Creating your own line: reflections from early career scientists.

The changing landscape of academia can be difficult to navigate for anyone at any point throughout their career. One thing is certainly clear: effective mentorship is key to ensuring success, fueling scientific curiosity, and creating a sense of community. This article is a collection of personal reflections and stories, offering advice directed to aspiring and junior graduate trainees; it is written by Ph.D. students, postdoctoral researchers, early-stage assistant professors, and life-long educators. The objective of this article is to inform, empower, and inspire the next generation of physiologists.NEW & NOTEWORTHY This article is a collection of personal reflections and stories, offering advice directed to aspiring and junior graduate trainees that is written by Ph.D. students, postdoctoral researchers, early-stage assistant professors, and life-long educators. The objective of this article is to inform, empower, and inspire the next generation of physiologists.

Undergraduate students' perception of cardiorespiratory physiology during exercise: teleological vs. mechanistic thinking.

BACKGROUND: Physiology is widely recognized as a difficult course, which can potentially increase students' withdrawal and failures rates. Several factors are likely contributing to the difficulties in learning physiology, including inherent features of the discipline as well as aspects related to instructions and/or students' perception. With regards to the later, it is currently unknown how students of exercise physiology think and explain physiology in terms of its cause or consequence (i.e., teleological or mechanistic thinking). Therefore, the aims of the present study were to determine 1) whether undergraduate students' perception of cardiorespiratory physiology during exercise follows a predominant teleological or mechanistic thinking, and 2) whether prior enrollment in physiology courses can influence the predominance of teleological vs. mechanistic thinking. METHODS: The test instrument was an online questionnaire about exercise physiology consisting of nine incomplete sentences about exercise physiology where students had to choose between a teleological or a mechanistic complement. The questionnaire was administered to undergraduate students in the following areas: 1) Movement Sciences (n = 152), 2) Health-related (n = 81) and, 3) Health-unrelated programs (n = 64). Students in Movement Sciences and Health-related programs were also analyzed separately in the following categories: 1) students who previously undertook physiology courses, and 2) students who did not take physiology courses. RESULTS: Overall, all groups presented a percentage of teleological thinking above 58%, which is considerably high. Teleological thinking was significantly higher in health-unrelated programs than health-related and movement sciences programs (76 ± 16% vs. 58 ± 26% vs. 61 ± 25%; P < 0.01). Further, students with prior enrollment in physiology classes presented a significantly lower percentage of teleological thinking than students without physiology classes (59 ± 25% vs. 72 ± 22%, respectively; P < 0.01), but the overall teleological reasoning remained predominant. CONCLUSIONS: These results confirm the hypothesis that undergraduate students tend to present teleological as opposed to mechanistic thinking in exercise physiology. Furthermore, although undergraduate students with prior enrollment in physiology classes presented significantly lower teleological thinking, it remained highly predominant suggesting that teleological thinking is partially independent of the degree of familiarity with this discipline.

Acute hypoxia elicits lasting reductions in the sympathetic action potential transduction of arterial blood pressure in males.

Post-hypoxia sympathoexcitation does not elicit corresponding changes in vascular tone, suggesting diminished sympathetic signalling. Blunted sympathetic transduction following acute hypoxia, however, has not been confirmed and the effects of hypoxia on the sympathetic transduction of mean arterial pressure (MAP) as a function of action potential (AP) activity is unknown. We hypothesized that MAP changes would be blunted during acute hypoxia but restored in recovery and asynchronous APs would elicit smaller MAP changes than synchronous APs. Seven healthy males (age: 24 (3) years; BMI: 25 (3) kg/m2 ) underwent 20 min isocapnic hypoxia (PET O2 : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 7 min) and late (last 7 min) recovery. AP groups were classified as synchronous APs, asynchronous APs (occurring outside an MSNA burst) and no AP activity. Sympathetic transduction of MAP was quantified using signal-averaging, with ΔMAP tracked following AP group cardiac cycles. Following synchronous APs, ΔMAP was reduced in hypoxia (+1.8 (0.9) mmHg) and early recovery (+1.5 (0.7) mmHg) compared with baseline (+3.1 (2.2) mmHg). AP group-by-condition interactions show that at rest asynchronous APs attenuate MAP reductions compared with no AP activity (-0.4 (1.1) vs. -2.2 (1.2) mmHg, respectively), with no difference between AP groups in hypoxia, early or late recovery. Sympathetic transduction of MAP is blunted in hypoxia and early recovery. At rest, asynchronous sympathetic APs contribute to neural regulation of MAP by attenuating nadir pressure responses. KEY POINTS: Acute isocapnic hypoxia elicits lasting sympathoexcitation that does not correspond to parallel changes in vascular tone, suggesting blunted sympathetic transduction. Signal-averaging techniques track the magnitude and temporal cardiovascular responses following integrated muscle sympathetic nerve activity (MSNA) burst and non-burst cardiac cycles. However, this does not fully characterize the effects of sympathetic action potential (AP) activity on blood pressure control. We show that hypoxia blunts the sympathetic transduction of mean arterial pressure (MAP) following synchronous APs that form integrated MSNA bursts and that sympathetic transduction of MAP remains attenuated into early recovery. At rest, asynchronous APs attenuate the reduction in MAP compared with cardiac cycles following no AP activity, thus asynchronous sympathetic APs appear to contribute to the neural regulation of blood pressure. The results advance our understanding of sympathetic transduction of arterial pressure during and following exposure to acute isocapnic hypoxia in humans.

A single high-fat Western meal modulates vascular responsiveness to sympathetic activation at rest and during exercise in humans: a randomized controlled trial.

A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest, but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10 females/8 males) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low (15% maximum contraction) and moderate (30% maximum contraction)-intensity rhythmic handgrip exercise. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1 h, 2 h, and 3 h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (Δ-54 ± 10%), and these responses were attenuated during low (Δ-17 ± 7%)- and moderate (Δ-8 ± 6%)-intensity handgrip exercise. Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3 h postprandial, Δ-47 ± 10%, P = 0.002 vs. preprandial) and blunted attenuation of FVC during low (3 h postprandial, Δ-23 ± 8%, P = 0.001 vs. preprandial)- and moderate (3 h postprandial, Δ-16 ± 6%, P < 0.001 vs. preprandial)-intensity handgrip exercise. The high-fat meal attenuated the magnitude of sympatholysis during low (preprandial, 38 ± 7 vs. 3 h postprandial, 23 ± 8%, P < 0.001)- and moderate (preprandial, 46 ± 11 vs. 3 h postprandial, 31 ± 10%, P < 0.001)-intensity handgrip exercise. The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults.NEW & NOTEWORTHY We observed that a single high-fat Western meal, but not an isocaloric low-fat meal, attenuated the sympathetic vasoconstriction at rest and the ability of the active skeletal muscle to counteract the vascular responsiveness to sympathetic activation (i.e., functional sympatholysis) during low- and moderate-intensity rhythmic handgrip exercise in healthy young adults. Our findings highlight the potential deleterious vascular effect associated with the consumption of a Western diet.

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia-induced sympathetic long-term facilitation.

Baroreflex resetting permits sympathetic long-term facilitation (sLTF) following hypoxia; however, baroreflex control of action potential (AP) clusters and AP recruitment patterns facilitating sLTF is unknown. We hypothesized that baroreflex resetting of arterial pressure operating points (OPs) of AP clusters and recruitment of large-amplitude APs would mediate sLTF following hypoxia. Eight men (age: 24 (3) years; body mass index: 24 (3) kg/m2 ) underwent 20 min isocapnic hypoxia ( PETO2${P_{{\rm{ET}}{{\rm{O}}_{\rm{2}}}}}$ : 47 (2) mmHg) and 30 min recovery. Multi-unit microneurography (muscle sympathetic nerve activity; MSNA) and a continuous wavelet transform with matched mother wavelet was used to detect sympathetic APs during baseline, hypoxia, early (first 5 min), and late recovery (last 5 min). AP amplitude (normalized to largest baseline AP amplitude), percentage APs occurring outside a MSNA burst (percentage asynchronous APs), and proportion of APs firing in small (1-3), medium (4-6) and large (7-10) normalized cluster sizes was calculated. Normalized clusters were used to assess baroreflex OPs and sensitivity. Hypoxia increased total MSNA activity, which remained elevated during recovery (P < 0.0001). Baroreflex OPs were shifted rightward for all clusters in recovery, with no effect on slope. Compared to baseline, AP amplitude was elevated by 3 (2)% and 4 (2)% while asynchronous APs were reduced by 9 (5)% and 7 (6)% in early and late recovery, respectively. In early recovery, the proportion of APs firing in large clusters was increased compared to baseline. Hypoxia-induced sLTF is mediated by baroreflex resetting of AP clusters to higher OPs, reduced asynchronous AP firing, and increased contribution from large-amplitude APs. KEY POINTS: Acute isocapnic hypoxia resets the arterial baroreflex and permits long-lasting sympathoexcitation, termed sympathetic long-term facilitation. Our understanding of sympathetic long-term facilitation following hypoxia in humans is based on multiunit muscle sympathetic nerve activity and does not fully characterize the underlying baroreflex control of sympathetic neuronal subpopulations or their discharge/recruitment strategies. We show that sympathetic long-term facilitation is mediated by baroreflex resetting of sympathetic action potential clusters to higher arterial pressure operating points, a reduction in the percentage of action potentials firing asynchronously, and a shift toward larger amplitude action potential activity. The results advance our fundamental understanding of how the sympathetic nervous system mediates sympathetic long-term facilitation following exposure to acute isocapnic hypoxia in humans.

Assessing functional sympatholysis during rhythmic handgrip exercise using Doppler ultrasound and near-infrared spectroscopy: sex differences and test-retest reliability.

The effects of sympathetic activity on vasoconstriction are dampened in active skeletal muscle during exercise, a phenomenon termed functional sympatholysis. Limited work has examined the influence of sex on the magnitude of sympatholysis or the test-retest reliability of measurements. In 16 women and 15 men, forearm blood flow (FBF; Doppler ultrasound), muscle oxygenation (near-infrared spectroscopy, NIRS), and beat-to-beat mean arterial pressure (MAP; photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction). Measures were taken twice within the same visit (separated by 15 min) and repeated on a second visit. Forearm vascular conductance (FVC) was calculated as FBF/MAP. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes between handgrip and rest. LBNP decreased FBF (Δ-45 ± 15%), FVC (Δ-45 ± 16%), and muscle oxygenation (Δ-14 ± 11%); however, these responses were attenuated when LBNP was applied during rhythmic handgrip exercise (Δ-7 ± 9%, Δ-9 ± 10%, and Δ-6 ± 9%, respectively). The magnitude of sympatholysis was not different between men and women (FBF: 40 ± 16% vs. 35 ± 9%, P = 0.37; FVC: 38 ± 16% vs. 35 ± 11%, P = 0.53; muscle oxygenation: 5 ± 9% vs. 11 ± 10%, P = 0.11). Furthermore, sympatholysis measurements demonstrated good to excellent intraday (intraclass-correlation coefficients; ICC ≥ 0.85) and interday (ICC ≥ 0.72) test-retest reliability (all P ≤ 0.01) in both sexes. The coefficients of variation were larger with NIRS (68-91%) than with Doppler ultrasound (16%-22%) assessments of functional sympatholysis. Collectively, these findings demonstrate that assessments of functional sympatholysis are not impacted by biological sex and that Doppler ultrasound-derived measures of sympatholysis have better within-subject reliability than NIRS-derived measures in young healthy adults.

Sympathetic transduction of blood pressure during graded lower body negative pressure in young healthy adults.

Sympathetic transduction of blood pressure (BP) is correlated negatively with resting muscle sympathetic nerve activity (MSNA) in cross-sectional data, but the acute effects of increasing MSNA are unclear. Sixteen (4 female) healthy adults (26 ± 3 years) underwent continuous measurement of heart rate, BP, and MSNA at rest and during graded lower body negative pressure (LBNP) at -10, -20, and -30 mmHg. Sympathetic transduction of BP was quantified in the time (signal averaging) and frequency (MSNA-BP gain) domains. The proportions of MSNA bursts firing within each tertile of BP were calculated. As expected, LBNP increased MSNA burst frequency (P < 0.01) and burst amplitude (P < 0.02), although the proportions of MSNA bursts firing across each BP tertile remained stable (all P > 0.44). The MSNA-diastolic BP low-frequency transfer function gain (P = 0.25) was unchanged during LBNP; the spectral coherence was increased (P = 0.03). Signal-averaged sympathetic transduction of diastolic BP was unchanged (from 2.1 ± 1.0 at rest to 2.4 ± 1.5, 2.2 ± 1.3, and 2.3 ± 1.4 mmHg; P = 0.43) during LBNP, but diastolic BP responses following nonburst cardiac cycles progressively decreased (from -0.8 ± 0.4 at rest to -1.0 ± 0.6, -1.2 ± 0.6, and -1.6 ± 0.9 mmHg; P < 0.01). As a result, the difference between MSNA burst and nonburst diastolic BP responses was increased (from 2.9 ± 1.4 at rest to 3.4 ± 1.9, 3.4 ± 1.9, and 3.9 ± 2.1 mmHg; P < 0.01). In conclusion, acute increases in MSNA using LBNP did not alter traditional signal-averaged or frequency-domain measures of sympathetic transduction of BP or the proportion of MSNA bursts firing at different BP levels. The factors that determine changes in the firing of MSNA bursts relative to oscillations in BP require further investigation.

Potentiation of GABAergic synaptic transmission by diazepam acutely increases resting beat-to-beat blood pressure variability in young adults.

Resting beat-to-beat blood pressure variability is a powerful predictor of cardiovascular events and end-organ damage. However, its underlying mechanisms remain unknown. Herein, we tested the hypothesis that a potentiation of GABAergic synaptic transmission by diazepam would acutely increase resting beat-to-beat blood pressure variability. In 40 (17 females) young, normotensive subjects, resting beat-to-beat blood pressure (finger photoplethysmography) was continuously measured for 5-10 min, 60 min after the oral administration of either diazepam (10 mg) or placebo. The experiments were conducted in a randomized, double-blinded, and placebo-controlled design. Stroke volume was estimated from the blood pressure waveform (ModelFlow) permitting the calculation of cardiac output and total peripheral resistance. Direct recordings of muscle sympathetic nerve activity (MSNA, microneurography) were obtained in a subset of subjects (n = 13), and spontaneous cardiac and sympathetic baroreflex sensitivity were calculated. Compared with placebo, diazepam significantly increased the standard deviation of systolic blood pressure (4.7 ± 1.4 vs. 5.7 ± 1.5 mmHg, P = 0.001), diastolic blood pressure (3.8 ± 1.2 vs. 4.5 ± 1.2 mmHg, P = 0.007), and mean blood pressure (3.8 ± 1.1 vs. 4.5 ± 1.1 mmHg, P = 0.002), as well as cardiac output (469 ± 149 vs. 626 ± 259 mL/min, P < 0.001) and total peripheral resistance (1.0 ± 0.3 vs. 1.4 ± 0.6 mmHg/L/min, P < 0.001). Similar results were found using different indices of variability. Furthermore, diazepam reduced MSNA (placebo: 22 ± 6 vs. diazepam: 18 ± 8 bursts/min, P = 0.025) without affecting the arterial baroreflex control of heart rate (placebo: 18.6 ± 6.7 vs. diazepam: 18.8 ± 7.0 ms/mmHg, P = 0.87) and MSNA (placebo: -3.6 ± 1.2 vs. diazepam: -3.4 ± 1.5 bursts/100 Hb/mmHg, P = 0.55). Importantly, these findings were not impacted by biological sex. We conclude that GABAA receptors modulate resting beat-to-beat blood pressure variability in young adults.

The exercise pressor reflex: An update.

The exercise pressor reflex is a feedback mechanism engaged upon stimulation of mechano- and metabosensitive skeletal muscle afferents. Activation of these afferents elicits a reflex increase in heart rate, blood pressure, and ventilation in an intensity-dependent manner. Consequently, the exercise pressor reflex has been postulated to be one of the principal mediators of the cardiorespiratory responses to exercise. In this updated review, we will discuss classical and recent advancements in our understating of the exercise pressor reflex function in both human and animal models. Particular attention will be paid to the afferent mechanisms and pathways involved during its activation, its effects on different target organs, its potential role in the abnormal cardiovascular response to exercise in diseased states, and the impact of age and biological sex on these responses. Finally, we will highlight some unanswered questions in the literature that may inspire future investigations in the field.

Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude.

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy young males at baseline and during 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 47 ± 3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA [Δ273 ± 208 vs. Δ254 ± 193 arbitrary units (AU), P = 0.84] and single-unit spike frequency (Δ8 ± 10 vs. Δ12 ± 13 spikes/min, P = 0.12). Among 19 identified single units, the proportions of activated (47% vs. 68%), nonresponsive (32% vs. 16%), and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P = 0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 nonresponsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (Δ595 ± 282 AU, P < 0.01) only one single unit was inhibited. These findings suggest that the proportions of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.NEW & NOTEWORTHY Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.

Blood pressure oscillations impact signal-averaged sympathetic transduction of blood pressure: implications for the association with resting sympathetic outflow.

Signal-averaged sympathetic transduction of blood pressure (BP) is inversely related to resting muscle sympathetic nerve activity (MSNA) burst frequency in healthy cohorts. Whether this represents a physiological compensatory adaptation or a methodological limitation, remains unclear. The current analysis aimed to determine the contribution of methodological limitations by evaluating the dependency of MSNA transduction at different levels of absolute BP. Thirty-six healthy participants (27 ± 7 yr, 9 females) underwent resting measures of beat-to-beat heart rate, BP, and muscle sympathetic nerve activity (MSNA). Tertiles of mean arterial pressure (MAP) were computed for each participant to identify cardiac cycles occurring below, around, and above the MAP operating pressure (OP). Changes in hemodynamic variables were computed across 15 cardiac cycles within each MAP tertile to quantify sympathetic transduction. MAP increased irrespective of sympathetic activity when initiated below the OP, but with MSNA bursts provoking larger rises (3.0 ± 0.9 vs. 2.1 ± 0.7 mmHg; P < 0.01). MAP decreased irrespective of sympathetic activity when initiated above the OP, but with MSNA bursts attenuating the drop (-1.3 ± 1.1 vs. -3.1 ± 1.2 mmHg; P < 0.01). In participants with low versus high resting MSNA (12 ± 4 vs. 32 ± 10 bursts/min), sympathetic transduction of MAP was not different when initiated by bursts below (3.2 ± 1.0 vs. 2.8 ± 0.9 mmHg; P = 0.26) and above the OP (-1.0 ± 1.3 vs. -1.6 ± 0.8 mmHg; P = 0.08); however, low resting MSNA was associated with a smaller proportion of MSNA bursts firing above the OP (15 ± 5 vs. 22 ± 5%; P < 0.01). The present analyses demonstrate that the signal-averaging technique for calculating sympathetic transduction of BP is influenced by the timing of an MSNA burst relative to cyclic oscillations in BP.NEW & NOTEWORTHY The current signal-averaging technique for calculating sympathetic transduction of blood pressure does not consider the arterial pressure at which each muscle sympathetic burst occurs. A burst firing when mean arterial pressure is above the operating pressure was associated with a decrease in blood pressure. Thus, individuals with higher muscle sympathetic nerve activity demonstrate a reduced sympathetic transduction owing to the weighted contribution of more sympathetic bursts at higher levels of arterial pressure.

Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency?

Calculating the blood pressure (BP) response to a burst of muscle sympathetic nerve activity (MSNA), termed sympathetic transduction, may be influenced by an individual's resting burst frequency. We examined the relationships between sympathetic transduction and MSNA in 107 healthy males and females and developed a normalized sympathetic transduction metric to incorporate resting MSNA. Burst-triggered signal averaging was used to calculate the peak diastolic BP response following each MSNA burst (sympathetic transduction of BP) and following incorporation of MSNA burst cluster patterns and amplitudes (sympathetic transduction slope). MSNA burst frequency was negatively correlated with sympathetic transduction of BP (r = -0.42; P < 0.01) and the sympathetic transduction slope (r = -0.66; P < 0.01), independent of sex. MSNA burst amplitude was unrelated to sympathetic transduction of BP in males (r = 0.04; P = 0.78), but positively correlated in females (r = 0.44; P < 0.01) and with the sympathetic transduction slope in all participants (r = 0.42; P < 0.01). To control for MSNA, the linear regression slope of the log-log relationship between sympathetic transduction and MSNA burst frequency was used as a correction exponent. In subanalysis of males (38 ± 10 vs. 14 ± 4 bursts/min) and females (28 ± 5 vs. 12 ± 4 bursts/min) with high versus low MSNA, sympathetic transduction of BP and sympathetic transduction slope were lower in participants with high MSNA (all P < 0.05). In contrast, normalized sympathetic transduction of BP and normalized sympathetic transduction slope were similar in males and females with high versus low MSNA (all P > 0.22). We propose that incorporating MSNA burst frequency into the calculation of sympathetic transduction will allow comparisons between participants with varying levels of resting MSNA.

Muscle sympathetic single-unit response patterns during progressive muscle metaboreflex activation in young healthy adults.

Muscle sympathetic single units can respond differentially to stress, but whether these responses are linked to the degree of sympathoexcitation is unclear. Fifty-three muscle sympathetic single units (microneurography) were recorded in 17 participants (8 women; 24 ± 3 yr). Five 40-s bouts of 10% static handgrip were performed during a 10-min forearm ischemia to progressively increase metabolite accumulation. Each static handgrip was separated by a 75-s ischemic rest [postexercise circulatory occlusion (PECO)] to assess the isolated action of the muscle metaboreflex. During each set of PECO, individual single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. From sets 1-5 of PECO, the proportion of single units with activated (34, 45, 68, 87, and 89%), nonresponsive (43, 44, 23, 7, and 9%), or inhibited (23, 11, 9, 6, and 2%) responses changed (P < 0.001) as total muscle sympathoexcitation increased. A total of 51/53 (96%) single units were activated in at least one set of PECO, 16 (31%) initially inhibited before activation. This response pattern delayed the activation onset compared with noninhibited units (set 3 ± 1 vs. 2 ± 1, P < 0.001). Once activated, the spike-frequency rate of rise was similar (8.5 ± 6.5 vs. 7.1 ± 6.0 spikes/min per set, P = 0.48). Muscle sympathetic single-unit firing demonstrated differential control during muscle metaboreflex activation. Single units that were initially inhibited during progressive metaboreflex activation were capable of being activated in later sets. These findings reveal that single-unit activity is influenced by convergent neural inputs (i.e., both inhibitory and excitatory), which yield heterogenous single-unit activation thresholds.NEW & NOTEWORTHY Muscle sympathetic single units respond differentially to sympathoexcitatory stress such that single units can increase firing to contribute to the sympathoexcitatory response or can be nonresponsive or even inhibited. We observed a subgroup of single units that can respond bidirectionally, being first inhibited before activated by progressive increases in forearm muscle metaboreflex activation. These results suggest convergent neural inputs (i.e., inhibitory and excitatory), which yield heterogenous muscle sympathetic single-unit activation thresholds.

Within-breath sympathetic baroreflex sensitivity is modulated by lung volume but unaffected by acute intermittent hypercapnic hypoxia in men.

Muscle sympathetic nerve activity (MSNA) exhibits well-described within-breath respiratory modulation, but the interactive contributions of the arterial baroreflex remain unclear. The present study assessed 1) within-breath modulation of sympathetic baroreflex sensitivity (BRS) and 2) the effect of acute intermittent hypercapnic hypoxia (IHH) on within-breath sympathetic BRS and respiratory-sympathetic entrainment. Seventeen men (24 ± 4 yr) underwent an 8- to 10-min spontaneously breathing baseline while continuous measures of blood pressure (BP), heart rate, MSNA, ventilation, and end-tidal gases were collected. A subset of 12 participants subsequently underwent a 40-min IHH exposure composed of 40 consecutive 1-min breathing cycles: 40 s of hypercapnic hypoxia and 20 s of normoxia. Data were compared between inspiration and expiration and low and high lung volume (calculated from the integral of spirometry-derived flow). Sympathetic BRS was determined by the slope of the weighted linear regression between diastolic BP and MSNA burst incidence. Respiratory-sympathetic entrainment was quantified as percentage of MSNA bursts during each respiratory epoch relative to the total burst count. Sympathetic BRS was similar between inspiration and expiration (-3.9 ± 2.0 vs. -3.6 ± 1.8 bursts·100 heartbeats-1·mmHg-1; P = 0.61) but greater during low versus high lung volumes (-4.6 ± 2.3 vs. -2.1 ± 1.6 bursts·100 heartbeats-1·mmHg-1; P < 0.01). High (r = -0.64; P < 0.01)- but not low (r = -0.24; P = 0.35)-lung volume sympathetic BRS was associated with resting MSNA. IHH increased resting MSNA burst frequency (15 ± 7 vs. 20 ± 7 bursts/min; P < 0.01) and diastolic BP (68 ± 5 vs. 77 ± 9 mmHg; P = 0.02), without altering resting or within-breath sympathetic BRS or respiratory-sympathetic entrainment (all P > 0.05). These findings provide novel insight into the mechanisms controlling within-breath modulation of sympathetic outflow in humans.NEW & NOTEWORTHY In resting spontaneously breathing men, the present study observed that sympathetic baroreflex sensitivity (BRS) was higher during low versus high lung volumes but not different between inspiration and expiration. High- but not low-lung volume BRS was negatively associated with resting muscle sympathetic nerve activity (MSNA). Acute intermittent hypercapnic hypoxia increased resting MSNA and diastolic blood pressure, without altering within-breath BRS. These findings provide novel insight into mechanisms controlling within-breath modulation of MSNA in humans.

Cardiovascular Control During Exercise: The Connectivity of Skeletal Muscle Afferents to the Brain.

The exercise pressor reflex (EPR) is engaged upon the activation of group III/IV skeletal muscle afferents and is one of the principal mediators of cardiovascular responses to exercise. This review explores the hypothesis that afferent signals from EPR communicate via GABAergic contacts within the brain stem to evoke parasympathetic withdrawal and sympathoexcitation to increase cardiac output, peripheral resistance, and blood pressure during exercise.

GABAA receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans.

KEY POINTS: The activation of the group III/IV skeletal muscle afferents is one of the principal mediators of cardiovascular responses to exercise; however, the neuronal circuitry mechanisms that are involved during the activation of group III/IV muscle afferents in humans remain unknown. Recently, we showed that GABAergic mechanisms are involved in the cardiac vagal withdrawal during the activation of mechanically sensitive (predominantly mediated by group III fibres) skeletal muscle afferents in humans. In the present study, we found that increases in muscle sympathetic nerve activity and mean blood pressure during isometric handgrip exercise and postexercise ischaemia were significantly greater after the oral administration of diazepam, a benzodiazepine that increases GABAA activity, but not after placebo administration in young healthy subjects. These findings indicate for the first time that GABAA receptors modulate sympathetic vasomotor outflow and the pressor responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. ABSTRACT: Animal studies have indicated that GABAA receptors are involved in the neuronal circuitry of the group III/IV skeletal muscle afferent activation-induced neurocardiovascular responses to exercise. In the present study, we aimed to determine whether GABAA receptors modulate the neurocardiovascular responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. In a randomized, double-blinded, placebo-controlled and cross-over design, 17 healthy subjects (eight women) performed 2 min of ischaemic isometric handgrip exercise at 30% of the maximal voluntary contraction followed by 2 min of postexercise ischaemia (PEI). Muscle sympathetic nerve activity (MSNA), blood pressure (BP) and heart rate (HR) were continuously measured and trials were conducted before and 60 min after the oral administration of either placebo or diazepam (10 mg), a benzodiazepine that enhances GABAA activity. At rest, MSNA was reduced, whereas HR and BP did not change after diazepam administration. During ischaemic isometric handgrip, greater MSNA (pre: ∆13 ± 9 bursts min-1 vs. post: ∆29 ± 15 bursts min-1 , P < 0.001), HR (pre: ∆23 ± 11 beats min-1 vs. post: ∆31 ± 17 beats min-1 , P < 0.01) and mean BP (pre: ∆33 ± 12 mmHg vs. post: ∆37 ± 12 mmHg, P < 0.01) responses were observed after diazepam. During PEI, MSNA and mean BP remained elevated from baseline before diazepam (∆10 ± 8 bursts min-1 and ∆25 ± 14 mmHg, respectively) and these elevations were increased after diazepam (∆17 ± 12 bursts min-1 and ∆28 ± 13 mmHg, respectively) (P ≤ 0.05). Importantly, placebo pill had no effect on neural, cardiac and pressor responses. These findings demonstrate for the first time that GABAA receptors modulate MSNA and the pressor responses to skeletal muscle metaboreflex activation in humans.

Circulatory responses at the onset of handgrip exercise in patients with Parkinson's disease.

NEW FINDINGS: What is the central question of this study? The initial circulatory response to isometric exercise in young healthy subjects is thought to be cholinergically mediated. Do patients with Parkinson's disease, a specific population known to present cholinergic dysfunction, present impairment in these initial circulatory responses? What is the main finding and its importance? The initial reduction in total peripheral resistance was absent in patients with Parkinson's disease and in older subjects, which augmented the pressor response at the onset of isometric handgrip exercise. Given that cholinergic mechanisms play an important role in the circulatory responses at the onset of isometric exercise in humans, our data suggest that cholinergic mechanisms might be compromised with ageing. ABSTRACT: Physical exercise has been used as coping strategy for Parkinson's disease (PD). Thus, a better understanding of circulatory responses to exercise in this population is warranted. During the onset of isometric handgrip (IHG) exercise there is an increase in blood pressure (BP) and a reduction in the total peripheral resistance (TPR) in young subjects. This immediate reduction of TPR is thought to be mediated by a cholinergic mechanism. Given that PD also affects cholinergic neurons, we hypothesized that patients with PD would present blunted circulatory responses at the onset of IHG exercise. Mean BP, stroke volume, heart rate, cardiac output and TPR were measured during performance of 20 s of IHG at 40% maximal voluntary contraction in 12 patients with PD (66 ± 2 years old, 171 ± 7 cm, 74 ± 7 kg), 11 older subjects (65 ± 9 years old, 171 ± 7 cm, 74 ± 10 kg) and 10 young subjects (21 ± 1 years old, 178 ± 6 cm, 79 ± 9 kg). Isometric handgrip elicited an augmented BP increase in patients with PD and older subjects at 10 and 20 s compared with young subjects. However, the BP augmentation was lower at 20 s in patients with PD. The IHG-induced reduction in TPR was attenuated in patients with PD and older subjects compared with young subjects. Our results show that the circulatory responses at the onset of IHG are impaired in patients with PD and older subjects. Overall, these findings suggest that the cholinergic mechanism might be compromised with ageing.

Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.

PURPOSE: To investigate the effect of isolated muscle metaboreflex activation on spontaneous cardiac baroreflex sensitivity (cBRS), and to characterize the potential sex-related differences in this interaction in young healthy subjects. METHODS: 40 volunteers (20 men and 20 women, age: 22 ± 0.4 year) were recruited. After 5-min rest period, the subjects performed 90 s of isometric handgrip exercise at 40% of maximal voluntary contraction followed by 3 min of post-exercise ischemia (PEI). Beat-to-beat heart rate and arterial blood pressure were continuously measured by finger photopletysmography. Spontaneous cBRS was assessed using the sequence technique and heart rate variability was measured in time (RMSSD-standard deviation of the RR intervals) and frequency domains (LF-low and HF-high frequency power). RESULTS: Resting cBRS was similar between men and women. During PEI, cBRS was increased in men (Δ3.0 ± 1.1 ms mmHg- 1, P = 0.03) but was unchanged in women (Δ-0.04 ± 1.0 ms mmHg- 1, P = 0.97). In addition, RMSSD and HF power of heart rate variability increased in women (Δ7.4 ± 2.6 ms, P = 0.02; Δ373.4 ± 197.3 ms2; P = 0.04, respectively) and further increased in men (Δ26.4 ± 7.1 ms, P < 0.01; Δ1874.9 ± 756.2 ms2; P = 0.02, respectively). Arterial blood pressure increased from rest during handgrip exercise and remained elevated during PEI in both groups, however, these responses were attenuated in women. CONCLUSIONS: These findings allow us to suggest a sex-related difference in spontaneous cBRS elicited by isolated muscle metaboreflex activation in healthy humans.

Muscle metaboreflex activation via postexercise ischemia as a tool for teaching cardiovascular physiology for undergraduate students.

The cardiovascular responses to exercise are mediated by several interactive neural mechanisms, including central command, arterial baroreflex, and skeletal muscle mechano- and metaboreflex. In humans, muscle metaboreflex activation can be isolated via postexercise ischemia (PEI), which increases sympathetic nerve activity and partially maintains the exercise-induced increase in arterial blood pressure. Here, we describe a practical laboratory class using PEI as a simple and useful technique to teach cardiovascular physiology. In an undergraduate exercise physiology class ( n = 47), a traditional 4-h lecture was conducted discussing the neural control mechanisms of cardiovascular regulation during exercise. Thereafter, eight students (4 men and 4 women) were selected to participate as a volunteer of a practical laboratory class. Each participant performed 90 s of isometric handgrip exercise at 40% of maximal voluntary contraction, followed by 3 min of PEI. Arterial blood pressure and heart rate were measured by digital monitors at rest and during isometric handgrip, PEI, and recovery. In addition, blood samples were collected from the tip of the exercising finger for blood lactate analyses. After the laboratory class, a survey was given to determine the perceptions of the students. The findings demonstrate that this laboratory class has proved to be highly popular with students, who self-reported a significant improvement in their understanding of several aspects of cardiovascular regulation during exercise.