Vascular Conductance Research Articles

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

A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10F/8M) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low- (15% maximum contraction) and moderate-intensity (30% maximum contraction) rhythmic handgrip. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1h, 2h, and 3h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (∆-54±10%), and these responses were attenuated during low- (∆-17±7%) and moderate-intensity handgrip (∆-8±6%). Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3h postprandial: ∆-47±10%, P=0.002 vs. preprandial), and blunted attenuation of FVC during low- (3h postprandial: ∆-23±8%, P=0.001 vs. preprandial) and moderate-intensity handgrip (3h postprandial: ∆-16±6%, P<0.001 vs. preprandial). The high-fat meal attenuated the magnitude of sympatholysis during low- (preprandial: 38±7% vs. 3h postprandial: 23±8%, P<0.001) and moderate-intensity handgrip (preprandial: 46±11% vs. 3h postprandial: 31±10%, P<0.001). The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults.

Abstract P217: The Role Of Angiotensin-(1-7) In Regulating Vascular Endothelial Function In Postmenopausal Women

Postmenopausal women (PMW) have reduced endothelial function, however, the mechanisms contributing to this decline remain unclear. Angiotensin-(1-7) [Ang-(1-7)] is a vasoactive peptide of the vasodilatory arm of the Renin-Angiotensin system and increasing bioavailable Ang-(1-7) enhances endothelial function in young women (YW) with pre-clinical cardiovascular disease. Circulating Ang-(1-7) decreases with aging and may be impacted by menopause. However, whether increasing bioavailable Ang-(1-7) improves endothelial function in PMW is unknown. The purpose of this study was to test the hypothesis that increasing bioavailable Ang-(1-7) improves endothelial function in PMW. We assessed skin blood flow responses to local heating in 8 healthy YW (27±9 yrs) and 5 healthy PMW (56±4 yrs). Cutaneous vasodilation was measured using laser-Doppler flowmetry directly over microdialysis perfusions of lactated Ringer’s (control) in YW and PMW, and in PMW only, 100 μM Ang-(1-7). Following 45 minutes of perfusion of lactated Ringer’s and Ang-(1-7), skin was heated to 42°C (0.1°C·sec -1 ) until laser-Doppler flux reached a stable plateau, indicative of endothelium-dependent dilation. Following the plateau, 28mM sodium nitroprusside was perfused while skin was heated to 43°C to achieve maximal vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/MAP, and normalized to maximal dilation (%CVC max ). Women were normotensive (MAP: YW 86±7 mmHg; PMW 85±9 mmHg) and not obese (BMI: YW 23±3 kg/m 2 ; PMW 23±4 kg/m 2 ). YW had greater dilation during local heating (control: YW 94.54±5.4 vs. PMW 82.59±10.72 %CVC max ; P=0.021). Contrary to our hypothesis, Ang-(1-7) did not enhance heating-induced vasodilation in PMW (80.10±9.43 %CVC max ; P=0.69). These preliminary results suggest that increasing bioavailable Ang-(1-7) may not improve endothelial function in PMW. Additional studies are needed to understand if these findings are due to estrogen deficiency in PMW.

Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans.

Divers are at enhanced risk of hypothermia, due to the independent action of the inspired inert gases on thermoregulation. Thus, narcosis induced by acute (≤2 h) exposure to either hyperbaric nitrogen or normobaric nitrous oxide (N2O) impairs shivering thermogenesis and accelerates body core cooling. Animal-based studies, however, have indicated that repeated and sustained N2O administration may prevent N2O-evoked hypometabolism. We, therefore, examined the effects of prolonged intermittent exposure to 30% N2O on human thermoeffector plasticity in response to moderate cold. Fourteen men participated in two ∼12-h sessions, during which they performed sequentially three 120-min cold-water immersions (CWIs) in 20°C water, separated by 120-min rewarming. During CWIs, subjects were breathing either normal air or a normoxic gas mixture containing 30% N2O. Rectal and skin temperatures, metabolic heat production (via indirect calorimetry), finger and forearm cutaneous vascular conductance (CVC; laser-Doppler fluxmetry/mean arterial pressure), and thermal sensation and comfort were monitored. N2O aggravated the drop in rectal temperature (P = 0.01), especially during the first (by ∼0.3°C) and third (by ∼0.4°C) CWIs. N2O invariably blunted the cold-induced elevation of metabolic heat production by ∼22%-25% (P < 0.001). During the initial ∼30 min of the first and second CWIs, N2O attenuated the cold-induced drop in finger (P ≤ 0.001), but not in forearm CVC. N2O alleviated the sensation of coldness and thermal discomfort throughout (P < 0.001). Thus, the present results demonstrate that, regardless of the cumulative duration of gas exposure, a subanesthetic dose of N2O depresses human thermoregulatory functions and precipitates the development of hypothermia.NEW & NOTEWORTHY Human thermoeffector plasticity was evaluated in response to prolonged iterative exposure to 30% N2O and moderate cold stress. Regardless of the duration of gas exposure, N2O-induced narcosis impaired in a persistent manner shivering thermogenesis and thermoperception.

Local Passive Heating Increases Vascular Conductance But Not Muscle Oxygenation Independent Of Sex

Local Passive Heating Increases Vascular Conductance But Not Muscle Oxygenation Independent Of Sex

Age- and sex-related differences in sympathetic vascular transduction and neurohemodynamic balance in humans.

Bursts of muscle sympathetic nerve activity (MSNA) and the ensuing vasoconstriction are pivotal determinants of beat-by-beat blood pressure regulation. Although age and sex impact blood pressure regulation, how these factors affect the central and peripheral arcs of the baroreflex remains unclear. In 27 young [25 (SD 3) yr] males (YM; n = 14) and females (YF; n = 13) and 23 older [71 (SD 5) yr] males (OM; n = 11) and females (OF; n = 12), femoral artery blood flow, blood pressure, and MSNA were recorded for 10 min of supine rest. Sympathetic baroreflex sensitivity (i.e., central arc) was quantified as the relationship between diastolic blood pressure and MSNA burst incidence. Signal averaging was used to determine sympathetic vascular transduction into leg vascular conductance (LVC) for 12 cardiac cycles following MSNA bursts (i.e., peripheral arc). Older adults demonstrated attenuated sympathetic transduction into LVC (both P < 0.001) following MSNA bursts, and smaller increases in sympathetic transduction as a function of MSNA burst size and firing pattern compared with young adults (range, P = 0.004-0.032). YM (r2 = 0.36; P = 0.032) and OM (r2 = 0.51; P = 0.014) exhibited an inverse relationship between the central and peripheral arcs of the baroreflex, whereas females did not (YF, r2 = 0.03, P = 0.621; OF, r2 = 0.06, P = 0.445). MSNA burst incidence was inversely related to sympathetic transduction in YM and OF (range, P = 0.03-0.046) but not in YF or OM (range, P = 0.360-0.603). These data indicate that age is associated with attenuated sympathetic vascular transduction, whereas age- and sex-specific changes are present in the relationship between the central and peripheral arcs of the baroreflex regulation of blood pressure.NEW & NOTEWORTHY Sympathetic vascular transduction is attenuated in older compared with young adults, regardless of biological sex. Males, but not females (regardless of age), demonstrate an inverse relationship between central (sympathetic baroreflex sensitivity) and peripheral (sympathetic vascular transduction) components of the baroreflex arc. Young males and older females exhibit an inverse relationship between resting sympathetic outflow and sympathetic vascular transduction. Our results indicate that age and sex exert independent and interactive effects on sympathetic vascular transduction and sympathetic neurohemodynamic balance in humans.

Evidence of impaired functional sympatholysis in patients with heart failure with preserved ejection fraction.

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., "functional sympatholysis"). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, -20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the "magnitude of sympatholysis" was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: -9.5 ± 5.5 vs. Con: -21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: -5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: -9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: -15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group.NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

Greater post-exercise hypotension in healthy young untrained men after exercising in a hot compared to a temperate environment

This research examined the effects of exercising in a hot compared to a temperate environment on post-exercise hemodynamics in untrained men. We hypothesized exercise in a hot compared to a temperate environment would elicit greater post-exercise hypotension, and this would be attributable to higher cutaneous vascular conductance and sweat loss, and lower heart rate variability (HRV) and cardiac baroreflex sensitivity (cBRS). In a randomized counterbalanced order, 12 untrained healthy men completed two trials involving 40-min leg-cycling exercise at either 23 °C (CON) or 35 °C (HOT). Post-exercise participants rested supine for 60 min at 23 °C whilst hemodynamic and thermoregulatory measurements were assessed. Post-exercise hypotension was greater after exercising in a hot than a temperate environment as indicated by a lower mean arterial pressure at 60 min recovery (CON 83 ± 5 mmHg, HOT 78 ± 5 mmHg, Mean difference [95% confidence interval], −5 [–8, −3] mmHg). Throughout recovery, cutaneous vascular conductance was higher, and cBRS and HRV were lower after exercising in a hot than in a temperate environment (P < 0.05). Sweat loss was greater on HOT than on CON (P < 0.001). Post-exercise hypotension after exercising in the hot environment was associated with sweat loss (r = 0.66, P = 0.02), and changes in cutaneous vascular conductance (r = 0.64, P = 0.03), and HRV (Root mean square of the successive difference in R-R interval [RMSSD]) r=0.75, P = 0.01 and and log high frequency [HF] r=0.66, P = 0.02), but not cBRS (all, r ≤ 0.2, P > 0.05). Post-exercise hypotension was greater after exercise in a hot compared to a temperate environment and may be partially explained by greater sweat loss and cutaneous vascular conductance, and lower HRV.

Effects of a Mitochondrial Targeted Ubiquinol (MitoQ) on Vascular Function and Exercise Capacity in Chronic Kidney Disease: A Randomized Controlled Pilot Study.

Mitochondrial derived oxidative stress is implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondrial targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (Mean±SEM: Age, 62±3years; eGFR, 45±3ml/min/1.732) received 4 weeks of 20mg/day MitoQ (MTQ) or placebo (PLB). Outcomes assessed at baseline and follow up included macrovascular function measured by flow mediated dilation; microvascular function assessed by laser Doppler flowmetry combined with intradermal microdialysis; aortic hemodynamics assessed by oscillometery; and exercise capacity by cardiopulmonary exercise testing. Compared to PLB, MTQ improved flow mediated dilation (baseline vs follow up: MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; p=0.04). MTQ improved microvascular function (DCVC: MTQ, 4.50 ± 2.57 vs. PLB -2.22 ± 2.67%; p=0.053). Central aortic systolic and pulse pressures were unchanged, however, MTQ prevented increases in augmentation pressures that were observed in the PLB group (p=0.026). MTQ did not affect exercise capacity. This study demonstrates potential for a mitochondrial targeted ubiquinol to improve vascular function in CKD. The findings hold promise for future investigations of mitochondrial targeted therapies in CKD.

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Modulation of red blood cell nitric oxide synthase phosphorylation in the quiescent and exercising human forearm.

In vitro investigations demonstrate that human erythrocytes synthesize nitric oxide via a functional isoform of endothelial nitric oxide synthase (NOS) (RBC-NOS). We tested the hypothesis that phosphorylation of RBC-NOS at serine residue 1177 (RBC-NOS1177) would be amplified in blood draining-active skeletal muscle. Furthermore, given hypoxemia modulates local blood flow and thus shear stress, and nitric oxide availability, we performed duplicate experiments under normoxia and hypoxia. Nine healthy volunteers performed rhythmic handgrip exercise at 60% of individualized maximal workload for 3.5 min while breathing room air (normoxia) and after being titrated to an arterial oxygen saturation ≈80% (hypoxemia). We measured brachial artery blood flow by high-resolution duplex ultrasound, while continuously monitoring vascular conductance and mean arterial pressure using finger photoplethysmography. Blood was sampled during the final 30 s of each stage from an indwelling cannula. Blood viscosity was measured to facilitate calculation of accurate shear stresses. Erythrocytes were assessed for levels of phosphorylated RBC-NOS1177 and cellular deformability from blood collected at rest and during exercise. Forearm exercise increased blood flow, vascular conductance, and vascular shear stress, which coincided with a 2.7 ± 0.6-fold increase in RBC-NOS1177 phosphorylation (P < 0.0001) and increased cellular deformability (P < 0.0001) under normoxia. When compared with normoxia, hypoxemia elevated vascular conductance and shear stress (P < 0.05) at rest, while cellular deformability (P < 0.01) and RBC-NOS1177 phosphorylation (P < 0.01) increased. Hypoxemic exercise elicited further increases in vascular conductance, shear stress, and cell deformability (P < 0.0001), although a subject-specific response in RBC-NOS1177 phosphorylation was observed. Our data yield novel insights into the manner that hemodynamic force and oxygen tension modulate RBC-NOS in vivo.

Galanin receptors modulate cutaneous vasodilation elicited by whole-body and local heating but not thermal sweating in young adults

Galanin receptor subtypes GAL1, GAL2, and GAL3 are involved in several biological functions. We hypothesized that 1) GAL3 receptor activation contributes to sweating but limits cutaneous vasodilation induced by whole-body and local heating without a contribution of GAL2; and 2) GAL1 receptor activation attenuates both sweating and cutaneous vasodilation during whole-body heating. Young adults underwent whole-body (n = 12, 6 females) and local (n = 10, 4 females) heating. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC; ratio of laser-Doppler blood flow to mean arterial pressure) were assessed during whole-body heating (water-perfusion suit circulated with warm (35 °C) water), while CVC was also assessed by local forearm heating (from 33 °C to 39 °C and elevated to 42 °C thereafter; each level of heating maintained for ∼30 min). Sweat rate and CVC were evaluated at four intradermal microdialysis forearm sites treated with either 1) 5% dimethyl sulfoxide (control), 2) M40, a non-selective GAL1 and GAL2 receptor antagonist, 3) M871 to selectively antagonize GAL2 receptor, or 4) SNAP398299 to selectively antagonize GAL3 receptor. Sweating was not modulated by any GAL receptor antagonist (P > 0.169), whereas only M40 reduced CVC (P ≤ 0.003) relative to control during whole-body heating. Relative to control, SNAP398299 augmented the initial and sustained increase in CVC during local heating to 39 °C, and the transient increase at 42 °C (P ≤ 0.028). We confirmed that while none of the galanin receptors modulate sweating during whole-body heating, GAL1 receptors mediate cutaneous vasodilation. Further, GAL3 receptors blunt cutaneous vasodilation during local heating.

Advanced glycation end products impair coronary artery BK channels via AMPK/Akt/FBXO32 signaling pathway.

Background: Advanced glycation end products (AGEs) impair vascular physiology in Diabetes mellitus (DM). However, the underlying mechanisms remain unclear. Vascular large conductance calcium-activated potassium (BK) channels play important roles in coronary arterial function.Purpose: Our study aimed to investigate the regulatory role of AGEs in BK channels.Research Design: Using gavage of vehicle (V, normal saline) or aminoguanidine (A) for 8 weeks, normal and diabetic rats were divided into four groups: C+V group, DM+V group, C+A group, and DM+A group.Study Sample: Coronary arteries from different groups of rats and human coronary smooth muscle cells were used in this study.Data Collection and Analysis: Data were presented as mean ± SEM (standard error of mean). Student's t-test was used to compare data between two groups. One-way ANOVA with post-hoc LSD analysis was used to compare data between multiple groups.Results: Compared to the C+V group, vascular contraction induced by iberiotoxin (IBTX), a BK channel inhibitor, was impaired, and BK channel densities decreased in the DM+V group. However, aminoguanidine administration reduced the impairment. Protein expression of BK-β1, phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), and protein kinase B (PKB or Akt) were down-regulated, while F-box protein 32 (FBXO32) expression increased in the DM+V group and in high glucose (HG) cultured human coronary smooth muscle cells. Treatment with aminoguanidine in vitro and in vivo could reverse the above protein expression. The effect of aminoguanidine on the improvement of BK channel function by inhibiting the generation of AGEs was reversed by adding MK2206 (Akt inhibitor) or Compound C (AMPK inhibitor) in HG conditions in vitro.Conclusions: AGEs aggravate BK channel dysfunction via the AMPK/Akt/FBXO32 signaling pathway.

Preserved endothelium-independent vascular function with aging in men and women: evidence from the peripheral and cerebral vasculature.

In the peripheral and cerebral vasculature, the impact of aging and sex on the endothelial-independent functional capacity of vascular smooth muscle cells (VSMCs) is not well understood, nor is it known whether such VSMC functions in these vascular beds reflect one another. Therefore, endothelium-independent dilation, at both the conduit (Δ diameter) and microvascular (Δ vascular conductance, VC) level, elicited by sublingual nitroglycerin (NTG, 0.8 mg of Nitrostat), compared with sham-delivery (control), was assessed using Doppler ultrasound in the popliteal (PA) and middle cerebral (MCA) artery of 20 young [23 ± 4 yr, 10 males (YM)/10 females (YF)] and 21 old [69 ± 5 yr, 11 males (OM)/10 females (OF)] relatively healthy adults. In the PA, compared with zero, NTG significantly increased diameter in all groups (YM: 0.29 ± 0.13, YF: 0.35 ± 0.26, OM: 0.30 ± 0.18, OF: 0.31 ± 0.14 mm), while control did not. The increase in VC only achieved significance in the OF (0.22 ± 0.31 mL/min/mmHg). In the MCA, compared with zero, NTG significantly increased diameter and VC in all groups (YM: 0.89 ± 0.30, 1.06 ± 1.28; YF: 0.97 ± 0.31, 1.84 ± 1.07; OM: 0.90 ± 0.42, 0.72 ± 0.99; OF: 0.74 ± 0.32, 1.19 ± 1.18, mm and mL/min/mmHg, respectively), while control did not. There were no age or sex differences or age-by-sex interactions for both the NTG-induced PA and MCA dilation and VC. In addition, PA and MCA dilation and VC responses to NTG were not related when grouped by age, sex, or as all subjects (r = 0.04-0.44, P > 0.05). Thus, peripheral and cerebral endothelial-independent VSMC function appears to be unaffected by age or sex, and variations in such VSMC function in one of these vascular beds are not reflected in the other.NEW & NOTEWORTHY To confidently explain peripheral and cerebral vascular dysfunction, it is essential to have a clear understanding of the endothelial-independent function of VSMCs across age and sex. By assessing endothelium-independent dilation using sublingual nitroglycerin, endothelial-independent VSMC function in the periphery (popliteal artery), and in the cerebral circulation (middle cerebral artery), was not different due to age or sex. In addition, endothelial-independent VSMC function in one of these vascular beds is not reflected in the other.

Effects of alpha-adrenergic receptor blockade on coronary circulation in postmenopausal women.

We sought to investigate the effect of the α1-adrenergic receptor blockade during handgrip exercise (Grip), isolated metaboreflex activation (Metabo), and cold pressor test (CPT) on coronary circulation in young (YW) and postmenopausal women (PMW). Ten YW and 9 PMW underwent two protocols: (1) 3min of baseline followed by 3min of CPT and (2) 3min of rest, 3min of Grip followed by 3min of Metabo. Protocols were carried out under control conditions and α1-adrenergic receptor blockade (oral prazosin 0.03mg·kg-1). Coronary blood velocity (CBV) and vascular conductance (CCI) were lower in PMW. Grip increased CBV only in YW (YW: Δ18.0 ± 21.1% vs. PMW: Δ4.2 ± 10.1%; p < 0.05), and the blockade did not change the CBV response to Grip in YW and PMW. During the Metabo, CBV returned to resting levels in YW and was unchanged from rest in PMW, before (YW:Δ1.7 ± 8.7% vs. PMW: Δ-1.5 ± 8.6) and under the blockade (YW: Δ4.5 ± 14.8% vs. PMW: Δ9.1 ± 29.5%). CPT did not change CBV in both groups (YW: Δ3.9 ± 8.0 vs. PMW: Δ-4.1 ± 6.2%), following the α1-blockade, CPT increased CBV only in YW (YW: Δ11.2 ± 12.8% vs. PMW: Δ2.2 ± 7.1%; p < 0.05 for group and condition). CCI decreased during Grip, Metabo, and CPT in YW and PMW, while the blockade prevented that decrease only in YW. The α1-adrenergic receptor plays a role in the control of coronary circulation in young women, evoking stronger vasoconstriction during CPT than Grip and Metabo in YW. PMW have impaired vasomotor control in the coronary circulation, which seems not to be caused by the α1-adrenergic receptor.

Blood flow restriction training activates the muscle metaboreflex during low-intensity sustained exercise.

Blood flow restriction training (BFRT) employs partial vascular occlusion of exercising muscle and has been shown to increase muscle performance while using reduced workload and training time. Numerous studies have demonstrated that BFRT increases muscle hypertrophy, mitochondrial function, and beneficial vascular adaptations. However, changes in cardiovascular hemodynamics during the exercise protocol remain unknown, as most studies measured blood pressure before the onset and after the cessation of exercise. With reduced perfusion to the exercising muscle during BFRT, the resultant accumulation of metabolites within the ischemic muscle could potentially trigger a large reflex increase in blood pressure, termed the muscle metaboreflex. At low workloads, this pressor response occurs primarily via increases in cardiac output. However, when increases in cardiac output are limited (e.g., heart failure or during severe exercise), the reflex shifts to peripheral vasoconstriction as the primary mechanism to increase blood pressure, potentially increasing the risk of a cardiovascular event. Using our chronically instrumented conscious canine model, we utilized a 60% reduction in femoral blood pressure applied to the hindlimbs during steady-state treadmill exercise (3.2 km/h) to reproduce the ischemic environment observed during BFRT. We observed significant increases in heart rate (+19 ± 3 beats/min), stroke volume (+2.52 ± 1.2 mL), cardiac output (+1.21 ± 0.2 L/min), mean arterial pressure (+18.2 ± 2.4 mmHg), stroke work (+1.93 ± 0.2 L/mmHg), and nonischemic vascular conductance (+3.62 ± 1.7 mL/mmHg), indicating activation of the muscle metaboreflex.NEW & NOTEWORTHY Blood flow restriction training (BFRT) increases muscle mass, strength, and endurance. There has been minimal consideration of the reflex cardiovascular responses that could be elicited during BFRT sessions. We showed that during low-intensity exercise BFRT may trigger large reflex increases in blood pressure and sympathetic activity due to muscle metaboreflex activation. Thus, we urge caution when employing BFRT, especially in patients in whom exaggerated cardiovascular responses may occur that could cause sudden, adverse cardiovascular events.

Attenuated pulsatile transition to the cerebral vasculature during high-intensity interval exercise in young healthy men.

What is the central question of this study? High-intensity interval exercise (HIIE) is recommended for its favourable haemodynamic stimulation, but excessive haemodynamic fluctuations may stress the brain: is the cerebral vasculature protected against exaggerated systemic blood flow fluctuation during HIIE? What is the main finding and its importance? Time- and frequency-domain indices of aortic-cerebral pulsatile transition were lowered during HIIE. The findings suggest that the arterial system to the cerebral vasculature may attenuate pulsatile transition during HIIE as a defence mechanism against pulsatile fluctuation for the cerebral vasculature. High-intensity interval exercise (HIIE) is recommended because it provides favourable haemodynamic stimulation, but excessive haemodynamic fluctuations may be an adverse impact on the brain. We tested whether the cerebral vasculature is protected against systemic blood flow fluctuation during HIIE. Fourteen healthy men (age 24 ± 2 years) underwent four 4-min exercises at 80-90% of maximal workload (Wmax ) interspaced by 3-min active rest at 50-60% Wmax . Transcranial Doppler measured middle cerebral artery blood velocity (CBV). Systemic haemodynamics (Modelflow) and aortic pressure (AoP, general transfer function) were estimated from an invasively recorded brachial arterial pressure waveform. Using transfer function analysis, gain and phase between AoP and CBV (0.39-10.0Hz) were calculated. Stroke volume, aortic pulse pressure and pulsatile CBV increased during exercise (time effect: P<0.0001 for all), but a time-domain index of aortic-cerebral pulsatile transition (pulsatile CBV/pulsatile AoP) decreased throughout the exercise bouts (time effect: P<0.0001). Furthermore, transfer function gain reduced, and phase increased throughout the exercise bouts (time effect: P<0.0001 for both), suggesting the attenuation and delay of pulsatile transition. The cerebral vascular conductance index (mean CBV/mean arterial pressure; time effect: P=0.296), an inverse index of cerebral vascular tone, did not change even though systemic vascular conductance increased during exercise (time effect: P<0.0001). The arterial system to the cerebral vasculature may attenuate pulsatile transition during HIIE as a defence mechanism against pulsatile fluctuation for the cerebral vasculature.

Renal vascular conductance is unrelated to leg vascular conductance or muscle sympathetic nerve activity at rest and during stress in humans.

The sympathetic nervous system is important for cardiovascular regulation, particularly during acute stress. Efferent sympathetic outflow can be regulated in an organ-dependent manner, but whether renal and leg vasoconstriction are associated at rest or during sympathetic stressors is unknown. Therefore, we sought to determine the relationships between muscle sympathetic nerve activity (MSNA), leg vascular conductance (LVC), and renal vascular conductance (RVC) at rest and during common laboratory-based sympathoexcitatory stimuli in a cohort of young healthy adults. Beat-to-beat arterial pressure (photoplethysmography), MSNA (microneurography), superficial femoral artery blood flow, and renal artery blood velocity (Doppler ultrasound) were measured at rest and during static handgrip exercise (30% maximal voluntary contraction), postexercise circulatory occlusion (PECO), and cold stress (hand in 3.8 ± 1.3°C water) in 37 young healthy adults (16 females, 21 males). At rest, RVC was unrelated to LVC (r = -0.11, P = 0.55) or MSNA burst frequency (ρ = -0.22, P = 0.26). Static handgrip, PECO, and cold stress each induced an increase in mean arterial pressure and MSNA and a reduction in RVC (all P < 0.001). LVC was unaltered during stress (all P ≥ 0.16), with the exception of a reduction during the second minute of cold stress (P = 0.03). During stress, changes in RVC were not associated with changes in LVC (handgrip: r = -0.24, P = 0.21; PECO: ρ = -0.04, P = 0.82; cold stress: r = -0.17, P = 0.38) or MSNA (handgrip: ρ = -0.14, P = 0.48; PECO: r = 0.27, P = 0.15; cold stress: r = -0.27, P = 0.16). Furthermore, MSNA was not associated with LVC at rest or during stress (all P ≥ 0.12). The present findings highlight the differential control of regional sympathetic vasoconstriction at rest and during stress in young healthy humans.NEW & NOTEWORTHY The sympathetic nervous system plays a critical role in cardiovascular regulation at rest and during stress. We demonstrate that renal artery vascular conductance is unrelated to superficial femoral artery vascular conductance or muscle sympathetic nerve activity at rest or during laboratory-based sympathetic stressors in young healthy adults. These findings support the concept of differential control of peripheral sympathetic outflow at rest and during stress in humans.

Nitric oxide‐mediated cutaneous microvascular function is not altered in middle‐aged‐to‐older adults following mild SARS‐CoV‐2 infection: A pilot study

We tested the hypothesis that post-COVID-19 adults (PC) would have impaired cutaneous nitric oxide (NO)-mediated vasodilation compared to controls (CON). We performed a cross-sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post-diagnosis). COVID-19 symptoms severity (survey) was assessed (0-100 scale for 18 common symptoms). NO-dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG-nitro-L-arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser-Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax , p = 0.77) and NO-dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO-dependent vasodilation (r < 0.01, p = 0.99 and r = 0.42, p = 0.35, respectively). In conclusion, middle-aged and older adults who have had COVID-19 did not have impaired NO-dependent cutaneous vasodilation. Additionally, in this cohort of PC, neither time since diagnosis nor symptomology were related to microvascular function.

Circadian and sex differences in post-ischemic vasodilation and reactive hyperemia in young individuals and elderly with and without type 2 diabetes.

Cardiovascular events show morning preference and sex differences, and are related to aging and type 2 diabetes. We assessed circadian variations and sex differences in vascular conductance (VC) and blood flow (BF) regulations following a brief bout of forearm ischemia. Young healthy individuals (H18-30) and elderly without (H50-80) and with type 2 diabetes (T2DM50-80) of both sexes were included. Forearm VC and BF, and mean arterial pressure (MAP) at baseline and following circulatory reperfusion were measured at 6 a.m. and 9 p.m. In the morning compared to evening, following reperfusion, the VC and BF increments were similar in H18-30 (p>.71), but lower in H50-80 (p<.001) and T2DM50-80 (p<.01). VC and BF following circulatory reperfusion were higher in men than women in H18-30 (p<.001), but similar between sexes in the older groups (p>.23). Forearm vasodilation following reperfusion is attenuated in the morning in the elderly, impairing BF towards an ischemic area. Diabetes does not affect the circadian regulation of VC and BF, but that of MAP. There are sex differences in VC and BF at baseline and after circulatory reperfusion at a young age, being greater in men, which disappear with aging without being affected by diabetes.