Cardiac autonomic function is preserved in young adults with major depressive disorder.

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, R2 = 0.004, P = 0.73) or cardiac BRS (overall gain, R2 = 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.

Sympathetic transduction at rest and during cold pressor test in young healthy non-Hispanic Black and White women.

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.

Daily Stress and Microvascular Dysfunction: The Buffering Effect of Physical Activity.

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.

Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder.

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 [NG-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 (R2 = 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.

Augmented T-cell mitochondrial reactive oxygen species in adults with major depressive disorder.

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.

Sympathetic transduction in humans: recent advances and methodological considerations.

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.

Hydrogen sulfide-dependent microvascular vasodilation is improved following chronic sulfhydryl-donating antihypertensive pharmacotherapy in adults with hypertension.

Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H2S)-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 H2S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-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 H2S 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 H2S 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 H2S-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 H2S-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 H2S-dependent mechanisms.

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder.

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.

AHA/ACC-defined stage 1 hypertensive adults do not display cutaneous microvascular endothelial dysfunction.

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 10-1M) alone and concurrently with the nonspecific nitric oxide (NO) synthase inhibitor NG-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.

Chronic statin therapy is associated with enhanced cutaneous vascular responsiveness to sympathetic outflow during passive heat stress.

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 (Tor ; 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 ∆Tor  = 1.0°C: normal = 36 ± 1%CVCmax , high = 32 ± 1%CVCmax , statin = 38 ± 1%CVCmax ; P < 0.01). ∆SSNA was not different (at ∆Tor  = 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%CVCmax /%baseline ) compared to both normocholesterolaemic (0.09 ± 0.02%CVCmax /%baseline ; P = 0.024) and statin-treated (0.12 ± 0.05%CVCmax /%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.

Endothelial function is impaired in the cutaneous microcirculation of adults with psoriasis through reductions in nitric oxide-dependent vasodilation.

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 NG-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.

The relationship between the sensory responses to ankle-joint loading and corticomotor excitability.

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.

Neurovascular mechanisms underlying augmented cold-induced reflex cutaneous vasoconstriction in human hypertension.

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 (logEC50 ; 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.

Measuring and quantifying skin sympathetic nervous system activity in humans.

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.

Folic acid supplementation increases cutaneous vasodilator sensitivity to sympathetic nerve activity in older adults.

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 (Tes) 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% CVCmax 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% CVCmax for placebo; P = 0.002); however, there was no difference between treatments at the NOS-inhibited site (53 ± 4% vs. 52 ± 4% CVCmax 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.

Rapid onset pressor response to exercise in young women with a family history of hypertension.

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.

Impaired increases in skin sympathetic nerve activity contribute to age-related decrements in reflex cutaneous vasoconstriction.

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.

Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature.

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.

Sympathetic reactivity in young women with a family history of hypertension.

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.

Exaggerated exercise pressor reflex in adults with moderately elevated systolic blood pressure: role of purinergic receptors.

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.