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Based on animal studies, it has been speculated that muscle metabolites sensitize muscle mechanoreceptors and increase mechanoreceptor-mediated muscle sympathetic nerve activity (MSNA). However, this hypothesis has not been directly tested in humans. In this study, we tested the hypothesis that in healthy individuals passive stretch of forearm muscles would evoke significant increases in mean MSNA when muscle metabolite concentrations were increased. In 12 young healthy subjects, MSNA, ECG, and blood pressure were recorded. Subjects performed static fatiguing isometric handgrip at 30% maximum voluntary contraction followed by 4 mm of postexercise muscle ischemia (PEMI). After 2 mm of PEMI, wrist extension (i.e., wrist dorsiflexion) was performed. The static stretch protocol was also performed during 1) a freely perfused condition, 2) ischemia alone, and 3) PEMI after nonfatiguing exercise. Finally, repetitive short bouts of wrist extension were also performed under freely perfused conditions. This last paradigm evoked transient increases in MSNA but had no significant effect on mean MSNA over the whole protocol. During the PEMI after fatiguing handgrip, static stretch induced significant increases in MSNA (552 ± 74 to 673 ± 90 U/mm, P < 0.01) and mean blood pressure (102 ± 2 to 106 ± 2 mmHg, P < 0.001). Static stretch performed under the other three conditions had no significant effects on mean MSNA and blood pressure. The present data verified that in healthy humans mechanoreceptor(s) stimulation evokes significant increases in mean MSNA and blood pressure when muscle metabolite concentrations are increased above a certain threshold. [ABSTRACT FROM AUTHOR]

Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n = 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to ~33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: ~502 ± Ill; post ketorolac: ~348 ± 62%, P = 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P = 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) patients have augmented blood pressure increases during exercise. It is unknown whether PAD patients have greater renal vasoconstriction during exercise and how much the muscle mechanoreflex or oxidative stress contribute to this response. Eleven PAD patients and 10 healthy controls (CON) performed 4 minutes of mild, rhythmic, plantarflexion exercise of increasing intensity (0.5-2kg) with each leg (most and least affected legs for PAD). Eight PAD patients also performed exercise with their most affected leg during intravenous, high-dose, ascorbic acid (AA) infusion. Renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; Finometer), and heart rate (HR; ECG) were measured. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. Statistical analysis involved repeated measures ANOVA and paired samples t-tests. Baseline RVR and MAP were similar while HR was higher in PAD compared to CON (RVR: 2.08±0.23 vs. 1.87±0.20 arbitrary units, MAP: 94±3 vs. 93±3 mmHg, and HR: 72±3 vs. 59±3 b.min-1 (p<0.05) for PAD and CON, respectively). PAD had greater RVR increases from baseline during exercise with both the most and least affected legs compared to CON, specifically during the first minute of exercise (PAD most: 2.08±0.23 to 2.60±0.29 (+26±5%) and PAD least: 1.96±0.24 to 2.22±0.25 (+17±5%) vs. CON: 1.87±0.20 to 1.91±0.20 (+3±3%) for the first minute of exercise, both p<0.05). AA infusion did not alter baseline RVR, MAP or HR. AA attenuated the augmented RVR increase in PAD during the first minute of exercise with the most affected leg (PAD most without AA: 2.10±0.31 to 2.78±0.38 (+33±2%) vs. PAD most with AA: 1.88±0.26 to 2.23±0.26 (+21±2%) for the first minute of exercise, p<0.05). In conclusion, these findings suggest that PAD patients have augmented renal vasoconstriction during exercise, with the muscle mechanoreflex and oxidative stress contributing to this increased response. [ABSTRACT FROM AUTHOR]

Epidemiological data suggest that blood pressure tends to be higher in winter and lower in summer, particularly in the elderly. Moreover, hospitalization and mortality rates due to cardiovascular disease have higher rates in winter than summer. Whether autonomic adjustment including muscle sympathetic nerve activity (MSNA) varies with season is unclear. To test the hypothesis that resting MSNA varies along the seasons, we retrospectively analyzed the supine baseline (6 min) MSNA and heart rate (from ECG) of 57 healthy subjects (33M, 24F, 29 ± 1 yrs, range 22-64 yrs) from studies in our laboratory (room temperature ~23 °C). Each of these subjects from central Pennsylvania was studied during 2 or more seasons (total 231 visits). A linear-mixed effects model, which is an extension of the analysis of variance model accounting for repeated measurements (i.e. season) per subject, was used to assess the association of season with the cardiovascular outcomes. The Tukey-Kramer procedure was used to account for multiple comparisons testing between the seasons. MSNA burst rate in winter (21.3 ± 1.0 burst/min) was significantly greater than in summer (13.7 ± 1.0 burst/min, P < 0.001), spring (17.5 ± 1.6 burst/min, P = 0.04) and fall (17.0 ± 1.2 burst/min, P < 0.002). There was no significant difference in MSNA in other comparisons (spring vs. summer, P = 0.12; spring vs. fall, P = 0.99; summer vs. fall, P = 0.054). Heart rate (63.6 ± 1.1 vs. 60.8 ± 1.2 beats/min, P = 0.048) was significantly greater in winter compared to summer. Blood pressure (automated sphygmomanometry of the brachial artery) was not significantly different between seasons. The results suggest that baseline sympathetic nerve activity varies along the seasons, with peak levels evident in winter. We speculate that the seasonal MSNA variation may contribute to seasonal variations in cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in peripheral arterial disease (PAD) patients. However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants.Methods Three physiological studies were conducted in PAD patients and controls. In Protocol 1, subjects underwent four minutes of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, PAD patients received high dose ascorbic acid intravenously prior to exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was the change in mean arterial pressure (ΔMAP) during the first 20 seconds of exercise (i.e. when mechanoreceptors within skeletal muscle activate the sympathetic nervous system).Results Compared to controls, PAD patients had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg of the most affected leg (11±2 vs. 2±1 mmHg) as well as the least affected leg (7±1 vs. 1±1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% (i.e. 6 mmHg) in the presence of ascorbic acid. Electrically evoked exercise also elicited larger hemodynamic changes in the PAD patients compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischemia had a larger BP response to exercise.Conclusions The BP response to low intensity exercise was enhanced in PAD. Chronic limb ischemia may sensitize muscle afferents and potentiate the autonomic response to muscle contraction in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

It was speculated that muscle metabolites can sensitize muscle mechanoreceptors, and accentuate muscle sympathetic nerve activity (MSNA) responses to mechanoreceptors stimulation in exercise. However, this hypothesis has not been verified directly in healthy subjects. To test whether the MSNA response to passive stretch could be accentuated with increasing metabolites in the muscles, MSNA, ECG and blood pressure (BP) were recorded in 14 young healthy subjects. Subjects performed static isometric handgrip at 30% maximum voluntary contraction (MVC) until fatigue followed by 4 min post exercise ischemia (PEMI). After 2 min of PEMI, the hand was passively stretched (dorsiflexion). In 10 of the subjects, the stretch protocol was also performed without preceding handgrip or ischemia, ischemia alone, and following non-fatigue handgrip at 30% MVC followed by ischemia. During the PEMI after fatigue handgrip, stretch induced significant increase in MSNA (26.4±2.6 to 30.7±2.8 bursts/min, P=0.002) and mean BP (106±2 to 108±2 mmHg, P=0.01). Stretch performed under the other 3 conditions had no significant effect on MSNA. The present data suggest that muscle metabolites accentuate MSNA response to mechanoreceptors stimulation, probably via sensitizing the mechanoreceptors. [ABSTRACT FROM AUTHOR]

R4729 --> 890.7 --> Changes in sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) influences on cardiac rhythm during exercise can be reflected in time‐ and frequency‐based heart rate variability (HRV) analysis and differ depending on exercise intensity. However, the SNS and PNS contributions to cardiac rhythm at the onset of exercise has not been investigated due to the complexity of applying HRV analysis during short durations of exercise. Continuous wavelet transform (CWT) combines time‐ and frequency‐based analyses to allow autonomic influences on beat‐to‐beat fluctuations in R‐R intervals (RRI) to be captured in rapidly changing signals, such as at the onset of exercise. Therefore, the objective of this study was to characterize the rapid autonomic adjustments influencing cardiac rhythm at the onset of exercise in healthy young adults. This study was a secondary analysis of data previously collected from 14 healthy young adults (26 ± 2 years, 6 male/8 female) during two trials: a 5‐minute baseline followed by performance of isometric, right‐calf exercise at 70% maximal voluntary contraction (MVC) for 30 seconds (70% MVC) or continued rest (0% trial). Heart rate was continuously measured using a three‐lead electrocardiogram from which RRIs were derived. Analysis involved applying CWT to the RRI data using low‐frequency (LF; 0.04‐0.15 Hz) and high‐frequency (HF; 0.15‐0.4 Hz) bands for HRV analysis. Log‐transformed absolute (aLF, aHF) and normalized (nLF, nHF) LF and HF time‐frequency bands and their ratio (LF/HF) were calculated for each time period (one baseline time period – 0‐30 seconds, and six rest/exercise time periods – 300‐305, 305‐310, 310‐315, 315‐320, 320‐325, and 325‐330 seconds) in each trial (0% and 70% MVC). Group means and standard deviations for all five variables were calculated for each time period in each trial. Statistical analysis involved two‐way repeated measures analysis of variance with post hoc analysis involving paired t tests and a Holm‐Bonferroni correction with statistical significance set at P < 0.05. It was hypothesized that the SNS influence on cardiac rhythm, measured by LF and LF/HF, would increase while the PNS influence on cardiac rhythm, measured by HF, would decrease at the onset of exercise in healthy young adults. There was a significant trial‐time interaction for aHF, aLF, and LF/HF (P < 0.001, P = 0.003, and P = 0.027, respectively). aHF was lower during 5‐30 seconds (all P ≤ 0.025), aLF was lower during 20‐30 seconds (all P ≤ 0.011), and LF/HF was higher during 5‐20 seconds (all P ≤ 0.045) following the start of exercise in the 70% MVC trial compared to the 0% trial. There were significant effects of trial for aHF, nLF, nHF, and LF/HF (all P ≤ 0.014) and time for aHF and LF/HF (all P ≤ 0.011). These results indicate that the reduction of the PNS influence on cardiac rhythm begins sooner than the augmentation of the SNS influence on cardiac rhythm at the onset of exercise in healthy young adults. [ABSTRACT FROM AUTHOR]

R859 --> 607.1 --> Prior reports suggest that oxidative stress plays an important role in the development of atherosclerotic diseases such as peripheral artery disease (PAD). The effects of acute hyperoxia, an important acute oxidative stressor, on autonomic function have not been well studied in PAD. We hypothesized that the autonomic responses to acute hyperoxia would be impaired in PAD. We studied 17 patients with PAD (12M, 5F, 67 ± 2 yrs) and 15 healthy controls (10M, 5F, 65 ± 2 yrs). The ankle‐brachial indexes in the patients were 0.57 ± 0.03 in the most affected leg and 0.77 ± 0.04 in the less affected leg, respectively. Beat‐by‐beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min under normoxic resting conditions and during 5‐min hyperoxia (100% oxygen) as an acute oxidative stress test. HR variability (HRV) was calculated and cardiac baroreflex sensitivity (BRS) was estimated with the sequence technique. Under resting conditions, mean HR and mean arterial pressure (MAP) were not significantly different between the groups. Resting values of the root mean square of successive differences between normal heartbeats (RMSSD, a HRV index for parasympathetic activity; 14.1 ± 1.0 vs. 19.8 ± 2.2 ms, P = 0.032) and cardiac BRS (6.43 ± 0.78 vs. 14.86 ± 2.56 ms/mmHg, P = 0.001) were significantly lower in PAD than in healthy controls. Hyperoxia lowered HR in both groups and raised MAP only in patients with PAD. During hyperoxia both HR and MAP were significantly higher in PAD than in controls. Hyperoxia induced an increase in RMSSD and the high frequency (HF) component of HRV (another index for parasympathetic activity) in healthy subjects. However, during hyperoxia no increase in parasympathetic activity was observed in PAD. Both RMSSD and the HF component of the whole trial (i.e. baseline and hyperoxia) in PAD were lower than those in healthy control subjects. Hyperoxia did not induce changes in cardiac BRS in either group, while cardiac BRS of the whole trial in PAD was lower than that in healthy controls. These data suggest that resting parasympathetic activity and cardiac baroreflex function are impaired in PAD. Moreover, the autonomic response to acute oxidative stress (i.e. an increase in parasympathetic activity) is also impaired in PAD. Further studies are needed to examine if antioxidant agents can improve autonomic function in PAD. [ABSTRACT FROM AUTHOR]

R867 --> 748.1 --> Autonomic neuropathy is a common complication in diabetes mellitus (DM). Decreased vagal nerve activity and augmented sympathetic nerve activity have been reported in patients with DM. However, the relationship between autonomic function and glycemic status in DM and in individuals without DM remains unclear. We hypothesized that indices of sympathetic and vagal nerve activity are related to glycemic status. Eleven patients who were clinically diagnosed with type‐2 DM (HbA1c, 6.8 ± 0.3%; age, 54 ± 3 yrs), and 20 healthy non‐DM individuals (including 10 pre‐DM; HbA1c < 6.5%; range 5.1‐6.1%; age, 59 ± 2 yrs) were studied (19 male, 12 female). Five DM patients had hypertension. Patients with DM and hypertensives were treated with standard medications. Beat‐by‐beat blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded under resting conditions. HR variability (HRV) was calculated and spontaneous cardiovagal baroreflex sensitivity (CBRS) was evaluated with the sequence method. CBRS in DM was lower than in non‐DM subjects (P < 0.05). MSNA in DM was also lower than in non‐DM subjects (P < 0.05). In linear regression analyses with data from all subjects, CBRS was negatively correlated with fasting blood glucose (FBG) (R = ‐0.47), insulin (R = ‐0.42), and homeostasis model assessment of insulin resistance (HOMA‐IR) (R = ‐0.43) (P < 0.05 for all). MSNA was negatively correlated with HbA1c and HOMA‐IR (R = ‐0.41, ‐0.42, respectively; both, P < 0.05). The high frequency (HF) component of HRV (i.e., an index of vagal tone) was negatively correlated with insulin (R = ‐0.46) and HOMA‐IR (R = ‐0.42) in all subjects (P < 0.05 for both). In non‐DM subjects, CBRS was negatively correlated with FBG (R = ‐0.53, P <0.05). HF was negatively correlated with FBG (R = ‐0.51), insulin (R = ‐0.66), and HOMA‐IR (R = ‐0.66) (P < 0.05 for all), but MSNA was not correlated with glycemic/insulin status in non‐DM subjects. Whereas in DM patients, MSNA tended to be negatively correlated with HOMA‐IR (R = ‐0.77, P = 0.07). In the present study, both MSNA and vagal activity (CBRS and HF) were decreased in relation to the glycemic/insulin status. Vagal nerve activity was associated with the glycemic/insulin status even in non‐DM subjects (i.e., healthy and pre‐DM). Based on these results, we speculate that both vagal and sympathetic nerves were injured by DM progression, and that vagal neuropathy preceded the sympathetic neuropathy. Our results differ from prior reports that showed that MSNA in DM was higher than in non‐DM. However, in our study subjects, the severity of DM was mild, and except for hypertension in 5 subjects, none had manifestations of diabetic end‐organ damage. Differences in the duration and severity of DM as well as the effects of the treatments could contribute to the differences in the results. Further studies on the autonomic function during the DM progression are warranted. [ABSTRACT FROM AUTHOR]

R2276 --> 556.6 --> It has been almost two years since the Covid‐19 pandemic hit, with over 5 million deaths globally. It is known that endothelial activation and dysfunction play a crucial role in Covid‐19 pathogenesis. Evidence of widespread endothelial injury is found in advanced cases of Covid‐19, especially in people with cardiovascular comorbidities. However, the effects of Covid‐19 on endothelial function in unique cohorts such as young athletes have been largely unexplored. This study evaluated endothelium function by noninvasive flow‐mediated dilation (FMD) in a sample of 14 college athletes (10M/4F, 18‐23 yrs, BMI, 23.8 ± 1.6 kg/m2) after testing positive for Covid‐19. All athletes had Covid‐19 with mild or no symptoms and did not require hospitalization. The study was performed 24 ± 10 days (13‐44 days) after having Covid‐19 positive tests. We also involved 10 BMI similar healthy young subjects as controls (7M/3F, 20‐25 yrs, BMI, 24.2±2.0 kg/m2). Baseline brachial artery diameters and the largest diameters after post cuff release were measured to calculate FMD. Brachial blood flow mean velocities and diameters were also recorded within 20 seconds after cuff release for calculating the shear rate (8 * mean velocity/ diameter). The baseline brachial artery diameter was significantly larger in the athlete group versus the control group (4.32±0.63 mm vs. 3.54±0.42 mm, p=0.02). The FMD was significantly lower in the athlete group than in the control group (6.49±2.05% vs. 11.05±4.08%, p=0.02). This finding is consistent with the previous reports that FMD was significantly lower in healthy athletes compared with controls. However, FMD adjusted for the ratio of flow‐mediated dilation and shear rate did not show a statistical difference between groups (0.058±0.028 %/s‐1 vs. 0.076±0.056 %/s‐1, p=0.33), even after evaluating baseline diameter as a covariate. Despite the need for extended acute and chronic observations and a healthy athlete control group, our findings suggest endothelial resilience in response to Covid‐19 infection in young athletes, which may explain their mild or asymptomatic status. [ABSTRACT FROM AUTHOR]

R2656 --> 560.3 --> Background: During exercise, blood pressure increases via augmented central command and stimulation of mechano‐ and metabosensitive muscle afferents (i.e., the exercise pressor reflex). Recent evidence has reported a strong role of acid sensing ion channels (ASIC's) in mediating this reflex, as well as exercise induced muscle pain. Therefore, it is logical to suspect that inhibiting ASIC's would mitigate the exaggerated blood pressure responses and exercise related muscle pain observed in individuals with peripheral artery disease (PAD). Purpose:. We tested the hypothesis that a single 10mg dose of amiloride (a K+‐sparing diuretic known to inhibit ASIC's) would attenuate the pressor response to blood flow restricted (BFR) plantar flexion exercise in young healthy adults. Methods: Six healthy subjects (5 male, 26 ± 2 y/o, 180.8 ± 12.1 cm, 79.7 ± 12.9 Kg) completed three separate visits. Each visit included two bouts of isometric plantar flexion, both performed until failure at 30% of the predetermined maximal voluntary isometric contraction. During one bout, blood flow to the limb was restricted via a pressurized cuff placed around the proximal portion of the lower leg (BFR); the other bout was performed under free flow conditions. In the first visit, subjects performed these two exercise bouts (in random order) under normal, non‐treated conditions. In the second and third visits, subjects performed these exercise bouts (same order as in visit 1) ~3 hrs after oral ingestion of 10mg of amiloride, or ingestion of a placebo (random order). Blood pressure and heart rate were continuously recorded throughout exercise, and time to fatigue and muscle pain (on a 12cm visual analog scale) was recorded at the end of each exercise bout. Only data from the placebo and amiloride conditions are presented here. Results: The addition of BFR reduced total exercise time by ~40.8% (t=2.99, p=0.03), but had no significant effect on peak muscle pain (p>0.10). Due to the preliminary nature of these data, no significant main effects of treatment (amiloride vs. placebo) were observed for free flow or BFR exercise (all p>0.05). However, we did observe a net decrease in the average heart rate response (+10.7 ± 3.0 bpm vs. +11.3 ± 3.7 bpm, ηp2=0.539, p>0.47), the total blood pressure response (5477.5 ± 373.7 mmHg*sec vs. 5841.3 ± 518.9 mmHg*sec, ηp2=0.250, p>0.30), the total time‐tension index (595.9 ± 406.5 Kg*sec vs. 691.6 ± 394.2 Kg*sec, ηp2=0.211, p>0.30), and the blood pressure to time‐tension index relationship (9.09 ± 4.40 mmHg/Kg vs. 11.38 ± 6.30 mmHg/Kg, ηp2=0.08, p>0.50) in the amiloride condition compared to the placebo condition during BFR exercise. Conclusions: While these preliminary findings do not indicate significant effects of treatment, these observations serve as strong pilot data to support the continued investigation of amiloride as a method of attenuating the pressor response to ischemic exercise. [ABSTRACT FROM AUTHOR]

R2277 --> 733.14 --> It is well‐known that hyperoxia evokes different effects in patients with different dieaseas conditions. Studies from this lab and others have shown that hyperoxia is a potent coronary vasoconstrictor. Recently, we found that hyperoxia exaggerates systolic blood pressure (BP) response in patients with PAD. The aim of this study is to characterize the coronary circulatory effects of hyperoxia in PAD patients and healthy controls. We recruited 20 PAD patients (14M, 6F, 66 ± 6yrs), and 16 age‐matched control subjects (10M, 6F, 65 ± 8yrs). The ankle‐brachial pressure index (ABI) in the most affected limbs of the patients was 0.58 ± 0.15, compared to the controls ABI of 1.04 ± 0.09. For the hyperoxia procedure the subjects breathed room air for three minutes and 100% oxygen for five minutes. BP and heart rate (HR) were monitored during baseline and hyperoxia. The rate pressure product (RPP), an index of myocardial oxygen consumption, was calculated as the product of systolic BP and HR. Transthoracic Coronary Echocardiography was used to record early and late peak coronary blood flow velocities (CBV1 and CBV2) in the left anterior descending artery. Early and late coronary vascular conductances (peak coronary blood velocity/diastolic blood pressure, CVC1 and CVC2) and coronary perfusion time fraction (CPTF, coronary perfusion time/R‐R interval) were calculated. All data was compared across time and between groups using Repeated Measures Analyses of Variance (RMANOVA). Results: At the baseline, RPP and coronary parameters (CBV2, CVC1, and CVC2) were higher in the PAD group compared to controls, also the PAD group showed significantly shorter CPTF. During hyperoxia, CBV1, CBV2, CVC1, and CVC2 decreased to varying degrees in both groups. However, no significant interactions were observed for RPP and all coronary parameters during hyperoxia between the groups (Table). Our findings suggest that the effect of hyperoxia on coronary circulation was not significantly different between PAD and healthy controls. [ABSTRACT FROM AUTHOR]

To examine the role of limb posture on vascular conductance during rapid changes in vascular transmural pressure, we determined brachial (n = 10) and femoral (n = 10) artery post-occlusive reactive hyperemic blood flow (RHBF, ultrasound/Doppler) and vascular conductance in healthy humans with each limb at three different positions-horizontal, up and down. Limb posture was varied by raising or lowering the arm or leg from the horizontal position by 45°. In both limbs, peak RHBF and vascular conductance were highest in the down or horizontal position and lowest in the up position (arm up 338 ± 38, supine 430 ± 52, down 415 ± 52 ml/min, P < 0.05; leg up 1,208 ± 88, supine 1,579 ± 130, down 1,767 ± 149 ml/min, P < 0.05). In contrast, the maximal dynamic fall in blood flow following peak RHBF (in ml/s/s) in both limbs was highest in the limb-down position and lowest with the limb elevated (P < 0.05). These data suggest that the magnitude and temporal pattern of limb reactive hyperemia is in part related to changes in vascular transmural pressure and independent of systemic blood pressure and sympathetic control. [ABSTRACT FROM AUTHOR]

Human studies of coronary circulation are limited because of methodological issues. Recently, a noninvasive transthoracic duplex ultrasound (TTD) technique has emerged as an important tool to measure coronary blood flow velocity (CBV) in conscious humans. We employed two protocols to determine whether noninvasive "native" coronary artery velocity responses to constrictor or dilator stimuli assessed by TTD provide reliable data. In the first protocol, coronary vascular resistance (CVR = diastolic blood pressure/CBV) responses to static handgrip were examined in the left internal mammary artery (LIMA) and native left anterior descending artery (LAD) into which the graft was inserted (patient age 63 ± 3 years). Our prior report documented increased CVR in the LIMA graft during static handgrip (Momen et al., J Appl Physiol 102: 735-739, 2007). We hypothesized that the magnitude of increases in CVR during handgrip would be similar in the LIMA graft and LAD in the same individual. Percent increases in CVR were similar in the LIMA and distal native LAD (27 ± 4% vs. 28 ± 6%). In the second protocol, we studied six patients (age 61 ± 3 years) who underwent cardiac catheterization of the LAD. We compared coronary vasodilator responses to intravenous adenosine infusion (0.14 mg·kg-1 mm-1) obtained by intracoronary Doppler guidewire technique and TTD on separate studies. The relative increases in CBV with adenosine obtained by intracoronary Doppler guidewire and TTD were similar (62 ± 10% vs. 65 ± 12%). Noninvasive TTD provides reliable human coronary circulatory constrictor and dilator data. [ABSTRACT FROM AUTHOR]

R1730 --> Prior reports suggest that exercise pressor reflex is heightened in peripheral artery disease (PAD). It is unclear if PAD alters the response in muscle sympathetic nerve activity (MSNA). We hypothesized that the MSNA responses to leg exercise would be greater than that in healthy control subjects. We studied a total of 21 PAD patients (67 ± 1 yrs) and 18 healthy control subjects (66 ± 2 yrs), while MSNA was recorded in 6 of 21 PAD patients and 5 of 18 healthy control subjects. The ankle‐brachial pressure index in the most affected leg in the patients was 0.57 ± 0.02. ECG and beat‐by‐beat blood pressure (BP, Finometer) and MSNA from the peroneal nerve in the non‐exercising leg were recorded for 10 min under resting conditions. Thereafter, the subjects performed rhythmic plantar flexion with incremental loading (2‐12 kg, + 1 kg/min) until the subject reached fatigue or exercised for a maximum of 14 min. The PAD patients performed the exercise with the most affected leg. The cardiac baroreflex (BRS) and the HR variability indices were also calculated. In PAD patients the resting MSNA (36.4 ± 4.0 vs. 31.2 ± 3.7 bursts/min) tended to be greater and cardiac BRS (8.0 ± 1.1 vs. 14.0 ± 2.2 ms/mmHg) and vagal tone were lower than those in the control subjects. BP responses to plantar flexion exercise were greater in PAD patients than those in healthy control subjects. MSNA activation during exercise occurred earlier than that seen in healthy controls. Importantly, the MSNA responses (i.e. changes) at the last min of exercise in PAD patients (Δ16.8 ± 4.8 bursts/min) were greater than that in control subjects at the same exercising time (Δ5.8 ± 4.2 bursts/min). We speculate that augmented MSNA responses contribute to the augmented pressor responses to exercise in PAD. Further studies are needed to examine if any (e.g. physical and/or pharmacological) intervention can reduce the augmented MSNA responses to exercise in PAD. [ABSTRACT FROM AUTHOR]

R3596 --> It is well known that acute oxidative stress evokes different effects in patients with atherosclerotic disease and in normal subjects. The effects of acute hyperoxia, an important acute oxidative stressor, on hemodynamics have not been well studied in patients with peripheral arterial disease (PAD). We recruited 20 PAD patients (14M, 6F, 66 ± 6yrs), and 16 age‐matched control subjects (10M, 6F, 65 ± 8yrs). The ankle‐brachial pressure index (ABI) in the most affected limbs of the patients was 0.58 ± 0.15, compared to 1.04 ± 0.09 in the controls. Blood pressure and ECG were monitored at baseline and during hyperoxia (100% oxygen for 5 mins, as an acute oxidative stress test). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), heart rate (HR), and rate‐pressure product (RPP) were averaged across the final minute of baseline and hyperoxia, and were compared across time and between groups using Repeated Measures Analyses of Variance (RMANOVA). Results indicated a significant interaction for SBP (F1,1=4.65, P=0.04), which was explained by a significant increase in SBP from baseline to hyperoxia in the PAD group (126 ± 13 mmHg vs. 137 ± 16 mmHg, respectively, P<0.001) that was not observed in the control group (115 ± 9 mmHg vs. 120 ± 7 mmHg at baseline and hyperoxia, respectively, P=0.06). In contrast, no significant interactions were observed for DBP (P=0.43), MBP (P=0.47), HR (P=0.71), or RPP (P=0.11). Considering 53% of PAD patients were on antihypertensive medicine, whereas none of the control subjects were on chronic antihypertensive agents, the likely effects of hyperoxia on systolic pressure may have been underestimated in our study. [ABSTRACT FROM AUTHOR]

Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1 ) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2 ) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults. NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD. NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Autonomic dysfunction is a common complication of type 2 diabetes mellitus (T2DM). However, the character of dysfunction varies in different reports. Differences in measurement methodology and complications might have influenced the inconsistent results. We sought to evaluate comprehensively the relationship between abnormal glucose metabolism and autonomic function at rest and the response to exercise in healthy individuals and T2DM patients. We hypothesized that both sympathetic and parasympathetic indices would decrease with the progression of abnormal glucose metabolism in individuals with few complications related to high sympathetic tone. Twenty healthy individuals and 11 T2DM patients without clinically evident cardiovascular disease other than controlled hypertension were examined. Resting muscle sympathetic nerve activity (MSNA), heart rate variability, spontaneous cardiovagal baroreflex sensitivity (CBRS), sympathetic baroreflex sensitivity and the MSNA response to handgrip exercise were measured. Resting MSNA was lower in patients with T2DM than in healthy control subjects (P = 0.011). Resting MSNA was negatively correlated with haemoglobin A 1c in all subjects (R = -0.45, P = 0.024). The parasympathetic components of heart rate variability and CBRS were negatively correlated with glycaemic/insulin indices in all subjects and even in the control group only (all, P < 0.05). In all subjects, the MSNA response to exercise was positively correlated with fasting blood glucose (R = 0.69, P < 0.001). Resting sympathetic activity and parasympathetic modulation of heart rate were decreased in relationship to abnormal glucose metabolism. Meanwhile, the sympathetic responses to handgrip were preserved in diabetics. The responses were correlated with glucose/insulin parameters throughout diabetic and control subjects. These results suggest the importance of a comprehensive assessment of autonomic function in T2DM., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Peripheral artery disease (PAD) refers to obstructed blood flow in peripheral arteries typically due to atherosclerotic plaques. How PAD alters aortic blood pressure and pressure wave propagation during exercise is unclear. Thus, this study examined central blood pressure responses to plantar flexion exercise by investigating aortic pulse wave properties in PAD. Thirteen subjects with PAD and 13 healthy [age-, sex-, body mass index (BMI) matched] subjects performed rhythmic plantar flexion for 14 min or until fatigue (20 contractions/min; started at 2 kg with 1 kg/min increment up to 12 kg). Brachial (oscillometric cuff) and radial (SphygmoCor) blood pressure and derived-aortic waveforms were analyzed during supine rest and plantar flexion exercise. At rest, baseline augmentation index ( P = 0.0263) and cardiac wasted energy ( P = 0.0321) were greater in PAD due to earlier arrival of the reflected wave ( P = 0.0289). During exercise, aortic blood pressure (aMAP) and aortic pulse pressure showed significant interaction effects ( P = 0.0041 and P = 0.0109, respectively). In particular, PAD had a greater aMAP increase at peak exercise ( P = 0.0147). Moreover, the tension time index was greater during exercise in PAD ( P = 0.0173), especially at peak exercise ( P = 0.0173), whereas the diastolic time index ( P = 0.0685) was not different between the two groups. Hence, during exercise, the subendocardial viability ratio was lower in PAD ( P = 0.0164), especially at peak exercise ( P = 0.0164). The results suggest that in PAD, the aortic blood pressure responses and myocardial oxygen demand during exercise are increased compared with healthy controls.

Introduction: Recent studies suggest that SARS-CoV-2 infection alters autonomic and vascular function in young, otherwise healthy, adults. However, whether these alterations exist in young competitive athletes remains unknown. This study aimed to assess the effects of COVID-19 on cardiac autonomic control and vascular function in collegiate athletes who tested positive for COVID-19, acknowledging the limitations imposed by the early stages of the pandemic. Methods: Sixteen collegiate athletes from various sports underwent a battery of commonly used autonomic and vascular function tests (23 ± 9, range: 12-44 days post-infection). Additionally, data from 26 healthy control participants were included. Results: In response to the Valsalva maneuver, nine athletes had a reduced early phase II blood pressure response and/or reduced Valsalva ratio. A depressed respiratory sinus arrhythmia amplitude was observed in three athletes. Three athletes became presyncopal during standing and did not complete the 10-min orthostatic challenge. Brachial artery flow-mediated dilation, when allometrically scaled to account for differences in baseline diameter, was not different between athletes and controls (10.0% ± 3.5% vs. 7.1% ± 2.4%, p = 0.058). Additionally, no differences were observed between groups when FMD responses were normalized by shear rate (athletes: 0.055% ± 0.026%/s-1, controls: 0.068% ± 0.049%/s-1, p = 0.40). Discussion: Few atypical and borderline responses to autonomic function tests were observed in athletes following an acute SARS-CoV-2 infection. The most meaningful autonomic abnormality being the failure of three athletes to complete a 10-min orthostatic challenge. These findings suggest that some athletes may develop mild alterations in autonomic function in the weeks after developing COVID-19, while vascular function is not significantly impaired., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luck, Blaha, Cauffman, Gao, Arnold, Cui and Sinoway.)

Background: Peripheral venous distension evokes a pressor reflex (venous distension reflex). Afferent group III and IV nerves innervating veins are suggested as the afferent arm of the venous distension reflex. Prostaglandins stimulate/sensitize group III/IV nerves. We hypothesized that inhibition of prostaglandin synthesis by local cyclooxygenase blockade would attenuate the muscle sympathetic nerve activity (MSNA) and blood pressure responses to venous distension., Methods: Nineteen healthy volunteers (age, 27±5 years) participated in the study with 2 visits. To induce venous distension, a volume of solution (saline alone or 9 mg ketorolac tromethamine in saline) was infused into the vein in the antecubital fossa of an arterially occluded forearm. During the procedure, beat-by-beat heart rate, blood pressure and MSNA were recorded simultaneously. The vein size was measured with ultrasound., Results: In both visits, the venous distension procedure significantly increased blood pressure, heart rate, and MSNA (all, P <0.05). The increase in mean arterial pressure and MSNA in the ketorolac visit was significantly lower than in the control visit (∆ mean arterial pressure, 7.0±6.2 versus 13.8±7.7 mm Hg; ∆MSNA, 6.0±7.1 versus 14.8±7.7 bursts/min; both, P <0.05). The increase in vein size induced by the infusion was not different between visits., Conclusions: The presented data show that cyclooxygenase blockade attenuates the responses in MSNA and blood pressure to peripheral venous distension reflex. The results suggest that cyclooxygenase products play a key role in evoking afferent activation responsible for the venous distension reflex.

Skeletal muscle perfusion and oxygenation are commonly evaluated using Doppler ultrasound and near-infrared spectroscopy (NIRS) techniques. However, a recently developed magnetic resonance imaging (MRI) sequence, termed PIVOT, permits the simultaneous collection of skeletal muscle perfusion and T2* (an index of skeletal muscle oxygenation)., Purpose: To determine the level of agreement between PIVOT, Doppler ultrasound, and NIRS-based assessments of skeletal muscle perfusion and oxygenation., Methods: Twelve healthy volunteers (8 females, 25 ± 3 years, 170 ± 11 cm, 71.5 ± 8.0 kg) performed six total reactive hyperemia protocols. During three of these reactive hyperemia protocols, Tissue Saturation Index (TSI) and oxygenated hemoglobin (O 2 Hb) were recorded from the medial gastrocnemius (MG) and tibialis anterior (TA), and blood flow velocity was recorded from the popliteal artery (BFv pop ) via Doppler Ultrasound. The other three trials were performed inside the bore of a 3 T MRI scanner, and the PIVOT sequence was used to assess perfusion (PIVOT perf ) and oxygenation (T2*) of the medial gastrocnemius and tibialis anterior muscles. Positive incremental areas under the curve (iAUC) and times to peak (TTP) were calculated for each variable, and the level of agreement between collection methods was evaluated via Bland-Altman analyses and Spearman's Rho correlation analyses., Results: The only significant bivariate relationships observed were between the T2* vs. TSI iAUC and PIVOT perf vs. BFv pop values recorded from the MG. Significant mean differences were observed for all comparisons (all P ≤ 0.038), and significant proportional biases were observed for the PIVOT perf vs. tHb TTP (R 2  = 0.848, P < 0.001) and T2* vs. TSI TTP comparisons in the TA (R 2  = 0.488, P = 0.011), and the PIVOT perf vs. BFv pop iAUC (R 2  = 0.477, P = 0.013) and time to peak (R 2  = 0.851, P < 0.001) comparisons in the MG., Conclusions: Our findings suggest that the PIVOT technique has, at best, a moderate level of agreement with Doppler ultrasound and NIRS assessment methods and is subject to significant proportional bias. These findings do not challenge the accuracy of either measurement technique but instead reflect differences in the vascular compartments, sampling volumes, and parameters being evaluated., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) influences on cardiac rhythm at the onset of exercise, a time of rapid autonomic adjustments, are clinically important areas of investigation. Continuous wavelet transform (CWT) involves time-frequency-based heart rate variability (HRV) analysis allowing investigation of autonomic influences on cardiac rhythm during short durations of exercise. Therefore, the purpose of this study was to characterize SNS and PNS influences on cardiac rhythm at the onset of isometric exercise in healthy young adults. CWT analysis was retrospectively applied to R-R interval data (electrocardiogram) previously collected from 14 healthy young adults (26 ± 2 years) who performed 30-s, one-legged, isometric, calf exercise at 70% maximal voluntary contraction (MVC; 70% MVC trial) or rested (0% MVC trial). Absolute and normalized low-frequency (aLF, nLF; 0.04-0.15 Hz) and high-frequency (aHF, nHF; 0.15-0.4 Hz) bands and LF/HF were used to analyze one 30-s baseline period and six 5-s time windows during the 30-s exercise (70% MVC) or rest (0% MVC). Statistical analysis involved two-way analysis of variance with post-hoc analysis. aHF, aLF, LF/HF, nHF, and nLF displayed a trial-time interaction (all p ≤ 0.027). In the 70% compared to the 0% MVC trial, aHF and nHF were lower after 5-30 s (all p ≤ 0.040), aLF was lower after 20-30 s (all p ≤ 0.011) and LF/HF and nLF were higher after 5-20 s (all p ≤ 0.045). These results indicate the reduction of the PNS influence on cardiac rhythm begins sooner than the augmentation of the SNS influence at the onset of isometric exercise in healthy young adults., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Amiloride has been shown to inhibit acid-sensing ion channels (ASICs), which contribute to ischemia-related muscle pain during exercise. The purpose of this study was to determine if a single oral dose of amiloride would improve exercise tolerance and attenuate blood pressure during blood-flow-restricted (BFR) exercise in healthy adults. Ten subjects (4 females) performed isometric plantar flexion exercise with BFR (30% maximal voluntary contraction) after ingesting either a 10-mg dose of amiloride or a volume-matched placebo (random order). Time to failure, time-tension index (TTI), and perceived pain (visual analog scale) were compared between the amiloride and placebo trials. Mean blood pressure, heart rate, blood pressure index (BPI), and BPI normalized to TTI (BPI norm ) were also compared between trials using both time-matched (TM 50 and TM 100 ) and effort-matched (T 50 and T 100 ) comparisons. Time to failure (+69.4 ± 63.2 s, P < 0.01) and TTI (+1,441 ± 633 kg·s, P = 0.02) were both significantly increased in the amiloride trial compared with placebo, despite no increase in pain (+0.4 ± 1.7 cm, P = 0.46). In contrast, amiloride had no significant influence on the mean blood pressure or heart rate responses, nor were there any significant differences in BPI or BPI norm between trials when matched for time (all P ≥ 0.13). When matched for effort, BPI was significantly greater in the amiloride trial (+5,300 ± 1,798 mmHg·s, P = 0.01), likely owing to an increase in total exercise duration. In conclusion, a 10-mg oral dose of amiloride appears to significantly improve the tolerance to BFR exercise in healthy adults without influencing blood pressure responses.

The venous distension reflex (VDR) is a pressor response evoked by peripheral venous distension and accompanied by increased muscle sympathetic nerve activity (MSNA). The effects of venous distension on the baroreflex, an important modulator of blood pressure (BP), have not been examined. The purpose of this study was to examine the effect of the VDR on baroreflex sensitivity (BRS). We hypothesized that the VDR will increase the sympathetic BRS (SBRS). Beat-by-beat heart rate (HR), BP, and MSNA were recorded in 16 female and 19 male young healthy subjects. To induce venous distension, normal saline equivalent to 5% of the forearm volume was infused into the veins of the occluded forearm. SBRS was assessed from the relationship between diastolic BP and MSNA during spontaneous BP variations. Cardiovagal BRS (CBRS) was assessed with the sequence technique. Venous distension evoked significant increases in BP and MSNA. Compared with baseline, during the maximal VDR response period, SBRS was significantly increased (-3.1 ± 1.5 to -4.5 ± 1.6 bursts·100 heartbeats -1 ·mmHg -1 , P < 0.01) and CBRS was significantly decreased (16.6 ± 5.4 to 13.8 ± 6.1 ms·mmHg -1 , P < 0.01). No sex differences were observed in the effect of the VDR on SBRS or CBRS. These results indicate that in addition to its pressor effect, the VDR altered both SBRS and CBRS. We speculate that these changes in baroreflex function contribute to the modulation of MSNA and BP during limb venous distension.

Acute whole body heat stress evokes sympathetic activation. However, the chronic effects of repeated moderate heat exposure (RMHE) on muscle sympathetic nerve activity (MSNA) in healthy individuals remain unclear. We performed RMHE with 4 wk (5 days/wk) of warm baths (∼40°C, for 30 min) in nine healthy older (59 ± 2 yr) volunteers. Hemodynamic variables and MSNA were examined before, 1 day after, and 1 wk following 4 wk of RMHE in a laboratory at ∼23°C. Cold pressor test (CPT) and handgrip (HG) exercise were performed during the tests. Under normothermic condition, the resting MSNA burst rate (prior, post, post 1-wk: 31.6 ± 2.0, 25.2 ± 2.0, and 27.7 ± 1.7 bursts/min; P < 0.001) and burst incidence ( P < 0.001) significantly decreased after RMHE. Moreover, the resting heart rate significantly decreased after RMHE (62 ± 2, 60 ± 2, and 58 ± 2 beats/min, P = 0.031). The sensitivity of baroreflex control of MSNA and heart rate were not altered by RMHE, although the operating points were reset. The MSNA and hemodynamic responses (i.e., changes) to handgrip exercise or cold pressor test were not significantly altered. These data suggest that the RMHE evoked by warm baths decreases resting sympathetic activity and heart rate, which can be considered beneficial effects. The mechanism(s) should be examined in future studies. NEW & NOTEWORTHY To our knowledge, this is the first study to observe the effects of repeated warm baths on sympathetic nerve activity during rest and stress in healthy middle age and older individuals. The data suggest that the repeated warm baths decreased resting sympathetic activity and heart rate, which can be considered beneficial effects. This study also provides the first evidence that the repeated warm baths did not alter the baroreflex sensitivity and the sympathetic responses to stress.

Cutaneous microcirculatory perfusion is commonly measured using laser Doppler flowmetry (LDF) probes, which provide a continuous, non-invasive quantification of skin blood flow (SkBF). However, inhomogeneities in the skin's microvasculature density contribute to a decrease in reproducibility whenever an LDF probe is removed and replaced, as is the case during pre- and post-intervention or between-day measurements. Therefore, this study aimed to determine whether increasing the total number of individual LDF probes in a localized area improves the reproducibility of the measurement. Seven laser Doppler probes were secured in a custom-made acrylic holder designed to attach to the skin's surface easily. SkBF, local skin temperature (Tsk), and blood pressure (BP) were assessed in 11 participants (6 M, 5 F, 42 ± 15 years). SkBF and Tsk were measured from the dorsal forearm (arm trial) for 5 min. Next, the multi-laser device was moved to the lateral side of the calf (leg trial), and measurements were obtained for 5 min. Each arm and leg trial was cyclically repeated three times, and all trials were separated by intermissions lasting 10-15 min. The average SkBF and the cutaneous vascular conductance (CVC) from all possible LDF probe combinations were not statistically different across the three arm and leg trials. Two-way mixed-effects models with absolute agreement were used to compute the intraclass correlation coefficient (ICC) for CVC, and the minimum ICC increased with the addition of LDF probes. The ICC of the average CVC from seven LDF probes was 0.96 between the arm trials and 0.91 between the leg trials, which suggests that there is excellent reliability and little difference between trials following the removal and replacement of the device. Moreover, all individual ICC values from ≥3 LDF probe combinations were greater than 0.70 (i.e., good reliability). These data suggest that SkBF measurements with multiple laser Doppler probes in a custom-made holder have excellent reproducibility after replacing the probes within the same participant. Therefore, this application could provide more reproducible assessments between repeated measurements (e.g., before and after exercise or clinical procedures) where the LDF probes must be removed and replaced within the same location., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luck, Kunselman, Herr, Blaha, Sinoway and Cui.)

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during 3rd-6th min ( post A ), and 7th-10th min ( post B ) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared with baseline, CBRS decreased significantly ( post A : 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), whereas SBRS increased significantly ( post A : 0.8 ± 0.2 to 1.5 ± 0.2 units·beat -1 ·mmHg -1 , P < 0.05) with an upward shift of the operating point. There were no differences in these variables between posts A and B . A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Purpose: Although it is known that peripheral arterial disease (PAD) is associated with chronic myopathies, the acute muscular responses to exercise in this population are less clear. This study used diffusion tensor imaging (DTI) to compare acute exercise-related muscle damage between PAD patients and healthy controls., Methods: Eight PAD patients and seven healthy controls performed graded plantar flexion in the bore of a 3T MRI scanner. Exercise began at 2 kg and increased by 2 kg every 2 min until failure, or completion of 10 min of exercise. DTI images were acquired from the lower leg pre- and post-exercise, and were analyzed for mean diffusivity, fractional anisotropy (FA), and eigenvalues 1-3 (λ 1-3 ) of the medial gastrocnemius (MG) and tibialis anterior (TA)., Results: Results indicated a significant leg by time interaction for mean diffusivity, explained by a significantly greater increase in diffusivity of the MG in the most affected legs of PAD patients (11.1 × 10 -4  ± 0.5 × 10 -4 mm 2 /s vs. 12.7 × 10 -4  ± 1.2 × 10 -4 mm 2 /s at pre and post, respectively, P = 0.02) compared to healthy control subjects (10.8 × 10 -4  ± 0.3 × 10 -4 mm 2 /s vs. 11.2 × 10 -4  ± 0.5 × 10 -4 mm 2 /s at pre and post, respectively, P = 1.0). No significant differences were observed for the TA, or λ 1-3 (all P ≥ 0.06). Moreover, no reciprocal changes were observed for FA in either group (all P ≥ 0.29)., Conclusion: These data suggest that calf muscle diffusivity increases more in PAD patients compared to controls after exercise. These findings are consistent with the notion that acute exercise results in increased muscle damage in PAD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Venous saline infusions in an arterially occluded forearm evoke reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e., muscle metaboreflex) would modify the venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A , saline (5% forearm volume) was infused into the veins of an arterially occluded arm (nonhandgrip trial). In trial B , subjects performed 2-min static handgrip followed by postexercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into the veins of the arm (handgrip trial). In trial A , the infusion increased MSNA and BP as expected (both P < 0.001). In trial B , handgrip significantly raised MSNA, BP, and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (Δ8.6 ± 1.5 to Δ10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure ( P = 0.844) evoked by the infusion during PECO were not significantly different from those in the nonhandgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.

Prior reports show that whole body heat stress attenuates the pressor response to exercise in young healthy subjects. The effects of moderate whole body heating (WBH; e.g., increase in internal temperature T core of ∼0.4°C-0.5°C) or limb heating on sympathetic and cardiovascular responses to exercise in older healthy humans remain unclear. We examined the muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), and heart rate (HR) in 14 older (62 ± 2 yr) healthy subjects during fatiguing isometric handgrip exercise and postexercise circulatory occlusion (PECO). The protocol was performed under normothermic, moderate WBH, and local limb (i.e., forearm) heating conditions during three visits. During the mild WBH stage (increase in T core of <0.3°C), HR increased, whereas BP and MSNA decreased from baseline. Under the moderate WBH condition (increase in T core of ∼0.4°C), BP decreased, HR increased, and MSNA was unchanged from baseline. Compared with the normothermic trial, the absolute MAP during fatiguing exercise and PECO was lower during the WBH trial. Moreover, MSNA and MAP responses (i.e., changes) to fatiguing exercise were also less than those seen during the normothermic trial. Limb heating induced a similar increase in forearm muscle temperature to that seen in the WBH trial (∼0.7°C-1.5°C). Limb heating did not alter resting MAP, HR, or MSNA. The MSNA and hemodynamic responses to exercise in the limb heating trial were not different from those in the normothermic trial. These data suggest that moderate WBH attenuates MSNA and BP responses to exercise in older healthy humans.

Earlier reports suggest that limb venous distension evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) (i.e., venous distension reflex). Our recent report also shows that suction of arterially occluded limb evokes venous distension reflex. We postulate that the venous distension reflex contributes to autonomic responses to orthostatic stress. In this study, we hypothesized that orthostatic tolerance would be linked to the MSNA response seen with lower limb suction. Fifteen healthy subjects were tested in the supine position. Negative pressure (-100 mmHg) was applied on an arterially occluded lower limb for 2 min. MSNA from the peroneal nerve in the limb not exposed to suction, ECG, and BP (Finometer) was recorded throughout the study. Limb occlusion without suction was used as a control trial. In a separate visit, the individual's orthostatic tolerance was assessed using a graded lower body negative pressure (LBNP) tolerance test. Mean arterial BP and MSNA (18.6 ± 1.9 to 23.6 ± 2.0 bursts/min) significantly (both P < 0.05) increased during limb suction. Orthostatic tolerance index positively correlated ( R  = 0.636, P = 0.011) with the MSNA response seen with suction during occlusion. Since the venous distension reflex strength correlates with the level of orthostatic tolerance, we speculate that lower-limb venous distension reflex engagement increases the sympathetic responses during orthostatic challenge and serves to maintain BP with postural stress.

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.

Radiofrequency catheter ablation (RFCA) is a frequently performed procedure in patients with atrial fibrillation. Prior studies have shown that the RFCA may directly stimulate vagal afferents during the procedure, whereas the vagal tone assessed by heart rate variability (HRV) is lowered weeks after the RFCA procedure. The effects of RFCA performed in the left atrium on sympathetic nerve activity have not been assessed. In the present study, we hypothesized that RFCA would lower muscle sympathetic nerve activity (MSNA) during ablation and would raise MSNA 1 day postablation. A total of 18 patients were studied. In protocol 1 ( n = 10), electrocardiogram, blood pressure, and MSNA in the peroneal nerve were recorded through the RFCA procedure performed in the electrophysiology laboratory. In protocol 2, eight patients were studied before the procedure and 1 day postablation. RFCA led to a decrease in MSNA immediately after the procedure (25.4 ± 3.2 to 17.2 ± 3.8 bursts/min, P < 0.05). Cardiac parasympathetic activity was determined using indexes of HRV and increased during the procedure. One day postablation, MSNA was above baseline values (21.3 ± 3.7 to 35.7 ± 2.6 bursts/min, P < 0.05). HRV indexes of cardiac parasympathetic activity fell, and the HRV index of sympathovagal balance was not significantly altered. The results show that RFCA raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. In addition, RFCA evokes differentiated sympathetic responses directed to the heart and skeletal muscles. NEW & NOTEWORTHY The effects of radiofrequency catheter ablation performed in the left atrium on muscle sympathetic nerve activity (MSNA) have not been assessed. The results of this study show that radiofrequency catheter ablation raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. We speculate that the partial autonomic afferent denervation induces these effects on autonomic activity.

Heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. The MSNA response to heat stress in chronic heart failure (CHF) is unknown. We hypothesized that the MSNA response to heat stress is attenuated in CHF. Passive whole body heating was applied with water-perfused suits in 13 patients (61 ± 2 yr) with stable class II-III CHF, 12 age-matched (62 ± 2 yr) healthy subjects, and 14 young (24 ± 1 yr) healthy subjects. Mild heating (i.e., increases in skin temperature ΔTsk ~2-4°C, internal temperature ΔTcore <0.3°C) significantly decreased MSNA in CHF patients; however, it did not significantly alter the MSNA in the age-matched and young healthy subjects. Heat stress (i.e., ΔTsk ~4°C and ΔTcore ~0.6°C) raised MSNA in the age-matched (32.9 ± 3.2 to 45.6 ± 4.2 bursts/min; P < 0.001) and young (14.3 ± 1.7 to 26.3 ± 2.4 bursts/min; P < 0.001) controls, but not in CHF (46.2 ± 5.3 to 50.5 ± 5.3 bursts/min; P = 0.06). The MSNA increase by the heat stress in CHF (Δ4.2 ± 2.0 bursts/min) was significantly less than those seen in the age-matched (Δ12.8 ± 1.7 bursts/min, P < 0.05) and young (Δ12.0 ± 2.7 bursts/min, P < 0.05) control groups. These data suggest that the MSNA response to heat stress is attenuated in CHF patients. We speculate that the attenuated MSNA response to heat stress may contribute to impaired cardiovascular adjustments in CHF in a hot environment., (Copyright © 2017 the American Physiological Society.)

Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR - 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV - 0% trial = Δ -3.8 ± 1.1 cm/s, 70% trial = Δ -2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans., (Copyright © 2017 the American Physiological Society.)

Low-dose aspirin inhibits thromboxane production and augments the sensitivity of carotid baroreflex (CBR) control of heart rate (HR) during concurrent muscle mechanoreflex and metaboreflex activation in healthy young humans. However, it is unknown how aging affects this response. Therefore, the effect of low-dose aspirin on carotid-cardiac baroreflex sensitivity during muscle mechanoreflex with and without metaboreflex activation in healthy older humans was examined. Twelve older subjects (6 men and 6 women, mean age: 62 ± 1 yr) performed two trials during two visits preceded by 7 days of low-dose aspirin (81 mg) or placebo. One trial involved 3 min of passive calf stretch (mechanoreflex) during 7.5 min of limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise (mechanoreflex and metaboreflex). HR (ECG) and mean arterial blood pressure (MAP; Finometer) were recorded. CBR function was assessed using rapid neck pressure application (+40 to -80 mmHg). Aspirin significantly decreased baseline thromboxane B2 production by 83 ± 4% (P < 0.05) but did not affect 6-keto-PGF1α. After aspirin, CBR-HR maximal gain and operating point gain were significantly higher during stretch with metabolite accumulation compared with placebo (maximal gain: -0.23 ± 0.03 vs. -0.14 ± 0.02 and operating point gain: -0.11 ± 0.03 vs. -0.04 ± 0.01 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively, P < 0.05). In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in healthy older humans. This increased sensitivity appears linked to reduced thromboxane sensitization of muscle mechanoreceptors, which consequently improves CBR-HR control., (Copyright © 2015 the American Physiological Society.)

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP). We hypothesized that the application of suction to the human limbs would activate this venous distension reflex and raise sympathetic outflow. We placed airtight pressure tanks and applied 100 mmHg negative pressure to an arterially occluded limb (occlusion and suction, O&S) to induce tissue deformation without fluid translocation. BP, heart rate (HR), and MSNA were assessed in 19 healthy subjects during 2 min of arm or leg O&S. Occlusion without suction served as a control. During a separate visit, saline (5% forearm volume) was infused into veins of the arterially occluded arm (n = 13). The O&S increased limb circumference, MSNA burst rate (arm: Δ6.7 ± 0.7; leg: Δ6.8 ± 0.7 bursts/min), and total activity (arm: Δ199 ± 14; leg: Δ172 ± 22 units/min) and BP (arm: Δ4.3 ± 0.3; leg: Δ9.4 ± 1.4 mmHg) from the baseline. The MSNA and BP responses during arm O&S correlated with those during leg O&S. Occlusion alone had no effect on MSNA and BP. MSNA (r = 0.607) responses during arm O&S correlated with those evoked by the saline infusion into the arm. These correlations suggest that sympathetic activation during limb O&S is likely, at least partially, to be evoked via the venous distension reflex. These data suggest that suction of an occluded limb evokes sympathetic activation and that the limb venous distension reflex exists in arms and legs of normal humans., (Copyright © 2015 the American Physiological Society.)

Classic canine studies suggest that central great vein distension evokes an autonomic reflex tachycardia (Bainbridge reflex). It is unclear whether central venous distension in humans is a necessary and sufficient stimulus to evoke a reflex increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Prior work from our laboratory suggests that limb venous distension evokes a reflex increase in BP and MSNA in humans. We hypothesized that in humans, compared with the limb venous distension, inferior vena cava (IVC) distension would evoke a less prominent increase in HR and MSNA. IVC distension (monitored with ultrasonography) was induced by two methods: 1) head-down tilt (HDT, N = 13); and 2) lower-body positive pressure (LBPP, N = 10). Two minutes of HDT induced IVC distension (Δ2.6 ± 0.2 mm, P < 0.001, ~27% in cross-sectional area), slightly increased mean BP (Δ2.3 ± 0.7 mmHg, P = 0.005), decreased MSNA (Δ5.2 ± 0.8 bursts/min, P < 0.001, N = 10), and did not alter HR (P = 0.37). LBPP induced similar IVC distension, increased BP (Δ2.0 ± 0.7 mmHg, P < 0.01), and did not alter HR (P = 0.34). Thus central venous distension leads to a rapid increase in BP and a subsequent fall in MSNA. Central venous distension does not evoke either bradycardia or tachycardia in humans. The absence of a baroreflex-mediated bradycardia suggests that the Bainbridge reflex is engaged. Clearly, this reflex differs from the powerful sympathoexcitation peripheral venous distension reflex described in humans.

Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in patients with peripheral arterial disease (PAD). However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants. Three physiological studies were conducted in patients with PAD and controls. In Protocol 1, subjects underwent 4 min of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, patients with PAD received high-dose ascorbic acid intravenously before exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was Δ mean arterial pressure (MAP) during the first 20 s of exercise (i.e. the onset of sympathoexcitation by muscle afferents). Compared to controls, patients with PAD had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg with the most affected leg (11 ± 2 vs. 2 ± 1 mmHg) as well as the least affected leg (7 ± 1 vs. 1 ± 1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% with ascorbic acid. Electrically evoked exercise also elicited larger haemodynamic changes in patients with PAD compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischaemia have a larger BP response to exercise. The BP response to low-intensity exercise was enhanced in PAD. Chronic limb ischaemia may sensitize muscle afferents and potentiate the BP response to muscle contraction in a dose-dependent manner.

We have recently shown that a saline infusion in the veins of an arterially occluded human forearm evokes a systemic response with increases in muscle sympathetic nerve activity (MSNA) and blood pressure. In this report, we examined whether this response was a reflex that was due to venous distension. Blood pressure (Finometer), heart rate, and MSNA (microneurography) were assessed in 14 young healthy subjects. In the saline trial (n = 14), 5% forearm volume normal saline was infused in an arterially occluded arm. To block afferents in the limb, 90 mg of lidocaine were added to the same volume of saline in six subjects during a separate visit. To examine whether interstitial perfusion of normal saline alone induced the responses, the same volume of albumin solution (5% concentration) was infused in 11 subjects in separate studies. Lidocaine abolished the MSNA and blood pressure responses seen with saline infusion. Moreover, compared with the saline infusion, an albumin infusion induced a larger (MSNA: Δ14.3 ± 2.7 vs. Δ8.5 ± 1.3 bursts/min, P < 0.01) and more sustained MSNA and blood pressure responses. These data suggest that venous distension activates afferent nerves and evokes a powerful systemic sympathoexcitatory reflex. We posit that the venous distension plays an important role in evoking the autonomic adjustments seen with postural stress in human subjects.

During exercise, sympathetic nervous system activity increases and this contributes to an increase in blood pressure (i.e. exercise pressor reflex). Although animal studies suggest that purinergic P2 receptors on thin fibre sensory nerves are stimulated and evoke this reflex, human data are lacking. In this study, young healthy volunteers performed fatiguing isometric handgrip before and after a local infusion of pyridoxine (i.e. vitamin B(6)) into the 'isolated' circulation of the human forearm. Pyridoxine is converted into a P2-purinoceptor antagonist. Muscle sympathetic nerve activity and blood pressure responses to fatiguing handgrip and post-exercise circulatory occlusion were significantly less after pyridoxine than they were before. These effects were not observed after infusion of saline. These data suggest that P2 receptors contribute to the exercise pressor reflex in humans.

The role adenosine plays in evoking the exercise pressor reflex in humans remains controversial. We hypothesized that localized forearm adenosine receptor blockade would attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing handgrip exercise in humans. Blood pressure (Finometer), heart rate, and MSNA from the peroneal nerve were assessed in 11 healthy young volunteers during fatiguing isometric handgrip, postexercise circulatory occlusion (PECO), and passive muscle stretch during PECO. The protocol was performed before and after adenosine receptor blockade by local infusion of 40 mg aminophylline in saline via forearm Bier block (regional intravenous anesthesia). In the second experiment, the same amount of saline was infused via the Bier block. After aminophylline, the MSNA and blood pressure responses to fatiguing handgrip, PECO, and passive stretch (all P < 0.05) were significantly greater than during the control condition. Saline Bier block had no similar effects on the MSNA and blood pressure responses. These data suggest that adenosine receptor antagonism in the exercising muscles may accentuate sympathetic activation during fatiguing exercise.

The aim of this investigation was to determine the acute effects of isometric fatiguing handgrip (IFHG) and lower body negative pressure (LBNP) on indices of central arterial stiffness. Thirteen subjects were studied. Renal blood velocity (Duplex Ultrasound) and blood pressure (Finapres) were monitored during IFHG and LBNP at -30 and -50 mmHg. Radial pulse-wave forms were recorded by applanation tonometry. Central aortic waveforms and other hemodynamic parameters were assessed using the Sphygmocor software. Renal vascular resistance index (RVRI; mean BP/renal blood velocity) was used as index of sympathetic nervous system (SNS) engagement. RVRI increased during both IFHG and LBNP indicating that SNS was engaged; however, BP increased only during the IFHG. Pulse-wave analysis showed that during the IFHG protocol the transit time of the pulse wave decreased and the peripheral pulse pressure/nonaugmented central pulse pressure ratio increased from baseline. Both of these measurements suggest an increase in central large artery stiffness. During LBNP no changes in the indices of central stiffness were noted, in spite of a similar level of sympathetic system engagement. Heart rate increased during both protocols, whereas augmentation index increased during the IFHG protocol and decreased during the LBNP. Our major conclusion was that blood pressure rather than sympathetic activity seems to play the major role in modulating the elastic properties of the central arteries. The decrease in augmentation index during the LBNP protocol can be attributed to the increased heart rate, given that there is a negative correlation between these two parameters.

Based on animal studies, it has been speculated that muscle metabolites sensitize muscle mechanoreceptors and increase mechanoreceptor-mediated muscle sympathetic nerve activity (MSNA). However, this hypothesis has not been directly tested in humans. In this study, we tested the hypothesis that in healthy individuals passive stretch of forearm muscles would evoke significant increases in mean MSNA when muscle metabolite concentrations were increased. In 12 young healthy subjects, MSNA, ECG, and blood pressure were recorded. Subjects performed static fatiguing isometric handgrip at 30% maximum voluntary contraction followed by 4 min of postexercise muscle ischemia (PEMI). After 2 min of PEMI, wrist extension (i.e., wrist dorsiflexion) was performed. The static stretch protocol was also performed during 1) a freely perfused condition, 2) ischemia alone, and 3) PEMI after nonfatiguing exercise. Finally, repetitive short bouts of wrist extension were also performed under freely perfused conditions. This last paradigm evoked transient increases in MSNA but had no significant effect on mean MSNA over the whole protocol. During the PEMI after fatiguing handgrip, static stretch induced significant increases in MSNA (552 +/- 74 to 673 +/- 90 U/min, P < 0.01) and mean blood pressure (102 +/- 2 to 106 +/- 2 mmHg, P < 0.001). Static stretch performed under the other three conditions had no significant effects on mean MSNA and blood pressure. The present data verified that in healthy humans mechanoreceptor(s) stimulation evokes significant increases in mean MSNA and blood pressure when muscle metabolite concentrations are increased above a certain threshold.

Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n = 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to approximately 33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Delta502 +/- 111; post ketorolac: Delta348 +/- 62%, P = 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P = 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex.