Joyner, Michael J.

The purpose of this study was to explore dose dependent vasodilation responses of the individual compounds of Shakuyakukanzoto (SKT), a 1:1 combination of extracts from Paeony and Licorice roots: glycyrrhetic acid (GA), paeoniflorin (PF), and isoliquiritigenin (ISO). 20 young, healthy participants (13M/7W) had four intradermal microdialysis fibers placed in the forearm skin for local delivery of: 1) control (diluent), 2) GA, 3) PF, or 4) ISO at doses of 1, 10, 50, or 100 μm. Cutaneous red cell flux, an index of skin blood flow, was measured by laser‐Doppler flowmetry. Blood pressure (BP) was monitored continuously during fixed measurement periods via finger photo‐plethsmography (Finapres). Cutaneous vascular conductance (CVC) was derived as red cell flux divided by BP and was normalized as a percentage of baseline (%CVCbl, saline at 4 μl/min) and the maximum CVC (%CVCmax, 28mM sodium nitroprusside at 4 μl/min, local temperature 43°C). Mean CVC did not statistically differ between baseline and individual compound plateau (average of last 5 minutes of infusion) at any dose. The peak flux was significantly higher from baseline at doses 50 and 100 μm for control (56.17±13.32 vs. 96.73±20.32 and 44.64±5.68 vs. 80.21±9.54), PF (62.70±10.09 vs. 115.72±16.16 and 62.37±16.2 vs. 150.21±34.26), GA (48.37±4.41 vs. 71.76±7.16 and 58.36±13.68 vs. 91.51±3.41), and ISO (96.50±23.20 vs. 128.57±27.90 and 44.95±8.78 vs. 91.18±20.37) (p<0.05). However, peak CVC was significantly higher only for GA at dose 50 μm, as well as for control and PF at dose 100 μm compared to their respected baselines (GA: 0.60±0.06 vs. 1.01±0.11, control: 0.61±0.09 vs.1.55±0.61, PF: 0.81±0.20 vs. 1.30±0.30, p<0.05). There were no other significant differences between the control and the compounds for change in CVC from baseline to peak (ΔCVC), %CVCbl, or %CVCmax. There were no significant differences between doses 1, 10, or 50 as compared to 100 μm for other variables. These results suggest that the doses may be lower or below the threshold to cause a vasodilatory effect. Future studies that investigate higher doses of these compounds may be needed. Support or Funding Information The University of Oxford Systems Biology Project sponsored by Tsumura.

Skeletal muscle blood flow during exercise is typically reduced in older compared with young adults, which may be mediated in part by age‐related reductions in local vasodilator molecules such as nitric oxide (NO) and ATP. Despite this, muscle blood flow does increase substantially to contracting muscle of older adults. We questioned whether reductions in muscle blood flow with age, particularly at the onset of exercise, leads to greater accumulation of local metabolites that could play a more prominent role in contraction‐induced vasodilation compared with young adults. Thus, in the present study we tested the hypothesis that the contribution of adenosine (ADO) to contraction‐induced vasodilation is greater in older vs. young adults. In young (25 ± 2 years; n=8) and older (65 ± 2 years; n=8) adults, forearm vascular conductance (FVC) responses to a single 20% maximum voluntary contraction (MVC) handgrip contraction and to 5 minutes of 10% MVC rhythmic handgrip exercise were measured using Doppler ultrasound of the brachial artery before and after brachial artery infusion of the ADO receptor blocker aminophylline (APH). In order to determine the effect of APH infusion that was due specifically to the blockade of ADO receptors as opposed to the elevated baseline FVC that often occurs as an off‐target effect of APH, FVC responses to contraction were also measured after sodium nitroprusside (SNP) infusion to match the APH‐induced increase in baseline FVC. In response to a single contraction, both total FVC area under the curve (AUC) and the absolute change in FVC from baseline to peak were lower in older vs. young adults (−61.2% and −56.1%, respectively; p < 0.05) under control conditions. There was no significant effect of APH on total FVC AUC in young (−5.4 ± 7.8%) or older (16.6 ± 12.4%) adults vs. control, whereas the absolute change in FVC from baseline to peak was significantly lower in young adults (−22.5 ± 7.7%; p < 0.05), but unaffected in older adults (4.1 ± 7.8%) vs. control. During rhythmic handgrip exercise, FVC was significantly lower in older adults in the first 60 sec of exercise (~45–50%) as well as during steady‐state (~25%; 110.0 ± 14.9 vs. 149.5 ±12.6 mL/min/100mmHg; both p < 0.05) under control conditions. APH had no effect on the FVC response throughout the first 3 min of exercise onset in young (range: 0.8–6.2%) or older (range: −3.9 to 10.5%) adults vs. control (p > 0.05), and did not alter the absolute change in FVC from baseline to steady‐state exercise in either group (p > 0.05). SNP had no effect on these FVC responses during single contractions or rhythmic handgrip exercise in either age group (p > 0.05). We conclude that that ADO contributes to the peak vasodilatory response to a single contraction in young but not older adults, and that advancing age is not associated with a greater reliance on ADO for local vasodilation during skeletal muscle contractions. Support or Funding Information HL095573, HL119337

Introduction Adenosine triphosphate (ATP) is postulated to be a major player in the local control of skeletal muscle vascular tone during exercise. Exercise during hypoxic conditions significantly augments skeletal muscle blood flow and elevates venous plasma levels of ATP compared to normoxic conditions in young healthy adults. This suggests that the elevated levels of ATP during hypoxic exercise contribute to the augmented vasodilation. Nitric oxide synthase (NOS) inhibition has also been shown to blunt the effects of hypoxia on exercise vasodilation. Therefore, the aim of the current study was to evaluate the effect of NOS inhibition and hypoxia on vasodilator responses and plasma ATP levels during exercise in healthy young adults. Methods 10 young volunteers (age = 28 ± 1 years, 6 men/4 women) performed four minutes of forearm handgrip exercise at 20% of their maximal voluntary contraction (MVC). The forearm handgrip exercise was performed under normoxia and hypoxia (SpO2 = ~80%) with and without NOS inhibitor, LNMMA administered via a brachial artery catheter. Beat to beat blood pressure and heart rate were recorded. Forearm blood flow was measured using Doppler ultrasound and normalized for arterial pressure to determine forearm vascular conductance (FVC). Venous blood was obtained from a retrograde intravenous catheter at rest and during the last minute of each exercise bout. Plasma ATP was measured using the luciferin‐luciferase technique. Results During saline and normoxia FVC was 43.4 ± 8.4 at rest and 307.8 ± 22.6 ml/min/100mmHg during exercise. With hypoxia FVC increased to 59.35 ± 10.5 at rest and 370.9 ± 33.3 ml/min/100mmHg during exercise (both p<0.05 vs. normoxia). During LNMMA and normoxia FVC did not change significantly compared to saline 33.9 ± 4.4 at rest and 283.5 ± 23.2 ml/min/100mmHg during exercise. With hypoxia and LNMMA FVC was 35.04 ± 4.1 at rest (p>0.05 vs. normoxia) and 326.0 ± 23.9 ml/min/100mmHg during exercise (p<0.05 vs. normoxia). When changes from baseline are evaluated, hypoxia augmented the vasodilator responses exercise to exercise during both saline and LNMMA. ATP was higher during 20% MVC exercise with saline during hypoxia as compared to normoxia (65.6 ± 12.1 vs. 108.1 ± 23.2 versus nmol/L, p=0.058). It was also higher during 20% MVC exercise with LNMMA (81.7 ± 9.5 vs. 106.1 ± 14.7 nmol/L, p=0.055). When changes from baseline are evaluated, hypoxia augmented venous ATP concentration with exercise during both saline and LNMMA. Conclusions Our results suggest that increased endogenous ATP release during hypoxic exercise continued to evoke vasodilation during NOS inhibition. A likely source of this ATP is from red blood cells and this interpretation is consistent with findings demonstrating that NOS inhibition has limited effects on ATP mediated dilation in the human forearm. Support or Funding Information This research was supported by National Institutes of Health Research Grants HL‐119337, CTSA UL1 TR000135 and the Caywood Professorship via the Mayo Foundation

Background Nitric oxide (NO) contributes ~30% to the rate of vasodilation during dynamic exercise in healthy humans. This NO‐mediated dilation occurs via increases in cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase‐5 (PDE‐5). Therefore, we sought to determine the nature of NO‐cGMP signalling to the exercise vasodilator response in healthy humans. We hypothesized the time‐course of exercise vasodilation would be: 1) accelerated by sildenafil citrate (SDF, PDE‐5 inhibitor) 2) slowed by the NO synthase inhibitor L‐N G ‐monomethyl arginine (L‐NMMA) 3) similarly slowed by the combination of SDF+L‐NMMA. Methods Data from 29 healthy individuals were included in the present study. All subjects completed 5‐min of dynamic forearm exercise at 15% of maximal voluntary contraction under control conditions (CON, arterial saline infusion), followed by an identical exercise protocol during: 1) PDE‐5 inhibition via SDF (100mg oral dose, n = 8), 2) NOS inhibition via intra‐arterial infusion of L‐NMMA (50 mg loading dose and 1 mg/min maintenance dose, n = 15), or 3) combined SDF+L‐NMMA (n = 6). Forearm blood flow (FBF; Doppler ultrasound) and mean brachial artery blood pressure (MAP, transducer) were measured continuously. To determine time to steady‐state vasodilation, forearm vascular conductance (FVC = FBF/100mmHg/dL FAV) data were curve fit with a monoexponential model and mean response time (MRT, time to achieve 63% of steady state response) was calculated. In addition, the increase in relative forearm vascular conductance from rest to steady state exercise (average of the last 30s of exercise, ΔFVC = FVC exercise − FVC rest ) was used to assess the total vasodilatory response. Results Data are reported as mean ± SE (FVC = mL/dL/100mmHg/min, MRT = s) . In contrast to our hypothesis, SDF alone had no effect on exercise vasodilation (Δ FVC CON = 20±3 vs. SDF = 21±3, p = 0.50) or time to steady‐state vasodilation (MRT: CON = 32± 7 vs SDF= 33±4, p = 0.90) in young healthy adults. NOS inhibition with L‐NMMA reduced ΔFVC (CON = 16±2 vs. L‐NNMA = 14±1, p = 0.049) and increased the time to reach steady‐state vasodilation (MRT: CON = 22±5 vs. L‐NMMA = 40±6, p = 0.01). Surprisingly, when subjects were given L‐NMMA combined with SDF, reductions in Δ FVC or increases in MRT were no longer observed (Δ FVC: CON = 23±4 vs. SDF+L‐NMMA = 23±6, p = 0.90; MRT: CON = 45±8 vs. SDF+L‐NMMA = 49±11, p = 0.80). Conclusion These data indicate inhibiting PDE‐5 during moderate exercise does not improve the magnitude or time‐course of vasodilation. Whereas, NOS inhibition limits the magnitude and time‐course of the vasodilatory response to dynamic handgrip exercise in healthy adults, combined inhibition of PDE‐5 restores the response to control levels. These data suggest PDE‐5 inhibition does not potentiate the NO‐cGMP pathway during moderate exercise. However, PDE‐5 inhibition may have therapeutic use in pathologies where limited NO bioavailability may contribute to impaired blood flow responses to exercise. Support or Funding Information American Heart Association (15POST23100020) ‐ JMKNational Institutes of Health (HL46493) ‐ MJJ National Institutes of Health (HL078019) ‐ MJJ National Institutes of Health (HL105820) ‐ WGS National Institutes of Health (RR17520) ‐ N/A National Institutes of Health (UL1 TR000135) ‐ N/A

Red blood cells (RBCs) release ATP in direct proportion to the degree of hemoglobin (Hb) deoxygenation, which binds to purinergic receptors on the endothelium and stimulates vasodilation. Accordingly, RBCs act as both a ‘sensor’ for oxygen demand and an ‘effector’ for increasing oxygen delivery to facilitate the matching of tissue oxygen supply and demand. We have recently demonstrated that Hb deoxygenation‐induced ATP release is impaired in RBCs from healthy older vs. young adults, but the underlying mechanisms are not fully understood. Cyclic AMP (cAMP) has been shown to be an important component of the signaling cascade for RBC ATP release, and decreased cAMP signaling contributes to impaired ATP release from RBCs of humans with type 2 diabetes. As such, treatment with cilostazol to inhibit phosphodiesterase 3 (PDE3) hydrolysis of cAMP improves Hb deoxygenation‐induced ATP release from RBCs of these patients. Whether similar alterations in cAMP signaling contribute to impaired RBC ATP release in healthy older adults is unclear. Thus, in the present study we tested the hypothesis that PDE3 inhibition would restore Hb deoxygenation‐induced ATP release from RBCs of healthy older adults. Isolated RBC ATP release in response to normoxic (PO 2 ~111 mmHg) and hypoxic (PO 2 ~26 mmHg) stimuli was quantified in RBCs from young (25 ± 1 years; n = 4) and older (65 ± 3 years; n = 6) adults using the luciferin‐luciferase technique following RBC incubation with either dimethylformamide (DMF; vehicle control) or 100 μM cilostazol (PDE3 inhibitor). The relative change in ATP release from normoxia to hypoxia in control conditions was impaired in RBCs from older (56.1 ± 11.0%) vs. young (129.1 ± 16.1%) adults (p < 0.05). Cilostazol resulted in a slight, but non‐significant improvement in RBC ATP release in older adults (74.2 ± 15.0%; p = 0.32 vs. control), whereas there was no effect on RBC ATP release in young adults (123.4 ± 37.5%; p = 0.84 vs. control). RBC intracellular ATP was not different between age groups or treatments (p > 0.05). These preliminary data suggest that greater cAMP hydrolysis via PDE3 in response to Hb deoxygenation is not a primary contributor to impaired RBC ATP release in older adults. Support or Funding Information HL119337, F31HL126377

Background The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. It is unclear whether exposure to acute hypoxia changes cerebral blood flow during central hypovolemia. We hypothesized that cerebral blood velocity during lower body negative pressure would be lower during hypoxic versus normoxic conditions. Methods Ten healthy subjects (35 ± 3 y, BMI 25 ± 1 kg/m 2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 minutes at 0, −15, −30, and −45 mmHg) during both normoxia and hypoxia (F i O 2 = 0.12–0.15 O 2 ). Normoxia and hypoxia protocols were randomized and blinded. Mean arterial blood pressure (MAP, brachial arterial catheter), middle cerebral artery blood velocity (MCAv, transcranial doppler) and end tidal CO 2 (ET CO2 , mass spectrometer) were continuously recorded. We calculated cardiac output (CO) and total peripheral resistance (TPR) from the arterial pressure waveform. Cerebral vascular conductance (CVC) was calculated as MCAv/MAP. The cumulative stress index (CSI) was calculated as the cumulative product of LBNP pressure and time at each LBNP stage. Results During the hypoxia protocol, 7 participants developed presyncopal symptoms and the protocol was terminated early. Three of these 7 did not complete the normoxia protocol due to presyncopal symptoms as well. Subsequently, CSI was lower during hypoxia (278 ± 63 vs. 513 ± 47 mmHg·min −1 , p < 0.01). MAP (p < 0.01), TPR (p < 0.01), MCAv (p = 0.06) and ET CO2 (p = 0.01) were lower during hypoxia than normoxia – . CO was higher (p = 0.03) during hypoxia than normoxia, while CVC (p = 0.35) was similar. Conclusion The attenuated rise in TPR during the hypoxia protocol was associated with a reduced MAP observed during hypoxia. These findings indicate that lower MCAv and LBNP tolerance during hypoxia are due to reductions in cerebral perfusion pressure (MAP). The similar CVC during both conditions renders it unlikely that significant changes in cerebrovascular resistance contribute to the differences between normoxia and hypoxia in LBNP tolerance and MCAv. Support or Funding Information Funding: W81XWH‐13‐2‐0038 Physiological responses to LBNP with hypoxia and normoxia Baseline LBNP−15mmHg LBNP−30mmHg LBNP−45mmHg MAP, mmHg Normoxia 103 ± 3 104 ± 3 101 ± 3 98 ± 41 Hypoxia 100 ± 3 94 ± 4 93 ± 4 83 ± 4 CO, 1/min Normoxia 4.6 ± 0.3 4.5 ± 0.3 4.1 ± 0.3 3.7 ± 0.31 Hypoxia 5.4 ± 0.3 4.8 ± 0.3 4.1 ± 0.3 3.6 ± 0.3 TPR, mmHg·min·mL −1 Normoxia 22.6 ± 1.3 23.7 ± 1.3 25.0 ± 1.3 26.6 ± 1.41 Hypoxia 18.5 ± 1.3 19.8 ± 1.3 22.7 ± 1.4 23.7 ± 1.6 MCAv, cm·s −1 Normoxia 65 ± 4 64 ± 4 61 ± 4 55 ± 5 Hypoxia 58 ± 4 59 ± 4 57 ± 5 54 ± 6 CVC, cm·s −1 ·mmHg −1 Normoxia 0.67 ± 0.05 0.65 ± 0.05 0.63 ± 0.05 0.58 ± 0.05 Hypoxia 0.61 ± 0.05 0.64 ± 0.05 0.63 ± 0.05 0.64 ± 0.06 ET CO2 , mmHg Normoxia 38 ± 1 38 ± 1 38 ± 1 36 ± 1 Hypoxia 37 ± 1 36 ± 1 35 ± 1 34 ± 2 Different vs. normoxia p<0.06, } indicates a main effect.

Background Hypoxia increases susceptibility to syncope during orthostatic stress. Furthermore, cardiac baroreflex sensitivity (cBRS) is attenuated during lower body negative pressure (LBNP). Recent studies suggest that there is cross‐talk between baroreceptors and carotid body chemoreceptors. With this in mind, hypoxia may further blunt cardiac baroreflex sensitivity (cBRS) during central hypovolemia in individuals susceptible to hypoxic syncope. Therefore, we hypothesized that participants susceptible to hypoxic syncope (“fainters”) during progressive central hypovolemia would have lower spontaneous cBRS during LBNP when compared to “nonfainters”. Methods Ten healthy male participants (35 ± 3 yr, BMI 25 ± 1 kg/m 2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 minutes at 0, −15, −30, −45 mmHg) during both normoxia and hypoxia (FiO 2 = 0.12 – 0.15; S p O 2 ~85%). LBNP protocols were terminated early if participants developed presyncopal symptoms. Data from uncompleted stages were excluded. Heart rate (HR, 3 lead electrocardiogram) and mean arterial blood pressure (MAP, brachial arterial catheter) were continuously recorded. Spectral cBRS was calculated from the heart rate and blood pressure signals. Following experimentation, participants were stratified as fainters (developed presyncopal symptoms during hypoxic conditions, n=7) and nonfainters (n=3). Results MAP was lower in fainters than in nonfainters during hypoxia (interaction with LBNP p<0.05) while HR (p=0.38) and cBRS (p=0.43) were similar – . Hypoxia had a main effect vs normoxia on MAP, HR and cBRS in fainters (all p<0.02). In nonfainters hypoxia had a main effect vs normoxia on HR and cBRS (all p<0.03) and an interaction effect with LBNP on MAP (p<0.01). Conclusion Spontaneous cardiac baroreflex sensitivity is not attenuated in participants susceptible to hypoxic syncope during lower body negative pressure. This suggests that spontaneous cardiac baroreflex sensitivity does not contribute to orthostatic intolerance during hypoxia. Support or Funding Information Funding: W81XWH‐13‐2‐0038 Physiological response in fainters and nonfainters to LBNP during hypoxia and normoxia MAP, mmHg HR, beats·min −1 cBRS, ms·mmHg −1 Nonfainters Fainters Nonfainters Fainters Nonfainters Fainters Baseline Normoxia 104 ± 5 102 ± 3 62 ± 5 61 ± 3 13 ± 3 19 ± 2 Hypoxia 106 ± 6 97 ± 4 80 ± 6 72 ± 4 9 ± 3 11 ± 2 LBNP −15 mmHg Normoxia 109 ± 5 103 ± 3 68 ± 5 64 ± 3 11 ± 3 14 ± 2 Hypoxia 106 ± 6 90 ± 4 88 ± 6 72 ± 4 9 ± 3 14 ± 2 LBNP −30 mmHg Normoxia 107 ± 5 98 ± 3 79 ± 5 74 ± 3 8 ± 3 11 ± 2 Hypoxia 103 ± 6 82 ± 5 95 ± 6 79 ± 5 8 ± 3 9 ± 3 LBNP −45 mmHg Normoxia 101 ± 5 99 ± 3 92 ± 5 84 ± 4 6 ± 2 5 ± 2 Hypoxia 89 ± 6 N/A 113 ± 6 N/A 3 ± 3 N/A Different vs. nonfainters p<0.05 Different vs. normoxia p<0.05

Background The risk of hypertension increases as women reach menopause. Our group has recently reported that autonomic support of blood pressure (BP) is increased in post‐menopausal women. Given regular exercise is known to decrease the risk of developing hypertension, we investigated the role of aerobic fitness on autonomic support of BP in women. We hypothesized that trained premenopausal, but not postmenopausal, women would have less autonomic support of BP than age‐matched untrained women. Methods Twelve healthy, young premenopausal (27±1yrs) and 10 older postmenopausal (56±1yrs) women completed VO 2max tests on cycle ergometers. The participants were then stratified by fitness level based on VO 2max percentiles from the American College of Sports Medicine's Guidelines (≤50 th percentile = untrained; >50 th percentile = trained; premenopausal: 7 untrained, 5 trained; postmenopausal: 5 untrained, 5 trained). On a separate day muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), heart rate (electrocardiography), and blood pressure (brachial arterial catheter) were recorded before and during ganglionic blockade using trimethaphan camsylate (dose:1.5–7mg/min). Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were calculated from the blood pressure waveform (WinCPRS). Results Muscle sympathetic nerve activity was higher in trained young women than in untrained young women (burst incidence: 35±11 vs. 12±2 bursts/100 heart beats, p=0.03). Young trained women had a smaller reduction in mean arterial pressure (MAP) with trimethaphan than young untrained women (ΔMAP:−5±3 vs. −15±4mmHg, p=0.01), despite a larger reduction in total peripheral resistance (ΔTPR: −6±1 vs. −2±1mmHg*min/L, p=0.02). The trained young women were able to maintain their MAP due to a greater increase in cardiac output (ΔCO: 1.4±0.4 vs. −0.3±0.3L/min, p= 0.01). In older postmenopausal women, MSNA and the fall in BP, CO, and TPR with trimethaphan were not different between trained and untrained individuals (p= 0.81, 0.16, 0.52 and 0.09, respectively). Conclusion Baseline MSNA was higher in trained premenopausal women when compared to untrained premenopausal women; however, aerobic fitness did not influence baseline MSNA in postmenopausal women. In young trained women, the fall in MAP following ganglionic blockade was only one‐third of the response seen in young untrained women. Baseline MSNA and the change in MAP, CO, and TPR with ganglionic blockade were not different between trained and untrained postmenopausal women. These data suggest aerobic fitness reduces autonomic support of blood pressure in young trained women, but not in trained postmenopausal women. Support or Funding Information Support: HL83947 (MJJ); HL131151 (SEB), DK 7352‐37 (SEB), HL118154 (JNB)

Purpose Obese adults exhibit increased levels of inflammation which may negatively affect blood pressure regulation. Based on existing literature, we hypothesized: 1) baroreflex sensitivity would be lower in obese adults when compared to lean adults and 2) acute ibuprofen (IBU, a cyclooxygenase inhibitor and nonsteroidal anti‐inflammatory agent) administration would increase baroreflex sensitivity in obese adults, with no effect in lean adults. Methods Seven lean (4M, 3F; 25±2 yrs; 23±1 kg/m 2 ) and six obese (5M, 1F; 30±3 yrs; 36±1 kg/m 2 ) adults completed two visits randomized to control (CON) or IBU (800 mg oral). On each visit, blood pressure (intra‐arterial catheter), heart rate (electrocardiogram), and muscle sympathetic nerve activity (MSNA, microneurography) were measured continuously and venous blood was sampled for measures of systemic inflammation [C‐Reactive protein (CRP) and Interleukin‐6 (IL‐6)]. Sympathetic and cardiac baroreflex sensitivity were assessed using the modified Oxford technique, which consisted of a 5‐min resting period, followed by a 100 μg intravenous bolus of sodium nitroprusside. One minute later, subjects were administered a 150 μg intravenous bolus of phenylephrine HCl and data were collected for an additional 2‐min. Results CRP and IL‐6 were higher in obese adults when compared to lean adults, and tended to decrease with IBU (IL‐6: p<0.05; CRP: p=0.14). Cardiac baroreflex sensitivity was lower in obese adults (14±2 vs 24±2 ms/mmHg, p=0.02), whereas sympathetic baroreflex sensitivity was higher in obese adults (−3.6±0.5 vs −2.1±0.5 bursts/100 beats/mmHg, p=0.03) when compared to lean. There was no effect of IBU on cardiac or sympathetic baroreflex sensitivity in either group (p‐value range 0.20 – 0.71). Conclusion In our present group of relatively healthy individuals with obesity, we observed lower cardiovagal baroreflex sensitivity but higher sympathetic baroreflex sensitivity in the obese group compared to lean controls. We found no effect of an acute dose of 800 mg ibuprofen on cardiac or sympathetic baroreflex sensitivity, suggesting that chronic effects of obesity‐related inflammation on baroreflex sensitivity may not be reversed by a single acute pharmacological anti‐inflammatory intervention. Support or Funding Information NIH HL083947 (NC, MJJ), DK082424 (TBC), AG038067 (JNB), and UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). AHA 0750036Z (NC) from the American Heart Association.

Adenosine triphosphate (ATP) is postulated to be a major exercise related vasodilating metabolite. In humans, ATP infusion mimics exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore we tested two hypotheses during a three‐hour intra‐arterial infusion of a high dose of ATP (20 μgrams ·100 mL forearm vol −1 ·min −1 ): (1) skeletal muscle blood flow would wane over time (tachyphalaxis); (2) exercise hyperemic responses during ATP administration would be blunted compared to baseline. Nine healthy young participants (25 ± 1 years) performed seven rhythmic handgrip exercise bouts (20% of maximum), two during saline (control) and five during 180 minutes of continuous ATP infusion. Forearm vascular conductance (FVC; ml min −1 (100 mmHg) −1 ) and percent (%) change from control were calculated. Five minutes of ATP infusion resulted in a 710% increase in FVC (4.8±0.3 vs 35.0±1.9 ml min −1 *100 mmHg −1 , P<0.05). FVC did not wane over time with values of 35.0±1.9 and 36±2.6 ml min −1 (100 mmHg) −1 (P>0.05) seen prior to the exercise bouts at 5 vs 150 minutes respectively. With superimposed exercise FVC increased from 35.0±1.9 to 49.6±2.2 ml min −1 *100 mmHg −1 at five minutes and 36.0±2.6 to 54.5±1.1 at 150 min (P<0.05). Our findings demonstrate (1) ATP vasodilation is sustained over time without tachyphalaxis; (2) vasodilator responses to exercise during high dose ATP infusion remain intact. This latter finding questions the extent to which ATP is obligatory for exercise hyperemia. Support or Funding Information This research was supported by National Institutes of Health Research Grants HL‐119337 and by CTSA UL1 TR000135. The Caywood Professorship via the Mayo Foundation also supported this research.