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Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D

NEW FINDINGS What is the central question of this study? What is the role of β- 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? β-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 β-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 β- 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 β-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. β-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. β-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

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 ( S a O 2 ), partial pressure of oxygen ( P a O 2 ) and carbon dioxide ( P aC O 2 ), 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 S a O 2 and P a O 2 , 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 S a O 2 and P a O 2 , 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.

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 ± 10 years) and nine hypertensive men (45 ± 11 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.

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.

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 ( VE ) 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 VE , 10 healthy men (24 ± 4 years) underwent 10 min trials of HX under saline and ascorbic acid infusion. VE , 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.

ATP-sensitive KATP-sensitive K

In vitro and animal model studies have demonstrated that oscillatory shear can trigger vascular hemostasis and remodeling. However, the roles of hemodynamic forces in vascular human biology are not well understood. This study aimed to determine the effects of increasing oscillatory shear stress (OSS) on coagulation/fibrinolysis factors and matrix metalloproteinase-9 activity in healthy subjects.Ten healthy males (35 ± 7 years) underwent a 30-minute dominant forearm cuff occlusion (75 mm Hg) to exacerbate OSS in the brachial artery. Blood flow was quantified (Doppler ultrasound), and plasma samples were obtained from both arms at rest and during the last 30 s of cuff occlusion on the dominant arm. A proximal cuff (40 mm Hg, close to axilla) was also occluded to facilitate venous blood biomarker trapping.The retrograde shear rate and oscillatory shear index were increased and the mean shear rate, mean blood velocity, and mean blood flow were decreased in the cuffed arm (p 0.05 vs. baseline and non-cuffed arm). Cuff occlusion induced increases in platelet microparticle release (p = 0.05 vs. baseline), prothrombin time (p 0.05 vs. baseline and non-cuffed arm), tissue plasminogen activator (p 0.01 vs. baseline and non-cuffed arm), plasminogen activator inhibitor-1 (p 0.02 vs. baseline and non-cuffed arm), and matrix metalloproteinase-9 activity (p = 0.01 vs. baseline). No significant changes were found in the non-cuffed arm throughout the protocol.Exacerbation of OSS induced in vivo disturbances in platelet microparticle release, coagulation-fibrinolysis, and matrix metalloproteinase-9 activity in healthy individuals. These are potential mechanisms involved in OSS-mediated endothelial dysfunction.

Key points Hypoxaemia evokes a repertoire of homeostatic adjustments that maintain oxygen supply to organs and tissues including the brain and skeletal muscles. Because hypertensive patients have impaired endothelial-dependent vasodilatation and an increased sympathetic response to arterial oxygen desaturation, we investigated whether hypertension impairs isocapnic hypoxia-induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. In middle-aged hypertensive men, vertebral and femoral artery blood flow do not increase in response to isocapnic hypoxia, limiting brain and peripheral hyperaemia and oxygen supply. Increased chemoreflex-induced sympathetic activation impairs skeletal muscle perfusion and oxygen supply, whereas an attenuation of local vasodilatory signalling in the posterior cerebrovasculature reduced brain hyperperfusion of hypertensive middle-aged men in response to isocapnic hypoxia. Abstract The present study investigated whether hypertension impairs isocapnic hypoxia (IH)-induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. Oxygen saturation (oxymetry), mean arterial pressure (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneugraphy), as well as femoral artery (FA), internal carotid artery and vertebral artery (VA) blood flow (BF; Doppler ultrasound), were quantified in nine normotensive (NT) (aged 40 ± 11 years, systolic pressure 119 ± 7 mmHg and diastolic pressure 73 ± 6 mmHg) and nine hypertensive men (HT) (aged 44 ± 12 years, systolic pressure 152 ± 11 mmHg and diastolic pressure 90 ± 9 mmHg) during 5 min of normoxia (21% O2) and IH (10% O2). Total cerebral blood flow (tCBF), brain (CDO2) and leg (LDO2) oxygen delivery were estimated. IH provoked similar oxygen desaturation without changing mean arterial pressure. Internal carotid artery perfusion increased in both groups during IH. However, VA and FA BF only increased in NT. Thus, IH-induced increase in tCBF was smaller in HT. CDO2 only increased in NT and LDO2 decreased in HT. Furthermore, IH evoked a greater increase in HT MSNA. Changes in MSNA were inversely related to FA BF, LDO2 and end-tidal oxygen tension. In conclusion, hypertension disturbs regional and total cerebrovascular and peripheral responses to IH and consequently limits oxygen supply to the brain and skeletal muscle. Although increased chemoreflex-induced sympathetic activation may explain impaired peripheral perfusion, attenuated vasodilatory signalling in the posterior cerebrovasculature appears to be responsible for the small increase in tCBF when HT were exposed to IH.

The increase in blood pressure observed during physical activities is exaggerated in patients with hypertension, exposing them to a higher cardiovascular risk. Neural signals from the skeletal muscles appear to be overactive, resulting in this abnormal response in hypertensive patients. In the present study, we tested whether the attenuation of these neural signals in hypertensive patients could normalize their abnormal increase in blood pressure during physical activity. Attenuation of the neural signals from the leg muscles with intrathecal fentanyl injection reduced the blood pressure of hypertensive men during cycling exercise to a level comparable to that of normotensive men. Skeletal muscle afferent overactivity causes the abnormal cardiovascular response to exercise and was reverted in this experimental model, appearing as potential target for treatment. Hypertensive patients present an exaggerated increase in blood pressure and an elevated cardiovascular risk during exercise. Although controversial, human studies suggest that group III and IV skeletal muscle afferents might contribute to this abnormal response. In the present study, we investigated whether attenuation of the group III and IV muscle afferent signal of hypertensive men eliminates the exaggerated increase in blood pressure occurring during exercise. Eight hypertensive men performed two sessions of 5 min of cycling exercise at 40 W. Between sessions, the subjects were provided with a lumbar intrathecal injection of fentanyl, a μ-opioid receptor agonist, aiming to attenuate the central projection of opioid-sensitive group III and IV muscle afferent nerves. The cardiovascular response to exercise of these subjects was compared with that of six normotensive men. During cycling, the hypertensive group demonstrated an exaggerated increase in blood pressure compared to the normotensive group (mean ± SEM: +17 ± 3 vs. +8 ± 1 mmHg, respectively; P 0.05). Fentanyl inhibited the blood pressure response to exercise in the hypertensive group (+11 ± 2 mmHg) to a level comparable to that of the normotensive group (P > 0.05). Moreover, fentanyl increased the responses of vascular conductance and stroke volume to exercise (P 0.05). The results of the present study show that attenuation of the exercise pressor reflex normalizes the blood pressure response to cycling exercise in hypertensive individuals.

Background Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. Methods Fourteen overweight/obese grade I men (27 ± 7 years; 29.7 ± 2.6 kg·m−2) underwent the Stroop Color Word Test for 5 min to induce MS after AA (3 g) or placebo (PL, 0.9% NaCl) intravenous infusions. Venous blood samples were collected at baseline and the last minute of MS to measure nitrite concentration (chemiluminescence), protein carbonylation, thiobarbituric acid reactive substances (TBARS) and catalase activity (colorimetric assays), superoxide dismutase (SOD; immunoenzymatic assay), activities of active/inactive (pro) forms of metalloproteinases-9 and -2 (MMP; zymography) and its respective tissue inhibitors concentration (TIMP-1 and TIMP-2; immunoenzymatic assays). Results At baseline, MMP-9 activity (p Conclusions AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.

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 [Formula: see text]) 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 [Formula: see text] 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, [Formula: see text] , 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% O(2)) 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 [Formula: see text]), 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 [Formula: see text] , 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 [Formula: see text]. These findings indicate that ROS play a role in CBF regulation and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage.

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 ± 15 yr) and eight hypertensive (HT; 34 ± 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.

KEY POINTS: Hypoxaemia evokes a repertoire of homeostatic adjustments that maintain oxygen supply to organs and tissues including the brain and skeletal muscles. Because hypertensive patients have impaired endothelial‐dependent vasodilatation and an increased sympathetic response to arterial oxygen desaturation, we investigated whether hypertension impairs isocapnic hypoxia‐induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. In middle‐aged hypertensive men, vertebral and femoral artery blood flow do not increase in response to isocapnic hypoxia, limiting brain and peripheral hyperaemia and oxygen supply. Increased chemoreflex‐induced sympathetic activation impairs skeletal muscle perfusion and oxygen supply, whereas an attenuation of local vasodilatory signalling in the posterior cerebrovasculature reduced brain hyperperfusion of hypertensive middle‐aged men in response to isocapnic hypoxia. ABSTRACT: The present study investigated whether hypertension impairs isocapnic hypoxia (IH)‐induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. Oxygen saturation (oxymetry), mean arterial pressure (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneugraphy), as well as femoral artery (FA), internal carotid artery and vertebral artery (VA) blood flow (BF; Doppler ultrasound), were quantified in nine normotensive (NT) (aged 40 ± 11 years, systolic pressure 119 ± 7 mmHg and diastolic pressure 73 ± 6 mmHg) and nine hypertensive men (HT) (aged 44 ± 12 years, systolic pressure 152 ± 11 mmHg and diastolic pressure 90 ± 9 mmHg) during 5 min of normoxia (21% O(2)) and IH (10% O(2)). Total cerebral blood flow (tCBF), brain (CDO(2)) and leg (LDO(2)) oxygen delivery were estimated. IH provoked similar oxygen desaturation without changing mean arterial pressure. Internal carotid artery perfusion increased in both groups during IH. However, VA and FA BF only increased in NT. Thus, IH‐induced increase in tCBF was smaller in HT. CDO(2) only increased in NT and LDO(2) decreased in HT. Furthermore, IH evoked a greater increase in HT MSNA. Changes in MSNA were inversely related to FA BF, LDO(2) and end‐tidal oxygen tension. In conclusion, hypertension disturbs regional and total cerebrovascular and peripheral responses to IH and consequently limits oxygen supply to the brain and skeletal muscle. Although increased chemoreflex‐induced sympathetic activation may explain impaired peripheral perfusion, attenuated vasodilatory signalling in the posterior cerebrovasculature appears to be responsible for the small increase in tCBF when HT were exposed to IH.

Introducao O endotelio e a monocamada celular que reveste o interior dos vasos sanguineos, incluindo arterias, veias e as câmaras do coracao, atuando como uma camada protetora entre os demais tecidos e o sangue circulante. Essas celulas sao denominadas celulas endoteliais. O endotelio exerce funcao determinante no controle da homeostase vascular, participando da regulacao de sinais intracelulares, permeabilidade e tonus vascular, cascata de coagulacao e angiogenese, entre outros. Uma das principais funcoes do endotelio e a liberacao de substâncias frente [...]

Mental stress induces transient endothelial dysfunction, which is an important finding for subjects at cardiometabolic risk. Thus, we tested whether aerobic exercise prevents this dysfunction among subjects with metabolic syndrome (MetS) and whether an increase in shear rate during exercise plays a role in this phenomenon. Subjects with MetS participated in two protocols. In protocol 1 ( n = 16), endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Subjects then underwent a mental stress test followed by either 40 min of leg cycling or rest across two randomized sessions. FMD was assessed again at 30 and 60 min after exercise or rest, with a second mental stress test in between. Mental stress reduced FMD at 30 and 60 min after the rest session (baseline: 7.7 ± 0.4%, 30 min: 5.4 ± 0.5%, and 60 min: 3.9 ± 0.5%, P < 0.05 vs. baseline), whereas exercise prevented this reduction (baseline: 7.5 ± 0.4%, 30 min: 7.2 ± 0.7%, and 60 min: 8.7 ± 0.8%, P > 0.05 vs. baseline). Protocol 2 ( n = 5) was similar to protocol 1 except that the first period of mental stress was followed by either exercise in which the brachial artery shear rate was attenuated via forearm cuff inflation or exercise without a cuff. Noncuffed exercise prevented the reduction in FMD (baseline: 7.5 ± 0.7%, 30 min: 7.0 ± 0.7%, and 60 min: 8.7 ± 0.8%, P > 0.05 vs. baseline), whereas cuffed exercise failed to prevent this reduction (baseline: 7.5 ± 0.6%, 30 min: 5.4 ± 0.8%, and 60 min: 4.1 ± 0.9%, P < 0.05 vs. baseline). In conclusion, exercise prevented mental stress-induced endothelial dysfunction among subjects with MetS, and an increase in shear rate during exercise mediated this effect.

Aims Increased matrix metalloproteinases activity and reduced nitric oxide (NO) bioavailability contributes to development of hypertension and this may be associated with a defective l -arginine-NO pathway. Exogenous l -arginine improves endothelial function to prevent the onset of cardiovascular disease, but the mechanism by which this is accomplished remains unclear. We determined the effects of exogenous l -arginine infusion on vascular biomarkers in patients with hypertension. Main methods Venous blood samples were obtained from seven patients with hypertension (45 ± 5 yrs., HT group) and eleven normotensive men (37 ± 3 yrs., CT group) before and during a 30-min intravenous l -arginine or saline infusion. Nitrite concentration was evaluated by ozone-chemiluminescence method; metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) activities were detected by zymography; tissue inhibitor of metalloproteinases-1 (TIMP-1) and 8-isoprostane concentrations were measured by enzyme-linked immunosorbent assay (ELISA); and thiobarbituric acid reactive substances (TBARS) were determined by colorimetric assay. Key findings At baseline, nitrite, TIMP-1, and MMP-2 activity were similar between the groups (P > 0.05), but MMP-9, TBARS and 8-isoprostane were higher in HT group (P ≤ 0.03). During l -arginine infusion, nitrite increased only in control group (P = 0.01), while MMP-2, MMP-9 activities, MMP-9/TIMP-1 ratio and 8-isoprostane decreased in HT group (P ≤ 0.02). There were no significant changes in vascular biomarkers between groups during the saline infusion (P > 0.05). Significance Exogenous l -arginine diminished metalloproteinase-2 and -9 activities and MMP-9/TIMP-1 ratio along with restoring the oxidative stress balance in patients with hypertension.

Background: Metabolic syndrome (MetS) is associated with a higher risk of all-cause mortality. High-sensitivity C-reactive protein (hsCRP) is a prototypic marker of inflammation usually increased in MetS. Women with MetS-related diseases present higher hsCRP levels than men with MetS-related diseases, suggesting sex differences in inflammatory markers. However, it is unclear whether serum hsCRP levels are already increased in men and/or women with MetS risk factors and without overt diseases or under pharmacological treatment. Objective: To determine the impact of the number of MetS risk factors on serum hsCRP levels in women and men. Methods One hundred and eighteen subjects (70 men and 48 women; 36 ± 1 years) were divided into four groups according to the number of MetS risk factors: healthy group (CT; no risk factors), MetS ≤ 2, MetS = 3, and MetS ≥ 4. Blood was drawn after 12 hours of fasting for measurement of biochemical variables and hsCRP levels, which were determined by immunoturbidimetric assay. Results: The groups with MetS risk factors presented higher serum hsCRP levels when compared with the CT group (p < 0.02). There were no differences in hsCRP levels among groups with MetS risk factors (p > 0.05). The best linear regression model to explain the association between MetS risk factors and hsCRP levels included waist circumference and HDL cholesterol (r = 0.40, p < 0.01). Women with MetS risk factors presented higher hsCRP levels when compared with men (psex < 0.01). Conclusions: Despite the absence of overt diseases and pharmacological treatment, subjects with MetS risk factors already presented increased hsCRP levels, which were significantly higher in women than men at similar conditions. Resumo Fundamento: A síndrome metabólica (SM) está associada a um maior risco de mortalidade por todas as causas. A proteína C reativa ultrassensível (PCRus) é um marcador prototípico de inflamação que está geralmente aumentado na SM. Mulheres com doenças relacionadas à SM apresentam níveis mais elevados de PCRus quando comparadas com homens com doenças relacionadas à SM, sugerindo diferenças associados ao gênero nos marcadores inflamatórios. No entanto, não é claro se os níveis séricos de PCRus já estão aumentados em homens e/ou mulheres com fatores de risco da SM, sem doenças pré-estabelecidas ou sob tratamento farmacológico. Objetivo: Determinar o impacto do número de fatores de risco da SM sobre os níveis séricos de PCRus em mulheres e homens. Métodos: Cento e dezoito pacientes (70 homens e 48 mulheres; 36±1 anos) foram divididos em quatro grupos de acordo com o número de fatores de risco da SM: grupo saudável (CT; sem fatores de risco), SM ≤ 2, SM = 3 e SM ≥ 4. Após 12 horas de jejum, amostras de sangue foram coletadas para determinação de variáveis bioquímicas e níveis de PCRus, analisada pelo método imunoturbidimétrico. Resultados: Os grupos com fatores de risco da SM apresentaram níveis séricos mais elevados de PCRus quando comparados com o grupo CT (p < 0,02). Não foram observadas diferenças nos níveis de PCRus entre os grupos com fatores de risco da SM (p > 0,05). O melhor modelo de regressão linear para explicar a associação entre fatores de risco da SM com níveis de PCRus foram a circunferência da cintura e os níveis de HDL-colesterol (r = 0,40, p < 0,01). Mulheres com fatores de risco da SM apresentaram valores mais elevados de PCRus quando comparadas com homens (psexo < 0,01). Conclusões: Apesar da ausência de doenças pré-estabelecidas e tratamento farmacológico, os indivíduos com fatores de risco da SM já apresentaram aumento nos níveis de PCRus, que foram significativamente mais elevados nas mulheres do que nos homens em condições semelhantes.

The increase in blood pressure observed during physical activities is exaggerated in patients with hypertension, exposing them to a higher cardiovascular risk. Neural signals from the skeletal muscles appear to be overactive, resulting in this abnormal response in hypertensive patients. In the present study, we tested whether the attenuation of these neural signals in hypertensive patients could normalize their abnormal increase in blood pressure during physical activity. Attenuation of the neural signals from the leg muscles with intrathecal fentanyl injection reduced the blood pressure of hypertensive men during cycling exercise to a level comparable to that of normotensive men. Skeletal muscle afferent overactivity causes the abnormal cardiovascular response to exercise and was reverted in this experimental model, appearing as potential target for treatment. Hypertensive patients present an exaggerated increase in blood pressure and an elevated cardiovascular risk during exercise. Although controversial, human studies suggest that group III and IV skeletal muscle afferents might contribute to this abnormal response. In the present study, we investigated whether attenuation of the group III and IV muscle afferent signal of hypertensive men eliminates the exaggerated increase in blood pressure occurring during exercise. Eight hypertensive men performed two sessions of 5 min of cycling exercise at 40 W. Between sessions, the subjects were provided with a lumbar intrathecal injection of fentanyl, a μ-opioid receptor agonist, aiming to attenuate the central projection of opioid-sensitive group III and IV muscle afferent nerves. The cardiovascular response to exercise of these subjects was compared with that of six normotensive men. During cycling, the hypertensive group demonstrated an exaggerated increase in blood pressure compared to the normotensive group (mean ± SEM: +17 ± 3 vs. +8 ± 1 mmHg, respectively; P0.05), whereas the increase in heart rate, stroke volume, cardiac output and vascular conductance was similar (P0.05). Fentanyl inhibited the blood pressure response to exercise in the hypertensive group (+11 ± 2 mmHg) to a level comparable to that of the normotensive group (P0.05). Moreover, fentanyl increased the responses of vascular conductance and stroke volume to exercise (P0.05), whereas the heart rate response was attenuated (P0.05) and the cardiac output response was maintained (P0.05). The results of the present study show that attenuation of the exercise pressor reflex normalizes the blood pressure response to cycling exercise in hypertensive individuals.