Curry, Timothy B.

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objective Insulin has known sympathoexcitatory effects that have been historically attributed to primarily central mechanisms. Although controversy exists, recent evidence from rodents suggests the carotid chemoreceptors may play a role in the sympathoexcitatory response to hyperinsulinemia. Therefore, we sought to examine the contribution of the carotid chemoreceptors to insulin‐mediated increases in sympathetic nervous system activity in humans. We hypothesized reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia in humans – thus supporting a role for the carotid chemoreceptors in insulin‐mediated sympathoexcitation. Methods Young, healthy adults (n=15, 8M/7F, 27±1 yrs, 24±1 kg/m 2 ) completed a 30‐min euglycemic baseline followed by a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (90–100 mg/dL) clamp. Heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were continuously measured. The role of the carotid chemoreceptors was assessed using the following protocols: 1) acute (1‐min) hyperoxia (n=13), 2) low‐dose dopamine (1–4 μg/kg/min; n=7), 3) acute hyperoxia + low‐dose dopamine (n=8). The nadir 15‐s value for MSNA within each hyperoxic condition was determined and the nadir at baseline was compared to the nadir during hyperinsulinemia. Results MSNA increased from baseline during the hyperinsulinemic, euglycemic clamp [12±2 to 18±2 bursts/min (p<0.01)]. In protocol 1, MSNA was reduced during acute hyperoxia at baseline (12±1 to 6±1 bursts/min, p<0.01) and during the hyperinsulinemic clamp (17±2 to 12±2 bursts/min, p=0.02); however, the fall in MSNA during hyperoxia did not differ between baseline and hyperinsulinemia (p=0.82). In protocol 2, when low‐dose dopamine was given prior to the hyperinsulinemic clamp, MSNA did not increase from baseline (19±2 to 22±5 bursts/min, p=0.51); this is in contrast to increases observed under saline conditions (14±3 to 22±4 bursts/min, p=0.03). In protocol 3, in the presence of low‐dose dopamine, MSNA was reduced during acute hyperoxia at baseline (16±3 to 9±2 bursts/min, p=0.048) and during the hyperinsulinemic clamp (16±4 to 9±3 bursts/min, p=0.02); however, the fall in MSNA with hyperoxia did not differ between baseline and hyperinsulinemia (p=0.97). Conclusions Low‐dose dopamine given prior to the onset of a hyperinsulinemic, euglycemic clamp attenuates the sympathoexcitatory response to hyperinsulinemia. In contrast, acute carotid chemoreceptor desensitization (1‐min hyperoxia) during steady‐state hyperinsulinemia does not augment the fall in MSNA observed at baseline. Our data suggest the carotid chemoreceptors do not contribute acutely to insulin‐mediated increases in sympathetic nervous system activity in healthy humans; however, they may play a role during longer‐term exposure. Support or Funding Information Support: DK090541 (MJJ); HL83947 (MJJ); HL130339 (JKL); AHA15SDG25080095 (JKL)

Post‐mortem analyses have identified carotid body hypertrophy in conditions of chronic hypoxemia, including sleep apnea; however, post‐mortem assessment limits the clinical relevance of such findings. We tested the hypotheses that: 1) carotid body size can be detected in living individuals by computed tomographic angiography (CTA), and 2) patients with sleep disordered breathing [Apnea Hypopnea Index (AHI) ≥ 30 events/hour] exhibit larger carotid bodies than those without sleep disordered breathing (AHI < 5 events/hour). A chart review was conducted from patients seen at the Mayo Clinic between January 2000 and February 2015 who had undergone neck CTA and polysomnography. From an initial pool of 583, 109 patients met our strict inclusion criteria. Widest axial measurements of the right and left carotid bodies were performed independently by two radiologists blinded to condition and average carotid body size was calculated for each patient of interest. Carotid body identification was possible in 81% of patients. Intra‐class correlation coefficients ranged from 0.93 to 0.95 (right carotid body: 0.93; left: 0.94; average: 0.95). From subjects with identifiable carotid bodies, widest axial measurements were greater in patients with high AHI (n=32; right: 2.9±0.2mm, left: 3.1±0.2mm, average: 3.0±0.1mm) compared to patients with low AHI (n=46; right: 2.5±0.1mm, left: 2.7±0.1mm, average: 2.6±0.1mm; p=0.04, p=0.04, p=0.02, respectively). Because participants in the high AHI group were significantly older than those in the low AHI group (65±2 years vs. 50±2 years; p<0.01), an analysis of covariance was performed to control for the influence of age on carotid body size. After adjusting for age, no differences in carotid body size were observed between the patient groups (p=0.45, p=0.59, p=0.54 for right, left, and average carotid body, respectively). Main findings are two‐fold: 1) carotid body size can be identified by CTA in approximately 80% of patients with good inter‐observer agreement, and 2) adults that exhibit sleep disordered breathing do not have larger carotid bodies when compared to controls, after adjusting for age. Support or Funding Information This work was supported by the National Institutes of Health [grant numbers T32 GM008685 (ARE), R01 DK090541 (MJJ)].

Introduction Adenosine triphosphate (ATP) is a vasodilating metabolite that plays a role in exercise hyperemia. In humans, exogenous infusion of ATP elevates skeletal muscle blood flow values to that observed during moderate‐intensity exercise. Recently ATP has been shown to evoke prolonged vasodilation over 150 minutes without tachyphylaxis. However, the steady‐state hyperemic responses to superimposed forearm exercise remain unaltered. The kinetics of blood flow during the initiation of exercise remains not well understood. Therefore we evaluated the effects of prolonged exogenous infusion of ATP on exercise hyperemia during the transition between rest and initiation of exercise. Methods While supine, eight healthy young participants (4M/4F; 25±1 years) performed 5 minutes of rhythmic dynamic handgrip exercise bouts (20% of maximum), first during saline (control), then at minute 5 and minute 150 during a continuous ATP infusion into the brachial artery. Each duty cycle consisted of 1 second contraction and 2 second relaxation. Mean blood velocity (MBV; cm/s), forearm vascular conductance (FVC; ml/minutes/100 mmHg), and shear rate (8*MBV/diameter; seconds −1 ) were calculated. The kinetics at the onset of exercise was assessed by calculating the slope of the FVC responses for the first 20 duty cycles after the start of contractions. Data are presented as means ± SEM. Results During saline control FVC was 3.9±0.3 at rest and with exercise rose to 22.7±0.84 and 27.8±1.2 ml/minute/100mmHg at 30 seconds and 1 minute, respectively (P<0.05 for both). Infusion of ATP increased FVC (3.9±0.3 vs 43.1±2.0 ml/minutes/100 mmHg, P<0.05) at five minutes and to 61.0±1.1 ml/minutes/100 mmHg at 150 minutes (P<0.05) with no systemic hemodynamic changes. Prolonged infusion of ATP did not alter the kinetics at the onset of contractions over 20 duty cycles of exercise hyperemic responses compared to control (0.71±0.1 control vs 1.01±0.1 ml/minutes/100mmHg/cycle at 5 minutes and vs 0.65±0.1 at 150 minutes, P>0.05 for all). Shear rate significantly increased compared to control (92±5 vs 751±57 seconds −1 , P<0.05) but was not different across exercise responses during ATP infusion (751±57 at 5 minutes vs 549±46 seconds −1 at 150 minutes, P>0.05). Conclusions Our findings demonstrate that despite the ability of ATP to elevate blood flow to that observed during exercise, the blood flow kinetics for the initiation of dynamic exercise hyperemic response are unaffected and remain unaltered after 150 minutes of prolonged ATP infusion. Further investigation in needed to understand the role of ATP in regulating the blood flow kinetics during dynamic exercise in humans. 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 study.

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

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)