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Background: Sympathetic and blood pressure (BP) hyper-reactivity to stress may contribute to increased cardiovascular disease (CVD) risk in adults with major depressive disorder (MDD); however, whether this is evident in young adults with MDD without comorbid disease remains unclear. We hypothesized that acute stress-induced increases in muscle sympathetic nerve activity (MSNA) and BP would be exaggerated in young adults with MDD compared to healthy non-depressed young adults (HA) and that, in adults with MDD, greater symptom severity would be positively related to MSNA and BP reactivity., Methods: In 28 HA (17 female) and 39 young adults with MDD of mild-to-moderate severity (unmedicated; 31 female), MSNA (microneurography) and beat-to-beat BP (finger photoplethysmography) were measured at rest and during the cold pressor test (CPT) and Stroop color word test (SCWT)., Results: There were no group differences in resting MSNA (p = 0.24). Neither MSNA nor BP reactivity to either the CPT [MSNA: ∆24 ± 10 HA vs. ∆21 ± 11 bursts/min MDD, p = 0.67; mean arterial pressure (MAP): ∆22 ± 7 HA vs. ∆21 ± 10 mmHg MDD, p = 0.46)] or the SCWT (MSNA: ∆-4 ± 6 HA vs. ∆-5 ± 8 bursts/min MDD, p = 0.99; MAP: ∆7 ± 8 HA vs ∆9 ± 5 mmHg MDD; p = 0.82) were different between groups. In adults with MDD, symptom severity predicted MAP reactivity to the CPT (β = 0.78, SE = 0.26, p = 0.006), but not MSNA (p = 0.42)., Limitations: The mild-to-moderate symptom severity reflects only part of the MDD spectrum., Conclusions: Neither sympathetic nor BP stress reactivity are exaggerated in young adults with MDD; however, greater symptom severity may amplify BP reactivity to stress, thereby increasing CVD risk., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The sympathetic nervous system is critical for regulating blood pressure (BP) via the arterial baroreflex and sympathetic transduction in the peripheral vasculature. These mechanisms interact, and both may be altered with aging and impacted by menopause. Although age-related decreases in sympathetic transduction have been demonstrated in women, it remains unclear whether sympathetic baroreflex sensitivity (BRS) is impaired in postmenopausal women (POST). We tested the hypothesis that sympathetic BRS would be enhanced in POST compared with premenopausal women (PRE). We examined beat-by-beat BP and muscle sympathetic nerve activity (MSNA) in 19 PRE (22 ± 2 yr, 22 ± 3 kg/m 2 ) and 12 POST (57 ± 5 yr, 24 ± 2 kg/m 2 ) during 10 min of rest. Spontaneous sympathetic BRS was quantified as the slope of a linear regression between MSNA burst incidence and diastolic BP. Sympathetic transduction to mean arterial pressure (MAP) for the 10 cardiac cycles following spontaneous MSNA bursts was assessed via signal averaging method. Resting MAP was similar (PRE: 82 ± 8 vs. POST: 85 ± 8 mmHg, P = 0.43), whereas resting MSNA was elevated in POST (PRE: 10 ± 6 vs. POST: 45 ± 16 bursts/100 heart beats, P < 0.0001). Spontaneous sympathetic BRS was enhanced in POST (PRE: -2.0 ± 1.2 vs. POST: -5.2 ± 1.9 bursts/beat/mmHg, P < 0.0005). Sympathetic transduction to MAP was attenuated in POST (time: P < 0.001, group: P < 0.001, interaction: P < 0.01). These data suggest that sympathetic BRS may be enhanced in POST. Consistent with recent hypotheses, enhanced sensitivity of the arterial baroreflex's neural arc may signify a compensatory response to reduced efficiency of the peripheral arterial baroreflex arc (i.e., sympathetic transduction) to preserve BP buffering capacity. NEW & NOTEWORTHY Studies examining sympathetic baroreflex function with aging remain equivocal, with some studies showing an increase, decrease, or no change in sympathetic baroreflex sensitivity (BRS) in older adults compared with younger adults. With aging, women experience unique physiological changes due to menopause that influence autonomic function. For the first time, we show that postmenopausal women exhibit a greater sympathetic BRS compared with young premenopausal women.

The purpose of this review is to synthesize results from studies examining the association between time-of-day for eating, exercise, and sleep with blood pressure (BP) in adults with elevated BP or hypertension. Six databases were searched for relevant publications from which 789 were identified. Ten studies met inclusion criteria. Four studies examined time-of-day for eating, five examined time-of-day for exercise, and one examined time-of-day for sleep and their associations with BP. Results suggested that later time-of-day for eating ( n  = 2/4) and later sleep mid-point ( n  = 1/1) were significantly related to higher BP in multivariable models, whereas morning ( n  = 3/5) and evening ( n  = 4/5) exercise were associated with significantly lower BP. Although this small body of work is limited by a lack of prospective, randomized controlled study designs and underutilization of 24 h ambulatory BP assessment, these results provide preliminary, hypothesis-generating support for the independent role of time-of-day for eating, exercise, and sleep with lower BP., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The prevalence of major depressive disorder (MDD) is highest in young adults and contributes to an increased risk of developing future cardiovascular disease (CVD). However, the underlying mechanisms remain unclear. The studies examining cardiac autonomic function that have included young unmedicated adults with MDD report equivocal findings, and few have considered the potential influence of disease severity or duration. We hypothesized that heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) would be reduced in young unmedicated adults with MDD (18-30 yr old) compared with healthy nondepressed young adults (HA). We further hypothesized that greater symptom severity would be related to poorer cardiac autonomic function in young adults with MDD. Heart rate and beat-to-beat blood pressure were continuously recorded during 10 min of supine rest to assess HRV and cardiac BRS in 28 HA (17 female, 22 ± 3 yr old) and 37 adults with MDD experiencing current symptoms of mild-to-moderate severity (unmedicated; 28 female, 20 ± 3 yr old). Neither HRV [root mean square of successive differences between normal heartbeats (RMSSD): 63 ± 34 HA vs. 79 ± 36 ms MDD; P = 0.14] nor cardiac BRS (overall gain, 21 ± 10 HA vs. 23 ± 7 ms/mmHg MDD; P = 0.59) were different between groups. In young adults with MDD, there was no association between current depressive symptom severity and either HRV (RMSSD, R 2 = 0.004, P = 0.73) or cardiac BRS (overall gain, R 2 = 0.02, P = 0.85). Taken together, these data suggest that cardiac autonomic dysfunction may not contribute to elevated cardiovascular risk factor profiles in young unmedicated adults with MDD of mild-to-moderate severity. NEW & NOTEWORTHY This study investigated cardiac autonomic function in young unmedicated adults with major depressive disorder (MDD). The results demonstrated that both heart rate variability and cardiac baroreflex sensitivity were preserved in young unmedicated adults with MDD compared with healthy nondepressed young adults. Furthermore, in young adults with MDD, current depressive symptom severity was not associated with any indices of cardiac autonomic function.

Non-Hispanic Black (BL) individuals have the highest prevalence of hypertension and cardiovascular disease (CVD) compared with all other racial/ethnic groups. Previous work focused on racial disparities in sympathetic control and blood pressure (BP) regulation between young BL and White (WH) adults, have mainly included men. Herein, we hypothesized that BL women would exhibit augmented resting sympathetic vascular transduction and greater sympathetic and BP reactivity to cold pressor test (CPT) compared with WH women. Twenty-eight young healthy women (BL: n = 14, 22 [Formula: see text] 4 yr; WH: n = 14, 22 [Formula: see text] 4 yr) participated. Beat-to-beat BP (Finometer), common femoral artery blood flow (duplex Doppler ultrasound), and muscle sympathetic nerve activity (MSNA; microneurography) were continuously recorded. In a subset (BL n = 10, WH n = 11), MSNA and BP were recorded at rest and during a 2-min CPT. Resting sympathetic vascular transduction was quantified as changes in leg vascular conductance (LVC) and mean arterial pressure (MAP) following spontaneous bursts of MSNA using signal averaging. Sympathetic and BP reactivity were quantified as changes in MSNA and MAP during the last minute of CPT. There were no differences in nadir LVC following resting MSNA bursts between BL (-8.70 ± 3.43%) and WH women (-7.30 ± 3.74%; P = 0.394). Likewise, peak increases in MAP following MSNA bursts were not different between groups (BL: +2.80 ± 1.42 mmHg; vs. WH: +2.99 ± 1.15 mmHg; P = 0.683). During CPT, increases in MSNA and MAP were also not different between BL and WH women, with similar transduction estimates between groups (ΔMAP/ΔMSNA; P = 0.182). These findings indicate that young, healthy BL women do not exhibit exaggerated sympathetic transduction or augmented sympathetic and BP reactivity during CPT. NEW & NOTEWORTHY This study was the first to comprehensively investigate sympathetic vascular transduction and sympathetic and BP reactivity during a cold pressor test in young, healthy BL women. We demonstrated that young BL women do not exhibit exaggerated resting sympathetic vascular transduction and do not have augmented sympathetic or BP reactivity during cold stress compared with their WH counterparts. Collectively, these findings suggest that alterations in sympathetic transduction and reactivity are not apparent in young, healthy BL women.

Although often short-lived, emotional responsiveness to daily stressors ( i.e. , routine and sometimes unexpected everyday hassles) is associated with increased cardiovascular disease (CVD), morbidity, and mortality. Here, we present the novel hypothesis that a disruption of microvascular homeostasis is a key antecedent. In addition, we postulate that physical activity may mitigate the psychobiological consequences of daily stress, thereby limiting pathophysiological CVD-related sequelae., (Copyright © 2022 by the American College of Sports Medicine.)

Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [ N G -nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before ( P = 0.023), but not after ( P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline ( R 2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before ( P < 0.01), but not after ( P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression. NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.

Background: Major depressive disorder (MDD) is associated with sympathetic overactivity and alterations in peripheral adrenergic receptor function; however, no studies have directly assessed vasoconstrictor responsiveness in adults with MDD. We tested the hypotheses that β-adrenergic receptor-mediated vasodilation would be blunted in adults with MDD compared with healthy nondepressed adults (HA) and would functionally contribute to exaggerated norepinephrine-induced vasoconstriction., Methods: In 13 HA (8 female; 24±4 years) and in 12 adults with MDD (8 female; 22±3 yrs), red blood cell flux was measured during graded intradermal microdialysis perfusion of the β-adrenergic receptor agonist isoproterenol (10 -10 to 10 - 4 mol/L) and, separately, during the perfusion of norepinephrine (10 - 12 to 10 - 2 mol/L), alone and in combination with the β-adrenergic receptor antagonist propranolol (2 mmol/L). Nonadrenergic vasoconstriction was assessed via perfusion of angiotensin II (10 - 12 to 10 - 4 mol/L)., Results: Isoproterenol-induced vasodilation was blunted in adults with MDD (188.9±70.1 HA versus 128.3±39.4 au MDD, P =0.025). Net norepinephrine-induced vasoconstriction was exaggerated in adults with MDD (-0.16±0.54 HA versus -0.75±0.56 au MDD, P =0.014); however, there were no group differences in angiotensin II-induced vasoconstriction. Propranolol potentiated norepinephrine-induced vasoconstriction in HA (-0.16±0.54 norepinephrine versus -1.60±1.40 au propranolol, P <0.01) but had no effect in adults with MDD (-0.75±0.56 norepinephrine versus -1.58±1.56 au propranolol, P =0.08)., Conclusions: β-adrenergic receptor-mediated microvascular vasodilation was blunted in adults with MDD and contributed to exaggerated adrenergic vasoconstriction. The relative loss of the vasoprotective effect of β-adrenergic receptor-mediated vasodilation may contribute to increased peripheral resistance, thereby driving the development of hypertension in adults with MDD.

The prevalence of major depressive disorder (MDD) is highest in young adulthood, an effect that has been magnified by the COVID-19 pandemic. Importantly, individuals with MDD are at a greater risk of developing cardiovascular disease (CVD). Accumulating evidence supports immune system dysregulation as a major contributor to the elevated CVD risk in older adults with MDD; however, whether this is present in young adults with MDD without comorbid disease remains unclear. Interestingly, recent data suggest augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) as a potent driver of immune dysregulation in animal models of psychiatric disease. With this background in mind, we tested the hypothesis that young adults with MDD would have augmented T-cell mitoROS and circulating proinflammatory cytokines compared with healthy young adults without MDD (HA). Whole blood was drawn from 14 young adults with MDD (age: 23 ± 2 yr) and 11 HA (age: 22 ± 1 yr). T-cell mitoROS (MitoSOX red; total: CD3 + , T-helper: CD4 + , T cytotoxic: CD8 + ) and serum cytokines were assessed by flow cytometry. Total T-cell mitoROS was significantly greater in adults with MDD compared with HA [median: 14,089 arbitrary units (AU); median: 1,362 AU, P = 0.01]. Likewise, both T-helper and T-cytotoxic cell mitoROS were significantly greater in adults with MDD compared with HA (both: P < 0.05). There were no differences in circulating cytokines between groups (all cytokines: P > 0.05). Collectively, these findings suggest that elevated T-cell mitoROS may represent an early marker of immune system dysregulation in young, otherwise healthy, adults with MDD. NEW & NOTEWORTHY To our knowledge, we provide the first evidence of augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) in young, otherwise healthy adults with MDD. Although the elevated T-cell mitoROS did not correspond to a proinflammatory profile, these findings suggest that elevated T-cell mitoROS may be an early marker of immune system dysregulation in young adults with MDD.

Introduction: Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses., Methods: Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts., Results: Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P < 0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P < 0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol., Conclusions: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW., (Copyright © 2021 by the American College of Sports Medicine.)

Background: In middle-aged adults with depression, cerebral vasodilatory reactivity is blunted; however, this has not been examined in treatment-naïve young adults with major depressive disorder (MDD). We tested the hypothesis that cerebrovascular reactivity would be blunted in young adults (18-30 yrs) with MDD compared to healthy non-depressed adults (HA) and would be attenuated to a greater extent in adults with symptomatic MDD (sMDD) compared to adults with MDD in remission (euthymic MDD; eMDD)., Methods: Sixteen adults with MDD [21±3yrs; n = 8 sMDD (6 women); n = 8 eMDD (5 women)] and 14 HA (22±3yrs; 9 women) participated. End-tidal carbon dioxide concentration (P ET CO 2 ; capnograph), beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), and internal carotid artery (ICA) diameter and blood velocity (Doppler ultrasound) were continuously measured during baseline and rebreathing-induced hypercapnia. Cerebrovascular reactivity was calculated as the relative increase in vascular conductance during hypercapnia., Results: In adults with MDD, cerebrovascular reactivity in the MCA (∆39±9 HA vs. ∆31±13% MDD, p = 0.04), but not the ICA (∆36±24 HA vs. ∆34±18% MDD, p = 0.84), was blunted compared to HA. In the MCA, cerebrovascular reactivity was reduced in adults with sMDD compared to adults with eMDD (∆36±11 eMDD vs. ∆25±13% sMDD, p = 0.02)., Limitations: The cross-sectional nature approach limits conclusions regarding the temporal nature of this link., Conclusion: These data indicate that MCA cerebrovascular reactivity is blunted in young adults with MDD and further modulated by current depressive symptomology, suggesting that the management of depressive symptomology may secondarily improve cerebrovascular health., (Copyright © 2021. Published by Elsevier B.V.)

Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H 2 S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H 2 S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H 2 S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10 -10 to 10 -1 M) alone (control) and in combination with an inhibitor of enzymatic H 2 S production [10 -3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028 M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16-wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H 2 S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55 AU post; P = 0.04) and increased the H 2 S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H 2 S-dependent mechanisms. NEW & NOTEWORTHY This is the first study to prospectively assess the effects of sulfhydryl antihypertensive treatment on microvascular endothelial function in adults with hypertension. Our data suggest that 16 wk of SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in middle-aged adults with hypertension, in part via H 2 S-dependent mechanisms.

Exposure to daily stressors specific to the COVID-19 pandemic (e.g., threat of infection) is associated with emotional distress, heightened stress reactivity, and increased depressive symptomology. Herein, we examined whether current depressive symptomology modulates the association between COVID-19-related daily stressor exposure and negative affective reactivity in young, otherwise healthy, college-aged adults. Fifty-eight adults (21 men; 22±3years) completed a daily web-based interview for eight consecutive days to assess COVID-19-related daily stress exposure and emotional responsiveness (September-November 2020). Depressive symptom severity was assessed using the Patient Health Questionnaire-9 (PHQ-9), and a score of ≥10 (range: 0-27) was used to define adults with a depressive episode ( n =20). Participants reported at least one COVID-19-related stressor on 35.8% of interview days. Depressive symptomology did not predict the likelihood of exposure to a COVID-19-related stressor ( p =0.46; OR=1.52; 95% CI: 0.492-4.718). However, negative affect (NA) was greater on days with an exposure to any COVID-19-specific daily stressor in adults with moderate-to-severe depressive symptoms ( b =0.28, SE=0.093, p =0.003) but not in those without ( b =0.009, SE=0.074, p =0.90), such that negative affective reactivity to COVID-19-related stressors was amplified in adults with a current depressive episode ( p =0.019). Depressive symptomology did not moderate positive affective reactivity ( p =0.686). Taken together, these data suggest that exposure to daily stressors related to COVID-19 further worsens NA in adults with a current depressive episode, potentially rendering them more susceptible to adverse mental health outcomes during the pandemic., 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 © 2021 Greaney, Darling, Turner, Saunders, Almeida and Mogle.)

Ever since their origin more than one half-century ago, microneurographic recordings of sympathetic nerve activity have significantly advanced our understanding of the generation and regulation of central sympathetic outflow in human health and disease. For example, it is now appreciated that a myriad of disease states exhibit chronic sympathetic overactivity, a significant predictor of cardiovascular morbidity and mortality. Although microneurographic recordings allow for the direct quantification of sympathetic outflow, they alone do not provide information with respect to the ensuing sympathetically mediated vasoconstriction and blood pressure (BP) response. Therefore, the study of vascular and/or BP responses to sympathetic outflow (i.e., sympathetic transduction) has now emerged as an area of growing interest within the field of neural cardiovascular control in human health and disease. To date, studies have primarily examined sympathetic transduction under two distinct paradigms: when reflexively evoking sympatho-excitation through the induction of a laboratory stressor (i.e., sympathetic transduction during stress) and/or following spontaneous bursts of sympathetic outflow occurring under resting conditions (i.e., sympathetic transduction at rest). The purpose of this brief review is to highlight how our physiological understanding of sympathetic transduction has been advanced by these studies and to evaluate the primary analytical techniques developed to study sympathetic transduction in humans. We also discuss the framework by which the assessment of sympathetic transduction during stress reflects a fundamentally different process relative to sympathetic transduction at rest and why findings from investigations using these different techniques should be interpreted as such and not necessarily be considered one and the same.

The magnitude of blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to laboratory stressors is commonly used to compare neurocardiovascular responsiveness between groups and conditions. However, no studies have rigorously examined the reproducibility of BP and MSNA responsiveness. Here, we assess the within-visit reproducibility of BP (finger photoplethysmography) and MSNA (microneurography) responses to isometric handgrip (HG) and postexercise ischemia (PEI) in young healthy adults ( n = 30). In a subset ( n = 21), we also examined the between-visit reproducibility of responsiveness to HG, PEI, and the cold pressor test (CPT). Intraclass correlation coefficients (ICCs) were used as a primary reproducibility measure (e.g., ICC >0.75 is considered very good). Within a visit, the increase in mean arterial pressure during HG [ICC = 0.85 (0.69-0.93); P < 0.001] and PEI [ICC = 0.85 (0.69-0.93); P < 0.001] demonstrated very good reproducibility. Furthermore, the between-visit reproducibility of the pressor response to HG [ICC = 0.85 (0.62-0.94); P < 0.001], PEI [ICC = 0.84 (CI = 0.58-0.94); P < 0.001], and the CPT [ICC = 0.89 (0.72-0.95) P < 0.001]) were also very good. However, there was greater variability in both the within- [HG: ICC = 0.58 (-0.22-0.85), P = 0.001; PEI: ICC = 0.33 (-0.24-0.69), P = 0.042] and between-visit reproducibility of MSNA responsiveness [HG: ICC = 0.87 (0.53-0.96), P = 0.001; PEI: ICC = 0.24 (-0.62-0.78), P = 0.27; CPT: ICC = 0.77 (0.29-0.93), P = 0.007]. The magnitude of the BP response to several standard laboratory stimuli was very good, whereas the variability of the MSNA response to these perturbations was generally less consistent, particularly during PEI. These data provide novel insight for both study design and data interpretation when comparing neurocardiovascular responsiveness between different conditions, groups, or studies, as well as before and after interventions/treatments. NEW & NOTEWORTHY The magnitude of the increases in blood pressure and muscle sympathetic nerve activity in response to sympathoexcitatory stimuli such as static handgrip, postexercise ischemia, and the cold pressor test are commonly used to assess neurocardiovascular responsiveness. However, limited studies have comprehensively examined the reproducibility of these responses. We demonstrate that the reproducibility of the pressor response to these perturbations was very good within an individual, whereas the reproducibility of the MSNA response was less consistent.

Reflex cutaneous vasodilation during heating is attenuated in healthy human aging secondary to blunted increases in efferent skin sympathetic nervous system activity (SSNA) and reductions in end-organ sensitivity. Whether age-related alterations in the mean body temperature ( T - b ) threshold for increasing SSNA and/or the sensitivity of responses are evident with aging have not been examined. We tested the hypotheses that the T b threshold for SSNA and cutaneous vascular conductance (CVC) would be increased, but the sensitivity would be reduced, with aging. Reflex vasodilation was induced in 13 young (23 ± 3 y) and 13 older (67 ± 7 y) adults using a water-perfused suit to systematically increase mean skin and esophageal temperatures. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome were continuously measured. SSNA was normalized to baseline; CVC was normalized as a percentage of maximal CVC. Baseline T - b was lower in older adults (36.0 ± 0.4°C vs 36.4 ± 0.3°C; p = 0.005). During passive heating, the ∆ T - b thresholds for increasing SSNA and CVC were greater (1.3 ± 0.4°C vs 0.9 ± 0.3°C; p = 0.007 and 1.3 ± 0.4°C vs 0.8 ± 0.3°C; p = 0.002, respectively) in older adults. The slope of the relation between both SSNA (0.31 ± 0.23 vs 0.13 ± 0.10 V⋅s⋅°C -1 ; p = 0.01) and CVC (87.5 ± 50.1 vs 32.4 ± 18.1%max⋅°C -1 ; p = 0.002) vs T - b was lower in older adults. The relative T - b threshold for activation of SSNA and the initiation of reflex cutaneous vasodilation is higher in older adults, and once activated, the sensitivity of both responses is diminished, supporting the concept that the efferent component of the thermoregulatory reflex arc is impaired in healthy aging. Abbreviations : CI: confidence interval; CVC: cutaneous vascular conductance; SSNA: skin sympathetic nervous system activity; T - b : mean body temperature; T es : esophageal temperature; T - sk : mean skin temperature., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 Informa UK Limited, trading as Taylor & Francis Group.)

In 2017, the American Heart Association (AHA) and American College of Cardiology (ACC) redefined stage 1 hypertension to systolic blood pressure (BP) 130-139 mmHg or diastolic BP 80-89 mmHg; however, the degree to which microvascular endothelial dysfunction is evident in adults with stage 1 hypertension remains equivocal. We tested the hypotheses that cutaneous microvascular endothelial dysfunction would be present in adults with stage 1 hypertension (HTN1) compared with normotensive adults (NTN; BP <120/<80 mmHg) but would be less severe compared with adults with stage 2 hypertension (HTN2; systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and that this graded impairment would be mediated by reductions in nitric oxide (NO)-dependent dilation. This retrospective analysis included 20 NTN (5 men; 45-64 yr; BP 94-114/60-70 mmHg), 22 HTN1 (11 men; 40-74 yr; BP 110-134/70-88 mmHg), and 44 HTN2 (27 men; 40-74 yr; BP 128-180/80-110 mmHg). BP and nocturnal dipping status were also assessed using 24-h ambulatory BP monitoring. Red cell flux (laser Doppler flowmetry) was measured during intradermal microdialysis perfusion of acetylcholine (ACh; 10 -10 to 10 -1 M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor N G -nitro-l-arginine methyl ester (l-NAME; 15 mM). ACh-induced dilation was impaired in HTN2 ( P < 0.01), but not in HTN1 ( P = 0.85), compared with NTN. Furthermore, reductions in NO-dependent dilation were evident in HTN2 ( P < 0.01) but not in HTN1 ( P = 0.76). Regardless of BP, endothelium-dependent dilation was impaired in nondippers (nighttime drop in systolic BP <10%) compared with dippers (nighttime drop in systolic BP ≥10%, P < 0.05). In conclusion, functional impairments in NO-mediated endothelium-dependent dilation were not evident in HTN1. However, regardless of BP classification, the lack of a nocturnal dip in BP was associated with blunted endothelium-dependent dilation. NEW & NOTEWORTHY This is the first study to pharmacologically assess the mechanistic regulation of endothelial function in adults with hypertension, classified according to the 2017 clinical guidelines set for by the American Heart Association (AHA) and American College of Cardiology (ACC). Compared with that in normotensive adults, nitric oxide-mediated endothelium-dependent dilation is impaired in adults with stage 2, but not stage 1, hypertension. Adults lacking a nighttime dip in blood pressure demonstrated reductions in endothelium-dependent dilation.

Background Epidemiological data suggest a link between psychological stress and increased cardiovascular disease risk; however, the underlying mechanisms remain incompletely understood. The purpose of this investigation was to directly examine the influence of daily psychosocial stress on microvascular adrenergic vasoconstrictor responsiveness in healthy adults. We hypothesized increased daily psychosocial stress would be positively related to increased norepinephrine-induced vasoconstriction. Methods and Results Eighteen healthy adults (19-36 years; 10 women) completed a daily psychosocial experiences telephone interview for 8 consecutive evenings in order to document their exposure and emotional responsiveness to common stressors (eg, arguments, work stress) over the preceding 24 hrs. On the last interview day, red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of norepinephrine (10 -12 to 10 -2  mol/L) and expressed as a percentage of baseline vascular conductance. Exogenous norepinephrine elicited progressive and robust vasoconstriction in all individuals (maximal vasoconstriction: 71±4% base ; cumulative vasoconstriction [area under the curve]: 118±102 arbitrary units). Participants experienced a stressor on 51±5% of days and a total of 5.2±0.9 stressors over the 8-day time frame. Increased daily frequency of stressor exposure was positively related to both maximal ( R 2 =0.26; P =0.03) and cumulative ( R 2 =0.31; P =0.02) vasoconstrictor responsiveness. Likewise, the total number of stressors was associated with increased maximal ( R 2 =0.40; P <0.01) and cumulative ( R 2 =0.27; P =0.03) norepinephrine-induced vasoconstriction. Neither stressor severity nor stress-related emotions were related to vasoconstrictor responsiveness. Conclusions Collectively, these data suggest that daily psychosocial stressor exposure by itself is sufficient to adversely influence microvascular vasoconstrictor function, regardless of the perceived severity or emotional consequences of the stressor exposure.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1 ) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2 ) NO-dependent and 3 ) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1 ) serotonin (10 -10 to 10 -1 mol/L) alone and in combination with a nonselective NO synthase inhibitor N G -nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 μmol/L); and 2 ) paroxetine ( n = 6; 10 -9 to 10 -2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment. NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Key Points: Impairments in both central sympathetic and peripheral microvascular function contribute to blunted reflex cutaneous vasodilatation during heat stress in healthy older adults. Hypercholesterolaemia is associated with decrements in neurovascular function; however, little is known about the impact of hypercholesterolaemia on the integrated responses to heat stress. Further, whether chronic statin therapy alters skin sympathetic outflow or its relation to cutaneous vascular conductance during heat stress is unknown. We demonstrate that reflex cutaneous vasodilatation is impaired in older hypercholesterolaemic adults but not in formerly hypercholesterolaemic adults currently treated with a statin compared to age-matched controls. Additionally, chronic statin treatment-induced improvements in reflex vasodilatation are mediated, in part, by increases in end-organ responsiveness to efferent sympathetic outflow during whole-body heating. These data add to the growing body of literature substantiating the beneficial pleiotropic neurovascular effects of chronic statin treatment and provide further support for the use of statins to confer additional cardioprotective benefits in older adults., Abstract: Attenuated reflex cutaneous vasodilatation in healthy human ageing is mediated by alterations in both central (sympathetic outflow) and peripheral (microvascular endothelial) function. Hypercholesterolaemia is associated with further impairments in neurovascular function. HMG-CoA reductase inhibitors (statins) improve cutaneous endothelium-dependent dilatation; however, whether statin therapy alters skin sympathetic nervous system activity (SSNA) or its relation to cutaneous vascular conductance (CVC) during passive heat stress is unknown. We hypothesized that (1) hypercholesterolaemic older adults would demonstrate blunted increases in both SSNA and CVC during passive heating and (2) chronic statin treatment would improve the response range and sensitivity of the SSNA:CVC relation. Reflex vasodilatation in response to a 1.0°C rise in oral temperature (T or ; water perfused suit) was induced in 13 healthy normocholesterolaemic adults (62 ± 2 years; LDL = 113 ± 7 mg/dl), 10 hypercholesterolaemic adults (60 ± 1 years; LDL = 183 ± 2 mg/dl), and 10 previously hypercholesterolaemic adults (64 ± 1 years; LDL = 102 ± 2 mg/dl) treated with lipophilic statin (10-40 mg daily). SSNA (peroneal microneurography) and red cell flux (laser-Doppler flowmetry) in the innervated dermatome (dorsum of foot) were continuously measured. Reflex vasodilatation was blunted in hypercholesterolaemic adults, but not in statin-treated adults, compared to normocholesterolaemic adults (at ∆T or  = 1.0°C: normal = 36 ± 1%CVC max , high = 32 ± 1%CVC max , statin = 38 ± 1%CVC max ; P < 0.01). ∆SSNA was not different (at ∆T or  = 1.0°C: normal: ∆ = 393 ± 96%, high: ∆ = 311 ± 120%, statin: ∆ = 256 ± 90%; P = 0.11). The slope of the SSNA:CVC relation was blunted in hypercholesterolaemic adults (0.02 ± 0.03%CVC max /% baseline ) compared to both normocholesterolaemic (0.09 ± 0.02%CVC max /% baseline ; P = 0.024) and statin-treated (0.12 ± 0.05%CVC max /% baseline ; P = 0.03) adults. Chronic statin treatment improves reflex cutaneous vasodilatation in formerly hypercholesterolaemic older adults by increasing end-organ responsiveness to sympathetic outflow during passive heat stress., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Background Despite the epidemiological associations between psychological stress, depression, and increased cardiovascular disease risk, no studies have examined the relation between naturally occurring psychosocial stressors and directly measured microvascular function in adults with major depressive disorder ( MDD ). We tested the hypothesis that young adults with MDD exposed to everyday psychosocial stressors would exhibit more severe impairments in endothelium-dependent dilation ( EDD ) compared with: (1) healthy nondepressed adults ( HCs ); and (2) adults with MDD without acute psychosocial stress exposure. Methods and Results Twenty HCs (22±1 years) and 23 otherwise healthy adults with MDD (20±0.3 years) participated in the study. Participants completed a psychosocial experiences survey to document their exposure to any of 6 stressors over the preceding 24 hours (eg, arguments, work stressors). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of acetylcholine (10 -10 to 10 -1 mol/L). EDD was expressed as a percentage of maximum vascular conductance (flux/mm Hg). Multiple linear regression was used to determine the associations between stress, EDD , and MDD . Adults with MDD reported a greater number and severity of psychosocial stressors compared with HCs (all P<0.05). EDD was blunted in adults with MDD ( HCs : 91±2 versus MDD : 74±3%; P<0.001). Exposure to any stressor was related to more severe impairments in EDD in patients with MDD (no stressor: 81±3 versus 1+ stressors: 69±5%; P=0.04) but not in HCs ( P=0.48). Conclusions These data indicate that exposure to everyday psychosocial stressors is associated with greater impairments in endothelial function in patients with MDD , suggesting a potential mechanistic link between daily stress and depression in increased cardiovascular risk.

Rationale: In rodent models of depression, oxidative stress-induced reductions in NO bioavailability contribute to impaired endothelium-dependent dilation. Endothelial dysfunction is evident in major depressive disorder (MDD); however, the molecular mediators remain undefined., Objective: We sought to translate preclinical findings to humans by testing the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential modulatory influences of sex, in MDD., Methods and Results: Twenty-four treatment-naive, otherwise healthy, young adults with MDD (14 women; 18-23 years) and 20 healthy adults (10 women; 19-30 years) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine, alone and in combination with an NO synthase inhibitor (L-NAME), a superoxide scavenger (Tempol), and an NADPH oxidase inhibitor (apocynin), as well as during perfusion of the endothelium-independent agonist sodium nitroprusside. Tissue oxidative stress markers (eg, nitrotyrosine abundance, superoxide production) were also quantified. Endothelium-dependent dilation was blunted in MDD and mediated by reductions in NO-dependent dilation. Endothelium-independent dilation was likewise attenuated in MDD. In MDD, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation. Acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Expression and activity of oxidative stress markers were increased in MDD. In a subset of adults with MDD treated with a selective serotonin reuptake inhibitor for their depressive symptoms and in remission (n=8; 7 women; 19-37 years), NO-mediated endothelium-dependent dilation was preserved, but endothelium-independent dilation was impaired, compared with healthy adults., Conclusions: Oxidative stress-induced reductions in NO-dependent dilation, as well as alterations in vascular smooth muscle function, directly contribute to microvascular dysfunction in MDD. Strategies targeting vascular oxidative stress may be viable therapeutic options for improving NO-mediated endothelial function and reducing cardiovascular risk in MDD.

Purpose: Maintaining joint stability is dependent on the ability of the nervous system to sense and react to potentially injurious loads. In attempts to understand the neurophysiologic mechanisms underlying joint stability, this afferent and efferent activity has been quantified separately at the cortical, segmental and peripheral levels using various electrophysiologic techniques in vivo. However, no studies have attempted to quantify sensory and motor activation at multiple levels of the nervous system in a single subset, to understand potential adaptations for optimizing joint stability., Materials and Methods: Muscle spindle afferent activity and sensory cortex event-related desynchronization were quantified during ankle-joint loading; and motor excitability was assessed through transcranial magnetic stimulation and the Hoffmann reflex in a subset of 42 able-bodied individuals. Microneurography and electroencephalography were used to collect the muscle spindle afferent and sensory cortex activation, respectively, as joint load was applied using an ankle arthrometer. Separately, motor-evoked potentials were obtained from the tibialis anterior (TA) and soleus (SOL) using transcranial magnetic stimulation over the motor cortex, and compared to the reflexive responses evoked via sciatic nerve electrical stimulation., Results: Correlation coefficients revealed significant correlations between the motor threshold of the soleus and early muscle spindle afferent activity (r = -0.494) and early cortical event-related desynchronization (r = 0.470), as well as tibialis anterior motor-evoked potential size and late muscle spindle afferent activity (r = 0.499)., Conclusions: The results of this study highlight the nervous system's capability to offset motor output based on the volume of sensory input at the segmental and cortical levels.

Psoriasis is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not fully understood. Deficits in conduit arterial function are evident in patients with psoriasis, but potential impairments in microcirculatory endothelial function remain unclear. We hypothesized that cutaneous microvascular dysfunction would be detectable in otherwise healthy individuals with psoriasis. Two intradermal microdialysis fibers were placed in (nonlesional) forearm skin of nine patients (3 men and 6 women, 39 ± 5 yr) with moderate (16 ± 2% of body surface area) plaque psoriasis and nine healthy (nonpsoriatic) control subjects (3 men and 6 women, 38 ± 5 yr) for local delivery of 1) lactated Ringer solution (control) and 2) 10 mM l-ascorbate (a nonspecific antioxidant). An index of skin blood flow was measured using laser-Doppler flowmetry during local heating (42°C). Nitric oxide (NO)-dependent vasodilation was directly quantified after perfusion of the nonspecific NO synthase inhibitor N G -nitro-l-arginine methyl ester (15 mM). A third fiber was perfused with increasing concentrations (10 -10 - 10 -2 M) of norepinephrine to elicit adrenoreceptor-mediated cutaneous vasoconstriction. NO-dependent vasodilation was attenuated in patients with psoriasis (57 ± 5% and 39 ± 7% maximum cutaneous vascular conductance in control subjects and adults with psoriasis, respectively, P < 0.01). l-Ascorbate did not improve NO-dependent vasodilation ( P > 0.05). There was no group difference in maximal vasoconstriction or microvascular sensitivity to norepinephrine ( P > 0.05). These data suggest that NO bioavailability is reduced in otherwise healthy individuals with psoriasis, which contributes to systemic microvascular dysfunction. NEW & NOTEWORTHY In adults with psoriasis, reduced nitric oxide bioavailability mediates impaired endothelium-dependent vasodilation, independent of increases in oxidative stress. Furthermore, the degree of psoriatic symptomology is directly related to greater reductions in nitric oxide-dependent vasodilation.

During moderate cold exposure, cardiovascular-related morbidity and mortality increase disproportionately in hypertensive adults (HTN); however, the mechanisms underlying this association are not well defined. We hypothesized that whole body cold stress would evoke exaggerated increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in HTN compared with normotensive adults (NTN) and that sympathetic baroreflex function would be altered during cooling in HTN. MSNA (peroneal microneurography) and beat-to-beat BP (Finometer) were measured continuously in 10 NTN (6 men/4 women; age 53 ± 3 yr; resting BP 125 ± 3/79 ± 1 mmHg) and 13 HTN (7 men/6 women; age 58 ± 2 yr; resting BP 146 ± 5/88 ± 2 mmHg) during whole body cooling-induced reductions in mean skin temperature (T sk ; water-perfused suit) from 34.0 to 30.5°C. During cooling, the increase in mean arterial pressure was greater in HTN (NTN: Δ6 ± 2 vs. HTN: Δ11 ± 1 mmHg; P = 0.02) and accompanied by exaggerated increases in MSNA (NTN: Δ8 ± 3 vs. HTN: Δ20 ± 3 bursts/100 heart beats; P < 0.01). The slope of the relation between MSNA and diastolic BP did not change during cooling in NTN (T sk 34.0°C: -4.4 ± 0.8 vs. T sk 30.5°C: -5.0 ± 0.3 bursts·100 heart beats -1 ·mmHg -1 ; P = 0.47) but increased in HTN (T sk 34.0°C: -3.6 ± 0.4 vs. T sk 30.5°C: -5.4 ± 0.4 bursts·100 heart beats) -1 ·mmHg -1 ; P = 0.02). These findings demonstrate that the cooling-induced increases in BP and MSNA are exaggerated in HTN. Furthermore, during cooling, sympathetic baroreflex sensitivity increases in HTN, but not NTN, presumably to allow for baroreflex-mediated buffering of excessive cooling-induced increases in BP. Collectively, these findings suggest that sympathetic function is altered during whole body cooling in hypertension. NEW & NOTEWORTHY These novel findings demonstrate that whole body cooling-induced reductions in mean skin temperature elicited greater increases in blood pressure and muscle sympathetic nerve activity in hypertensive adults. In addition, during moderate cold exposure, sympathetic baroreflex sensitivity increased in hypertensive, but not normotensive, adults.

Development of the technique of microneurography has substantially increased our understanding of the function of the sympathetic nervous system (SNS) in health and in disease. The ability to directly record signals from peripheral autonomic nerves in conscious humans allows for qualitative and quantitative characterization of SNS responses to specific stimuli and over time. Furthermore, distinct neural outflow to muscle (MSNA) and skin (SSNA) can be delineated. However, there are limitations and caveats to the use of microneurography, measurement criteria, and signal analysis and interpretation. MSNA recordings have a longer history and are considered relatively more straightforward from a measurement and analysis perspective. This brief review provides an overview of the development of the technique as used to measure SSNA. The focus is on the utility of measuring sympathetic activity directed to the skin, the unique issues related to analyzing and quantifying multiunit SSNA, and the challenges related to its interpretation., (Copyright © 2017 the American Physiological Society.)

New Findings: What is the central question of this study? Alterations in blood pressure control at exercise onset are apparent in older adults with established cardiovascular disease. It is currently not known whether these alterations are evident in young adults with a family history of hypertension. What is the main finding and its importance? We demonstrate that young women with a family history of hypertension display a larger change in blood pressure within the first 10 s of isometric exercise. These data suggest altered blood pressure control in young women with a family history of hypertension. Hypertensive adults demonstrate atypical increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) at the immediate onset of static muscle contraction. However, it is unknown whether these abnormal responses occur in young, otherwise healthy adults at risk for developing future disease, such as those with a family history of hypertension (+FH). We tested the hypothesis that +FH young women have exaggerated increases in BP and MSNA at the onset of static muscle contraction compared with those without a family history of hypertension (-FH). We retrospectively examined beat-by-beat BP and MSNA during the initial 30 s of isometric handgrip exercise (30% of maximal voluntary contraction) in 16 +FH (22 ± 2 years old, 22 ± 3 kg m -2 ) and 16 -FH (22 ± 3 years old, 22 ± 3 kg m -2 ) women. Resting mean arterial pressure (+FH 80 ± 11 mmHg versus -FH 84 ± 13 mmHg), MSNA burst frequency (+FH 7 ± 3 bursts min -1 versus -FH 9 ± 5 bursts min -1 ) and burst incidence [+FH 12 ± 4 bursts (100 heart beats) -1 versus -FH 12 ± 8 bursts (100 heart beats) -1 ] were similar between groups (all P > 0.05). Within the first 10 s of exercise, changes in mean arterial pressure (+FH Δ8 ± 6 mmHg versus -FH Δ3 ± 2 mmHg, P < 0.05) and heart rate (+FH Δ8 ± 5 beats min -1 versus -FH Δ4 ± 4 beats min -1 , P < 0.05) were greater in +FH women. Absolute MSNA burst frequency during the first 30 s of exercise was not different between groups (-FH 7 ± 5 bursts min -1 versus +FH 9 ± 3 bursts min -1 ). Cardiovascular and sympathetic responses during the cold pressor test were not different between groups. These data demonstrate that young women at risk for developing cardiovascular disease exhibit greater changes in BP at the onset of static muscle contraction., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

During heat stress, blunted increases in skin sympathetic nervous system activity (SSNA) and reductions in end-organ vascular responsiveness contribute to the age-related reduction in reflex cutaneous vasodilation. In older adults, folic acid supplementation improves the cutaneous vascular conductance (CVC) response to passive heating; however, the influence of folic acid supplementation on SSNA:CVC transduction is unknown. Fourteen older adults (66 ± 1 yr, 8 male/6 female) ingested folic acid (5 mg/day) or placebo for 6 wk in a randomized, double-blind, crossover design. In protocol 1 , esophageal temperature (T es ) was increased by 1.0°C (water-perfused suit) while SSNA (peroneal microneurography) and red cell flux in the innervated dermatome (laser Doppler flowmetry; dorsum of the foot) were continuously measured. In protocol 2 , two intradermal microdialysis fibers were placed in the skin of the lateral calf for graded infusions of acetylcholine (ACh; 10 -10 to 10 -1 M) with and without nitric oxide synthase (NOS) blockade (20 mM nitro-l-arginine methyl ester). Folic acid improved reflex vasodilation (46 ± 4% vs. 31 ± 3% CVC max for placebo; P < 0.001) without affecting the increase in SSNA (Δ506 ± 104% vs. Δ415 ± 73% for placebo; NS). Folic acid increased the slope of the SSNA-to-CVC relation (0.08 ± 0.02 vs. 0.05 ± 0.01 for placebo; P < 0.05) and extended the response range. Folic acid augmented ACh-induced vasodilation (83 ± 3% vs. 66 ± 4% CVC max for placebo; P = 0.002); however, there was no difference between treatments at the NOS-inhibited site (53 ± 4% vs. 52 ± 4% CVC max for placebo; NS). These data demonstrate that folic acid supplementation enhances reflex vasodilation by increasing the sensitivity of skin arterioles to central sympathetic nerve outflow during hyperthermia in aged human subjects., (Copyright © 2017 the American Physiological Society.)

Reductions in hydrogen sulfide (H 2 S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H 2 S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H 2 S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H 2 S-dependent vasodilation, and vascular responsiveness to exogenous H 2 S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H 2 S biosynthetic enzyme expression (Western blot) and substrate-dependent H 2 S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10 -6 -10 -1 mol/L) and sodium sulfide (10 -5 -10 1 mol/L) using intradermal microdialysis; the functional role of H 2 S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H 2 S biosynthetic enzyme expression and substrate-dependent H 2 S production were reduced in HTN adults (all P <0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults ( P =0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P =0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P =0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H 2 S, reductions in endogenous synthesis and H 2 S-dependent vasodilation contribute to endothelial dysfunction in human hypertension., (© 2017 American Heart Association, Inc.)

Key Points: In hypertensive adults (HTN), cardiovascular risk increases disproportionately during environmental cold exposure. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in HTN. The findings of the present study show that whole-body cold stress elicits greater increases in sympathetic outflow directed to the cutaneous vasculature and, correspondingly, greater reductions in skin blood flow in HTN. We further demonstrate an important role for non-adrenergic sympathetic co-transmitters in mediating the vasoconstrictor response to cold stress in hypertension. In the context of thermoregulation and the maintenance of core temperature, sympathetically-mediated control of the cutaneous vasculature is not only preserved, but also exaggerated in hypertension. Given the increasing prevalence of hypertension, clarifying the mechanistic underpinnings of hypertension-induced alterations in neurovascular function during cold exposure is clinically relevant., Abstract: Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in hypertensive adults (HTN). We hypothesized that (i) whole-body cooling would elicit greater cutaneous vasoconstriction and greater increases in skin sympathetic nervous system activity (SSNA) in HTN (n = 14; 56 ± 2 years) compared to age-matched normotensive adults (NTN; n = 14; 55 ± 2 years) and (ii) augmented reflex vasoconstriction in HTN would be mediated by an increase in cutaneous vascular adrenergic sensitivity and a greater contribution of non-adrenergic sympathetic co-transmitters. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (water-perfused suit). Sympathetic adrenergic- and non-adrenergic-dependent contributions to reflex cutaneous vasoconstriction and vascular adrenergic sensitivity were assessed pharmacologically using intradermal microdialysis. Cooling elicited greater increases in SSNA (NTN: +64 ± 13% baseline  vs. HTN: +194 ± 26% baseline ; P < 0.01) and greater reductions in skin blood flow (NTN: -16 ± 2% baseline  vs. HTN: -28 ± 3% baseline ; P < 0.01) in HTN compared to NTN, reflecting an increased response range for sympathetic reflex control of cutaneous vasoconstriction in HTN. Norepinephrine dose-response curves showed no HTN-related difference in cutaneous adrenergic sensitivity (logEC 50 ; NTN: -7.4 ± 0.3 log M vs. HTN: -7.5 ± 0.3 log M; P = 0.84); however, non-adrenergic sympathetic co-transmitters mediated a significant portion of the vasoconstrictor response to cold stress in HTN. Collectively, these findings indicate that hypertension increases the peripheral cutaneous vasoconstrictor response to cold via greater increases in skin sympathetic outflow coupled with an increased reliance on non-adrenergic neurotransmitters., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Reflex cutaneous vasodilation in response to passive heating is attenuated in human aging. This diminished response is mediated, in part, by age-associated reductions in endothelial function; however, the contribution of altered skin sympathetic nervous system activity (SSNA) is unknown. We hypothesized that 1) healthy older adults would demonstrate blunted SSNA responses to increased core temperature compared with young adults and 2) the decreased SSNA response would be associated with attenuated cutaneous vasodilation. Reflex vasodilation was elicited in 13 young [23 ± 1 (SE) yr] and 13 older (67 ± 2 yr) adults using a water-perfused suit to elevate esophageal temperature by 1.0°C. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome (the dorsum of foot) were continuously measured. SSNA was normalized to, and expressed as, a percentage of baseline. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and expressed as a percentage of maximal CVC (local heating, 43°C). Reflex vasodilation was attenuated in older adults (P < 0.001). During heating, SSNA increased in both groups (P < 0.05); however, the response was significantly blunted in older adults (P = 0.01). The increase in SSNA during heating was linearly related to cutaneous vasodilation in both young (R 2 = 0.87 ± 0.02, P < 0.01) and older (R 2 = 0.76 ± 0.05, P < 0.01) adults; however, slope of the linear regression between ΔSSNA and ΔCVC was reduced in older compared with young (older: 0.05 ± 0.01 vs. young: 0.08 ± 0.01; P < 0.05). These data demonstrate that age-related impairments in reflex cutaneous vasodilation are mediated, in part, by blunted efferent SSNA during hyperthermia., (Copyright © 2016 the American Physiological Society.)

Humans control their core temperature within a narrow range via precise adjustments of the autonomic nervous system. In response to changing core and/or skin temperature, several critical thermoregulatory reflex effector responses are initiated and include shivering, sweating, and changes in cutaneous blood flow. Cutaneous vasomotor adjustments, mediated by modulations in sympathetic nerve activity (SNA), aid in the maintenance of thermal homeostasis during cold and heat stress since (1) they serve as the first line of defense of body temperature and are initiated before other thermoregulatory effectors, and (2) they are on the efferent arm of non-thermoregulatory reflex systems, aiding in the maintenance of blood pressure and organ perfusion. This review article highlights the sympathetic responses of humans to thermal stress, with a specific focus on primary aging as well as impairments that occur in both heart disease and type 2 diabetes mellitus. Age- and pathology-related changes in efferent muscle and skin SNA during cold and heat stress, measured directly in humans using microneurography, are discussed., (Copyright © 2015 Elsevier B.V. All rights reserved.)

During supine passive heating, increases in skin blood flow (SkBF) and cardiac output (Qc) are both blunted in older adults. The aim here was to determine the effect of acutely correcting the peripheral vasodilatory capacity of aged skin on the integrated cardiovascular responses to passive heating. A secondary aim was to examine the SkBF-Qc relation during hyperthermia in the presence (upright posture) and absence (dynamic exercise) of challenges to central venous pressure. We hypothesized that greater increases in SkBF would be accompanied by greater increases in Qc. Eleven healthy older adults (69 ± 3 yr) underwent supine passive heating (0.8°C rise in core temperature; water-perfused suit) after ingesting sapropterin (BH4, a nitric oxide synthase cofactor; 10 mg/kg) or placebo (randomized double-blind crossover design). Twelve young (24 ± 1 yr) subjects served as a comparison group. SkBF (laser-Doppler flowmetry) and Qc (open-circuit acetylene wash-in) were measured during supine heating, heating + upright posture, and heating + dynamic exercise. Throughout supine and upright heating, sapropterin fully restored the SkBF response of older adults to that of young adults but Qc remained blunted. During heat + upright posture, SkBF failed to decrease in untreated older subjects. There were no age- or treatment-related differences in SkBF-Qc during dynamic exercise. The principal finding of this study was that the blunted Qc response to passive heat stress is directly related to age as opposed to the blunted peripheral vasodilatory capacity of aged skin. Furthermore, peripheral impairments to SkBF in the aged may contribute to inapposite responses during challenges to central venous pressure during hyperthermia., (Copyright © 2015 the American Physiological Society.)

This Synthesis highlights a series of recent studies that has systematically interrogated age-related deficits in cold-induced skin vasoconstriction. In response to cold stress, a reflex increase in sympathetic nervous system activity mediates reductions in skin blood flow. Reflex vasoconstriction during cold exposure is markedly impaired in aged skin, contributing to the relative inability of healthy older adults to maintain core temperature during mild cold stress in the absence of appropriate behavioral thermoregulation. This compromised reflex cutaneous vasoconstriction in healthy aging can occur as a result of functional deficits at multiple points along the efferent sympathetic reflex axis, including blunted sympathetic outflow directed to the skin vasculature, reduced presynaptic neurotransmitter synthesis and/or release, and altered end-organ responsiveness at several loci, in addition to potential alterations in afferent thermoreceptor function. Arguments have been made that the relative inability of aged skin to appropriately constrict is due to the aging cutaneous arterioles themselves, whereas other data point to the neural circuitry controlling those vessels. The argument presented herein provides strong evidence for impaired efferent sympathetic control of the peripheral cutaneous vasculature during whole body cold exposure as the primary mechanism responsible for attenuated vasoconstriction., (Copyright © 2015 the American Physiological Society.)

Exaggerated pressor and muscle sympathetic nerve activity (MSNA) responses have been reported during static handgrip in hypertensive (HTN) adults. Recent work suggests that such responses may occur much more rapidly in HTN patients; however, this has not been extensively studied. Thus, we examined the blood pressure (BP) and MSNA responses at the immediate onset of muscle contraction and tested the hypothesis that older HTN adults would exhibit rapid onset pressor and sympathetic responses compared with normotensive (NTN) adults. Heart rate (HR), BP (Finometer) and MSNA (peroneal microneurography) were retrospectively analyzed in 15 HTN (62 ± 1 years; resting BP 153 ± 3/91 ± 5 mm Hg) and 23 age-matched NTN (60 ± 1 years; resting BP 112 ± 1/67 ± 2 mm Hg) subjects during the first 30 s of static handgrip at 30 and 40% of maximal voluntary contraction (MVC). HTN adults demonstrated exaggerated increases in mean BP during the first 10 s of both 30% (NTN: Δ1 ± 1 vs HTN: Δ7 ± 2 mm Hg; P < 0.05) and 40% (NTN: Δ2 ± 1 vs HTN: Δ8 ± 2 mm Hg; P < 0.05) intensity handgrip. Likewise, HTN adults exhibited atypical increases in MSNA within 10 s. Increases in HR were also greater in HTN adults at 10 s of 30% MVC handgrip, although not at 40% MVC. There were no group differences in 10 s pressor or sympathetic responses to a cold pressor test, suggesting no differences in generalized sympathetic responsiveness. Thus, static handgrip evokes rapid onset pressor and sympathetic responses in older HTN adults. These findings suggest that older HTN adults likely have greater cardiovascular risk even during short duration activities of daily living that contain an isometric component.

Key Points: The reduction in skin blood flow during whole-body cooling is impaired in healthy older adults. However, the relative contributions of altered skin sympathetic nerve activity (SSNA), transduction of this efferent neural outflow to the cutaneous vasculature, and peripheral vascular responsiveness to adrenergic stimuli to the impaired reflex vasoconstrictor response to whole-body cooling in human ageing remain unclear. We report that the SSNA response to whole-body cooling is blunted in healthy older adults, and this attenuated sympathetic response is related to a marked impairment in reflex cutaneous vasoconstriction. Further, the reflex SSNA response to a non-thermoregulatory stimulus was preserved in older adults during cooling. We additionally show that cutaneous vascular responsiveness to adrenergic stimuli is not reduced in older adults. These results further our understanding of the physiological mechanisms underlying impaired thermal-cardiovascular integration in healthy ageing., Abstract: Reflex cutaneous vasoconstriction is impaired in older adults; however, the relative roles of altered skin sympathetic nerve activity (SSNA) and end-organ peripheral vascular responsiveness are unclear. We hypothesized that in older adults whole-body cooling would elicit a blunted SSNA response and cutaneous adrenergic responsiveness would be reduced. Twelve young adults (Y; 24 ± 1 years) and 12 older adults (O; 57 ± 2 years) participated in two protocols. In Protocol 1, SSNA (peroneal microneurography) and red cell flux in the affected dermatome (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (mean skin temperature (Tsk ) 30.5°C; water-perfused suit). Mental stress was performed at mean Tsk 34.0°C (thermoneutral) and at 30.5°C. In Protocol 2, an intradermal microdialysis fibre was placed in the skin of the lateral calf for graded infusions of noradrenaline (norepinephrine) (NA; 10(-12) to 10(-2)  m). Cutaneous vascular conductance (CVC = flux/mean arterial pressure) was expressed as a change from baseline (ΔCVCbase ). Vasoconstriction was attenuated in O. SSNA increased significantly during cooling in Y (+184 ± 37%; P < 0.05) but not O (+51 ± 12%; P > 0.05). Mental stress at Tsk 30.5°C further increased SSNA in both groups. There was no age-related difference in adrenergic responsiveness to exogenous NA (logEC50 : -6.41 ± 0.24 in Y, -6.37 ± 0.25 in O; P > 0.05). While the SSNA response to whole-body cooling is impaired with ageing, SSNA can be further increased by a non-thermoregulatory stimulus. Cutaneous adrenergic sensitivity is not reduced in O. These findings suggest that alterations in afferent signalling or central processing likely contribute to blunted SSNA responses to cooling and subsequent impairments in reflex cutaneous vasoconstriction in ageing., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Key Points: Hydrogen sulphide (H2 S) is vasoprotective, attenuates inflammation and modulates blood pressure in animal models; however, its specific mechanistic role in the human vasculature remains unclear. In the present study, we report the novel finding that the enzymes responsible for endogenous H2 S production, cystathionine-γ-lyase and 3-mercaptopyruvate sulphurtransferase, are expressed in the human cutaneous circulation. Functionally, we show that H2 S-induced cutaneous vasodilatation is mediated, in part, by tetraethylammonium-sensitive calcium-dependent potassium channels and not by ATP-sensitive potassium channels. In addition, nitric oxide and cyclo-oxygenase-derived byproducts are required for full expression of exogenous H2 S-mediated cutaneous vasodilatation. Future investigations of the potential role for H2 S with respect to modulating vascular function in humans may have important clinical implications for understanding the mechanisms underlying vascular dysfunction characteristic of multiple cardiovascular pathologies., Abstract: The present study aimed to identify the presence of cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST), which endogenously produce hydrogen sulphide (H2 S), and to functionally examine the mechanisms of H2 S-induced vasodilatation in the human cutaneous microcirculation. CSE and 3-MST were quantified in forearm skin samples from 5 healthy adults (24 ± 3 years) using western blot analysis. For functional studies, microdialysis fibres were placed in the forearm skin of 12 healthy adults (25 ± 3 years) for graded infusions (0.01-100 mm) of sodium sulphide (Na2 S) and sodium hydrogen sulphide (NaHS). To define the mechanisms mediating H2 S-induced vasodilatation, microdialysis fibres were perfused with Ringer solution (control), a ATP-sensitive potassium channel (KATP ) inhibitor, an intermediate calcium-dependent potassium channel (KCa ) inhibitor, a non-specific KCa channel inhibitor or triple blockade. To determine the interaction of H2 S-mediated vasodilatation with nitric oxide (NO) and cyclo-oxygenase (COX) signalling pathways, microdialysis fibres were perfused with Ringer solution (control), a non-specific NO synthase inhibitor, a non-selective COX inhibitor or combined inhibition during perfusion of increasing doses of Na2 S. CSE and 3-MST were expressed in all skin samples. Na2 S and NaHS elicited dose-dependent vasodilatation. Non-specific KCa channel inhibition and triple blockade blunted Na2 S-induced vasodilatation (P < 0.05), whereas KATP and intermediate KCa channel inhibition had no effect (P > 0.05). Separate and combined inhibition of NO and COX attenuated H2 S-induced vasodilatation (all P < 0.05). CSE and 3-MST are expressed in the human microvasculature. Exogenous H2 S elicits cutaneous vasodilatation mediated by KCa channels and has a functional interaction with both NO and COX vasodilatatory signalling pathways., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Young adults with a family history of hypertension (+FH) have increased risk of developing hypertension. Furthermore, the blood pressure (BP) response to sympathoexcitatory stimuli in young adults can predict the future development of hypertension. Therefore, we hypothesized young women with a +FH would have exaggerated cardiovascular and sympathetic reactivity compared with young women without a family history of hypertension (-FH). Beat-by-beat mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) were measured in 14 women +FH (22 ± 1 yr, 21 ± 1 kg/m(2), MAP 80 ± 2 mmHg) and 15 women -FH (22 ± 1 yr, 22 ± 1 kg/m(2), MAP 78 ± 2 mmHg) during acute sympathoexcitatory maneuvers: cold pressor test, 2 min of isometric handgrip (HG) exercise at 30% of maximal voluntary contraction, and 3 min of postexercise ischemia (PEI; isolated activation of the skeletal muscle metaboreflex). During cold pressor test, the increase in BP was greater in women +FH (ΔMAP: +FH 16 ± 2 vs. -FH 11 ± 1 mmHg, P < 0.05), which was accompanied by an exaggerated increase in MSNA (ΔMSNA: +FH 17 ± 2 vs. -FH 8 ± 2 burst/min, P < 0.05). The increase in BP was greater in +FH during the last minute of HG (ΔMAP: +FH 23 ± 3 vs. -FH 12 ± 1 mmHg, P < 0.05) and during PEI (ΔMAP: +FH 17 ± 3 vs. -FH 9 ± 2 mmHg, P < 0.05). Similarly, the increase in MSNA was greater in +FH during both HG (ΔMSNA: +FH 12 ± 2 vs. -FH 6 ± 2 burst/min, P < 0.05) and PEI (ΔMSNA: +FH 16 ± 2 vs. -FH 4 ± 2 burst/min, P < 0.05). These data demonstrate that +FH women have greater BP and sympathetic reactivity compared with -FH women., (Copyright © 2015 the American Physiological Society.)

Physical activity is a cornerstone therapy for the primary prevention and treatment of hypertension, which is becoming increasingly prevalent in modern societies. During exercise, heart rate and blood pressure (BP) increase in order to acutely meet the metabolic demands of the working skeletal muscle. In hypertensive adults, isometric exercise-induced increases in BP are excessive, potentially increasing the risk of an acute cardiovascular event during or after physical activity. Recently, the skeletal muscle metaboreflex has emerged as a significant contributor to the development of aberrant cardiovascular control during isometric exercise in this clinical population. Our laboratory has conducted a series of studies characterizing the skeletal muscle metaboreflex in hypertensive humans. We and others have demonstrated that hypertension is characterized by greater increases in muscle sympathetic nerve activity and BP during selective activation of the metaboreflex during post-exercise muscle ischemia compared to the increases noted in healthy age-matched normotensive adults, suggesting that the skeletal muscle metaboreflex is exaggerated in human hypertension. The focus of this review is the skeletal muscle metaboreflex (i.e., the metabolic component of the exercise pressor reflex) in hypertension, with particular emphasis on the potential role of purinergic receptors in mediating the exaggerated responses to muscle metaboreflex activation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The cutaneous circulation is used to examine vascular adrenergic function in clinical populations; however, limited studies have examined whether there are regional limb and sex differences in microvascular adrenergic responsiveness. We hypothesized that cutaneous adrenergic responsiveness would be greater in the leg compared with the arm and that these regional limb differences would be blunted in young women (protocol 1). We further hypothesized that cutaneous vasoconstriction to exogenous norepinephrine (NE) during β-adrenergic receptor antagonism would be augmented in young women (protocol 2). In protocol 1, one microdialysis fiber was placed in the skin of the calf and the ventral forearm in 20 healthy young adults (11 men and 9 women). Laser-Doppler flowmetry was used to measure red blood cell flux in response to graded intradermal microdialysis infusions of NE (10(-12) to 10(-2) M). In protocol 2, three microdialysis fibers were placed in the forearm (6 men and 8 women) for the local perfusion of lactated Ringer (control), 5 mM yohimbine (α-adrenergic receptor antagonist), or 2 mM propranolol (β-adrenergic receptor antagonist) during concurrent infusions of NE (10(-12) to 10(-2) M). There were no limb or sex differences in cutaneous adrenergic responsiveness (logEC50) to exogenous NE. During α-adrenergic receptor blockade, women had greater exogenous NE-induced cutaneous vasodilation at the lowest doses of NE (10(-12) to 10(-10) M). Collectively, these data indicate that there are no limb or sex differences in cutaneous adrenergic responsiveness to exogenous NE; however, young women have a greater β-adrenergic receptor-mediated component of the vascular responsiveness to exogenous NE., (Copyright © 2014 the American Physiological Society.)

Local heating of the skin is commonly used to assess cutaneous microvasculature function. Controversy exists as to whether there are limb or sex differences in the nitric oxide (NO)-dependent contribution to this vasodilation, as well as the NO synthase (NOS) isoform mediating the responses. We tested the hypotheses that 1) NO-dependent vasodilation would be greater in the calf compared with the forearm; 2) total NO-dependent dilation would not be different between sexes within limb; and 3) women would exhibit greater neuronal NOS (nNOS)-dependent vasodilation in the calf. Two microdialysis fibers were placed in the skin of the ventral forearm and the calf of 19 (10 male and 9 female) young (23 ± 1 yr) adults for the local delivery of Ringer solution (control) or 5 mM N(ω)-propyl-l-arginine (NPLA; nNOS inhibition). Vasodilation was induced by local heating (42°C) at each site, after which 20 mM N(G)-nitro-l-arginine methyl ester (l-NAME) was perfused for within-site assessment of NO-dependent vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and normalized to maximum (28 mM sodium nitroprusside, 43°C). Total NO-dependent vasodilation in the calf was lower compared with the forearm in both sexes (Ringer: 42 ± 5 vs. 62 ± 4%; P < 0.05; NPLA: 37 ± 3 vs. 59 ± 5%; P < 0.05) and total NO-dependent vasodilation was lower in the forearm for women (Ringer: 52 ± 6 vs. 71 ± 4%; P < 0.05; NPLA: 47 ± 6 vs. 68 ± 5%; P < 0.05). NPLA did not affect total or NO-dependent vasodilation across limbs in either sex (P > 0.05). These data suggest that the NO-dependent component of local heating-induced cutaneous vasodilation is lower in the calf compared with the forearm. Contrary to our original hypothesis, there was no contribution of nNOS to NO-dependent vasodilation in either limb during local heating., (Copyright © 2014 the American Physiological Society.)

Cardiovascular mortality increases in cold weather in older adults, and physical activity may impart even greater cardiovascular risk than cold exposure alone. Human aging is associated with exaggerated pressor responses to whole body cooling; however, the sympathetic response to cold stress alone and in combination with isometric exercise is unknown. We hypothesized that cold stress would 1) increase muscle sympathetic nerve activity (MSNA) and 2) augment the MSNA response to isometric handgrip in older adults. Whole body cooling (water-perfused suit) was conducted in 11 young (23 ± 1 yr) and 12 healthy older adults (60 ± 2 yr). Blood pressure (BP; Finometer) and MSNA (microneurography) were measured throughout cooling and during isometric handgrip at 30% maximal voluntary contraction performed at a mean skin temperature (Tsk) of 34 and 30.5°C. MSNA was greater in older adults at Tsk = 34.0°C and throughout cooling (P < 0.05). MSNA increased during cooling in older, but not young, adults (young: Δ0 ± 1 vs. older: Δ8 ± 1 bursts/min; P < 0.05). The cooling-induced increase in BP was greater in older adults (P < 0.05). During handgrip, the increases in MSNA and BP were not different between conditions in either young (Δ14 ± 2 Tsk 34°C vs. Δ12 ± 3 Tsk 30.5°C bursts/min; Δ20 ± 3 Tsk 34°C vs. Δ19 ± 3 Tsk 30.5°C mmHg; both P > 0.05) or older adults (Δ12 ± 1 Tsk 34°C vs. Δ8 ± 1 Tsk 30.5°C bursts/min; Δ18 ± 3 Tsk 34°C vs. Δ17 ± 2 Tsk 30.5°C mmHg; both P > 0.05). In summary, MSNA increased during cold stress in older, but not young, adults. Furthermore, concomitant cold stress did not alter the sympathetic responses to isometric exercise in either age group, suggesting preserved sympathetic responsiveness during exercise in the cold in healthy aging., (Copyright © 2014 the American Physiological Society.)

The neurocirculatory responses to exercise are exaggerated in hypertension, increasing cardiovascular risk, yet the mechanisms remain incompletely understood. The aim of this study was to examine the in vitro effectiveness of pyridoxal-5-phosphate as a purinergic (P2) receptor antagonist in isolated murine dorsal root ganglia (DRG) neurons and the in vivo contribution of P2 receptors to the neurocirculatory responses to exercise in older adults with moderately elevated systolic blood pressure (BP). In vitro, pyridoxal-5-phosphate attenuated the ATP-induced increases in [Ca(2+)](i) (73 ± 15 vs. 11 ± 3 nM; P < 0.05). In vivo, muscle sympathetic nerve activity (MSNA; peroneal microneurography) and arterial BP (Finometer) were assessed during exercise pressor reflex activation (static handgrip followed by postexercise ischemia; PEI) during a control trial (normal saline) and localized P2 receptor blockade (pyridoxal-5-phosphate). Compared with normotensive adults (63 ± 2 yr, 117 ± 2/70 ± 2 mmHg), adults with moderately elevated systolic BP (65 ± 1 yr, 138 ± 5/79 ± 3 mmHg) demonstrated greater increases in MSNA and BP during handgrip and PEI. Compared with the control trial, local antagonism of P2 receptors during PEI partially attenuated MSNA (39 ± 4 vs. 34 ± 5 bursts/min; P < 0.05) in adults with moderately elevated systolic BP. In conclusion, these data demonstrate pyridoxal-5-phosphate is an effective P2 receptor antagonist in isolated DRG neurons, which are of particular relevance to the exercise pressor reflex. Furthermore, these findings indicate that exercise pressor reflex function is exaggerated in older adults with moderately elevated systolic BP and further suggest a modest role of purinergic receptors in evoking the abnormally large reflex-mediated increases in sympathetic activity during exercise in this clinical population.

Sympathetic baroreflex sensitivity is increased during selective activation of the skeletal muscle metaboreflex with postexercise ischaemia (PEI) in young adults. However, to date, there are no data demonstrating this neural interaction between the arterial baroreflex and the muscle metaboreflex in healthy older adults. Therefore, the goal of the present study was to examine the influence of healthy ageing on the metabolic component of the exercise pressor reflex and its interaction with the arterial baroreflex in the control of sympathetic outflow. Postexercise ischaemia following static hand grip performed at 30% maximal voluntary contraction was used to isolate muscle metaboreflex activation in young [n = 10; 24 ± 1 years old; resting blood pressure (BP) 116 ± 3/64 ± 3 mmHg] and older men (n = 9; 59 ± 2 years old; resting BP 120 ± 2/77 ± 2 mmHg). Arterial BP (Finometer) and muscle sympathetic nerve activity (MSNA) were measured continuously. Weighted linear regression analysis between MSNA and diastolic BP was used to estimate arterial baroreflex MSNA gain. There were no age-related differences in the increase in mean BP (young, Δ14 ± 3 mmHg versus older, Δ15 ± 2 mmHg; P > 0.05) or MSNA burst frequency (young, Δ11 ± 2 bursts min(-1) versus older, Δ9 ± 1 bursts min(-1); P > 0.05) during PEI. Likewise, the gain of arterial baroreflex control of total MSNA increased to a similar extent in both groups during PEI (young, -4.2 ± 0.9 baseline versus -6.3 ± 1.1 PEI a.u. beat(-1) mmHg(-1); and older, -3.7 ± 1.1 baseline versus -6.7 ± 1.4 PEI a.u. beat(-1) mmHg(-1); P < 0.05 for both). Collectively, these findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of MSNA is preserved in healthy ageing.

Background: Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure., Method: Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300-350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ± 1 mmHg; high-sodium: 85 ± 2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet., Results: Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ± 0.9%, high: 7.3 ± 0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05)., Conclusion: These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Animal studies have reported dietary salt-induced reductions in vascular function independent of increases in blood pressure (BP). The purpose of this study was to determine if short-term dietary sodium loading impairs cutaneous microvascular function in normotensive adults with salt resistance. Following a control run-in diet, 12 normotensive adults (31 ± 2 years) were randomized to a 7 day low-sodium (LS; 20 mmol day(-1)) and 7 day high-sodium (HS; 350 mmol day(-1)) diet (controlled feeding study). Salt resistance, defined as a 5 mmHg change in 24 h mean BP determined while on the LS and HS diets, was confirmed in all subjects undergoing study (LS: 84 ± 1 mmHg vs. HS: 85 ± 2 mmHg; P > 0.05). On the last day of each diet, subjects were instrumented with two microdialysis fibres for the local delivery of Ringer solution and 20 mm ascorbic acid (AA). Laser Doppler flowmetry was used to measure red blood cell flux during local heating-induced vasodilatation (42°C). After the established plateau, 10 mm l-NAME was perfused to quantify NO-dependent vasodilatation. All data were expressed as a percentage of maximal cutaneous vascular conductance (CVC) at each site (28 mm sodium nitroprusside; 43°C). Sodium excretion increased during the HS diet (P < 0.05). The plateau % CVCmax was reduced during HS (LS: 93 ± 1 % CVCmax vs. HS: 80 ± 2 % CVCmax; P < 0.05). During the HS diet, AA improved the plateau % CVCmax (Ringer: 80 ± 2 % CVCmax vs. AA: 89 ± 3 % CVCmax; P < 0.05) and restored the NO contribution (Ringer: 44 ± 3 % CVCmax vs. AA: 59 ± 6 % CVCmax; P < 0.05). These data demonstrate that dietary sodium loading impairs cutaneous microvascular function independent of BP in normotensive adults and suggest a role for oxidative stress.

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN (n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip (P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip (P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.