Baker, Sarah E.

AbstractThe present study investigated the impact of central α2‐adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2‐adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg−1; maintenance infusion of 0.1–0.5 µg kg h−1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats−1, P = 0.003) most strongly for medium‐sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats−1; P < 0.001). Dexmedetomidine progressively de‐recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de‐recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats−1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ –0.09 ± 0.07 to Δ –0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium‐sized APs (normalized cluster 2: –6.0 ± 5 to –1.6 ± 2 % mmHg−1; P = 0.008). These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. imageKey points Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2‐adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

Menopausal females who experience frequent hot flashes (episodes of increased body temperature and sweating) have a greater risk of hypertension and cardiovascular disease than females without hot flashes. Individuals with exaggerated blood pressure (BP) responses to cold stress have a higher risk of hypertension than those with lower responses. It is unknown if females who experience hot flashes have exaggerated pressor responses to cold stress, indicating their greater risk of hypertension. The aim of this study was to determine the pressor responses to cold stress in females who experience hot flashes and those who do not. An additional goal was to understand the relation between daily hot flash frequency and pressor responses. We hypothesized that females with hot flashes would have exaggerated pressor responses to cold stress compared to females without hot flashes. We also hypothesized that pressor responses would be positively correlated to daily hot flash frequency. We recruited 17 females, ages 45-60 years, without hypertension or cardiovascular disease, who did and did not have hot flashes. They reported hot flash frequency in a 3-day written diary. On the study day, continuous BP (finger photoplethysmography, calibrated to brachial cuff BP) and heart rate (HR; 3-lead ECG) were recorded while the participant rested during a 2-minute baseline period, then subsequently had an ice-water pack placed on their forehead for 3 minutes. The changes in mean BP (MBP) and HR are calculated as the change in MBP or HR during the cold pressor test minus the average MBP or HR during baseline. Data were analyzed using the Student’s t-test and Pearson correlation. Twelve females reported hot flashes (age: 51±4 years; average number of hot flashes: 3 per day) and five did not (age: 49±5 years). These groups did not differ in age, body mass index, resting MBP, or resting HR (p>0.05 for all). The change in MBP from baseline to the cold pressor test did not differ between females with and without hot flashes (Δ17±10 vs. Δ19±14 mmHg, respectively; p=0.860). The change in HR with the cold pressor test also did not differ between females who did and did not report hot flashes (Δ10±6 vs. Δ12±8 mmHg, respectively; p=0.647). In females with hot flashes, the number of hot flashes reported per day (range: 1-12 per day) was not correlated with the change in MBP (p=0.824) or HR (p=0.460) during the cold pressor test. These current data show that menopausal females who experience hot flashes do not exhibit exaggerated BP or HR responses to cold stress in comparison to females who do not experience hot flashes. In addition, BP and HR responses are not correlated with daily hot flash frequency. There are likely other vascular mechanisms that place menopausal females with hot flashes at an increased risk for hypertension. In addition, incorporating information on the age at which hot flashes began, as well as hot flash severity, might help us to further understand cardiovascular risk in this population. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. 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.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. 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.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome via the sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is >80% female who typically have few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Risk of a recurrent SCAD is reported as high as 19% at 3 years after an initial SCAD. Mechanisms underlying SCAD (re)occurrence are unknown. Common triggers for SCAD include sympathoexcitatory stimuli, including heavy exercise and intense Valsalva-like activities. This study tested the hypothesis that SCAD patients exhibit greater neurocardiovascular responses (e.g., blood pressure, heart rate, muscle sympathetic nerve activity) to isometric handgrip and post-exercise ischemia compared to healthy females. Methods: Eight females with a history of SCAD (age: 56±6 yrs, BMI: 28±4 kg/m2) and 6 age- and BMI-matched healthy female controls (CON, age: 55±8 yrs, BMI: 26±5 kg/m2) participated. Continuous blood pressure (finger photoplethysmography) and heart rate (3-lead ECG) were measured during rest (1 minute), isometric handgrip at 30% maximal voluntary contraction (2 minutes), and post-exercise ischemia at 220 mmHg (2 minutes) to isolate the skeletal muscle metaboreflex. Muscle sympathetic nerve activity (MSNA, peroneal microneurography) was measured in a subset of participants (5 SCAD/4 CON). Data are presented as an absolute change from rest (mean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (SCAD: 96±8 vs CON: 91±9 mmHg, p=0.354), heart rate (SCAD: 56±11 vs CON: 59±10 bpm, p=0.666), and MSNA (SCAD: 50±19 vs CON: 43±32 bursts/100 heartbeats, p=0.697) were not different between groups. Relative to healthy controls, SCAD patients elicited greater increases in mean blood pressure during isometric handgrip (SCAD: Δ9±3 vs CON: Δ4±4 mmHg, p=0.034) and post-exercise ischemia (SCAD: Δ7±4 vs CON: Δ3±3 mmHg, p=0.046). There were no group differences regarding heart rate responses during isometric handgrip (SCAD: Δ3±4 vs CON: Δ4±4 bpm, p=0.359) and post-exercise ischemia (SCAD: Δ3±4 vs CON: Δ2±3 bpm, p=0.861). Responses in MSNA during isometric handgrip (SCAD: Δ12±8 vs CON: Δ9±8 bursts/100 heartbeats, p=0.536) and post-exercise ischemia (SCAD: Δ11±2 vs CON: Δ13±10 bursts/100 heartbeats, p=0.713) also were not different between groups. Conclusion: These preliminary data suggest that compared to healthy females, female patients who experienced a SCAD exhibit greater pressor, but not chronotropic or sympathetic, responses to isometric handgrip and post-exercise ischemia. Exaggerated pressor responses to these perturbations may be a potential risk factor for SCAD (re)occurrence. NIH K23 HL155506, NIH T32 DK07352, NIH K01 HL148144, NIH UL1 TR0022377, and AHA 898649. 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.

Background: Females who experience menopausal hot flashes ([MHF]; episodes of sudden warmth and sweating) have greater risk of developing hypertension than females without MHF. MHF symptom severity and frequency are positively associated with hypertension. Considering that augmented arterial stiffness contributes to hypertension, this work aimed to investigate the relations between MHF severity and frequency with arterial stiffness. We hypothesized that females with moderate to severe MHF symptoms would exhibit greater arterial stiffness compared to females without MHF symptoms. Further, we hypothesized that there would be a positive relation between MHF frequency and arterial stiffness. Methods: Twenty-five females (51±5 [SD] years) with no history of hypertension or cardiovascular disease participated. The Menopausal Rating Scale was used to categorize participants by symptom severity (None MHF: n=7, Mild MHF: n=9, Moderate/Severe MHF: n=9). Participants self-reported MHF frequency over three consecutive days in real time using a hot flash diary (4±5 MHF/day, Range: 0-16). After 15 minutes of supine rest, brachial cuff blood pressures (sphygmomanometer) and heart rate (electrocardiogram) were recorded. Arterial stiffness was measured as pulse wave velocity ([PWV]; SphygmoCor®). PWV was measured using a carotid tonometer simultaneously with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Aortic systolic pressure, aortic diastolic pressure, and augmentation index (AIx) were measured via pulse wave analysis ([PWA]; SphygmoCor®) using a brachial cuff. Data were analyzed using one-way analysis of variance (ANOVA) and Spearman Rho (ρ). Results: Age, body mass index, resting mean blood pressure, and resting heart rate were not different among MHF severity groups (P>0.05 for all). PWV was not different among severity groups (None: 6.2±0.67 vs. Mild: 6.4±1.0 vs. Moderate/Severe: 6.6±1.0 cm/s, P=0.72). MHF frequency did not correlate with PWV (P=0.42). Aortic systolic pressure (None: 110±6 vs. Mild: 114±5 vs. Moderate/Severe: 112±11 mmHg, P=0.66), aortic diastolic pressure (None: 76±9 vs. Mild: 77±6 vs. Moderate/Severe: 76±10 mmHg, P=0.93), and AIx (None: 31.9±9.0 vs. Mild: 38.7±11.1 vs. Moderate/Severe: 30.4±7.4 %, P=0.16) were not different among severity groups. MHF frequency did not correlate with metrics of PWA (Systolic: P=0.61; Diastolic: P=0.89, AIx: P=0.42). Conclusion: Arterial stiffness and metrics of PWA were not different among females with varying MHF symptom severity. MHF frequency was also not correlated with aortic stiffness and metrics of PWA. Other mechanisms of vascular function (e.g., autonomic function, vasodilation, and/or vasoconstriction) should be investigated to determine potential contributors of hypertension risk in females with MHF. AHA 898649, NIH T32 DK07352, K01 HL148144, NCATS UL1 TR002377. 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.

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). 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.

Cardiogenic pulmonary edema is a life-threatening complication in patients with heart failure (HF) resulting from increased alveolar Cl- secretion and inhibition of alveolar epithelial Na+ channels (ENaC). Not all HF patients develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic component to edema formation in response to cardiac failure. The ENaC are crucial for alveolar fluid clearance, with the alpha subunit demonstrating particular importance. We have previously found that genetic variation of the alpha subunit (SCNN1A) of ENaC, an alanine (A) to threonine (T) substitution, influences ion regulation during exercise and in response to albuterol. In the present study, we sought to determine the influence of the threonine variant (T663; AT/TT group) on lung fluid regulation in response to normobaric hypoxia, an environmental condition known to increase pulmonary capillary hydrostatic stress in healthy humans. Lung ion and fluid changes were assessed using exhaled Na+ (ENa+) and the lung diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar-capillary membrane conductance (DM). 19 healthy subjects (n=8 vs. 11, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m2 , for AA and AT/TT, respectively) completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo (P) or inhaled amiloride (Aml, 1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa+, DLCO, and DM assessed at baseline and following 12 hours of hypoxic exposure. There was an effect of genotype on the ENa+ response to hypoxia with placebo that was abolished with amiloride, but no effect of genotype on the diffusing capacity of the lung (Table). These results suggest that genetic variation of SCNN1A may influence ion regulation in the lung under conditions of elevated hydrostatic stress.

Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.