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Background Maintaining baroreflex sensitivity is integral to ensuring blood pressure maintenance and end‐organ perfusion during hemorrhage. This is especially true under conditions of hypoxemia, where decreased tolerance to central hypovolemia is commonly observed. Hypoxia activates peripheral chemoreceptors and reduces baroreceptor‐vascular resistance reflex sensitivity. However, a direct role for the peripheral chemoreceptors in the hemodynamic response to hemorrhage in hypoxia remains unclear. Objective We tested the hypothesis that attenuation of peripheral chemoreceptor activity (low‐dose dopamine; 1–2 μg/kg/min) during acute hypoxia would promote maintenance of mean arterial pressure, pulse pressure, and other hemodynamic markers [heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)] during simulated hemorrhage. Methods Ten healthy men (35±3 years, BMI 25±1 kg/m 2 ) participated in a randomized, double‐blind, placebo controlled study. Participants completed two experimental visits (saline and low‐dose dopamine) at which lower body negative pressure (LBNP) was conducted during hypoxia (SpO 2 ~85%; PaO2 ~52 mmHg) delivered via a non‐rebreather mask. Ventilation [V̇ (turbine transducer)], arterial blood pressure (brachial artery catheter), HR (ECG), and central venous pressure (peripherally inserted central catheter) were measured continuously and SV, CO, and TPR were calculated. Following a 5‐min rest, participants underwent LBNP for 5‐min at 3 intervals (−15, −30, and −45 mmHg). Outcome values were analyzed and compared using a mixed linear model (SAS PROC MIXED) with a direct product AR(1) covariance structure using indicator variables for saline vs. dopamine. Data from the mixed linear model are reported as an estimated change per 15 mmHg of LBNP. Results Dopamine had no effect on hypoxia P a O 2 , P a CO 2 , V̇ or respiratory rate (all P >0.05) and this relationship persisted throughout all LBNP stages. The mixed linear model showed no effect of dopamine vs. saline on changes in: central venous pressure (−1.1±0.4 vs −1.3±0.3 mmHg, P =0.15), mean arterial pressure (−4.7±2.3 vs −5.3±1.4 mmHg, P =0.25), pulse pressure (−6.7±1.5 vs −8.3±1.4 mmHg, P =0.50), HR (7.8±1.5 vs 6.1±1.5 bpm, P =0.41), SV (−10.9±1.9 vs −11.6±3.3 mL, P =0.41), CO (−0.3±0.2 vs −0.4±0.4 L · min −1 , P =0.31) or TPR (0.2±0.4 vs 0.7±0.6 mmHg · L · min −1 P =0.27). Discussion Intravenous infusion of low‐dose dopamine designed to attenuate peripheral chemoreflex activity during acute hypoxia did not alter the integrated hemodynamic response to simulated hemorrhage. Our data suggests that peripheral chemoreceptors have a limited role during hypoxic central hypovolemia. More research is needed to understand the sensitivity and cross‐talk between chemoreceptors and baroreceptors during hemorrhage. Support or Funding Information Funding: W81XWH‐13‐2‐0038 (DOD), DK90541 (NIH), UL1 TR000135 (NIH).

Background Sympathetic nerve activity and its effect on blood pressure are altered by female sex hormones; however, this effect differs between exogenous and endogenous hormones. With oral contraceptive (OC) use, cross‐sectional data has demonstrated higher blood pressure (BP) with no corresponding change in muscle sympathetic nerve activity (MSNA). This results in a higher BP/MSNA ratio with OC use although contributing mechanisms are unclear. The higher BP/MSNA ratio in women on OC suggests OC use may limit the ability of sympathetic baroreflex (sBRS) to suppress MSNA. Alternatively, a “burst” of MSNA could result in a greater change in BP (augmented neurovascular transduction). Objective The goal of this study was to determine if OCs alter blood pressure control through autonomic mechanisms in young women. Hypotheses We hypothesized (1) sympathetic baroreflex sensitivity would be decreased and (2) neurovascular transduction would be augmented in women on OCs compared to naturally cycling women. Methods We conducted a retrospective analysis of data from healthy young women taking OCs (n=30, 25±4yrs) and with natural menstrual cycles (n=23, 27±4yrs). Women were studied during the placebo phase of OC use or early follicular phase of the menstrual cycle. Heart rate (HR, 3‐lead ECG), BP (arterial line or photoplethysmography for both groups), and MSNA (peroneal nerve microneurography) were measured over 5 min of quiet rest and data were analyzed for measures of sBRS and neurovascular transduction (Ensemble, Elucimed Inc., Dunedin, New Zealand). Results Groups did not differ in mean BP (Control: 94±9, OC:92±8mmHg, p=0.60), or HR (Control: 61±8, OC: 62±9 bpm, p=0.57), but women on OCs had lower MSNA than controls (Control: 16±6, OC: 12±5 bursts/min, p=0.006). There were no significant differences in TPR (Control: 0.022±0.005, OC: 0.020±0.005 mmHg min/L, p=0.12), however there was a trend toward increased cardiac output in women on OCs (Control: 4.45±0.86, OC: 4.94±1.02 L/min, p=.068). There were no significant group differences in sBRS (Control: −4.3±2.1, OC: −4.0±2.6 bursts ·100 heartbeats −1 ·mmHg −1 , p=0.79), or neurovascular transduction (Control: 0.093±0.042, OC: 0.091±0.058 ΔmmHg/% burst area, p=0.87). Furthermore, there were no significant correlations between BP and BRS, MSNA, or transduction in either group. Conclusions Our data strengthen previous findings which have shown women taking OCs have higher BP for a given MSNA. The analysis we performed build on these results and demonstrate that the increase in BP for a given MSNA in women taking OCs is not due to attenuated sBRS or augmented neurovascular transduction. This work has advanced our understanding of the alteration of blood pressure with OC use in young women. Support or Funding Information NIH HL083947

Objectives We aimed to determine if epinephrine played a beneficial role on middle cerebral artery velocity (MCAv) during physiologically stressful stimuli prior to cardiovascular collapse. MCAv was assessed during lower body negative pressure (LBNP) under conditions of a saline or epinephrine infusion. We hypothesized that (1) epinephrine would augment the change in MCAv from baseline to LBNP tolerance, (2), epinephrine would increase MCAv for a given LBNP stimulus, (3) at a given percent of LBNP tolerance epinephrine and saline will be similar and (4) that epinephrine would improve LBNP tolerance. Methods Nine participants (35±9yrs, n=5 male, 4 female) underwent a LBNP protocol to physiological tolerance during two study visits, performed at least two weeks apart, and randomized to saline or epinephrine (dose=0.1μg/kg/min) infusions (peripherally‐ inserted central catheter). Blood pressure (radial artery catheter) and middle cerebral artery velocity (transcranial Doppler) were assessed. MCAv and cerebrovascular conductance index (CvCi) were analyzed during baseline (three minutes), physiological tolerance (one minute), during LBNP at a given stimulus (three minutes; −15, −30, −45 mmHg of LBNP), and during relative percentages of LBNP tolerance [three minutes; 20, 40, 60, and 80% of LBNP tolerance time (s)]. Baseline was defined as measures taken after 15 minutes of saline or epinephrine infusion. Results In both saline and epinephrine conditions, MCAv and CvCi decreased from baseline to tolerance (Saline MCAv: 69.7±7.5 vs 44.9±4.9 cm/s, p<0.05; Epinephrine MCAv: 80.9±5.9 vs 56.5±6.7 cm/s, p<0.05; Saline CvCi: 0.69±0.06 vs 0.58±0.067 cm/s/mmHg, p>0.05; Epinephrine CvCi: 0.80±0.06 vs 0.70±0.078 cm/s/mmHg, p<0.05). Epinephrine augmented MCAv at a given LBNP stimulus from baseline to −15, −30, and −45 mmHg (MCAv: Treatment effect: p<0.05; CvCi: Treatment effect: p=0.05). At a relative percent of LBNP tolerance, epinephrine increased MCAv, but when blood pressure was controlled for with CvCi there was no treatment effect between epinephrine and saline (MCAv: Treatment effect: p<0.05; CvCi: Treatment effect: p>0.05). Time to tolerance was not significantly different between saline and epinephrine conditions (1469±168 vs. 1445±82s, p=0.88). Conclusions Epinephrine increased MCAv during LBNP. These data suggest that epinephrine plays a beneficial role during stressful physiological stimuli such as hemorrhage in humans by augmenting cerebral blood flow prior to cardiovascular collapse. However, epinephrine did not improve LBNP tolerance. Support or Funding Information The United States Department of Defense W81XWH‐13‐2‐0038

Background Despite improvements in military aircraft safety, many aviation incidents are attributed to hypoxia. The correlation between moderate hypoxia and cognitive function are well studied but results remain controversial. Comparatively, the effects of severe hypoxia are still not well understood. In the present study, we examined the executive cognitive function and physiological indices under both moderate and severe hypoxia conditions. Purpose To examine the relationship between executive function and physiological indices during acute hypoxia exposure. Methods Ten young healthy participants (4M/6F, 29±4 years) completed two different levels of hypoxia: 1) 10 minute moderate hypoxia (MH; F i O 2 = 0.118) and 2) 3 minute severe hypoxia (SH; F i O 2 = 0.077) following 3 minute baseline (BL; F i O 2 =0.209). Reaction time and errors of commission (defined as a response to a non‐target stimulus) were evaluated continuously using a custom Go/No‐go test at baseline and throughout hypoxia exposure. In this Go/No‐go test, participants were required to push a key when upper case “A” or “@” appeared but not when lower case “a” appeared on a computer monitor as quick and as accurately as possible. The stimuli were presented one at a time at any one of nine differing locations across the screen. Cerebral oxygenation (rSO 2 ) was continuously monitored with near‐infrared spectroscopy (NIRS) positioned above the left supraorbital ridge. Finger oxygen saturation (S p O 2 ) was continuously assessed using a pulse oximetry. Data were analyzed in every 30 seconds and are presented as mean±SE. Two‐way ANOVA and Bonferroni test for multiple comparisons was used to evaluate significant differences. Results Both S p O 2 and rSO 2 were reduced with SH (S p O 2 %, BL: 99.3±0.1% vs. SH: 70.7±1.5%, P<0.01; rSO 2 %, BL: 70±4% vs. SH: 58±4%, P<0.01). In SH, correlations of S p O 2 and rSO 2 were significant to the number of errors during the cognitive performance task (S p O 2 ; R= −0.65, rSO 2 ; R= −0.58, Both P<0.01). SH significantly increased errors of commission of the last 30 seconds in 3 minute hypoxic exposure. (BL: 0.6±0.2 errors vs. SH: 1.7±0.5 errors, P<0.01). SH significantly decreased reaction time over hypoxic exposure (BL: 0.43±0.01 sec vs. SH: 0.41±0.01 sec, P<0.01). Comparatively, MH did not elicit an increase in the number of errors of commission nor a decrease in reaction time (Both, P>0.05). Conclusion Executive function deteriorated during severe hypoxia. Oxygenation of the prefrontal lobe which controls inhibition may be related to the increase in commission errors. Devices that monitor physiological indices such as S p O 2 or rSO 2 might be beneficial for a model to predict executive deterioration. Support or Funding Information This project was funded by the Office of Naval Research (ONR), grant number N00014‐18‐D‐7001‐TO1.

Background Cognitive deficits resulting from mild hypoxia are difficult to quantify and reproduce consistently. The changes in executive function during acute hypoxia are still controversial. The purpose of present study was to assess changes in executive function during acute moderate hypoxia using a continuous performance test (Connors’ Continuous Performance test, CCPT‐II). Methods Nine young, healthy adults (7 women; 28 ± 1 years; BMI: 24.5 ± 3.0 kg·m −2 ) performed two sets of CCPT‐II during two different conditions: 1) 7 minutes of baseline (fraction of inspired oxygen (F i O 2 ) = 0.21) and 2) 10 minutes of hypoxia (F i O 2 =0.118). The CCPT‐II is a test of executive cognitive function which requires subjects to strike a key when any letter except the letter X appeared on a computer monitor as quickly and accurately as possible. Reaction time, commission errors (response to X), and omission errors (failure to respond to a letter other than X) were recorded for each 140s of the CCPT‐II block. Arterial oxygen concentration (P a O 2 ) was measured during the last 30sec of baseline and hypoxia from brachial artery catheter samples. Results P a O 2 was reduced in hypoxia ( baseline : 103.1 ± 1.5 mmHg vs. hypoxia : 43.2 ± 1.0 mmHg, P <0.01). During the trials of the CCPT‐II performed during hypoxia, reaction time was lower (i.e. faster) than during baseline ( baseline : 451 ± 18 ms. vs. hypoxia : 437 ± 13 ms., P<0.01). Additionally, the number of commission errors was greater in hypoxia ( baseline : 1.3 ± 0.6 errors·block −1 vs. hypoxia : 2.1 ± 0.8 errors·block −1 , P<0.01). However, the number of omission errors was not different between the two conditions ( baseline : 0.4 ± 0.2 errors·block −1 vs. hypoxia : 0.2 ± 0.1 errors·block −1 , P=0.92). Conclusions The number of commission errors increased and the reaction time decreased during the CCPT‐II test performed in moderate hypoxia compared to baseline, demonstrating a decline in cognitive function during hypoxia. The faster and less accurate responses during hypoxia suggest a suppression of inhibitory pathways in the prefrontal or motor cortex that may contribute to the observed acute reduction in executive cognitive function. Support or Funding Information This project was funded by the Office of Naval Research (ONR), grant number N00014‐18‐D‐7001‐TO1.

New Findings What is the central question of this study? What is the role of β2‐adrenergic receptor (β2AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2AR‐mediated vasodilatation in both groups of women? What is the main finding and its importance? β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women. Abstractβ2‐Adrenergic receptor (β2AR)‐mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β2AR‐mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra‐arterial infusions of terbutaline at 0.1–2.0 µg (100 ml tissue)−1 min−1 with and without the NO synthase inhibitor l‐NG‐monomethylarginine (l‐NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l‐NMMA co‐infusion vs. without l‐NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l‐NMMA co‐infusion (P > 0.05 for all). These data suggest that β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women.

New Findings What is the central question of this study? How do locomotor muscle metabo‐ and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase‐2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. AbstractHeart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo‐ and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase‐2 (COX‐2), purinergic 2X3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), acid‐sensing ion channel 3 (ASIC3), Piezo 1 and Piezo 2 protein expression. TRPV1 and COX‐2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3, ASIC3, and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX‐2 protein expression was related to the percentage change in ventilation (r = −0.66) and mean arterial pressure (MAP) (r = −0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV1 protein expression was related to the percentage change in systolic blood pressure (r = −0.77, P = 0.02) and MAP (r = −0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV1 and COX‐2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV1 and COX‐2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.

Key points Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange. AbstractThe longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50 = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50 = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end‐exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects’ oxyhaemoglobin saturation () was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake () (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in between trials was related to the change in (r = −0.75, p < 0.0001). Compared to normoxia, the controls’ alveolar‐to‐arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

New Findings What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high‐dose intra‐arterial infusion of either adenosine or ATP, on the rapid‐onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. AbstractThe hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid‐onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high‐dose intra‐arterial infusion of either adenosine (ADO) or ATP. Twenty‐four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% maximal voluntary contraction) 75 min after commencement of a continuous infusion of ADO (n = 6), ATP (n = 8) or saline (control; n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100 mmHg per decilitre of forearm volume) was significantly higher during ADO (33 ± 17) and ATP infusion (33 ± 17) compared with the control infusion (8 ± 3; P < 0.05). The peak FVCs post‐contraction during ADO and ATP infusions were significantly greater than during the control infusion (P < 0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14 ± 1; ADO, 24 ± 2; and ATP, 23 ± 6; P = 0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333 ± 69 and 440 ± 125); however, total FVC during ATP infusion was significantly greater compared with the control value (150 ± 19; P < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

We examined the contribution of the carotid chemoreceptors to insulin-mediated increases in muscle sympathetic nerve activity (MSNA) in healthy humans. We hypothesized that reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia. Young, healthy adults (9 male/9 female, 28 ± 1 yr, 24 ± 1 kg/m2) completed a 30-min euglycemic baseline followed by a 90-min hyperinsulinemic (1 mU·kg fat-free mass−1·min−1), euglycemic infusion. MSNA (microneurography of the peroneal nerve) was continuously measured. The role of the carotid chemoreceptors was assessed at baseline and during hyperinsulinemia via 1) acute hyperoxia, 2) low-dose dopamine (1–4 µg·kg−1·min−1), and 3) acute hyperoxia + low-dose dopamine. MSNA burst frequency increased from baseline during hyperinsulinemia ( P < 0.01). Acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.74) or during hyperinsulinemia ( P = 0.83). The insulin-mediated increase in MSNA burst frequency ( P = 0.02) was unaffected by low-dose dopamine ( P = 0.60). When combined with low-dose dopamine, acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.17) or during hyperinsulinemia ( P = 0.85). Carotid chemoreceptor desensitization in young, healthy men and women does not attenuate the sympathoexcitatory response to hyperinsulinemia. Our data suggest that the carotid chemoreceptors do not contribute to acute insulin-mediated increases in MSNA in young, healthy adults.