Joyner, Michael J.

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.

Biological sex impacts baroreflex control of integrated muscle sympathetic nerve activity (MSNA), yet our knowledge remains incomplete regarding sex differences in baroreflex regulation of the differently sized APs contributing to variations in MSNA burst frequency and size. We hypothesized that sex differences in baroreflex control of sympathetic action potential (AP) discharge contribute to higher resting AP activity in males compared to females. We measured diastolic blood pressure (DBP; Finometer or brachial arterial catheter) and MSNA (peroneal microneurography and continuous wavelet transform, APs normalized to 10 clusters) in 24 healthy individuals (aged 18-30, 12 females) during a 5-minute supine baseline. Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and DBP. Sympathetic AP baroreflex sensitivity gain was measured as the slope of the linear relationship between AP clusters per burst and DBP. Analyses were performed during DBP rises and falls to explore baroreflex hysteresis. Mixed-effects analyses and t-tests were performed. Data are reported as mean ± SD. In the aggregate cohort, baroreflex control of medium-sized APs exhibited hysteresis. Compared to rises in DBP, DBP falls were associated with greater AP firing probabilities (cluster 3; DBP rise: 20 ± 11, DBP fall: 26 ± 12%; p < 0.01) and greater AP baroreflex gains (cluster 3; DBP rise: -4.36 ± 2.43, DBP fall: -5.32 ± 3.09 %/mmHg; p < 0.01). In the aggregate cohort, baroreflex hysteresis was not detected for small- or large-sized AP clusters (both p ≥ 0.56). Similar observations were detected for medium-sized APs in male (M) and female (F) cohorts when analyses were stratified by sex. Compared to females, males exhibited greater medium-sized AP firing probabilities during DBP rises (cluster 3; M: 23 ± 12, F: 16 ± 8%; p < 0.01) and falls (cluster 3; M: 32 ± 13, F: 20 ± 8%; p < 0.01). However, AP baroreflex gains were not different between sexes during DBP rises (cluster 3; M: -4.87 ± 2.05, F: -3.84 ± 2.75%/mmHg; p = 0.13) and falls (cluster 3; M: -5.87 ± 2.25, F: -4.76 ± 3.77 %/mmHg; p = 0.15). In the aggregate cohort, the number of AP clusters per burst and the AP baroreflex sensitivity gain were not different between rises and falls in DBP. However, compared to females, males demonstrated a greater number of AP clusters per burst during DBP rises (M: 4 ± 0.9, F: 3 ± 0.6 clusters/burst; p < 0.01) and falls (M: 4 ± 0.8, F: 3 ± 0.7 clusters/burst; p < 0.01). No sex differences in AP baroreflex sensitivity gain were detected during DBP rises (M: -0.08 ± 0.09, F: -0.30 ± 0.07 clusters/burst/mmHg; p = 0.14) or falls (M: -0.08 ± 0.08, F: -0.02 ± 0.08 clusters/burst/mmHg; p = 0.09). These data suggest that 1) hysteresis exists in baroreflex regulation of medium-sized but not small or large sympathetic APs firing under baseline conditions and 2) in line with earlier integrated MSNA studies, compared to females, males demonstrate greater resting sympathetic outflow from greater sympathetic AP discharge and more AP clusters firing per burst in periods of rising and falling DBPs. 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.

The maximal expiratory flow-volume (MEFV) curve is a valuable tool for assessing pulmonary function and diagnosing respiratory disease. Quantifying the shape of the MEFV curve may provide additional insight into pulmonary dysfunction compared to spirometry alone. We questioned if the shape of the MEFV curve could detect signs of abnormal lung emptying dynamics in asymptomatic ex-smokers when compared to never smokers free of cardiopulmonary disease. A retrospective analysis of routine spirometry from 22 asymptomatic ex-smokers (50% female) without a formal diagnosis of chronic obstructive pulmonary disease or other chronic respiratory disease was compared against 48 healthy never smokers (65% female). The shape of the MEFV curve was quantified via the slope-ratio method which generates a unitless value corresponding to the ratio between a line of tangency at a specific lung volume and a chord line intersecting the point of interest and residual volume. A SR of 1 would indicate a linear decrease in flow with decreasing lung volume, whereas a SR >1 or <1 would indicate a convex ( i.e., scooped) or concave ( i.e., bump) shape to the MEFV curve; respectively. Slope-ratio was assessed between 80-20% vital capacity in 2% vital capacity increments. A single average slope-ratio was taken as the mean of all slope-ratio values between 80-20% vital capacity per individual. Data are presented as mean ± SD. Patient demographics, including age, height and weight were not different between ex-smokers and never smokers (all p >0.05). No differences in pulmonary function between ex-smokers and never smokers were observed (FEV 1 : 89±22 vs. 95±20%predicted; FVC: 94±21 vs. 98±19%predicted; FEV 1 /FVC: 94±8 vs. 96±9%predicted, all p >0.05). The average slope-ratio was greater in ex-smokers compared to never smokers (1.74±0.29 vs. 1.45±0.41, p <0.0001). This difference was driven by a greater slope-ratio between 70-50% vital capacity (all, p <0.05). These preliminary data suggest slope-ratio analyses reveal a dysfunctional pattern of lung emptying in asymptomatic ex-smokers with no formal diagnosis of pulmonary disease compared to never smokers n that is not observed through spirometry alone. NSERC (PDF-577750-2023; AHR), NIH (HL139854; MJJ) 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.

Introduction: Regulation of cerebral blood flow (CBF) is vital for ensuring blood supply to cerebral tissue, and studies have shown that CBF increases to match the demands of whole-body exercise. Additionally, studies have shown that an inspiratory muscle metaboreflex induced by fatiguing inspiratory work causes a decrease in blood flow to limbs and splanchnic organs, presumably redirecting blood flow to the activated inspiratory muscles. However, it is unknown if the metaboreflex response is greater when targeting the diaphragm during inspiration as opposed to using all inspiratory muscles. We aimed to determine if middle cerebral artery velocity (MCAv), a surrogate for global CBF, was affected by inspiratory muscle metaboreflex, and if so, if MCAv is affected differently when targeting diaphragmatic pressure (PTL-diaphragm; PTL di ) vs targeting mouth pressure (PTL-mouth; PTL mo ). We hypothesized that MCAv will be preserved with fatiguing inspiratory work, in both PTL di and PTL mo breathing patterns. Methods: We studied 11 (5 females) participants without any cardiorespiratory, metabolic, or musculoskeletal diseases (36±9 yrs, FEV 1 /FVC: 100±8%predicted). Each participant had gastric and esophageal balloon catheters placed to measure respiratory pressures. Blood pressure was continuously recorded via finger photoplethysmography. Transcranial doppler ultrasound continuously recorded MCAv. Participants performed breathing trials through a custom-built inspiratory pressure loading (IPTL) device, designed to open when negative pressure was generated. Each trial was comprised of 15 breaths/minute, with each breath consisting of 70% inspiration and 30% expiration. Trial 1 involved 5 minutes of PTL mo targeting 60% of their maximal inspiratory pressure, and trial 2 consisted of 5 minutes of PTL di targeting 60% transdiaphragmatic pressure. CO 2 was administered during IPTL to avoid hypocapnia. Cerebrovascular conductance index (CVCi) was calculated from MCAv. A paired t-test compared the 2 trials, deltas are calculated from end task to baseline, and data are reported as mean±SD. Results: The transdiaphragmatic pressures (PTP di ) between the two trials were different (PTL mo : 5,051±2,620, PTL di : 7,082±2,200 cmH 2 O·s/min; p=0.009). The change inMAP were not different between trials (PTL mo : 8±4, PTL di : 13±9 ΔmmHg; p=0.10). There was no difference in the change in MCAv (PTL mo : 10.07±21.51, PTL di : 9.66±22.10 Δcm/s; p=0.96) or CVCi (PTL mo : 0.03±0.23, PTL di : -0.01±0.17 Δcm/s/mmHg; p=0.55) between the two trials. Conclusion: These findings suggest that the inspiratory muscle metaboreflex does not impair CBF regulation during IPTL; this is true regardless of inspiratory muscle recruitment. Further work should focus on continuing the breathing exercises until exhaustion. NIH (HL139854); NSERC (PDF-577750-2023) 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.