Muscle blood flow and vasodilation are blunted at the onset of exercise following an acute bout of ischemia-reperfusion.

Ischemia-reperfusion (I/R) injury can attenuate endothelial function and impair nitric oxide bioavailability. We tested the hypothesis that I/R also blunts the rapid and steady-state hyperemic and vasodilatory responses to handgrip exercise. Ten subjects (8M/2F; 24 ± 4 yr) performed handgrip exercises before and after I/R (20 min of ischemia/20 min of reperfusion) and time control (40-min supine rest) trials. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were assessed with Doppler ultrasound during single forearm contractions and 3 min of rhythmic handgrip exercise. Venous blood samples were drawn at rest and during exercise to assess plasma [nitrite]. Peak ΔFBF (from baseline) and ΔFVC following single contractions were attenuated following I/R (134 ± 48 vs. 103 ± 42 mL·min-1; 160 ± 55 vs. 118 ± 48 mL·min-1·100 mmHg-1, P < 0.05 for both), but not following time control (115 ± 63 vs. 124 ± 57 mL·min-1; 150 ± 80 vs. 148 ± 64 mL·min-1·100 mmHg-1, P = 0.16 and P = 0.95, respectively). Steady-state ΔFBF and ΔFVC during rhythmic exercise were unchanged in both I/R (192 ± 52 vs. 190 ± 53 mL·min-1; 208 ± 56 vs. 193 ± 60 mL·min-1·100 mmHg-1) and time control (188 ± 54 vs. 196 ± 48 mL·min-1; 206 ± 60 vs. 207 ± 49 mL·min-1·100 mmHg-1) trials (group × time interactions P = 0.34 and 0.21, respectively). Plasma [nitrite] under resting conditions and during steady-state rhythmic exercise was attenuated following I/R (P < 0.05 for both), but not following time control (P = 0.54 and 0.93). These data indicate that I/R blunts hyperemia and vasodilation at the onset of muscle contractions but does not attenuate these responses during steady-state exercise.NEW & NOTEWORTHY Ischemia-reperfusion can impair endothelial function; however, it remains unknown whether exercise hyperemia and vasodilation are also impaired. This study presents novel findings that ischemia-reperfusion blunts the hyperemic and vasodilatory responses at the onset of muscle contractions but not during steady-state exercise. Plasma [nitrite] was also blunted at baseline and during steady-state exercise following ischemia-reperfusion compared with time control. These attenuated responses at the onset of exercise may be associated with ischemia-reperfusion reductions in NO bioavailability.

Intermittent versus continuous handgrip exercise and peripheral endothelial function: impact of shear rate fluctuations.

Sustained exercise-induced elevations in shear rate (SR) have been well established as beneficial for improving endothelial function. However, the impact of intermittent fluctuations in SR is not understood. We investigated the effect of intermittent SR elevations compared with sustained elevations on peripheral endothelial function. Brachial artery flow-mediated dilation (FMD) was assessed in 13 adults (9 M/4 F; 22 ± 4 yr) before and after 30 min of handgrip exercise. Three different rhythmic forearm exercise interventions were performed at a rate of 20 contractions/min. Intermittent exercises (6 × 3 min exercise interspersed by 2 min of rest) were performed at 25% (INT-25%) and 15% (INT-15%) maximum voluntary contraction (MVC), and continuous exercise was completed at 15% MVC. Brachial artery diameter and velocity were measured using Doppler ultrasound. The total increase in SR above baseline throughout exercise was greater during INT-25% (4,441 ± 516 s-1) and continuous (4,070 ± 407 s-1) compared with INT-15% (2,811 ± 342 s-1, P < 0.05). The %FMD increased following all exercises (INT-25%: 5.7 ± 1.2% to 8.1 ± 1.2%; INT-15%: 5.2 ± 1.2% to 7.0 ± 1.1%; continuous: 5.5 ± 1.3% to 6.8 ± 1.3%, P < 0.05 for all). The increase following INT-25% was significantly greater than INT-15% and continuous (P < 0.05 for both). Normalized FMD to shear rate area under the curve increased with intermittent exercise (INT-25%: 2.2 ± 0.2% to 3.4 ± 0.3%; INT-15%: 2.1 ± 0.2% to 3.2 ± 0.2%, P < 0.05 for both) but did not following continuous (2.1 ± 0.2% to 2.5 ± 0.1%, P = 0.06). The increase in normalized FMD with intermittent exercises were greater than continuous (P < 0.05 for both). These findings suggest intermittent fluctuations in SR during handgrip exercise may be more beneficial than sustained elevations on improving peripheral endothelial function.NEW & NOTEWORTHY Exercise-induced increases in shear rate is a well-established stimulus for improving peripheral endothelial function. This study presents novel findings that intermittent elevations in shear rate may be more effective at acutely improving endothelial function compared with continuous elevations. Despite similar increases in total shear rate during handgrip exercise intermittent elevations produced a significantly greater increase in endothelial function when compared with continuous elevations potentially indicating intermittent elevations as a more effective stimulus for acute improvements.

Eight weeks of inorganic nitrate/nitrite supplementation improves aerobic exercise capacity and the gas exchange threshold in patients with type 2 diabetes.

Patients with type 2 diabetes mellitus (T2DM) have reduced exercise capacity, indexed by lower maximal oxygen consumption (V̇o2max) and achievement of the gas exchange threshold (GET) at a lower % V̇o2max. The ubiquitous signaling molecule nitric oxide (NO) plays a multifaceted role during exercise and, as patients with T2DM have poor endogenous NO production, we investigated if inorganic nitrate/nitrite supplementation (an exogenous source of NO) improves exercise capacity in patients with T2DM. Thirty-six patients with T2DM (10F, 59 ± 9 yr, 32.0 ± 5.1 kg/m2, HbA1c = 7.4 ± 1.4%) consumed beetroot juice containing either inorganic nitrate/nitrite (4.03 mmol/0.29 mmol) or a placebo (0.8 mmol/0.00 mmol) for 8 wk. A maximal exercise test was completed before and after both interventions. V̇o2max was determined by averaging 15-s data, whereas the GET was identified using the V-slope method and breath-by-breath data. Inorganic nitrate/nitrite increased both absolute (1.96 ± 0.67 to 2.07 ± 0.75 L/min) and relative (20.7 ± 7.0 to 21.9 ± 7.4 mL/kg/min, P < 0.05 for both) V̇o2max, whereas no changes were observed following placebo (1.94 ± 0.40 to 1.90 ± 0.39 L/min, P = 0.33; 20.0 ± 4.2 to 19.7 ± 4.6 mL/kg/min, P = 0.39). Maximal workload was also increased following inorganic nitrate/nitrite supplementation (134 ± 47 to 140 ± 51 W, P < 0.05) but not placebo (138 ± 32 to 138 ± 32 W, P = 0.98). V̇o2 at the GET (1.11 ± 0.27 to 1.27 ± 0.38L/min) and the %V̇o2max in which GET occurred (56 ± 8 to 61 ± 7%, P < 0.05 for both) increased following inorganic nitrate/nitrite supplementation but not placebo (1.10 ± 0.23 to 1.08 ± 0.21 L/min, P = 0.60; 57 ± 9 to 57 ± 8%, P = 0.90) although the workload at GET did not achieve statistical significance (group-by-time P = 0.06). Combined inorganic nitrate/nitrite consumption improves exercise capacity, maximal workload, and promotes a rightward shift in the GET in patients with T2DM. This manuscript reports data from a registered Clinical Trial at ClinicalTrials.gov ID: NCT02804932.NEW & NOTEWORTHY We report that increasing nitric oxide bioavailability via 8 wk of inorganic nitrate/nitrite supplementation improves maximal aerobic exercise capacity in patients with type 2 diabetes mellitus. Similarly, we observed a rightward shift in the gas exchange threshold. Taken together, these data indicate inorganic nitrate/nitrite may serve as a means to improve fitness in patients with type 2 diabetes mellitus.

Hypoxia offsets the decline in brachial artery flow-mediated dilation after acute inactivity.

Intermittent (IH), as opposed to continuous hypoxia (CH), is thought to have beneficial effects on cardiovascular function and health. In the present study, we examined the acute effects of IH and CH (∼80% pulse oxygen saturation via 10% oxygen tank) on peripheral vascular function. Brachial artery flow-mediated dilation (FMD) was used to assess vascular function in 12 young adults (23 ± 5 yr; 8 M/4 F) before and after 50 min of IH (5 cycles; 4-min normoxia/6-min hypoxia per cycle), CH (20-min normoxia followed by 30-min hypoxia), or time control (50-min normoxia) interventions. Brachial artery diameter and velocity were measured using Doppler ultrasound to assess blood flow and shear rate. The total change in shear rate was greater during IH (634 ± 1,073·s-1, P < 0.05) and CH (321 ± 833·s-1, P = 0.05) than during time control (-412 ± 789·s-1). %FMD was reduced following time control (7.4 ± 1.2 to 5.9 ± 1.1%, P < 0.05) but was maintained following both hypoxia trials (IH: 7.2 ± 1.5 to 7.5 ± 1.5%, P = 0.52; CH: 6.9 ± 1.6 to 6.8 ± 1.4%, P = 0.73). Normalized %FMD for shear rate area under the curve (%FMDSRAUC) was reduced following the time control trial (4.2 ± 1.4 to 3.7 ± 0.9%, P < 0.05) with no change observed with CH (4.0 ± 1.5 to 3.9 ± 1.4%, P = 0.71). However, %FMDSRAUC increased with IH (3.8 ± 1.1 to 4.5 ± 1.5%, P < 0.05). Our data suggest that acute exposure to hypoxia (both intermittently and continuously) offsets the decline in vascular function after brief inactivity. The potential beneficial effect of hypoxia on peripheral vascular function observed in the current study may be associated with enhanced brachial artery shear in response to the hypoxic challenge.

Impact of Interrepetition Rest on Muscle Blood Flow and Exercise Tolerance during Resistance Exercise.

Background and Objectives: Muscle blood flow is impeded during resistance exercise contractions, but immediately increases during recovery. The purpose of this study was to determine the impact of brief bouts of rest (2 s) between repetitions of resistance exercise on muscle blood flow and exercise tolerance. Materials and Methods: Ten healthy young adults performed single-leg knee extension resistance exercises with no rest between repetitions (i.e., continuous) and with 2 s of rest between each repetition (i.e., intermittent). Exercise tolerance was measured as the maximal power that could be sustained for 3 min (PSUS) and as the maximum number of repetitions (Reps80%) that could be performed at 80% one-repetition maximum (1RM). The leg blood flow, muscle oxygenation of the vastus lateralis and mean arterial pressure (MAP) were measured during various exercise trials. Alpha was set to p ≤ 0.05. Results: Leg blood flow was significantly greater, while vascular resistance and MAP were significantly less during intermittent compared with continuous resistance exercise at the same power outputs (p < 0.01). PSUS was significantly greater during intermittent than continuous resistance exercise (29.5 ± 2.1 vs. 21.7 ± 1.2 W, p = 0.01). Reps80% was also significantly greater during intermittent compared with continuous resistance exercise (26.5 ± 5.3 vs. 16.8 ± 2.1 repetitions, respectively; p = 0.02), potentially due to increased leg blood flow and muscle oxygen saturation during intermittent resistance exercise (p < 0.05). Conclusions: In conclusion, a brief rest between repetitions of resistance exercise effectively decreased vascular resistance, increased blood flow to the exercising muscle, and increased exercise tolerance to resistance exercise.

Sex-related differences in rapid-onset vasodilation: impact of aging.

Rapid-onset vasodilation (ROV) in response to a single muscle contraction is attenuated with aging. Moreover, sex-related differences in muscle blood flow and vasodilation during dynamic exercise have been observed in young and older adults. The purpose of the present study was to explore if sex-related differences in ROV exist in young (n = 36, 25 ± 1 yr) and older (n = 32, 66 ± 1 yr) adults. Subjects performed single forearm contractions at 10%, 20%, and 40% maximal voluntary contraction. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, and forearm vascular conductance (mL·min-1·100 mmHg-1) was calculated from blood flow (mL·min-1) and mean arterial pressure (mmHg) and used as a measure of ROV. Peak ROV was attenuated in women across all relative intensities in the younger and older groups (P < 0.05). In a subset of subjects with similar absolute workloads (∼5 kg and ∼11 kg), age-related differences in ROV were observed among both women and men (P < 0.05). However, only older women demonstrated an attenuated peak ROV compared with men (91 ± 6 vs. 121 ± 11 mL·min-1·100 mmHg-1, P < 0.05), a difference not observed in the young group (134 ± 8 vs. 154 ± 11 mL·min-1·100 mmHg-1, P = 0.15). Additionally, examining the slope of peak ROV across contraction intensities indicated a blunted response in older women compared with their younger counterparts (P < 0.05), with no differences observed between older and young men (P = 0.38). Our data suggest that sex-related differences in the rapid vasodilatory response to single muscle contractions exist in older but not young adults, such that older women have a blunted response compared with older men.NEW & NOTEWORTHY While rapid-onset vasodilation (ROV) has been shown to decrease in older individuals, it is unclear if sex contributes to the decline with aging. We sought to identify if sex-related differences exist in the ROV response to single forearm contractions in young and older adults. Our data suggest sex-related differences are present among older but not young individuals, with women having an attenuated response. These data indicate sex plays a role in decreased vasodilation with aging.

Acute inorganic nitrate supplementation and the hypoxic ventilatory response in patients with obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) have increased cardiovascular disease risk largely attributable to hypertension. Heightened peripheral chemoreflex sensitivity (i.e., exaggerated responsiveness to hypoxia) facilitates hypertension in these patients. Nitric oxide blunts the peripheral chemoreflex, and patients with OSA have reduced nitric oxide bioavailability. We therefore investigated the dose-dependent effects of acute inorganic nitrate supplementation (beetroot juice), an exogenous nitric oxide source, on blood pressure and cardiopulmonary responses to hypoxia in patients with OSA using a randomized, double-blind, placebo-controlled crossover design. Fourteen patients with OSA (53 ± 10 yr, 29.2 ± 5.8 kg/m2, apnea-hypopnea index = 17.8 ± 8.1, 43%F) completed three visits. Resting brachial blood pressure and cardiopulmonary responses to inspiratory hypoxia were measured before, and 2 h after, acute inorganic nitrate supplementation [∼0.10 mmol (placebo), 4.03 mmol (low dose), and 8.06 mmol (high dose)]. Placebo increased neither plasma [nitrate] (30 ± 52 to 52 ± 23 µM, P = 0.26) nor [nitrite] (266 ± 153 to 277 ± 164 nM, P = 0.21); however, both increased following low (29 ± 17 to 175 ± 42 µM, 220 ± 137 to 514 ± 352 nM) and high doses (26 ± 11 to 292 ± 90 µM, 248 ± 155 to 738 ± 427 nM, respectively, P < 0.01 for all). Following placebo, systolic blood pressure increased (120 ± 9 to 128 ± 10 mmHg, P < 0.05), whereas no changes were observed following low (121 ± 11 to 123 ± 8 mmHg, P = 0.19) or high doses (124 ± 13 to 124 ± 9 mmHg, P = 0.96). The peak ventilatory response to hypoxia increased following placebo (3.1 ± 1.2 to 4.4 ± 2.6 L/min, P < 0.01) but not low (4.4 ± 2.4 to 5.4 ± 3.4 L/min, P = 0.11) or high doses (4.3 ± 2.3 to 4.8 ± 2.7 L/min, P = 0.42). Inorganic nitrate did not change the heart rate responses to hypoxia (beverage-by-time P = 0.64). Acute inorganic nitrate supplementation appears to blunt an early-morning rise in systolic blood pressure potentially through suppression of peripheral chemoreflex sensitivity in patients with OSA.NEW & NOTEWORTHY The present study is the first to examine the acute effects of inorganic nitrate supplementation on resting blood pressure and cardiopulmonary responses to hypoxia (e.g., peripheral chemoreflex sensitivity) in patients with obstructive sleep apnea (OSA). Our data indicate inorganic nitrate supplementation attenuates an early-morning rise in systolic blood pressure potentially attributable to blunted peripheral chemoreflex sensitivity. These data show proof-of-concept that inorganic nitrate supplementation could reduce the risk of cardiovascular disease in patients with OSA.

Indices of leg resistance artery function are independently related to cycling V̇O2 max.

PURPOSE: While maximum blood flow influences one's maximum rate of oxygen consumption (V̇O2 max), with so many indices of vascular function, it is still unclear if vascular function is related to V̇O2 max in healthy, young adults. The purpose of this study was to determine if several common vascular tests of conduit artery and resistance artery function provide similar information about vascular function and the relationship between vascular function and V̇O2 max. METHODS: Twenty-two healthy adults completed multiple assessments of leg vascular function, including flow-mediated dilation (FMD), reactive hyperemia (RH), passive leg movement (PLM), and rapid onset vasodilation (ROV). V̇O2 max was assessed with a graded exercise test on a cycle ergometer. RESULTS: Indices associated with resistance artery function (e.g., peak flow during RH, PLM, and ROV) were generally related to each other (r = 0.47-77, p < .05), while indices derived from FMD were unrelated to other tests (p < .05). Absolute V̇O2 max (r = 0.57-0.73, p < .05) and mass-specific V̇O2 max (r = 0.41-0.46, p < .05) were related to indices of resistance artery function, even when controlling for factors like body mass and sex. FMD was only related to mass-specific V̇O2 max after statistically controlling for baseline artery diameter (r = 0.44, p < .05). CONCLUSION: Indices of leg resistance artery function (e.g., peak flow during RH, PLM, and ROV) relate well to each other and account for ~30% of the variance in V̇O2 max not accounted for by other factors, like body mass and sex. Vascular interventions should focus on improving indices of resistance artery function, not conduit artery function, when seeking to improve exercise capacity.

Intermittent hypoxia enhances shear-mediated dilation of the internal carotid artery in young adults.

Cyclic intermittent hypoxia (IH) increases cerebral blood velocity. This enhanced velocity augments the commensurate shear stimulus and may subsequently increase cerebrovascular endothelial function. This study aimed to examine the effects of cyclic IH on hypercapnia-induced shear-mediated dilation of the internal carotid artery (ICA), a potential index of cerebrovascular endothelial function. Shear-mediated dilation was measured in nine adults (22 ± 4 yr) before as well as after 50 min of cyclic IH [5 cycles, 4 min of normoxia, followed by 6 min of hypoxia (target 80% [Formula: see text]) per cycle] and control normoxia (sham, 50 min of continuous normoxia) on separate days (≥72 h apart). ICA diameter and velocity were measured using Doppler ultrasound during cyclic IH and hypercapnia. Shear-mediated dilation was induced by 3 min of hypercapnia (Δ[Formula: see text]; IH: pre 10.1 ± 1.0 mmHg, post 10.8 ± 1.3 mmHg; sham: pre 10.5 ± 1.5 mmHg, post 10.8 ± 1.5 mmHg) and was calculated as the percent rise in peak relative to baseline diameter. Hypoxia increased ICA blood flow and shear rate (SR) during each cycle [blood flow: 322 ± 90 to 406 ± 74 mL/min, P < 0.01; SR: 179 ± 42 to 207 ± 55/s, P = 0.06, baseline to hypoxia (average of last minute of each cycle)], which was normalized during the succeeding normoxic period (blood flow: 322 ± 90 to 329 ± 68 mL/min, P = 0.54, SR: 179 ± 42 to 176 ± 32/s, P = 0.56). As such, shear-mediated dilation increased following cyclic IH (4.6 ± 1.3% to 6.2 ± 2.2%, P < 0.01), but not control normoxia (4.9 ± 1.4% to 4.9 ± 1.4%, P = 0.92). Our data indicate that increased blood flow and SR during cyclic IH enhance shear-mediated dilation of the ICA in young adults. These results suggest that cyclic IH could be used to optimize cerebral vascular health.NEW & NOTEWORTHY We explored the effects of cyclic intermittent hypoxia (IH) on shear-mediated dilation of the internal carotid artery (ICA), a potential index of cerebral endothelial function, in young adults. Cyclic IH increased blood flow and shear rate in the ICA and, as a result, increased shear-mediated dilation of the ICA. These data suggest that cyclic IH could potentially be applied as a nonpharmacological therapy to optimize cerebral vascular health.

Vascular function is related to blood flow during high-intensity, but not low-intensity, knee extension exercise.

While vascular function, assessed as the ability of the vasculature to dilate in response to a stimulus, is related to cardiovascular health, its relationship to exercise hyperemia is unclear. This study sought to determine if blood flow during submaximal and maximal exercise is related to vascular function. Nineteen healthy adults completed multiple assessments of vascular function specific to the leg, including passive leg movement (PLM), rapid onset vasodilation (ROV), reactive hyperemia (RH), and flow-mediated dilation (FMD). On a separate day, exercise blood flow (Doppler ultrasound) was assessed in the same leg during various intensities of single-leg, knee-extension (KE) exercise. Vascular function, determined by PLM, ROV, and RH, was related to exercise blood flow at high intensities, including maximum work rate (WRmax) (r = 0.58-0.77, P < 0.001), but not low intensities, like ~21% WRmax (r = 0.12-0.34, P = 0.12-0.62). Relationships between multiple indices of vascular function and peak exercise blood flow persisted when controlling for quadriceps mass and exercise work rate (P < 0.05), indicating vascular function is independently related to the blood flow response to intense exercise. When divided into two groups based upon the magnitude of the PLM response, subjects with a lower PLM response exhibited lower exercise flow at several absolute work rates, as well as lower peak flow (P < 0.05). In conclusion, leg flow during dynamic exercise is independently correlated with multiple different indices of microvascular function. Thus microvascular function appears to modulate the hyperemic response to high-intensity, but not low-intensity, exercise.NEW & NOTEWORTHY While substantial evidence indicates that individuals with lower vascular function are at greater risk for cardiovascular disease, with many redundant vasodilator pathways present during exercise, it has been unclear if low vascular function actually impacts blood flow during exercise. This study provides evidence that vascular function, assessed by multiple noninvasive methods, is related to the blood flow response to high-intensity leg exercise in healthy young adults. Importantly, healthy young adults with lower levels of vascular function, particularly microvascular function, exhibit lower blood flow during high-intensity, and maximal knee extension exercise. Thus it appears that in addition to increasing one's risk of cardiovascular disease, lower vascular function is also related to a blunted blood flow response during high-intensity exercise.