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We sought to investigate possible impaired hyperaemia during dynamic handgrip exercise (HGE) in young healthy individuals who had recovered from COVID-19. We tested the vascular function in individuals recovered from COVID-19 using a nitric oxide donor (i.e., sodium nitroprusside; SNP), which could revert a possible impaired endothelial function during HGE. Further, we tested whether individuals who recovered from COVID-19 would present exaggerated brachial vascular resistance under an adrenergic agonist (i.e., phenylephrine; PHE) stimuli during HGE. Participants were distributed into two groups: healthy controls (Control; men: n = 6, 30 ± 3 years, 26 ± 1 kg/m2; and women: n = 5, 25 ± 1 years, 25 ± 1 kg/m2) and subjects recovered from COVID-19 (post-COVID; men: n = 6, 29 ± 3 years, 25 ± 1 kg/m2; and women: n = 10, 32 ± 4 years, 22 ± 1 kg/m2). Participants in the post-COVID group tested positive (RT-PCR) 12-14 weeks before the protocol. Heart rate (HR), brachial blood pressure (BP), brachial blood flow (BBF) and vascular conductance (BVC) at rest were not different between groups. The HGE increased HR (Control: Δ9 ± 0.4 bpm; and post-COVID: Δ11 ± 0.4 bpm) and BP (Control: Δ6 ± 1 mmHg; and post-COVID: Δ12 ± 0.6 mmHg) in both groups. Likewise, BBF (Control: Δ632 ± 38 ml/min; and post-COVID: Δ620 ± 27 ml/min) and BVC (Control: Δ6.6 ± 0.4 ml/min/mmHg; and post-COVID: Δ6.1 ± 0.3 ml/min/mmHg) increased during HGE. SNP did not change HGE-induced hyperaemia but did decrease BP, which induced a reflex-related increase in HR. PHE infusion also did not change the HGE-induced hyperaemia but raised BP and reduced HR. In conclusion, exercise-induced hyperaemia is preserved in healthy young subjects 12-14 weeks after recovery from COVID-19 infection.

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Ascorbic acid (AA) may contribute to restoring hemostatic balance after mental stress (MS) in overweight/obese adults. We aimed to determine the effects of AA administration on hemostatic responses to MS in overweight/obese men. Fourteen overweight/obesity men (27 ± 7 years; BMI: 29.7 ± 2.6 kg m-2) performed the Stroop color-word stress task for 5 min after non-simultaneous infusion of placebo (PL, 0.9% NaCl) and AA (3 g). Blood was collected at baseline, during MS, and 60 min after MS to measure: activated partial thromboplastin time, prothrombin time, and fibrinogen concentration, by coagulometer; platelet-derived microvesicles (PMV, mv/µL), by flow cytometry; nitrite (µM), by chemiluminescence. In PL session, MS led to decreases in PTs (stress, p = 0.03; 60 min, p < 0.001), PT-INR (stress, p < 0.001; 60 min, p < 0.01), aPTTs (60 min, p = 0.03), aPTT ratio (60 min, p = 0.04) and fibrinogen (60 min, p = 0.04), while increased PT activity (60 min, p = 0.01) when compared to baseline. Furthermore, AA increased PTs (60 min, p < 0.001), PT-INR (60 min, p = 0.03) and decreased PT activity (60 min, p < 0.001) and fibrinogen (stress, p = 0.04) when compared to PL. Nitrite was increased in response to stress during AA session (p < 0.001 vs PL). There was no difference in PMV. Ascorbic acid prevented the impaired hemostatic profile and improved nitrite response to stress in the overweight and obese adults.

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Exposure to prolonged stress in pregnancy and/or lactation can lead to the future development of diseases. We aimed to study the effects of maternal stress on the biometry, metabolism, and penile morphology of young Wistar rats. Animals were divided into two experimental groups: Control Group (C) - pups from control mothers, without any intervention (n=5); and Chronic Stress Group (S) - pups from mothers who suffered variable stress in the third week of pregnancy (14th to 21st day; n=5). Food intake and body mass of the pups (n=10, in the C group and n=9 in the S group) were checked; at euthanasia (three months old), fat deposits and penis were removed. At birth and weaning, S animals were lighter than C animals, [-33.72% (p=0.0422) and -17.07% (p=0.0018)], respectively. However, the final body mass and body mass delta showed no differences. Food intake and fat deposits also did not differ. However, the S group was hyperglycemic at 30 and 60 days of life [+20.59% (p=0.0042) and +14.56% (p=0.0079), respectively], despite the glycemia measured at 90 days showing no difference between groups. Penile areas and surface densities of the corpora cavernosa components were similar between groups. The results indicate that maternal stress is an important metabolic programmer, which generates low birth weight and accelerated recovery of body mass after birth (catch-up). However, in an early analysis (90 days of life), exposure to gestational stress did not change the morphology of the offspring's penis in adulthood.

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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) 3 min of baseline followed by 3 min of CPT and (2) 3 min of rest, 3 min of Grip followed by 3 min of Metabo. Protocols were carried out under control conditions and α1-adrenergic receptor blockade (oral prazosin 0.03 mg·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.

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PURPOSE: We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women. METHODS: The protocol consisted of 3 min of trigeminal nerve stimulation (TGS) with cold stimuli to the face, in two conditions: (1) control and ß-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). RESULTS: Thirty-one healthy young subjects (women: n = 13; men: n = 18) participated in the study. By design, TGS decreased heart rate (HR), and increased blood pressure (BP) and cardiac output (CO). Before the ß-blockade coronary blood velocity (CBV-Δ1.4 ± 1.3 cm s-1) increased along with the decrease of coronary vascular conductance index (CVCi-Δ-0.04 ± 0.04 cm s-1 mmHg-1) during TGS and the ß-blockade abolished the CBV increase and a further decrease of CVCi was observed with TGS (Δ-0.06 ± 0.07 cm s-1 mmHg-1). During the α-blockade condition before the blockade, the CBV increased (Δ0.93 ± 1.48 cm s-1) along with the decrease of CVCi (Δ-0.05 ± 1.12 cm s-1 mmHg-1) during TGS, after the α-blockade CBV (Δ0.98 ± cm s-1) and CVCi (Δ-0.03 ± 0.06 cm s-1 mmHg-1) response to TGS did not change. CONCLUSION: Coronary circulation increases during sympathetic stimulation even with a decrease in heart rate.

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The main goal was to determine the impact of mental stress (MS) on blood flow regulation in overweight/obese men. Fourteen overweight/obese men (27 ± 7 years; 29.8 ± 2.6 kg/m2 ) participated in two randomized experimental sessions with oral administration of the AT1R blocker Olmesartan (40 mg; AT1RB) or placebo (PL). After 2 h, a 5-min acute MS session (Stroop Color Word Test) was administered. Blood flow was assessed at baseline and during the first 3 min of MS by vascular ultrasound in the brachial artery. Blood was collected before (baseline) and during mental stress (MS) for measurement of nitrite (chemiluminescence) and endothelin-1 (ELISA kit). The AT1R blocker was able to reverse the MS responses observed in the placebo session for retrograde flow (p < 0.01), retrograde SR (p < 0.01) and oscillatory shear index (p = 0.01). Regarding vasoactive substances, no differences were observed in ET-1 (p > 0.05) responses to MS between experimental sessions. However, for nitrite responses, the administration of the AT1R blocker was able to increase circulating levels of NO (p = 0.03) Blockade of AT1R appears to prevent the decrease in endothelial function by reducing low shear stress and maintaining the vasoactive substances balance after MS in overweight/obese men.

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PURPOSE: We investigate the impact of menopause on cardiovascular adjustments to the cold pressor test (CPT) and the role of the α1-adrenergic receptor. METHODS: Ten young women (YW) and nine postmenopausal women (MW) underwent 1 min of CPT in control and α1-blockade conditions (0.03 mg‧kg-1 of oral prazosin). RESULTS: CPT increased heart rate (HR) (YW: ∆20 ± 3 bpm; MW: ∆13 ± 2 bpm) and stroke volume (SV; YW: ∆15 ± 8 ml; MW: ∆9 ± 6 ml; p = 0.01 for time) and evoked a greater increase in cardiac output (CO) in YW (YW: ∆2.1 ± 0.2 l‧m-1; MW: ∆1.3 ± 0.5 l‧m-1; p = 0.01). α1-Blockade increased baseline HR and did not change HR, SV, and CO responses to CPT. MW presented an exaggerated systolic blood pressure (BP) response (YW: ∆38 ± 9 mmHg; MW: ∆56 ± 24 mmHg; p = 0.03). The α1-blockade did not change baseline BP while blunting its response. Total vascular resistance (TVR) was similar between groups at baseline and increased during CPT only in MW (YW: ∆2.3 ± 1.4 mmHg‧L-1‧min; MW:∆6.8 ± 5.9 mmHg‧L-1‧min). Under α1-blockade, the TVR increase during CPT was attenuated in MW and abolished in YW (YW: ∆0.3 ± 1.2 mmHg‧L-1‧min and MW: ∆3.0 ± 2.0 mmHg‧L-1‧min). CPT did not change femoral vascular conductance (FVC) in either group before the blockade (YW: ∆-0.3 ± 4.0 ml‧min-1‧mmHg-1; MW: ∆-0.2 ± 0.8 ml‧min-1‧mmHg-1); however, FVC tended to increase in young women (YW: ∆1.3 ± 1.0 ml‧min-1‧mmHg-1; MW: ∆0.1 ± 1.5 ml‧min-1‧mmHg-1; p = 0.06) after the α1-blockade. CONCLUSION: In postmenopausal women, the cardiac ability to adjust to CPT is blunted and α1-adrenergic receptor stimulation is important for the increase in stroke volume. In addition, the peripheral effect of α1-adrenergic receptor stimulation seems to be increased in postmenopausal women.

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Aims: Both postprandial lipemia (PPL) and disturbed blood flow (DBF) induce endothelial dysfunction. However, the interactive effect of these stimuli on endothelial function is currently unknown. In the present study, we tested whether PPL plus DBF causes a greater reduction in flow-mediated dilation (FMD) than PPL and if this response is associated with elevations in oxidative stress and endothelial microvesicles (EMVs). Methods: Eighteen individuals (aged 28 ± 1yrs, 3 females, and BMI 24.43 ± 0.8kg/m2) randomly underwent two experimental sessions: PPL and PPL plus DBF. FMD and venous blood samples were obtained at baseline and 30, 70, and 110 min after stimulation. PPL was induced by fat overload via mozzarella pizza ingestion and DBF by forearm cuff inflation to 75 mm Hg per 30 min. Lipidic profile, oxidative stress (thiobarbituric acid reactive substances, TBARS; ferric reducing/antioxidant power, FRAP; hydrogen peroxide, H2O2) and EMVs were measured in blood samples. Results: Hypertriglyceridemia was observed in both sessions. Retrograde shear rate and oscillatory index responses were significantly higher in the PPL plus DBF compared with PPL. PPL plus DBF evoked a greater reduction in FMD than did PPL and EMVs, NADPH oxidase, and H2O2 similarly increased in both sessions, but TBARS and FRAP did not change. Conclusion: These data indicate that the association of PPL plus DBF additively impairs endothelium-dependent function in 110 min after stimulus in healthy individuals, despite a similar increase in oxidative stress and EMVs. Further studies are needed to understand the mechanisms associated with the induced-endothelial dysfunction by association of PPL and DBF.

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NEW FINDINGS: What is the central question of this study? What is the role of ß- and α-adrenergic receptors in the control of the coronary circulation during handgrip exercise and isolated muscle metaboreflex activation in humans? What is the main finding and its importance? ß-Adrenergic receptor, but not α-adrenergic receptor, blockade significantly blunted the increases in coronary blood velocity observed during handgrip. Coronary blood velocity was unchanged from baseline during isolated muscle metaboreflex activation. This highlights the important role of ß-adrenergic receptors in the coronary circulation during handgrip in humans, and the more limited involvement of the α-adrenergic receptors. ABSTRACT: We sought to investigate the role of ß- and α-adrenergic receptors in coronary circulation during static handgrip exercise and isolated muscle metaboreflex activation in humans. Seventeen healthy young men underwent two experimental sessions, consisting of 3 min of static handgrip exercise at a target force of 40% maximum voluntary force (not achieved for the full 3 min), and 3 min of metaboreflex activation (post-exercise ischaemia) in two conditions: (1) control and ß-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). In both sessions, coronary blood velocity (CBV, echocardiography) was increased during handgrip (Δ8.0 ± 7.4 cm s-1 ) but unchanged with metaboreflex activation (Δ2.5 ± 3.2 cm s-1 ) under control conditions. ß-Blockade abolished the increase in CBV during handgrip, while CBV was unchanged from control with α-blockade. Cardiac work, estimated from rate pressure product (RPP; systolic blood pressure multiplied by heart rate), increased during handgrip and metaboreflex in control conditions in both sessions. ß-Blockade reduced RPP responses to handgrip and metaboreflex, whereas α-blockade increased RPP, but the responses to handgrip and metaboreflex were unchanged. CBV and RPP were only significantly correlated during handgrip under control (r = 0.71, P < 0.01) and ß-blockade (r = 0.54, P = 0.03) conditions, and the slope of this relationship was unaltered with ß-blockade. Collectively, these findings indicate that ß-adrenergic receptors play the primary role to the increase of coronary circulation during handgrip exercise, but CBV is unchanged with metaboreflex activation, while α-adrenergic receptor stimulation seems to exert no effect in the control of the coronary circulation during handgrip exercise and isolated muscle metaboreflex activation in humans.

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KEY POINTS: The proposed mechanism for the increased ventilation in response to hyperoxia includes a reduced brain CO2 -[H+ ] washout-induced central chemoreceptor stimulation that results from a decrease in cerebral perfusion and the weakening of the CO2 affinity for haemoglobin. Nonetheless, hyperoxia also results in excessive brain reactive oxygen species (ROS) formation/accumulation, which hypothetically increases central respiratory drive and causes hyperventilation. We then quantified ventilation, cerebral perfusion/metabolism, arterial/internal jugular vein blood gases and oxidant/antioxidant biomarkers in response to hyperoxia during intravenous infusion of saline or ascorbic acid to determine whether excessive ROS production/accumulation contributes to the hyperoxia-induced hyperventilation in humans. Ascorbic acid infusion augmented the antioxidant defence levels, blunted ROS production/accumulation and minimized both the reduction in cerebral perfusion and the increase in ventilation observed during saline infusion. Hyperoxic hyperventilation seems to be mediated by central chemoreceptor stimulation provoked by the interaction between an excessive ROS production/accumulation and reduced brain CO2 -[H+ ] washout. ABSTRACT: The hypothetical mechanism for the increase in ventilation ( V̇E ) in response to hyperoxia (HX) includes central chemoreceptor stimulation via reduced CO2 -[H+ ] washout. Nonetheless, hyperoxia disturbs redox homeostasis and raises the hypothesis that excessive brain reactive oxygen species (ROS) production/accumulation may increase the sensitivity to CO2 or even solely activate the central chemoreceptors, resulting in hyperventilation. To determine the mechanism behind the HX-evoked increase in V̇E , 10 healthy men (24 ± 4 years) underwent 10 min trials of HX under saline and ascorbic acid infusion. V̇E , arterial and right internal right jugular vein (ijv) partial pressure for oxygen (PO2 ) and CO2 (PCO2 ), pH, oxidant (8-isoprostane) and antioxidant (ascorbic acid) markers, as well as cerebral blood flow (CBF) (Duplex ultrasonography), were quantified at each hyperoxic trial. HX evoked an increase in arterial partial pressure for oxygen, followed by a hyperventilatory response, a reduction in CBF, an increase in arterial 8-isoprostane, and unchanged PijvCO2 and ijv pH. Intravenous ascorbic acid infusion augmented the arterial antioxidant marker, blunted the increase in arterial 8-isoprostane and attenuated both the reduction in CBF and the HX-induced hyperventilation. Although ascorbic acid infusion resulted in a slight increase in PijvCO2 and a substantial decrease in ijv pH, when compared with the saline bout, HX evoked a similar reduction and a paired increase in the trans-cerebral exchanges for PCO2 and pH, respectively. These findings indicate that the poikilocapnic hyperoxic hyperventilation is likely mediated via the interaction of the acidic brain interstitial fluid and an increase in central chemoreceptor sensitivity to CO2 , which, in turn, seems to be evoked by the excessive ROS production/accumulation.

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Most everyday actions engender interactions with meaningful emotionally-laden stimuli. This study aimed to select pictures of objects as emotional stimulus of affordance to be grasped. The participant's depression trait was also assessed to examine its effect on the judgment of these pictures, and time spent in the classification was computed. Sixty-three participants joined this study. Self-Assessment-Manikin scale was used to classify pictures of the objects, and Beck Depression Inventory was applied to distribute the sample according depression trait. Cluster analysis was used in the classification of 123 objects based on valence and arousal values. Cluster results returned 102 classified pictures in three categories: pleasant (21), neutral (48) and unpleasant (33). Where cluster analysis did not agree, the picture was excluded and not used any further (21). Pleasant pictures presented the highest valence values and unpleasant pictures the lowest, and both categories returned the highest arousal level. In the middle of the valence range, the neutral category evoked the lowest arousal levels. Participants were slower to classify unpleasant pictures in valence sub-scale and faster to classify neutral pictures in arousal one. There was no effect of depression in the response time needed to score the pictures. Thus, agreement of high-performance soft clustering algorithms emerged as a good tool to classify pictures representing objects based on valence and arousal dimensions. Depression trait does not significantly affect the accuracy or time-order of emotional classification. Finally, we presented a set of emotional stimuli that can be employed to examine distinct aspects of emotion over physiology and behavior.

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INTRODUCTION: Disturbed blood flow, characterized by high retrograde and oscillatory shear rate (SR), is associated with a proatherogenic phenotype. The impact of disturbed blood flow in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. We tested the hypothesis that acute elevation to retrograde and oscillatory SR provoked by local circulatory occlusion would increase endothelial microparticles (EMPs) and decrease brachial artery flow-mediated dilation (FMD) in patients with HFrEF. METHODS: Eighteen patients with HFrEF aged 55 ± 2 years, with left ventricular ejection fraction (LVEF) 26 ± 1%, and 14 control subjects aged 49 ± 2 years with LVEF 65 ± 1 randomly underwent experimental and control sessions. Brachial artery FMD (Doppler) was evaluated before and after 30 min of disturbed forearm blood flow provoked by pneumatic cuff (Hokanson) inflation to 75 mm Hg. Venous blood samples were collected at rest, after 15 and 30 min of disturbed blood flow to assess circulating EMP levels (CD42b-/CD31+; flow cytometry). RESULTS: At rest, FMD was lower in patients with HFrEF compared with control subjects (P < 0.001), but blood flow patterns and EMPs had no differences (P > 0.05). The cuff inflation provoked a greater retrograde SR both groups (P < 0.0001). EMPs responses to disturbed blood flow significantly increased in patients with HFrEF (P = 0.03). No changes in EMPs were found in control subjects (P > 0.05). Disturbed blood flow decreased FMD both groups. No changes occurred in control condition. CONCLUSION: Collectively, our findings suggest that disturbed blood flow acutely decreases FMD and increases EMP levels in patients with HFrEF, which may indicate that this set of patients are vulnerable to blood flow disturbances.

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NEW FINDINGS: What is the central question of this study? What are the mechanisms underlying the cardiac protective effect of aerobic training in the progression of a high fructose-induced cardiometabolic disease in Wistar rats? What is the main finding and its importance? At the onset of cardiovascular disease, aerobic training activates the p-p70S6K, ERK and IRß-PI3K-AKT pathways, without changing the miR-126 and miR-195 levels, thereby providing evidence that aerobic training modulates the insulin signalling pathway. These data contribute to the understanding of the molecular cardiac changes that are associated with physiological left ventricular hypertrophy during the development of a cardiovascular disease. ABSTRACT: During the onset of cardiovascular disease (CVD), disturbances in myocardial vascularization, cell proliferation and protein expression are observed. Aerobic training prevents CVD, but the underlying mechanisms behind left ventricle (LV) hypertrophy are not fully elucidated. The aim of this study was to investigate the mechanisms by which aerobic training protects the heart from LV hypertrophy during the onset of fructose-induced cardiometabolic disease. Male Wistar rats were allocated to four groups (n = 8/group): control sedentary (C), control training (CT), fructose sedentary (F) and fructose training (FT). The C and CT groups received drinking water, and the F and FT groups received d-fructose (10% in water). After 2 weeks, the CT and FT rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min/day, 4 days/week). After 10 weeks, LV morphological remodelling, cardiomyocyte apoptosis, microRNAs and the insulin signalling pathway were investigated. The F group had systemic cardiometabolic alterations, which were normalised by aerobic training. The LV weight increased in the FT group, myocardium vascularisation decreased in the F group, and the cardiomyocyte area increased in the CT, F and FT groups. Regarding protein expression, total insulin receptor ß-subunit (IRß) decreased in the F group; phospho (p)-IRß and phosphoinositide 3-kinase (PI3K) increased in the FT group; total-AKT and p-AKT increased in all of the groups; p-p70S6 kinase (p70S6K) protein was higher in the CT group; and p-extracellular signal-regulated kinase (ERK) increased in the CT and FT groups. MiR-126, miR-195 and cardiomyocyte apoptosis did not differ among the groups. Aerobic training activates p-p70S6K and p-ERK, and during the onset of a CVD, it can activate the IRß-PI3K-AKT pathway.

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OBJECTIVE: The purpose of this pilot study was to evaluate the feasibility of testing an intervention protocol and measuring the immediate effects of a rib mobilization technique (RMT) and a diaphragm release technique (DRT) on the autonomic nervous system of patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a pilot study of a randomized controlled trial. Fourteen individuals were evaluated. Eligibility criteria were being a sedentary person with a diagnosis of COPD, age between 50 and 72 years, and being clinically stable. Exclusion criteria were heart disease, other respiratory comorbidities, and body mass index above 30kg/m2. Participants first underwent cardiorespiratory evaluation and were then allocated into 2 groups: the RMT + DRT group and the DRT group. Clinical assessments were performed immediately before and after the intervention. Statistical analysis was carried out through a paired-sample Wilcoxon test, and the comparison between groups was performed using the Mann-Whitney test. RESULTS: All randomized participants completed the assessment and intervention protocol. Sample size was estimated at 24 individuals per group. The DRT group decreased resting heart rate by 5 bpm (P = .03) and increased variance (P = .04) and mean R-R interval (P = .03). The RMT + DRT group decreased mean R-R interval (P = .02). CONCLUSION: The design for this study appears to be feasible for evaluating manual-therapy intervention in the nonmusculoskeletal function of patients with COPD. It was possible to determine the sample size for future studies. Preliminary data show that the diaphragm release technique may reduce mean resting heart rate and increase heart-rate variability immediately after the intervention.

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OBJECTIVE: The inability of the organism to appropriately respond to hypoxia results in abnormal cell metabolism and function. Hypoxia-induced angiogenesis seems to be suppressed in experimental models of hypertension; however, this hypothesis has not been tested in humans. We examined changes in endothelial biomarkers and vascular chemoattraction/angiogenic capacity in response to isocapnic hypoxia in hypertensive men. METHODS: Twelve normotensive (38 ±â€Š10 years) and nine hypertensive men (45 ±â€Š11 years) were exposed to 5-min trials of normoxia (21% O2) and isocapnic hypoxia (10% O2). During the last minute of each trial, venous blood was drawn. Endothelial progenitor cells (EPCs; CD45/CD34/VEGFR2), endothelial microvesicles (apoptotic EMVs, CD42b/CD31/AnnexinV; endothelial activation, CD62E/CD144), nitrite, vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) were measured. RESULTS: During normoxia, EPCs, nitrite, endothelial activation, and SDF-1 were similar between groups, whereas VEGF was lower (P = 0.02) and apoptotic EMVs tended to increase (P = 0.07) in hypertensive men. During isocapnic hypoxia, endothelial activation increased in both groups (normotensive, P = 0.007 vs. normoxia; hypertensive, P = 0.006 vs. normoxia), whereas EMVs were higher only in the hypertensive group (P = 0.03 vs. normotensive). EPCs (P = 0.01 vs. normoxia; P = 0.03 vs. hypertensive men), NO (P = 0.01 vs. normoxia; P = 0.04 vs. hypertensive), and VEGF (P = 0.02 vs. normoxia; P = 0.0005 vs. hypertensive) increased only in normotensive individuals in response to isocapnic hypoxia. SDF-1 did not change in either group. CONCLUSION: These results suggest that hypertension-induced impairment in angiogenesis in response to isocapnic hypoxia is related to disrupted NO bioavailability, VEGF chemotactic signaling, and EPC mobilization.

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KEY POINTS: ATP-sensitive K+ (KATP ) channels mediate hypoxia-induced cerebral vasodilatation and hyperperfusion in animals. We tested whether KATP channels blockade affects the increase in human cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2 ) during hypoxia. Hypoxia-induced increases in the anterior circulation and total cerebral perfusion were attenuated under KATP channels blockade affecting the relative changes of brain oxygen delivery. Therefore, in humans, KATP channels activation modulates the vascular tone in the anterior circulation of the brain, contributing to CBF and CDO2 responses to hypoxia. ABSTRACT: ATP-sensitive K+ (KATP ) channels mediate hypoxia-induced cerebral vasodilatation and hyperperfusion in animals. We tested whether KATP channels blockade affects the increase in cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2 ) during hypoxia in humans. Nine healthy men were exposed to 5-min trials of normoxia and isocapnic hypoxia (IHX, 10% O2 ) before (BGB) and 3 h after glibenclamide ingestion (AGB). Mean arterial pressure (MAP), arterial saturation ( SaO2 ), partial pressure of oxygen ( PaO2 ) and carbon dioxide ( PaCO2 ), internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF), total (t)CBF (Doppler ultrasound) and CDO2 were quantified during the trials. IHX provoked similar reductions in SaO2 and PaO2 , while MAP was not affected by oxygen desaturation or KATP blockade. A smaller increase in ICABF (ΔBGB: 36 ± 23 vs. ΔAGB 11 ± 18%, p = 0.019) but not in VABF (∆BGB 26 ± 21 vs. ∆AGB 27 ± 27%, p = 0.893) was observed during the hypoxic trial under KATP channels blockade. Thus, IHX-induced increases in tCBF (∆BGB 32 ± 19 vs. ∆AGB 14 ± 13%, p = 0.012) and CDO2 relative changes (∆BGB 7 ± 13 vs. ∆AGB -6 ± 14%, p = 0.048) were attenuated during the AGB hypoxic trial. In a separate protocol, 6 healthy men (5 from protocol 1) underwent a 5-min exposure to normoxia and IHX before and 3 h after placebo (5 mg of cornstarch) ingestion. IHX reduced SaO2 and PaO2 , but placebo did not affect the ICABF, VABF, tCBF, or CDO2 responses. Therefore, in humans, KATP channels activation modulates vascular tone in the anterior rather than the posterior circulation of the brain, contributing to tCBF and CDO2 responses to hypoxia.

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Isocapnic hyperoxia (IH) evokes cerebral and peripheral hypoperfusion via both disturbance of redox homeostasis and reduction in nitric oxide (NO) bioavailability. However, it is not clear whether the magnitude of the vasomotor responses depends on the vessel network exposed to IH. To test the hypothesis that the magnitude of IH-induced reduction in peripheral blood flow (BF) may differ from the hypoperfusion response observed in the cerebral vascular network under oxygen-enriched conditions, nine healthy men (25 ± 3 yr, mean ± SD) underwent 10 min of IH during either saline or vitamin C (3 g) infusion, separately. Femoral artery (FA), internal carotid artery (ICA), and vertebral artery (VA) BF (Doppler ultrasound), as well as arterial oxidant (8-isoprostane), antioxidant [ascorbic acid (AA)], and NO bioavailability (nitrite) markers were simultaneously measured. IH increased 8-isoprostane levels and reduced nitrite levels; these responses were followed by a reduction in both FA BF and ICA BF, whereas VA BF did not change. Absolute and relative reductions in FA BF were greater than IH-induced changes in ICA and VA perfusion. Vitamin C infusion increased arterial AA levels and abolished the IH-induced increase in 8-isoprostane levels and reduction in nitrite levels. Whereas ICA and VA BF did not change during the vitamin C-IH trial, FA perfusion increased and reached similar levels to those observed during normoxia with saline infusion. Therefore, the magnitude of IH-induced reduction in femoral blood flow is greater than that observed in the vessel network of the brain, which might involve the determinant contribution that NO has in the regulation of peripheral vascular perfusion.

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KEY POINTS: It is unknown whether excessive reactive oxygen species (ROS) production drives the isocapnic hyperoxia (IH)-induced decline in human cerebral blood flow (CBF) via reduced nitric oxide (NO) bioavailability and leads to disruption of the blood-brain barrier (BBB) or neural-parenchymal damage. Cerebral metabolic rate for oxygen (CMR O2 ) and transcerebral exchanges of NO end-products, oxidants, antioxidants and neural-parenchymal damage markers were simultaneously quantified under IH with intravenous saline and ascorbic acid infusion. CBF and CMRO2 were reduced during IH, responses that were followed by increased oxidative stress and reduced NO bioavailability when saline was infused. No indication of neural-parenchymal damage or disruption of the BBB was observed during IH. Antioxidant defences were increased during ascorbic acid infusion, while CBF, CMRO2 , oxidant and NO bioavailability markers remained unchanged. ROS play a role in the regulation of CBF and metabolism during IH without evidence of BBB disruption or neural-parenchymal damage. ABSTRACT: To test the hypothesis that isocapnic hyperoxia (IH) affects cerebral blood flow (CBF) and metabolism through exaggerated reactive oxygen species (ROS) production, reduced nitric oxide (NO) bioavailability, disturbances in the blood-brain barrier (BBB) and neural-parenchymal homeostasis, 10 men (24 ± 1 years) were exposed to a 10 min IH trial (100% O2 ) while receiving intravenous saline and ascorbic acid (AA, 3 g) infusion. Internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF) and total CBF (tCBF, Doppler ultrasound) were determined. Arterial and right internal jugular venous blood was sampled to quantify the cerebral metabolic rate of oxygen (CMR O2 ), transcerebral exchanges (TCE) of NO end-products (plasma nitrite), antioxidants (AA and AA plus dehydroascorbic acid (AA+DA)) and oxidant biomarkers (thiobarbituric acid-reactive substances (TBARS) and 8-isoprostane), and an index of BBB disruption and neuronal-parenchymal damage (neuron-specific enolase; NSE). IH reduced ICABF, tCBF and CMRO2 , while VABF remained unchanged. Arterial 8-isoprostane and nitrite TCE increased, indicating that CBF decline was related to ROS production and reduced NO bioavailability. AA, AA+DA and NSE TCE did not change during IH. AA infusion did not change the resting haemodynamic and metabolic parameters but raised antioxidant defences, as indicated by increased AA/AA+DA concentrations. Negative AA+DA TCE, unchanged nitrite, reductions in arterial and venous 8-isoprostane, and TBARS TCE indicated that AA infusion effectively inhibited ROS production and preserved NO bioavailability. Similarly, AA infusion prevented IH-induced decline in regional and total CBF and re-established CMRO2 . These findings indicate that ROS play a role in CBF regulation and metabolism during IH without evidence of BBB disruption or neural-parenchymal damage.

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RESUMO

AIMS: The influence of blood flow disturbances on vascular function, endothelial activation and repair capacity has not been fully elucidated either in physiological conditions or in cardiovascular disease. We aimed to determine the impact of increases in retrograde blood flow (RBF) on vascular function, endothelial biomarkers and repair capacity in healthy subjects and patients with hypertension. MAIN METHODS: In seven healthy (CT; 32 ±â€¯15 yr) and eight hypertensive (HT; 34 ±â€¯23 yr) men, flow mediated-dilation (FMD) was assessed before and 10 min after a 30-min maneuver to increase brachial artery RBF in which a pneumatic cuff was inflated to 75 mm Hg on forearm. Blood samples were obtained at rest and during the last minute of the maneuver. KEY FINDINGS: Endothelial activation, apoptosis and endothelial progenitor cells (EPC) were measured by flow cytometry; nitrite was measured by ozone-chemiluminescence. No significant disparities were observed in FMD, endothelial activation and circulating EPC between groups at baseline (p > 0.05). However, HT presented higher resting endothelial apoptosis (p = 0.01 vs CT). Exacerbated RBF induced reductions in FMD (p = 0.02 vs baseline) and increases in endothelial activation in both groups (p = 0.049 vs baseline). Endothelial apoptosis increased only in HT (p = 0.02 vs baseline; p = 0.004 vs CT), whereas EPC (p = 0.02 vs baseline; p = 0.03 vs HT) and nitrite (p = 0.04 vs baseline; p = 0.004 vs HT) increased only in CT during the maneuver. SIGNIFICANCE: While findings indicate that increased RBF impairs endothelial function and triggers the EPC mobilization in healthy subjects, patients with hypertension presented greater apoptosis and impaired repair capacity in response to RBF.

Assuntos