Helena N. M. Rocha

Intrathecal fentanyl abolishes the exaggerated blood pressure response to cycling in hypertensive men

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.

Aerobic exercise acutely prevents the endothelial dysfunction induced by mental stress among subjects with metabolic syndrome: the role of shear rate

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.

Exogenous l-arginine reduces matrix metalloproteinase-2 and -9 activities and oxidative stress in patients with hypertension.

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±5yrs., HT group) and eleven normotensive men (37±3yrs., 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.

Reduced arterial vasodilatation in response to hypoxia impairs cerebral and peripheral oxygen delivery in hypertensive men

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.

Sex Differences in High Sensitivity C-Reactive Protein in Subjects with Risk Factors of Metabolic Syndrome.

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.

Oscillatory shear stress induces hemostatic imbalance in healthy men

INTRODUCTION 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Disturbed blood flow induces endothelial apoptosis without mobilizing repair mechanisms in hypertension

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.

Methods of Endothelial Function Assessment: Description and Applications

O endotélio é a monocamada celular que reveste o interior dos vasos sanguíneos, incluindo artérias, veias e as câmaras do coração,1 atuando como uma camada protetora entre os demais tecidos e o sangue circulante.2 Essas células são denominadas células endoteliais. O endotélio exerce função determinante no controle da homeostase vascular, participando da regulação de sinais intracelulares,1 permeabilidade e tônus vascular,3 cascata de coagulação e angiogênese,4 entre outros. Uma das principais funções do endotélio é a liberação de substâncias frente a estímulos, que atuam de forma autócrina e/ou parácrina.2 Dessa forma, agressões ao endotélio geram uma resposta inflamatória, com atuação de diversos tipos celulares (linfócitos, monócitos, plaquetas e células musculares lisas),5 levando a um quadro de disfunção da célula endotelial, enrijecimento da parede vascular e formação da placa de aterosclerose.6