Cortisol level after dexamethasone suppression test in patients with non-functioning adrenal incidentaloma is positively associated with the duration of reactive hyperemia response on microvascular bed.

PURPOSE: Data on endothelial derangements in patients with non-functioning adrenal incidentaloma (NFAI) are scarce. METHODS: We investigated if NFAI patients present clinical, biochemical and endothelial alterations compared to individuals without an adrenal lesion and also the associations among these variables. Forty-two NFAI and 40 controls were evaluated. NFAI diagnosis and controls were defined according to the current guidelines and based on a normal adrenal imaging exam, respectively. Body composition was evaluated by dual emission X-ray absorptiometry. Endothelial reactivity was assessed by two methods: tonometry (Endo-PAT®) and laser speckle contrast imaging (LSCI). RESULTS: There were no differences between groups regarding age, gender, ethnicity, smoking status, and statin use. The frequency of metabolic syndrome according to the International Diabetes Federation criteria was 69% and 57.9%, respectively in NFAI and controls (p = 0.36), whereas the atherosclerotic cardiovascular disease (ASCVD) risk was 63.4% and 66.7% (p = 0.81). The clinical, laboratory, and anthropometric characteristics, as well as body composition, were similar between the groups. Additionally, any differences between groups were observed on endothelial reactivity tests. Nevertheless, we noted an association between cortisol levels after 1 mg-dexamethosone suppression test (1 mg-DST) and the duration of post-occlusive reactive hyperemia tested on microcirculation (r = 0.30; p = 0.03). NFAI patients require more antihypertensive drugs to achieve blood pressure control (p = 0.04). The number of antihypertensive drugs used to control blood pressure correlated with cortisol levels after 1 mg-DST (r = 0.29; p = 0.03). CONCLUSIONS: Since both groups herein investigated had a high frequency of metabolic syndrome and ASCVD risk, it might explain similarities observed on endothelial reactivity. Nevertheless, prolonged reactive hyperemia response on microcirculation was correlated with cortisol levels under suppression.

Effects of preadipocytes derived from mice fed with high fat diet on the angiogenic potential of endothelial cells.

BACKGROUND AND AIMS: Obesity promotes a persistent inflammatory process in the adipose tissue, activating the endothelium and leading to vascular dysfunction. Preadipocytes can interact with endothelial cells in a paracrine way stimulating angiogenesis. However, the potential of preadipocytes from adipose tissue of high fat diet (HFD) fed animal to stimulate angiogenesis has not been evaluated yet. The aim of this study was to investigate the effects of such diet on the angiogenic potential of preadipocytes in a mice model. METHODS AND RESULTS: We have evaluated body weight gain, fasting glucose levels and insulin resistance, mRNA expression in preadipocytes and endothelial cells after co-culture with preadipocytes, in vivo vascular function and in vitro endothelial cell migration and tubulogenesis. High fat diet promoted an increase in body weight, glycemic index and insulin resistance in mice. Preadipocytes mRNA expression of factors involved in angiogenesis was higher in these animals. In endothelial tEnd cells mRNA expression of factors involved in vessel growth were higher after co-culture with preadipocytes derived from mice fed with HFD. Although no significant differences were observed in in vivo vasodilatation response between control and HFD groups, endothelial tEnd cells showed an increase in migration and tubulogenesis when cultivated with conditioned media from preadipocytes derived from mice fed with HFD. CONCLUSION: Hypoxic and growth factors produced by preadipocytes derived from mice fed with HFD have higher capacity than preadipocytes derived from mice fed with standard diet to stimulate the angiogenic potential of endothelial cells, contributing to vascular disorders in obesity.

Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function.

Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters the secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue. Mechanistically, contracting muscles release bioactive molecules known as myokines, which alter the metabolic phenotype of adipose tissue. In adipose tissue, myokines induce browning, enhance fatty acid oxidation and improve insulin sensitivity. In the past years, the perivascular adipose tissue (PVAT) which surrounds the vasculature, has been shown to control vascular tone and inflammation through local release of adipokines. In obesity, an increase in mass and inflammation of PVAT culminate in dysregulation of adipokine secretion, which contributes to vascular dysfunction. This review describes our current understanding of the mechanisms by which active muscles interact with adipose tissue and improve vascular function. Aside from the exercise-dependent regulation of canonical adipose tissue function, we will focus on the interactions between skeletal muscle and PVAT and the role of novel myokines, such as IL-15, FGF21 and irisin, in these interactions. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Oxygen uptake, respiratory exchange ratio, or total distance: a comparison of methods to equalize exercise volume in Wistar rats.

This study compared strategies to equalize the volume of aerobic exercise performed with different intensities by Wistar rats, based on the distance covered during exercise bouts and energy expenditure (EE, isocaloric sessions) obtained from oxygen uptake (V̇O2) or respiratory exchange ratio (RER). Thirty-three male rats (270.5±12.8 g) underwent maximal exercise tests to determine V̇O2 reserve (V̇O2R), being randomly assigned to three groups: moderate-intensity continuous exercise at speed corresponding to 50% V̇O2R (MIC; n=11); high-intensity continuous exercise at 80% V̇O2R (HIC; n=11); and high-intensity intermittent exercise (HII; n=11) at 60% V̇O2R (3 min) and 80% V̇O2R (4 min). Exercise duration was calculated individually to elicit EE of 5 kcal in each session. No difference between groups was found for total running distance (MIC: 801±46, HIC: 734±42, HII: 885±64 m; P=0.13). Total EE measured by RER was systematically underestimated compared to values obtained from V̇O2 (HII: 4.5% and MIC: 6.2%, P<0.05). Total EE (calculated from V̇O2), and duration of HIC bouts (2.8 kcal and 30.8±2.2 min) were lower (P<0.0001) than in MIC (4.9 kcal and 64.7±1.8 min) and HII (4.7 kcal and 46.9±2.2 min). Predicted and actual values of total V̇O2, total EE, and duration of isocaloric sessions were similar in MIC and HII (P>0.05), which were both higher than in HIC (P<0.0001). In conclusion, the time to achieve a given EE in exercise bouts with different intensities did not correspond to the total distance. Therefore, the volume of aerobic exercise in protocols involving Wistar rats should be equalized using EE rather than total covered distance.

Low-dose estradiol and endothelial and inflammatory biomarkers in menopausal overweight/obese women.

OBJECTIVE: We aimed to investigate the effects of low-dose transdermal estrogen on endothelial and inflammatory biomarkers in menopausal overweight/obese women. METHODS: We recruited 44 menopausal women (47-55 years; body mass index 27.5-34.9 kg/m(2)) and divided them into estradiol (1 mg/day; n = 22) or placebo groups (n = 22). They were double-blinded, followed and treated for 3 months. At baseline and post-intervention, inflammatory biomarkers (hs-CRP, IL-1ß, IL-6, MCP-1 and TNF-α) and of vascular injury (activated circulating endothelial cells, CEC-a) and repair (endothelial progenitor cells, EPC) were quantified. Resting CECs (CEC-r) were also assessed. Microvascular reactivity and vasomotion were analyzed by laser-Doppler flowmetry. RESULTS: Volunteers (51.8 ± 2.3 years; mean body mass index 31.5 ± 2.5 kg/m(2)) had been menopausal for 3 (range 2-5) years. After treatment, no changes were observed in the placebo group, while levels of CEC-r and EPC increased in the estradiol group. In this group, no changes in inflammatory biomarkers were observed but it required a lower cumulative dose of acetylcholine to achieve peak velocity during endothelial-dependent vasodilatation and there was increased endothelial-independent vasodilatation. CONCLUSIONS: The short-term use of low-dose transdermal estradiol therapy in overweight/obese menopausal women increased markers of vascular repair and improved microvascular reactivity without changing the inflammatory biomarkers. CLINICAL TRIAL REGISTRATION: NCT01295892 at www.clinicaltrials.gov .

Microcirculatory effects of zinc on fructose-fed hamsters.

BACKGROUND AND AIMS: Fructose is a major dietary component directly related to vascular dysfunction and diseases such as obesity, diabetes, and hypertension. Zinc is considered a non-pharmacological alternative for treating diabetes due to its antioxidant and hyperglycemia-lowering effects in diabetic animals. Therefore, the aim of this study was to evaluate the effects of dietary zinc supplementation on the microcirculatory parameters of fructose-fed hamsters. METHODS AND RESULTS: Male hamsters (Mesocricetus auratus) were fed drinking water substituted by 10% fructose solution for 60 days, whereas control animals were fed drinking water alone. Their microcirculatory function was evaluated using cheek pouch preparation, as well as their blood glucose and serum insulin levels. Their microcirculatory responses to acetylcholine (ACh, an endothelium-dependent vasodilator) and to sodium nitroprusside (SNP, an endothelium-independent vasodilator) as well as the increase in macromolecular permeability induced by 30 min of ischemia/reperfusion (I/R) were noted. Endothelium-dependent vasodilation was significantly increased in control animals with high zinc supplementation compared to the groups without zinc supplementation. Zinc was able to protect against plasma leakage induced by I/R in all control and fructose-fed groups, although the microvascular permeability was higher in animals fed drinking water substituted by 10% fructose solution compared to those fed filtered drinking water alone. CONCLUSION: Our results indicate that dietary zinc supplementation can improve microvascular dysfunction by increasing endothelial-dependent dilatation and reducing the increase in macromolecular permeability induced by I/R in fructose-fed animals.

Oxygen uptake, respiratory exchange ratio, or total distance: a comparison of methods to equalize exercise volume in Wistar rats

This study compared strategies to equalize the volume of aerobic exercise performed with different intensities by Wistar rats, based on the distance covered during exercise bouts and energy expenditure (EE, isocaloric sessions) obtained from oxygen uptake (V̇O2) or respiratory exchange ratio (RER). Thirty-three male rats (270.5±12.8 g) underwent maximal exercise tests to determine V̇O2 reserve (V̇O2R), being randomly assigned to three groups: moderate-intensity continuous exercise at speed corresponding to 50% V̇O2R (MIC; n=11); high-intensity continuous exercise at 80% V̇O2R (HIC; n=11); and high-intensity intermittent exercise (HII; n=11) at 60% V̇O2R (3 min) and 80% V̇O2R (4 min). Exercise duration was calculated individually to elicit EE of 5 kcal in each session. No difference between groups was found for total running distance (MIC: 801±46, HIC: 734±42, HII: 885±64 m; P=0.13). Total EE measured by RER was systematically underestimated compared to values obtained from V̇O2 (HII: 4.5% and MIC: 6.2%, P<0.05). Total EE (calculated from V̇O2), and duration of HIC bouts (2.8 kcal and 30.8±2.2 min) were lower (P<0.0001) than in MIC (4.9 kcal and 64.7±1.8 min) and HII (4.7 kcal and 46.9±2.2 min). Predicted and actual values of total V̇O2, total EE, and duration of isocaloric sessions were similar in MIC and HII (P>0.05), which were both higher than in HIC (P<0.0001). In conclusion, the time to achieve a given EE in exercise bouts with different intensities did not correspond to the total distance. Therefore, the volume of aerobic exercise in protocols involving Wistar rats should be equalized using EE rather than total covered distance.

Can Heart Rate Variability be used to Estimate Gas Exchange Threshold in Obese Adolescents?

This study investigated the agreement and reliability of oxygen uptake (V̇O2), V̇O2 reserve (V̇O2 R), heart rate (HR) and power output at intensities corresponding to the gas exchange threshold (GET) and heart rate variability threshold (HRVT) during maximal cardiopulmonary exercise testing (CPET) in obese and eutrophic adolescents. A further aim was to establish whether the HRVT was able to detect changes in cardio-respiratory fitness in obese adolescents after 3 months of recreational soccer practice. First, 25 obese and 10 eutrophic adolescents (ages 12-17) visited the laboratory twice to perform cycling CPET to test the reliability of CPET outcomes at GET and HRVT. Furthermore, the level of agreement between GET and HRVT was determined for a subgroup of 10 obese adolescents after performing a 3-month recreational soccer program. No significant difference was found for V̇O2, %V̇O2 R, HR and power output at the GET and HRVT (P>0.05), which were equally able to detect improvements in aerobic fitness after the soccer intervention. Correlations between GET and HRVT for V̇O2 and %V̇O2 R ranged from 0.89 to 0.95 (P<0.001) and test-retest reliability ranged from 0.59 to 0.82 (P<0.006). Overall, HRVT seems to be a reliable alternative for prescribing aerobic exercise intensity in obese adolescents.

Aerobic exercise improves microvascular dysfunction in fructose fed hamsters.

Fructose is a major diet component directly related to severe damages to the microcirculation and to diseases such as obesity, diabetes and hypertension to which physical activity is pointed out as an important non-pharmacological treatment since its positive effects precede anthropometric improvements. In this study we have investigated the effects of a light/moderate aerobic exercise training (AET) on microcirculatory dysfunction elicited by carbohydrate overload during a period of 5 months. Male hamsters (Mesocricetus auratus) whose drinking water was substituted (F) or not (C) by 10% fructose solution, during 20 weeks, associated or not to AET in the last 4 weeks (EC and EF subgroups) had their microcirculatory function evaluated on the cheek pouch preparation, glucose and insulin tolerance (GTT and ITT) tested. Arterial blood was collected for pO2, pCO2, HCO3(-), pH, total CO2, saturated O2 and lactate determinations. Liver fragments were observed using an electron microscope. Microcirculatory responses to acetylcholine [Ach, an endothelium-dependent vasodilator; 10(-8)M - *123.3±7.5% (C), 119.5±1.3% (EC), *98.1±3.2% (F) and 133.6±17.2% (EF); 10(-6)M - *133.0±4.1% (C), 135.6±4.3% (EC), *103.4±4.3% (F) and 134.1±5.9% (EF); 10(-4)M - *167.2±5.0% (C), 162.8±5.4% (EC), *123.8±6.3% (F) and 140.8±5.0% (EF)] and to sodium nitroprusside [SNP, an endothelium-independent vasodilator; 10(-8)M - 118.8±6.8% (C), 114.0±5.0% (EC), 100.2±2.9% (F), 104.9±4.4% (EF); 10(-6)M - 140.6±11.7% (C), 141.7±5.5% (EC), 125.0±4.7% (F), 138.3±2.8% (EF); 10(-4)M - 150.4±10.9% (C), 147.9±6.5% (EC), 139.2±7.3% (F), 155.9±4.7% (EF)] and macromolecular permeability increase induced by 30 min ischemia/reperfusion (I/R) procedure [14.4±3.5 (C), 30.0±1.9 (EC), *112.0±8.8 (F) and *22.4±0.9 leaks/cm(2) (EF)] have shown that endothelium-dependent vasodilatation was significantly reduced and I/R induced macromolecular permeability augmented in sedentary fructose (F) subgroup and both improved after AET. Electron microscopy analysis of the liver showed significant differences between exercised and sedentary subgroups with greater amount of glycogen in F subgroups compared to other ones. No significant changes on mean arterial pressure, heart rate or blood gase between subgroups could be detected. Our results point out that AET could normalize microcirculatory dysfunction elicited by long term substitution of drinking water by 10% fructose solution.

In elderly women moderate hypercholesterolemia is associated to endothelial and microcirculatory impairments.

How cholesterol influences the microcirculation on aging subjects is not well known. This study evaluated moderate hypercholesterolemia effects in, treated or not, lean elderly women on brachial artery reactivity and microcirculatory function using venous occlusion plethysmography (VOP) and nailfold videocapillaroscopy (NVC). Patients (mean age 73 years) were divided into healthy elderly (HE, n=15), treated dyslipidemia with statins during at least 6 months (TDL, n=9) and dyslipidemia (DL, n=9, cholesterol, 257±11 and LDL-cholesterol, 157±24 mg/dl). Young, mean age 23 years, women (YC, n=24), served as controls. Laboratory and anthropometrical analysis, VOP peak forearm blood flow (FBF) during the reactive hyperemia response/baseline FBF (%HYPER) and peak FBF after 0.4 mg sublingual nitroglycerin/baseline FBF (%NITRO) were assessed. NVC capillary density and diameters, maximum red blood cell velocity (RBCV(max)) during reactive hyperemia/baseline RBCV and time to reach RBCV(max) were evaluated. Correlations between %HYPER, %NITRO and plasma cholesterol fractions were performed. Total and LDL-cholesterol were increased only in DL group. Capillary diameters were larger in elderly groups than YC. RBCV(max)/baseline RBCV was reduced in the DL group compared to HE, TDL and YC. %HYPER was lower in DL and normalized in TDL group. YC %HYPER was double of HE. %NITRO decreased from (HE=YC) to TDL and DL groups. There was a significant inverse correlation between LDL-cholesterol, non-HDL-cholesterol and %HYPER/% Nitro. In conclusion, moderate hypercholesterolemia reversibly impaired the vasodilatatory response in the microcirculation but the endothelial-independent vasodilator response to nitroglycerine remained irreversibly lower in healthy aged women.

Effects of resistance training on cytokines.

It is speculated that exercise training decreases resting levels of tumor necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP); reduces body mass and leptin (LP); and increases adiponectin (AD) and insulin sensitivity. This systematic review analyzed the effectiveness of resistance training (RT) longitudinal clinical studies on AD, LP, CRP and TNF-alpha. Seventeen studies were included and the majority of randomized controlled trials support that RT produces increases in AD, and decreases in both LP and CRP. Greater responses in AD and LP were evident in overweight and obese individuals; while RT appeared to be effective in reducing CRP in obese individuals, and older adults. Additionally, women may be more responsive to RT effects on AD, LP and CRP. Training duration and intensity may affect the response of AD and CRP with greater responses shown with 16 weeks or more of training and/or with intensities greater than 80% of one repetition maximum. No response to RT of TNF-alpha levels was apparent. Although based on a limited number of studies, some of which are uncontrolled non-randomized in design, our review suggests some positive effects of RT programs on cytokine levels, but specifics of the responses in different populations need further elucidation.

Rosiglitazone decreases intra- to extramyocellular fat ratio in obese non-diabetic adults with metabolic syndrome.

BACKGROUND: Insulin resistance is intrinsically related to intramyocellular (IMCL) rather than extramyocellular (EMCL) triglyceride content. Conflicting results have been reported on the ability of insulin sensitizer agents, such as thiazolidinediones, to modify muscle fat distribution. The aim of this study was to investigate the role of rosiglitazone on muscle fat compartment distribution in an adult population of obese non-diabetic metabolic syndrome patients. PATIENTS AND METHODS: Fifteen obese, non-diabetic, metabolic syndrome patients were studied by means of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy before and after treatment with rosiglitazone 8 mg/day for 6 months. Anthropometrical and metabolic variables were assessed. RESULTS: After rosiglitazone, body weight and hip circumference increased [100.9 (91.12-138.7) vs. 107.0 (79.6-142.8) kg and 118 (107-126) vs. 122 (110-131) cm]; while waist-hip ratio (WHR) decreased from 0.93 (0.87-1.00) to 0.89 (0.82-0.97) (P < 0.001 for all). Additionally, fasting plasma glucose, insulin and homeostatis model assessment of insulin resistance (HOMA-IR) significantly decreased while adiponectin increased over threefold [9.7 (3.7-17.7) vs. 38.0 (19.3-42.4) microg/ml] without any changes in resistin. Finally, the IMCL did not change [267.54 (213.94-297.94) vs. 305.75 (230.80-424.75) arbitrary units (AU), P = 0.15] while the EMCL increased [275.53 (210.39-436.66) vs. 411.39 (279.92-556.59) AU; P < 0.01] therefore decreasing the IMCL-to-EMCL (IMCL/EMCL) ratio [1.07 (0.78-1.23) vs. 0.71 (0.53-0.96); P < 0.01]. CONCLUSION: Rosiglitazone treatment increased body weight and hip circumference and decreased WHR. More importantly, it decreased the IMCL/EMCL ratio by increasing the EMCL without any significant change on the IMCL.

Microvascular dysfunction: a direct link among BMI, waist circumference and glucose homeostasis in young overweight/obese normoglycemic women?

OBJECTIVE: Capillary recruitment is impaired in obesity (OB), possibly worsening glucose and insulin availability to target organs. In this study, we investigated whether functional microvascular parameters were correlated with clinical-anthropometrical data and whether these parameters would influence OB-related metabolic disorders, especially glucose homeostasis, in young overweight (OW)/obese women. DESIGN: Cross-sectional clinical study of microvascular reactivity in young OW/obese women. SUBJECTS AND METHODS: A total of 10 lean (23.1 + or - 3.2 years, body mass index (BMI) 22.3 + or - 1.6 kg m(-2)) and 42 OW/obese (24.9 + or - 3.5 years; BMI 34.5 + or - 5.7 (25.7-46.5) kg m(-2)) sedentary non-smoking women were evaluated. Lipid profile, fasting plasma glucose (PG), post-load PG (75 g-2 h), insulin, C-reactive protein, HOMA-IR (homeostasis model assessment for insulin resistance) index and anthropometric variables (weight, BMI, waist and hip circumferences, waist-to-hip ratio and blood pressure (BP)) were determined. Functional microvascular parameters (functional capillary density, red blood cell velocity at baseline and peak (RBCV(max)), and time taken to reach RBCV(max) (TRBCV(max)) during post-occlusive reactive hyperemia after 1 min arterial occlusion) were evaluated by nailfold videocapillaroscopy. RESULTS: The time taken to reach RBCV(max) was significantly longer in OW/obese patients compared with control subjects (8.6 + or - 2.4 versus 5.7 + or - 1.1 s, P<0.001), and its delay was directly associated with adiposity levels, systolic BP and insulin resistance, and inversely related to high-density lipoprotein-cholesterol. Post-load PG could be correlated with TRBCV(max) (R = 0.48, P<0.05) and RBCV(max) (R = -0.29, P<0.05), and it was influenced by weight, waist circumference and TRBCV(max) (adjusted R(2) = 24%) as well. CONCLUSIONS: In the investigated group of young OW/obese women, the direct correlation between post-load PG and TRBCV(max) links microvascular parameters with metabolic variables and suggests a key role for microcirculation in OB-related metabolic disorders.

Adiponectin is related to intramyocellular lipid content in non-diabetic adults.

OBJECTIVE: Insulin resistance (IR) is associated with intramyocellular lipid (IMCL) content and low serum adiponectin (ADP) levels and ADP is also involved in muscle fat oxidation. However, the relationship between ADP and IMCL content is still controversial and in this study we explored it further in non-diabetic adults. DESIGN: Cross-sectional clinical study. SUBJECTS: Thirty-three adult subjects, 24 obese non-diabetic patients with metabolic syndrome (MS) and 9 lean healthy controls. MEASUREMENTS: Proton nuclear magnetic resonance spectroscopy (1H-NMRS) was performed to quantify IMCL content. The latter plus serum ADP, anthropometrics and biochemical parameters were evaluated and compared in these 2 groups. RESULTS: MS patients had higher body mass index, waist, waist-to- hip ratio, glucose, insulin, and triglycerides and lower HDL cholesterol (HDLc) compared to controls. Homeostasis model assessment of IR (HOMA-IR) [3.25 (2.58-4.13) vs 1.02 (0.73- 1.29); p<0.0001] and IMCL content [266.1 (189.9-296.3) vs 72.85 (55.3-109.4) AU, p<0.0001] were higher, and quantitative insulin-sensitivity check index (QUICKI) [0.32 (0.31-0.33) vs 0.38 (0.37-0.40); p<0.0001] and ADP [8.6 (4.05-15.95) vs 21.1 (12.9- 24.4) microg/ml; p=0.02] were lower in MS subjects compared to controls. IMCL content was directly associated to glucose, insulin, triglycerides, and HOMA-IR and inversely to HDLc, QUICKI and, more importantly, to ADP (r=-0.41; p<0.05). Only in the MS group, ADP partially influenced IMCL content. CONCLUSION: ADP is inversely related to IMCL content in non-diabetic adults. This finding has possible implications for the role of ADP in muscle fat oxidation, IR, and MS.

Changes on venous diameter and leg perimeter with different clinical treatments for moderate chronic venous disease: evaluation using Duplex scanning and perimeter measurements.

AIM: To evaluate changes on venous diameter and perimeter of lower limbs in chronic venous disorder (CVD) patients after different clinical treatments for four weeks. METHODS: Fifty-two female patients classified as C2,s or C2,3,s (CEAP classification) were allocated consecutively in three groups: Cirkan (40 mg of the root extract of Ruscus aculeatus + 100 mg of flavonoid hesperidine methylchalcone + 200 mg of vitamin C per pill); elastic compression stockings (ECS) and no treatment (NT). Diameters were determined by duplex ultrasound and perimeter with Leg-O-Meter. RESULTS: After treatment, Cirkan significantly decreased popliteal vein and great saphenous vein (GSV) diameters bilaterally and ECS decreased popliteal vein diameter bilaterally and GSV and varices only on the left limb. Perimeters changed only with ECS. Clinical scores changed between Cirkan x NT and ECS x Cirkan. Disability score varied for ECS x NT and Cirkan x NT. chi2 test detected different distribution frequency for C3 and C2 classes according to treatment: ECS (both limbs) and Cirkan (only left limb). Varices and anatomical scores did not change. CONCLUSIONS: ECS emerges as the most effective clinical treatment tested but improvements with Cirkan on vein diameter and CEAP class were also observed. Clinical scores improved due to pain relief and edema reduction (ECS). These findings point to a positive effect of Cirkan, suggesting that venotonic drugs should be taken into account in the treatment of CVD.

Different flavonoids present in the micronized purified flavonoid fraction (Daflon 500 mg) contribute to its anti-hyperpermeability effect in the hamster cheek pouch microcirculation.

AIM: This study evaluated microcirculatory effects of the flavonoid substances that constitute the micronized purified flavonoid fraction (MPFF) (Daflon 500 mg) in comparison to diosmin. METHODS AND RESULTS: In groups of 3 male hamsters, oral treatment with MPFF or diosmin (15 min before anesthesia) did not alter blood pressure. At 10 or 30 mg/kg, both MPFF and diosmin significantly decreased the leaky sites caused by ischemia/reperfusion (I/R) (30 min) in the hamster cheek pouch; the effect was significantly higher with MPFF (39+/-1% and 52+/-1%, respectively) than diosmin (18+/-1% and 37+/-3%, respectively). Eight groups of 3 hamsters each were treated with the components of MPFF. Diosmetin only decreased the number leaky sites at 30 mg/kg (decrease: 15+/-2%). The decrement at 10 and 30 mg/kg averaged at: 17+/-3% and 44+/-1%, respectively, for hesperidin; 19+/-1% and 46+/-2%, respectively, for linarin; and 30+/-1% and 44+/-1%, respectively, for isorhoifolin. Hesperidin, linarin, and isorhoifolin each displayed an anti-leakage effect comparable to or greater than diosmin. MPFF decreases permeability more than any of its single constituents, suggesting that the flavonoids present in its formulation have a synergistic action. CONCLUSION: These results illustrate that MPFF is more potent than single diosmin in this model of hyperpermeability and that each of the flavonoid substances present in MPFF contribute to its action.

Microcirculation and the metabolic syndrome.

The present review, to the authors' knowledge, is the first to specifically address the relationships between microcirculation and metabolic syndrome, a cluster of metabolic and cardiovascular modifications highly prevalent in the general population. Its close link to overweight and insulin resistance makes it the main cause of the worldwide burden of type 2 diabetes. However, metabolic syndrome is also observed in many other diseases, particularly, but not exclusively, those where insulin resistance is a main feature. Analysis of the literature reveals that this clinical situation is invariably linked to microvascular disturbances, such as abnormalities in arteriolar reactivity, capillary recruitment, permeability, and hemorheology. A particularly interesting observation is that these defects in small vessel structure and function are seen very early in life or disease. Very importantly, they further suggest that microcirculatory abnormalities may be not only secondary but also causal to the development and/or aggravation of insulin resistance and metabolic syndrome. Mechanisms responsible for these modifications remain largely unknown, but insulin's vascular effects in the microvascular network, detailed in this review, are at least one example of such connections. The existing data point to a clear, at least bidirectional, relationship between microcirculation and metabolic syndrome. Additional studies should determine the level of reciprocal causality.

Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome.

AIMS: Insulin resistance and a parental history of diabetes mellitus are independently associated with endothelial dysfunction. Oxidative stress has a pivotal role in the pathophysiology of vascular injury. Metformin, in addition to its glucose-lowering properties, has vasculoprotective effects. We investigated whether metformin has beneficial effects on the nutritive skin capillary circulation and deceases oxidative stress in a group at high risk for Type 2 diabetes mellitus (T2DM) and cardiovascular disease. METHODS: Thirty normoglycaemic subjects with the metabolic syndrome (MS),who had first-degree relatives with T2DM, participated. The mean age was 39.1 +/- 8.4 years and body mass index (BMI) 35.7 +/- 4.8 kg/m2 (mean +/- SD). SUBJECTS: were randomized 1 : 1 to receive placebo (n=14) or metformin (n=16; 1700 mg/day) in a double-blind study. At baseline and post treatment, blood and urine samples were collected for biochemical and 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) analysis, respectively. Microcirculation was assessed by nailfold videocapillaroscopy, analysing afferent (AF), efferent (EF) and apical (AP) diameters of capillary loops, functional capillary density (FCD), red blood cell velocity at rest (RBCV), after 1 min arterial occlusion (RBCVmax) and time (TRBCVmax)taken to reach it. RESULTS: Groups did not differ significantly in anthropometric, clinical, laboratory or microvascular measurements at baseline. In the metformin group, weight,BMI, systolic blood pressure and fasting plasma glucose fell, and lipid profile and microcirculatory parameters FCD, AF, EF, AP, RBCVmaxand TRBCVmax improved (all P<0.01). No relationship between clinico-laboratory parameters and microvascular reactivity was observed, except for changes in total and low density lipoprotein-cholesterol and RBCVmax* 8-epi-PGF2alpha did not change significantly in either group. CONCLUSIONS: Metformin improved skin capillary reactivity in normoglycaemic MS subjects independently of significant changes in 8-epi-PGF2alpha levels.

Characterization of cardiopulmonary function and cardiac muscarinic and adrenergic receptor density adaptation in C57BL/6 mice with chronic Trypanosoma cruzi infection.

Circulating antibodies in chagasic patients interact with myocardial beta adrenergic and muscarinic cholinergic receptors, triggering intracellular signals that alter cardiac function along the course of the disease. However, until now, experimental data in models of chronically infected chagasic mice linking the effects on myocardial beta adrenergic and muscarinic receptors to cardiopulmonary dysfunction is lacking. Thus, we studied C57BL/6 mice 8 months after intraperitoneal injection of 100 trypomastigote forms of the Colombian strain of T. cruzi. Uninfected mice, matched in age, were used as controls. Histopathological analyses (inflammation and fibrosis) and radio-ligand binding assays for estimation of muscarinic and adrenergic receptor density were performed in myocardium tissue samples. When compared to controls, infected mice had electrical conduction disturbances, diastolic dysfunction, lower O2 consumption and anaerobic threshold. In addition, hearts of chronic chagasic mice had intense inflammation and fibrosis, and decreased beta adrenergic and increased muscarinic receptor densities than normal controls. Our data suggest that chronic T. cruzi infection causes alterations in cardiac receptor density and fibrosis deposition which can be associated with cardiac conduction abnormalities, diastolic dysfunction and lower exercise capacity, associating for the first time all these functional and histopathological alterations in chagasic mice.