml · min−1 and 32 ± 4.9 ml O2 · min−1, respectively. As intended, SNP infusion increased resting FBF (152 ± 26 ml · min−1) and O2D (31 ± 5.3 ml O2 · min−1) to levels similar to those observed during CON exercise in MAT (both P = NS), and further elevated FBF (196 ± 19 ml · min−1) and O2D (40 ± 4.0 ml O2 · min−1) to levels exceeding CON exercise in EXC (both P < 0.05). However, resting O2 extraction decreased in MAT (9 ± 5 %) and EXC (7 ± 4 %) compared to CON (49 ± 7 %; P < 0.05), and thus resting mVO2 was not different between conditions (range: ~2–3 ml O2 · min−1; P = NS). Despite elevating resting FBF and O2D to levels adequate to sustain muscle contractile work, the change in FBF in response to exercise remained intact during MAT (Δ FBF; 112 ± 20 ml · min−1) and EXC (Δ FBF; 133 ± 18 ml · min−1) compared to CON (Δ FBF; 123 ± 24 ml · min−1; all P = NS). As predicted, O2 extraction remained lower during steady‐state exercise in the MAT (45 ± 7 %) and EXC (39 ± 7 %) conditions compared to CON (66 ± 3 %; P < 0.05). However, the change in O2 extraction from rest to steady‐state exercise was not reduced (Δ O2 extraction: CON; 17 ± 5, MAT; 36 ± 5, EXC; 32 ± 5 %; P = NS), and thus mVO2 was not different between conditions (CON; 21 ± 2.9, MAT; 24 ± 4.5, EXC; 27 ± 5.6 ml O2 · min−1; P = NS). We conclude that changes in blood flow and oxygen extraction remain intact when oxygen delivery is artificially elevated prior to exercise, which highlights the importance of feedforward mechanisms capable of initiating changes in skeletal muscle blood flow independent of oxygen delivery. Support or Funding Information NIH HL119337

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Circulating ATP is a potent vasodilator believed to assist in the matching of tissue oxygen delivery to oxygen demand. Older adults have impaired skeletal muscle hemodynamic responses to hypoxia and exercise and blunted increases in circulating ATP during these stimuli, which may be due to reduced deoxygenation‐mediated red blood cell (RBC) ATP release. We recently demonstrated that treatment of isolated RBCs with a Rho‐kinase inhibitor improves RBC membrane deformability and restores ATP release from RBCs of older adults. Thus, the goal of the present study was to test the hypothesis that in vivo Rho‐kinase inhibition would improve hemodynamic responses and circulating ATP during hypoxia and exercise in older adults. Healthy young (Y; 27 ± 1 years; n = 5) and older (O; 67 ± 2 years; n = 7) adults participated in a double‐blind, randomized, placebo‐controlled, crossover design study on two days (≥ 5 days between visits). A deep venous catheter in the forearm was used to administer the placebo (100 ml saline/60 min) or the Rho‐kinase inhibitor (60 mg fasudil/60 min) and to sample blood for plasma [ATP]. Forearm vascular conductance (FVC; mean arterial pressure from finometry and forearm blood flow (FBF) from Doppler ultrasound) was calculated at rest, during 5 min of isocapnic hypoxia (80% SpO2), and during graded intensity rhythmic handgrip exercise at 5, 15 and 25% of maximum voluntary contraction (MVC; 4 min per workload). Plasma [ATP] was measured at rest and at the end of each condition, and RBCs were isolated to measure ATP release in response to normoxic (PO2 ~120 mmHg) and hypoxic (PO2 ~24 mmHg) stimuli using the luciferin‐luciferase technique. In the placebo trial, the increase in FVC during hypoxia was ~50% lower in O vs Y, and during exercise the greatest age impairment occurred at 25% MVC (266.4 ± 27.6 vs 394.9 ± 35.0 ml/min/100 mmHg; P < 0.05). Plasma [ATP] and ATP effluent (FBF × [ATP]; an index of the total circulating rate of ATP) tended to be lower in O vs Y during hypoxia (75.3 ± 16.6 vs 100.6 ± 18.8 nmol/L and 2.3 ± 0.7 vs 3.1 ± 0.7 nmol/min, respectively) and were lower at 25% MVC (92.8 ± 12.6 vs 168.7 ± 31.5 nmol/L and 28.1 ± 4.9 vs 66.9 ± 9.6 nmol/min, respectively; P < 0.05). The increase in isolated RBC ATP release from normoxia to hypoxia was also impaired in O vs Y (21.4 ± 17.2% vs 77.8 ± 13.3%; P < 0.05). Compared to control, fasudil in O improved FVC during hypoxia (35.2 ± 3.7 ml/min/100 mmHg; P < 0.05) and 25% MVC exercise (324.4 ± 21.7 ml/min/100 mmHg; P < 0.05), and abolished the impairment vs Y. Fasudil tended to improve plasma [ATP] and ATP effluent during hypoxia in O (98.7 ± 29.0 nmol/L and 3.34 ± 0.8 nmol/min), and during 25% MVC exercise (152.2 ± 26.7 nmol/L and 48.3 ± 6.7 nmol/min). Fasudil also tended to improve isolated RBC ATP release (55.6 ± 17.5% vs 21.4 ± 17.2%) and abolished the impairment vs Y. These preliminary data suggest that in vivo Rho‐kinase inhibition improves hemodynamic responses to hypoxia and exercise in older adults, and that this may be related to elevated circulating ATP.Support or Funding InformationHL119337, F31HL126377This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Objectives Research suggests blueberries and their (poly)phenols may improve endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). The objective of this study was to investigate the impact of consuming 22 g/day for 12 weeks of freeze-dried highbush blueberry powder on endothelial function and other measures of cardiovascular health, oxidative stress, and circulating (poly)phenol metabolites in postmenopausal women with above-normal blood pressure. Methods We performed a randomized, double-blind, placebo-controlled, parallel-arm trial in estrogen-deficient postmenopausal women aged 45–65 years with elevated blood pressure or stage 1-HTN. Endothelial function was assessed as brachial artery flow-mediated dilation (FMD) and normalized to individual shear rate area under the curve (FMD/SRAUC) to control for inter-individual variability in reactive hyperemia-induced shear stress. To assess whether improvements in FMD were mediated by reduced oxidative stress, FMD was assessed before and after intravenous infusion of a supra-physiologic dose of ascorbic acid. Blood pressure, arterial stiffness, and plasma (poly)phenol metabolites were also assessed. Results A total of 43 women completed the trial (n = 32 for endothelial function). Compliance in the Blueberry and Placebo groups were 93% and 91%, respectively. Mean total plasma (poly)phenol metabolite concentrations were increased at 4 (250,053 nmol/L, P &lt; 0.05) and 8 (303,053 nmol/L, P &lt; 0.05) weeks in the Blueberry group compared to baseline (125,798 nmol/L) with a strong trend at 12 weeks (227,971 nmol/L, P &lt; 0.05), and no changes in Placebo. Blood pressure and arterial stiffness were unchanged with both treatments. At 12 weeks, FMD/SRAUC was increased by 96% from baseline (P &lt; 0.05) in the Blueberry group but unchanged in Placebo, and changes in FMD/SRAUC from baseline to 12 weeks were higher (P &lt; 0.05) than Placebo. The response in FMD/SRAUC to ascorbic acid infusion was lower (P &lt; 0.05) at 12 weeks compared to baseline in the Blueberry group but not Placebo. Conclusions These findings suggest blueberries improve endothelial function, and is mediated, in part, by reduced oxidative stress in postmenopausal women with above-normal blood pressure, a high-risk population for developing CVD. Funding Sources US Highbush Blueberry Council and USDA National Institute of Food and Agriculture.