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Endothelin-1 (ET-1) has been linked to increased hypoxic sensitivity of the chemoreceptors and the development of cardiometabolic disease. Repeated hypoxic exposures [i.e., intermittent hypoxia (IH)] elicit increases in ET-1, muscle sympathetic nerve activity (MSNA), and blood pressure (BP). In this brief review, we summarize data from our group(s) which examined the effect of acute IH on MSNA, BP, and indices of adipose tissue lipolysis [i.e., free fatty acids (FFAs)], as well as the role of ET-1 in these responses. Herein, we show that acute ET receptor inhibition (oral bosentan) attenuates the rise in BP during hypoxia and the fall in BP during hyperoxia in healthy young men. Although the effect of IH on MSNA and BP was not attenuated following ET-receptor inhibition, IH increased plasma ET-1, epinephrine, and FFA concentrations. Notably, inhibition of ET-1 receptors with oral bosentan attenuated the IH-mediated rise in epinephrine and FFA. With these findings, we demonstrate a role for ET-1 in the maintenance of resting BP in young men, possibly through a chemoreceptor-mediated mechanism. We further speculate that the effect of ET-1 receptor inhibition on circulating FFA is secondary to its ability to reduce sympathoadrenal tone during IH exposure. Results highlighted in this review may serve as the basis for future work exploring ET-1 as a therapeutic target for cardiometabolic dysfunction associated with IH.

Introduction: Menopausal hot flashes are defined as rapid, intense sweating and/or an intense feeling of warmth. Subjective recordings of menopausal hot flashes can be difficult to obtain due to inconvenience to the individual and poor recall. This calls for an improved method to quantify hot flashes that are less dependent on human interaction. The goal of this study was to determine if an ambulatory skin conductance hot flash monitor would detect menopausal hot flash occurrence and frequency to the same degree as those reported by study participants. Methods: Thirty-five peri- and postmenopausal females (age: 53±4 years) participated in this study. An ambulatory, noninvasive sternal skin conductance monitor was placed on each participant for a 24-hour recording period. The monitor recorded a hot flash when an increase of 0.2 micromhos was detected in the participant’s sweat level compared to their baseline (objective). Participants manually recorded perceived hot flash occurrence on the monitor (subjective). For analysis, a monitor recording with ≥20 consecutive hours of intact data was included. Hot flash frequency was defined as the number of hot flashes per recording period. A Mann-Whitney test was conducted to compare subjective and objective hot flash frequencies. Statistical analyses for agreement in hot flash occurrence (yes/no; Cohen’s Kappa) and frequency (Bland-Altman) were completed. Data are reported as mean±SD or median (IQR). Results: The average hot flash monitor recording consisted of 23.8±0.7 hours of data. Twenty-eight females reported at least one hot flash during their recording period (5 [3-9] subjective hot flashes) while 7 females did not report any hot flashes. The monitor detected at least one hot flash in 30 females (10 [5-21] objective hot flashes) and no hot flashes in 5 females. For 3 participants, both the subjective and objective reports showed zero hot flashes. There was a significant difference between the frequency of hot flashes reported by all participants (3 [1-8] subjective hot flashes) and those detected by the hot flash monitor (8 [4-19] objective hot flashes; p=0.006). There was no agreement between the subjective (self-report) and objective (monitor) assessments of hot flash occurrence (k= -0.1734). The Bland-Altman showed a mean bias of 7.1±8.6 towards objective hot flash frequency with limits of agreement of -9.8 to 23.9. Conclusion: The ambulatory sternal skin conductance monitor used in the current study showed no agreement in detecting menopausal hot flashes compared to self-reported hot flashes. Overall, the monitor substantially overestimated the frequency of menopausal hot flashes that participants reported. While further investigation might be needed to improve the monitor’s sensitivity for accurate hot flash detection, it is possible that the monitor may be detecting subclinical menopausal hot flashes that are less recognizable to the individual. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) is a common type of myocardial infarction in females under the age of 50 years, caused by sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is mostly females (~80%) with few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Common triggers for SCAD include sympathoexcitatory stimuli, such as intense physical and emotional stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate sympathetic nervous system responses to mental stress in patients with a history of SCAD. We hypothesized that females with a history of SCAD exhibit a greater increase in muscle sympathetic nerve activity (MSNA) with acute exposure to mental stress compared to healthy females. Methods: Seven females with a history of SCAD (age: 48±9 yrs, BMI: 29±6 kg/m 2 ) and seven age- and BMI-matched healthy female controls (CON, age: 49±9 yrs, BMI: 26±6 kg/m 2 ) participated in the study (both p>0.05). MSNA was measured via peroneal microneurography during a 2-minute rest, a 5-minute Stroop Color Word Test aimed at inducing mental stress, and a 2-minute recovery. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during each stage. Data are presented as an absolute change from rest (Δmean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (MBP, SCAD: 96±14 vs CON: 89±7 mmHg, p=0.27), heart rate (HR, SCAD: 56±11vs CON: 65±16 bpm, p=0.25), MSNA burst frequency (SCAD: 22±9 vs CON: 18±7 bursts/minute, p=0.40) and total MSNA (SCAD: 1135±471 vs CON: 951±245 au/min, p=0.41) were not different between the groups. During the Stroop Color Word Test, average changes in MBP (SCAD: Δ10±9 vs CON: Δ8±5 mmHg, p=0.67) and HR (SCAD: Δ11±7 vs CON: Δ14±5 bpm, p=0.35) were not different between the groups. Similarly, average changes in MBP (SCAD: Δ3±4 vs CON: Δ-2±5 mmHg, p=0.13) and HR (SCAD: Δ3±4 vs CON: Δ3±2 bpm, p=0.62) were not different during the recovery. Changes in MSNA burst frequency with the Stroop Color Word Test (SCAD: Δ1±7 vs CON: Δ6±7 bursts/minute, p=0.22) and recovery (SCAD: Δ0±5 vs CON: Δ4±4 bursts/minute, p=0.13) were not different between the groups. Total MSNA changes were also not different during the Stroop Color Word Test (SCAD: Δ267±335 vs CON: Δ606±432 au/min, p=0.15) and recovery (SCAD: Δ68±666 vs CON: Δ217±217 au/min, p=0.61) between the two groups. Conclusion: These preliminary data suggest that contrary to our hypothesis, sympathetic nervous system responses to acute mental stress exposure are not different between females with a history of SCAD and healthy females. Further investigation is needed to understand MSNA association with chronic stress exposure in females with a history of SCAD. Funding: NIH K23 HL155506 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Our knowledge regarding baroreflex regulation of subpopulations of differently sized sympathetic action potentials (APs) remains incomplete. This study tested the hypothesis that baroreflex sigmoid morphology varies across AP subpopulations. In 12 healthy individuals (6 females; 32 ± 5 years), we measured diastolic blood pressure (DBP; brachial artery catheter) and muscle sympathetic APs (peroneal microneurography; continuous wavelet transform) during a modified Oxford protocol (100 μg nitroprusside bolus, 150 μg phenylephrine bolus). Baroreflex sigmoids (four-parameter logistic functions) modelled the relationship between DBP and sympathetic AP discharge probability for 10 normalized AP clusters. For each AP cluster, baroreflex sigmoid morphology was quantified by max gain, threshold, centering, and saturation pressures, and operating and response ranges. One-way analyses of variance and Dunnett post-hoc tests were performed. Data are mean ± SD. At the centering pressure of the baroreflex sigmoid, max gain was greater for medium APs (e.g., Cluster 3: -5.6 ± 2.9%/mmHg) compared to small (e.g., Cluster 1: -1.4 ± 1.1%/mmHg; P < 0.01) and large APs (e.g., Cluster 9: -0.6 ± 0.4%/mmHg; P < 0.01). Discharge probability at the centering pressure was also greater for medium APs (e.g., Cluster 3: 61 ± 22%) compared to small (e.g., Cluster 1: 12 ± 10%; P < 0.01) and large APs (e.g., Cluster 9: 3 ± 3%; P < 0.01). There were no differences in the saturation pressure (i.e., DBP where any further reduction does not elicit an increase in AP discharge probability) between AP clusters (main effect P = 0.22). The threshold pressure (i.e., DBP where any further reductions elicit an increase in AP discharge probability) was greater for medium (e.g., Cluster 3: 78 ± 8mmHg) compared to large APs (e.g., Cluster 9: 74 ± 11mmHg; P = 0.03). The operating range (i.e., Threshold – Saturation DBP) was greater for medium (e.g., Cluster 3: 14 ± 3mmHg) compared to large APs (e.g., Cluster 9: 8 ± 5mmHg; P < 0.01). There were no differences in the threshold pressure or operating range of medium compared to small APs (both P ≥ 0.82). The response range (i.e., Saturation – Threshold discharge probability) was greater for medium (e.g., Cluster 3: 26 ± 13%) compared to small (e.g., Cluster 1: 5 ± 4%; P < 0.01) and large APs (e.g., Cluster 9: 1 ± 1%; P < 0.01). These data confirm prior work using linear modeling and spontaneous approaches to quantify sympathetic AP baroreflex gain and extend to demonstrate variation in the morphology of the baroreflex sigmoid. During large changes in blood pressures, we identify differences in broader features of baroreflex control (e.g., threshold pressure, operating range, and response range) between AP subpopulations that support strong baroreflex regulation over medium-sized APs. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

AbstractFatiguing inspiratory work has been shown to evoke a sympathetically mediated reflex that has systemic cardiovascular consequences, including increases in heart rate and blood pressure and a decrease in resting limb vascular conductance. Moreover, the response to this reflex appears to be attenuated in females compared with males. It remains to be seen whether this respiratory muscle metaboreflex also exerts an effect on cerebral blood flow. Cerebral blood flow is tightly regulated to maintain homeostasis and critical function. Therefore, it stands to reason that cerebrovascular haemodynamics would not be compromised through this respiratory muscle metaboreflex. We hypothesized that fatiguing inspiratory work would reduce resting limb conductance, but cerebral blood flow would be minimally impaired. Females (34 ± 10 years old, n = 12) and males (31 ± 8 years old, n = 12) performed a 5 min, high‐intensity bout of inspiratory pressure threshold loading (IPTL) designed to evoke the respiratory muscle metaboreflex. In response to IPTL, mean arterial pressure increased in both males and females (p < 0.001), and limb vascular conductance decreased to a greater degree in males than in females (p = 0.005). The cerebrovascular conductance index was higher in females (p = 0.007) but not affected by IPTL (p = 0.417). Our findings suggest that cerebral blood flow is spared from the redistribution of blood flow in response to fatiguing inspiratory work and that this protection is true in both males and females.

Intravenous dexmedetomidine infusion (selective α 2 -adrenergic receptor agonist) 1) reduced the firing probability and strength of baroreflex control over medium-sized sympathetic action potentials in muscle sympathetic nerve activity (MSNA) and 2) attenuated the transduction of MSNA bursts to changes in blood pressure (BP) by reducing the magnitude of BP responses and increasing the time to peak BP. These data suggest that neural and vascular α 2 -adrenergic mechanisms contribute to sympathetic baroreflex regulation of human BP.

Sympathetic control of human blood pressure is mechanistically regulated by α 2 -adrenergic receptors distributed throughout the nervous system and cardiovascular end-targets. Recently, we discovered the sympathoinhibitory effects of central α 2 -adrenergic mechanisms on human sympathetic neuronal emission patterns. However, our knowledge remains incomplete regarding the impact of α 2 -adrenergic mechanisms on beat-by-beat transduction of muscle sympathetic nerve activity (MSNA) bursts to changes in blood pressure and heart rate (HR). Based on evidence of α 2 -adrenergic receptors within central and peripheral sympathetic neural sites and on the vasculature, this study tested the hypothesis that activation of α 2 -adrenergic receptors with dexmedetomidine (DEX) would reduce sympathetic transduction to blood pressure. In eight healthy participants (5 females; 28 ± 7 years), diastolic blood pressure (DBP; brachial arterial catheter), HR (ECG), and MSNA (peroneal microneurography) were recorded during a 5-minute supine baseline (BSL) and an intravenous DEX infusion consisting of a loading dose (10 minutes at 0.225 μg/kg/hr) and a maintenance dose (~0.15 μg/kg/hr). Signal averaging quantified sympathetic transduction to DBP and HR for 12 cardiac cycles following integrated MSNA bursts. We also quantified sympathetic transduction to DBP using a transduction gain estimate derived from the slope of the linear relationship between the peak DBP response and the number of cardiac cycles until peak DBP response. Data (mean ± SD) are reported for the 5-minute BSL and the last 5-minute period during the DEX infusion. Mixed-effects modeling and t -tests were performed. Non-parametric tests were performed for non-normally distributed data. DEX reduced resting MAP (BSL: 92 ± 7, DEX: 82 ± 6 mmHg: p < 0.001) but did not affect resting HR (BSL: 62 ± 14, DEX: 61 ± 14 bpm; p = 0.853). DEX reduced resting integrated MSNA burst frequency (BSL: 14 ± 6, DEX: 4 ± 3 bursts/min; p = 0.001) and total integrated MSNA (BSL: 663 ± 252, DEX: 188 ± 142 AU/min; p < 0.001). DEX attenuated the DBP transduction response, particularly for the cardiac cycle associated with peak DBP during BSL (cardiac cycle 6: BSL: 4.3 ± 3.2, DEX: 3.3 ± 2.0 mmHg; p = 0.025) and prolonged the time to peak DBP transduction (BSL: 6 ±1, DEX: 10 ± 3 cardiac cycles; p = 0.014). Also, DEX reduced DBP transduction gain (BSL: 1.6 ± 2.4, DEX: 0.9 ± 1.3 mmHg/cardiac cycle; p = 0.029). By contrast, DEX did not affect the mean transduction of MSNA bursts to changes in HR (BSL: 3.2 ± 3.1, DEX: 3.9 ± 4.6 mmHg; p = 0.668). These data suggest that α 2 -adrenergic mechanisms distributed among central and peripheral sympathetic neural regions and the cardiovascular system influence moment-to-moment sympathetic regulation of blood pressure homeostasis, but not HR, in humans. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) is an acute separation of coronary artery wall layers that blocks blood flow to the heart and leads to acute coronary syndrome. Patients with SCAD are relatively young females (~40-50 years) who have few cardiovascular risk factors. Sympathoexcitatory stress often precedes SCAD events (i.e. intense physical and/or emotional stress), suggesting that patients with SCAD may have augmented hemodynamic responses to sympathoexcitatory stressors. As such, we aimed to evaluate hemodynamic responses to cold stress in females with a history of SCAD and females without a history of SCAD. We hypothesized that females with a history of SCAD would have augmented hemodynamic responses to cold stress relative to females without a history of SCAD. Methods: Females with a history of SCAD were matched to females without a history of SCAD for age and body mass index. Heart rate (electrocardiogram) and beat-to-beat blood pressure (finger photoplethysmography) were recorded and averaged during two minutes of resting baseline and the minute during the cold pressor test that produced the peak hemodynamic response. Delta (Δ) values of the hemodynamic parameters were calculated. Data are reported as mean ± SD. Unpaired t-tests were used to analyze demographics, anthropometrics, resting hemodynamics, and hemodynamic responses between females with a history of SCAD and females without a history of SCAD. Results: Age (50±9 vs 56±8 years) and body mass index (27±6 vs 24±3 kg/m 2 ) did not differ between females with a history of SCAD (n=20) and females without a history of SCAD (n=12, both p>0.05), respectively. Resting heart rate ([HR], 57±10 vs 59±11 bpm), systolic blood pressure ([SBP], 112±14 vs 110±13 mmHg), diastolic blood pressure ([DBP], 72±10 vs 72±9 mmHg), and mean arterial pressure ([MAP], 86±11 vs 85±9 mmHg) were not different between females with a history of SCAD and females without a history of SCAD, respectively (all p>0.05). Hemodynamic responses to cold stress (ΔHR, 6±5 vs 7±5 bpm; ΔSBP, 20±16 vs 18±7 mmHg; ΔDBP, 7±11 vs 11±6 mmHg; ΔMAP, 10±14 vs 13±5 mmHg; all p>0.05) were not different between females with a history of SCAD and females without a history of SCAD, respectively. Conclusion: Hemodynamic responses to cold stress were not different between females with a history of SCAD and females without a history of SCAD, indicating that an augmented pressor response to this stress is likely not a primary predisposing factor to a SCAD. However, it remains important to assess other forms of stress to inform future care and counseling of patients with history of SCAD. Funding: K23HL155506 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.