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.

Effects of Combined Inorganic Nitrate and Nitrite Supplementation on Cardiorespiratory Fitness and Skeletal Muscle Oxidative Capacity in Type 2 Diabetes: A Pilot Randomized Controlled Trial.

Nitric oxide (NO) stimulates mitochondrial biogenesis in skeletal muscle. However, NO metabolism is disrupted in individuals with type 2 diabetes mellitus (T2DM) potentially contributing to their decreased cardiorespiratory fitness (i.e., VO2max) and skeletal muscle oxidative capacity. We used a randomized, double-blind, placebo-controlled, 8-week trial with beetroot juice containing nitrate (NO3−) and nitrite (NO2−) (250 mg and 20 mg/day) to test potential benefits on VO2max and skeletal muscle oxidative capacity in T2DM. T2DM (N = 36, Age = 59 ± 9 years; BMI = 31.9 ± 5.0 kg/m2) and age- and BMI-matched non-diabetic controls (N = 15, Age = 60 ± 9 years; BMI = 29.5 ± 4.6 kg/m2) were studied. Mitochondrial respiratory capacity was assessed in muscle biopsies from a subgroup of T2DM and controls (N = 19 and N = 10, respectively). At baseline, T2DM had higher plasma NO3− (100%; p < 0.001) and lower plasma NO2− levels (−46.8%; p < 0.0001) than controls. VO2max was lower in T2DM (−26.4%; p < 0.001), as was maximal carbohydrate- and fatty acid-supported oxygen consumption in permeabilized muscle fibers (−26.1% and −25.5%, respectively; p < 0.05). NO3−/NO2− supplementation increased VO2max (5.3%; p < 0.01). Further, circulating NO2−, but not NO3−, positively correlated with VO2max after supplementation (R2= 0.40; p < 0.05). Within the NO3−/NO2− group, 42% of subjects presented improvements in both carbohydrate- and fatty acid-supported oxygen consumption in skeletal muscle (vs. 0% in placebo; p < 0.05). VO2max improvements in these individuals tended to be larger than in the rest of the NO3−/NO2− group (1.21 ± 0.51 mL/(kg*min) vs. 0.31 ± 0.10 mL/(kg*min); p = 0.09). NO3−/NO2− supplementation increases VO2max in T2DM individuals and improvements in skeletal muscle oxidative capacity appear to occur in those with more pronounced increases in VO2max.

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.

Dietary Inorganic Nitrate/Nitrite Supplementation Reduces Central and Peripheral Blood Pressure in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk due to elevated blood pressure (BP). As low levels of nitric oxide (NO) may contribute to increased BP, we determined if increasing NO bioavailability via eight weeks of supplementation with beetroot juice containing inorganic nitrate/nitrite (4.03 mmol nitrate, 0.29 mmol nitrite) improves peripheral and central BP relative to nitrate/nitrite-depleted beetroot juice. METHODS: Peripheral and central BP were assessed at heart-level in supine subjects using a brachial artery catheter and applanation tonometry, respectively. RESULTS: Nitrate/nitrite supplementation reduced peripheral systolic BP (148 ± 16 to 142 ± 18 mm Hg, P < 0.05) but not placebo (150 ± 19 to 149 ± 17 mm Hg, P = 0.93); however, diastolic BP was unaffected (supplement-by-time P = 0.08). Central systolic BP (131 ± 16 to 127 ± 17 mm Hg) and augmented pressure (13.3 ± 6.6 to 11.6 ± 6.9 mm Hg, both P < 0.05) were reduced after nitrate/nitrite, but not placebo (134 ± 17 to 135 ± 16 mm Hg, P = 0.62; 14.1 ± 6.6 to 15.2 ± 7.4 mm Hg, P = 0.20); central diastolic BP was unchanged by the interventions (supplement-by-time P = 0.16). Inorganic nitrate/nitrite also reduced AIx (24.3 ± 9.9% to 21.0 ± 9.6%) whereas no changes were observed following placebo (24.6 ± 9.3% to 25.6 ± 9.9%, P = 0.46). CONCLUSIONS: Inorganic nitrate/nitrite supplementation improves peripheral and central BP as well as AIx in T2DM. CLINICAL TRIALS REGISTRATION: Trial Number NCT02804932.

Sodium nitrate supplementation improves blood pressure reactivity in patients with peripheral artery disease.

BACKGROUND & AIMS: Peripheral artery disease (PAD) is characterized by elevated blood pressure (BP), low nitric oxide availability (NO), and exaggerated pressor responses to sympatho-excitatory stressors. Inorganic nitrate reduces peripheral BP in healthy and chronically diseased populations. The objective of this study was to investigate the effects of eight-weeks of sodium nitrate (NaNO3) supplementation on indices of BP in PAD patients. METHODS: 21 patients with PAD were recruited to participate in this study, undergoing 8-weeks of NaNO3 (n = 13; 73 ± 9 years) or placebo (n = 8; 69 ± 10 years) supplementation. BP responsiveness to a cold pressor test (CPT) were examined prior to and following the supplementation period. The systolic BP response (change from rest) during the first (26 ± 10 vs. 19 ± 11 mmHg) and second minutes (32 ± 10 vs. 26 ± 12 mmHg) of CPT were reduced following NaNO3 (P < 0.05 for both) but not after placebo (first minute: 22 ± 10 vs. 24 ± 10 mmHg, P = 0.30; second minute 26 ± 10 vs 27 ± 10 mmHg, P = 0.72) supplementation. CONCLUSION: Our data suggest that eight-weeks of NaNO3 supplementation reduces BP responsiveness to sympatho-excitatory stimuli. CLINICAL TRIALS REGISTRATION NUMBER: NCT01983826.

Combined inorganic nitrate/nitrite supplementation blunts α-mediated vasoconstriction during exercise in patients with type 2 diabetes.

AIMS: Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS: Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS: ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P < 0.05) during exercise were augmented following BRA, but not BRP (P = 0.96 and 0.51). Phenylephrine-induced vasoconstriction during exercise was blunted following BRA (-17.1 ± 5.9 to -12.6 ± 3.1%, P < 0.01), but not BRP (P = 0.58) supplementation; the magnitude of sympatholysis was unchanged by either (beverage-by-time P = 0.15). BRA supplementation reduced dexmedetomidine-induced vasoconstriction during exercise (-23.3 ± 6.7 to -19.7 ± 5.2%) and improved the corresponding magnitude of sympatholysis (25.3 ± 11.4 to 34.4 ± 15.5%, both P < 0.05). CONCLUSIONS: BRA supplementation improves the hyperemic and vasodilatory responses to exercise in patients with T2DM which appears to be attributable to reduced α-adrenergic mediated vasoconstriction in contracting skeletal muscle.

Glycemic management is inversely related to skeletal muscle microvascular endothelial function in patients with type 2 diabetes.

Microvascular endothelial dysfunction precipitates cardiovascular disease mortality in patients with type 2 diabetes mellitus (T2DM). However, the relationship between glycemic management and microvascular endothelial function of these patients remains ill defined. We investigated the association between skeletal muscle microvascular endothelial function with glycemic management (HbA1c) and responses to an oral glucose challenge (OGTT) in 30 patients with T2DM (59 ± 9 years, 31.2 ± 5.1 kg/m2 , HbA1c = 7.3 ± 1.3%). On study day 1, microvascular endothelial function was quantified as the increase (Δ from rest) in forearm vascular conductance (FVC, ml/min/100 mmHg) during intra-arterial acetylcholine infusion at 4.0 and 8.0 µg/dl forearm volume/min (ACh4 and ACh8, respectively). [Glucose] and [insulin] were measured in a fasted state as well as following a 75 g OGTT on a second day with an additional fasting blood sample collected to measure HbA1c. FVC increased (Δ) 221 ± 118 and 251 ± 144 ml/min/100 mm Hg during ACh4 and ACh8 trials, respectively (p < 0.05 between doses). [Glucose] and [insulin] increased at the 1-h time point, relative to fasting levels, and remained elevated 2 h post-consumption (p < 0.05 for both variables and time points). [Glucose] nor [insulin], fasting or during the OGTT, were associated with ΔFVC during ACh4 or ACh8, respectively (p = 0.11-0.86), although HbA1c was inversely related (r = -0.47 and -0.46, respectively, p < 0.01 for both). Patients whose HbA1c met the ADA's therapeutic target of ≤7.0% had greater ΔFVC to ACh4 (272 ± 147 vs. 182 ± 74 ml/100 mm Hg/min) and ACh8 (324 ± 171 vs. 196 ± 90 ml/100 mm Hg/min, p < 0.05 for both trials) compared to those with >7.0%, respectively. Our data show glycemic management is related to acetylcholine-mediated vasodilation (e.g., microvascular endothelial function) in skeletal muscle of patients with T2DM.

Inorganic nitrate supplementation attenuates conduit artery retrograde and oscillatory shear in older adults.

Aging causes deleterious changes in resting conduit artery shear patterns and reduced blood flow during exercise partially attributable to reduced nitric oxide (NO). Inorganic nitrate increases circulating NO bioavailability and may, therefore, improve age-associated changes in shear rate as well as exercise hyperemia. Ten older adults (age: 67 ± 3 yr) consumed 4.03 mmol nitrate and 0.29 mmol nitrite (active) or devoid of both (placebo) daily for 4 wk in a randomized, double-blinded, crossover fashion. Brachial artery diameter (D) and blood velocity (Vmean) were measured via Doppler ultrasound at rest for the characterization of shear profile as well as during two handgrip exercise trials (4 and 8 kg) for calculation of forearm blood flow (Vmean × cross-sectional area, FBF) and conductance [FBF/mean arterial pressure, forearm vascular conductance (FVC)]. Plasma [nitrate] and [nitrite] increased following active (P < 0.05 for both) but not placebo (P = 0.68 and 0.40, respectively) supplementation. Neither mean nor antegrade shear rate changed following either supplement (beverage-by-time P = 0.14 and 0.21, respectively). Retrograde (-13.4 ± 7.0 to -9.7 ± 6.8·s-1) and oscillatory (0.20 ± 0.08 to 0.15 ± 0.09 A.U., P < 0.05 for both) shear decreased following active, but not placebo (P = 0.81 and 0.70, respectively), supplementation. The FBF response (Δ from rest) to neither 4-kg nor 8-kg trials changed following either supplement (beverage-by-time P = 0.53 and 0.11, respectively). Similarly, no changes were observed in FVC responses to 4-kg or 8-kg trials (beverage-by-time P = 0.23 and 0.07, respectively). These data indicate that inorganic nitrate supplementation improves conduit artery shear profiles, but not exercise hyperemia, in older adults.NEW & NOTEWORTHY We report for the first time, to our knowledge, that 4 wk of inorganic nitrate supplementation attenuates retrograde and oscillatory shear in the brachial artery of older adults. However, this was not associated with greater hyperemic or vasodilatory responses to exercise. In sum, these data highlight favorable changes in shear patterns with aging, which may reduce the risk of atherosclerotic cardiovascular disease.

Arterial Stiffness Predicts General Anesthesia-Induced Vasopressor-Resistant Hypotension in Patients Taking Angiotensin-Converting Enzyme Inhibitors.

OBJECTIVES: Patients chronically treated with angiotensin-converting enzyme inhibitors (ACEIs) may develop hypotension after induction of general anesthesia. A fraction of these patients are resistant to therapeutic doses of vasopressors, which poses serious concerns for hemodynamic management. The authors hypothesized that the patients who develop refractory hypotension, compared with those who do not, show lower central arterial stiffness due to the profound effect of ACEIs. DESIGN: Prospective observational study. SETTING: Single tertiary center. INTERVENTIONS: Fifty surgical patients chronically treated with ACEIs were enrolled. Prior to surgery, all the patients had central arterial stiffness assessment measured by carotid-femoral pulse-wave velocity. Patients were categorized into 2 groups according to the systolic blood pressure response during the first 10 minutes after induction of general anesthesia: a vasopressor-resistant hypotension group requiring more than 200 µg phenylephrine, or a control group requiring no more than 200 µg of phenylephrine to maintain systolic blood pressure above 90 mmHg during the study period. MEASUREMENTS AND MAIN RESULTS: Carotid-femoral pulse-wave velocity was significantly lower in the vasopressor-resistant hypotension group compared to the control group (7.6 [7.2-8.3] m/s v 9.9 [8.7-12.0] m/s, p = 0.001 [Hodges-Lehman median difference 2.2, 95% confidence interval = 1.1-4.4]). CONCLUSION: These findings suggested that preoperative measurement of carotid-femoral pulse-wave velocity in patients chronically treated with ACEIs could help identify patients at increased risk of developing hypotension refractory to vasopressors after induction of general anesthesia.

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.

Effects of menstrual cycle and menopause on internal carotid artery shear-mediated dilation in women.

This study aimed to elucidate the effects of change in estrogen during the menstrual cycle and menopause on shear-mediated dilation of the internal carotid artery (ICA), a potential index of cerebrovascular endothelial function. Shear-mediated dilation of the ICA and serum estradiol were measured in 11 premenopausal (Pre-M, 21 ± 1 yr), 13 perimenopausal (Peri-M, 49 ± 2 yr), and 10 postmenopausal (Post-M, 65 ± 7 yr) women. Measurements were made twice within the Pre-M group at their early follicular (EF, lower estradiol) and late follicular (LF, higher estradiol) phases. Shear-mediated dilation was induced by 3 min of hypercapnia (target PETCO2 + 10 mmHg from individual baseline) and was calculated as the percent rise in peak diameter relative to baseline diameter. ICA diameter and blood velocity were simultaneously measured by Doppler ultrasound. In Pre-M, shear-mediated dilation was higher during the LF phase than during the EF phase (P < 0.01). Comparing all groups, shear-mediated dilation was reduced across the menopausal transition (P < 0.01), and Pre-M during the LF phase showed the highest value (8.9 ± 1.4%) compared with other groups (Pre-M in EF, 6.4 ± 1.1%; Peri-M, 5.5 ± 1.3%; Post-M, 5.2 ± 1.9%, P < 0.05 for all). Shear-mediated dilation was positively correlated with serum estradiol even after adjustment of age (P < 0.01, r = 0.55, age-adjusted; P = 0.02, r = 0.35). Collectively, these data indicate that controlling the menstrual cycle phase is necessary for the cross-sectional assessments of shear-mediated dilation of the ICA in premenopausal women. Moreover, current findings suggest that a decline in cerebrovascular endothelial function may be partly related to the reduced circulating estrogen levels in peri- and postmenopausal women.NEW & NOTEWORTHY The present study evaluated the effects of the menstrual cycle and menopause stages on the shear-mediated dilation of the ICA, a potential index of cerebrovascular endothelial function, in pre-, peri-, and postmenopausal women. Shear-mediated dilation of the ICA was increased from the low- to high-estradiol phases in naturally cycling premenopausal women and was reduced with advancing menopause stages. Furthermore, lower estradiol was associated with reduced shear-mediated dilation of the ICA, independent of age.

Greater α1-adrenergic-mediated vasoconstriction in contracting skeletal muscle of patients with type 2 diabetes.

Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to handgrip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM (n = 30) as well as nondiabetic controls (n = 15) with similar age (59 ± 9 vs. 60 ± 9 yr, P = 0.69) and body mass index (31.4 ± 5.2 vs. 29.5 ± 4.6 kg/m2, P = 0.48). Intra-arterial infusion of phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were used to induce vasoconstriction: [(FVCwith drug - FVCpredrug)/FVCpredrug × 100%]. Subjects completed rest and dynamic handgrip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147 ± 71 vs. 199 ± 63 ml/min) and FVC (126 ± 58 vs. 176 ± 50 ml·min-1·100 mmHg-1, P < 0.01 for both) during exercise compared with controls, respectively. During exercise, patients with T2DM had greater α1- (-16.9 ± 5.9 vs. -11.3 ± 3.8%) and α2-mediated vasoconstriction (-23.5 ± 7.1 vs. -19.0 ± 6.5%, P < 0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9 ± 12.2 vs. 23.1 ± 8.1%, P < 0.05) whereas groups were similar during DEX trials (24.6 ± 12.3 vs. 27.6 ± 13.4%, P = 0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise, which could be attributable to greater α1-mediated vasoconstriction in contracting skeletal muscle.NEW & NOTEWORTHY Findings presented in this article are the first to show patients with type 2 diabetes mellitus have blunted hyperemic and vasodilatory responses to dynamic handgrip exercise. Moreover, we illustrate greater α1-adrenergic-mediated vasoconstriction may contribute to our initial observations. Collectively, these data suggest patients with type 2 diabetes may have impaired functional sympatholysis, which can contribute to their reduced 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.

Aerobic exercise offsets endothelial dysfunction induced by repetitive consumption of sugar-sweetened beverages in young healthy men.

Consumption of a single, sugar-sweetened beverage (SSB) impairs vascular endothelial function. Regular aerobic exercise improves endothelium-dependent vasodilation; however, it is unknown whether these beneficial effects persist with frequent SSB consumption. Therefore, the purpose of this study was twofold; we studied the effects of repetitive SSB consumption (75 g d-glucose, 3 times/day) for 1 wk (Glu, n = 13, 23 ± 4 yr, 23.5 ± 3.4 kg/m2) on endothelium-dependent vasodilation (FMD). Then, in a separate cohort, we investigated whether 45 min of moderate-intensity aerobic exercise on five separate days offset the hypothesized decrease in FMD during the Glu protocol (Glu+Ex, n = 11, 21 ± 3 yr, 23.8 ± 2.4 kg/m2). Baseline, fasting [glucose] (P = 0.15), [insulin] (P = 0.25), %FMD (P = 0.48), absolute FMD (P = 0.66), and shear rate area under the curve (SRAUC; P = 0.82) were similar between groups. Following the interventions, fasting [glucose] (Glu: 94 ± 6 to 92 ± 6 mg/dL, Glu+Ex: 89 ± 8 to 87 ± 6 mg/dL, P = 0.74) and [insulin] (Glu: 11.3 ± 6.2 to 11.8 ± 8.9 µU/mL, Glu+Ex: 8.7 ± 2.9 to 9.4 ± 3.2 µU/mL, P = 0.89) were unchanged. %FMD was reduced in Glu (6.1 ± 2.2 to 5.1 ± 1.3%) and increased in Glu+Ex (6.6 ± 2.2 to 7.8 ± 2.4%, P < 0.05 for both). SRAUC increased similarly in both Glu [17,715 ± 8,275 to 22,922 ± 4,808 arbitrary units (A.U.)] and Glu+Ex (18,216 ± 4,516 to 21,666 ± 5,392 A.U., main effect of time P < 0.05). When %FMD was adjusted for SRAUC, attenuation was observed in Glu (0.41 ± 0.18 to 0.23 ± 0.08%/s × 103, P < 0.05) but not Glu+Ex (0.38 ± 0.14 to 0.38 ± 0.13%/s × 103, P = 0.88). Despite unchanged fasting [glucose] and [insulin], repeated consumption of SSBs impaired conduit artery vascular endothelial function. Additionally, subjects who engaged in regular moderate-intensity aerobic exercise did not demonstrate the same SSB-induced endothelial dysfunction. Collectively, these data suggest aerobic exercise may offset the deleterious effects of repetitive SSB consumption.

Dietary nitrate does not acutely enhance skeletal muscle blood flow and vasodilation in the lower limbs of older adults during single-limb exercise.

PURPOSE: Blood flow (BF) and vasodilator responses to knee-extension exercise are attenuated in older adults across an exercise transient (onset, kinetics, and steady-state), and reduced nitric oxide bioavailability (NO) has been hypothesized to be a primary mechanism contributing to this attenuation. We tested the hypothesis acute dietary nitrate (NO3-) supplementation (~ 4.03 mmol NO3- and 0.29 mmol NO2-) would improve leg vasodilator responses across an exercise transient during lower limb exercise in older adults. METHODS: Older (n = 10) untrained adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax) prior to and 2-h after consuming a NO3- or placebo beverage in a double-blind, randomized fashion. Femoral artery BF was measured by Doppler ultrasound. Vascular conductance was calculated using BF and mean arterial pressure. RESULTS: Acute ingestion of dietary NO3- enhanced plasma [NO3-] and [NO2-] (P < 0.05). Neither dietary NO3- or placebo enhanced vasodilator responses at the onset of exercise or during steady state at 20% and 40% WRmax (P > 0.05). Leg vasodilator kinetics during rhythmic exercise remained unchanged following NO3- and placebo ingestion (P > 0.05). CONCLUSIONS: The key findings of this study are that despite increasing plasma [NO3-] and [NO2-], acute dietary NO3- intake had no effect on (1) rapid hyperaemic or vasodilator responses at the onset of exercise; (2) hyperaemic and vasodilator responses during steady-state submaximal exercise; or (3) kinetics of vasodilation preceding steady-state responses. Collectively, these findings suggest that low dose dietary NO3- supplementation does not improve hyperaemic and vasodilator responses across an exercise transient in older adults.