Role of endogenous GLP-1 on arterial stiffness and renal haemodynamics following bariatric surgery.

BACKGROUND: Cardiovascular trials have revealed the positive impact of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes (T2D). However, the specific effects of endogenous GLP-1 on arterial stiffness and renal function remain understudied. This study aimed to explore the influence of endogenous GLP-1 response post-bariatric surgery on arterial stiffness and renal haemodynamic. METHODS: Thirty individuals with morbid obesity and without T2D, scheduled for Roux-en-Y Gastric Bypass (RYGB), were included. Clinical parameters, 3-hour oral glucose tolerance test (OGTT) with serial sampling for glycaemia, GLP-1 and insulin, carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient (carotid-DC) and renal resistive index (RRI) measurements were conducted pre-surgery and 1-year post-surgery. Participants were categorized into high-response and low-response groups based on their post-surgery increase in GLP-1 (median increase of 104% and 1%, respectively, pre- vs. post-surgery). RESULTS: Post-surgery, high-response group demonstrated a greater reduction in cf-PWV (p = .033) and a greater increase (p = .043) in carotid DC compared to low-response group. These enhancements were observed independently of weight loss or blood pressure changes. High-response group exhibited a reduction in RRI (p = .034), although this association was influenced by improvement in pulse pressure. Finally, a multivariate stepwise regression analysis indicated that the percentage increase of GLP1, Δ-GLP1(AUC)%, was the best predictor of percentage decrease in cf-PWV (p = .014). CONCLUSIONS: Elevated endogenous GLP-1 response following RYGB was associated with improved arterial stiffness and renal resistances, suggesting potential cardio-renal benefits. The findings underscore the potential role of endogenous GLP-1 in influencing vascular and renal haemodynamics independent of traditional weight loss.

Predictive value of dynamic renal resistive index (DRIN) for renal outcome in type 2 diabetes and essential hypertension: a prospective study.

BACKGROUND: Hypertension (EH) and type 2 diabetes (T2DM) are major causes of chronic kidney disease (CKD) and identification of predictors of CKD onset is advisable. We aimed to assess whether dynamic renal resistive index (DRIN), as well as other markers of systemic vascular damage, are able to predict albuminuria onset and estimated glomerular filtration rate (eGFR) decline in patients with T2DM or EH. METHODS: In this prospective observational cohort study, 27 T2DM and 43 EH patients, free of CKD at baseline, were followed-up for 4.1 ± 0.6 years. Resistive Index (RI), endothelium-dependent (FMD) and independent vasodilation in the brachial artery (after glyceryl trinitrate - GTN - 25 µg s.l.), carotid-femoral Pulse Wave Velocity (PWV), Augmentation Index (AIx), DRIN (%RI change after GTN 25 µg s.l.) were evaluated. RESULTS: Patients developing microalbuminuria were older, more frequently T2DM, with higher UACR at baseline, and showed higher DRIN (-2.8 ± 6.7 vs -10.6 ± 6.4 %, p = 0.01) and PWV (9.9 ± 1.3 vs 7.9 ± 1.5 m/s, p = 0.004) at baseline. The best predictors of microalbuminuria onset were DRIN > -5.16 % in T2DM (sensitivity 0.83, specificity 0.80) and PWV > 8.6 m/s in EH (sensitivity 0.96, specificity 1.00). Individuals whose eGFR declined (n = 27) had higher eGFR at baseline, but similar vascular characteristics; however in EH showing eGFR decline, baseline DRIN and PWV were higher. PWV showed a steeper progression during follow-up in patients developing albuminuria (Visit-outcome interaction: p = 0.01), while DRIN was early compromised but no further impaired (Visit-outcome interaction: p = 0.04). CONCLUSIONS: PWV and DRIN are able to predict microalbuminuria onset in newly diagnosed EH and T2DM. DRIN is early compromised in T2DM patients developing microalbuminuria.

In vitro activity of novel in silico-developed antimicrobial peptides against a panel of bacterial pathogens.

Antimicrobial-peptide-based therapies could represent a reliable alternative to overcome antibiotic resistance, as they offer potential advantages such as rapid microbicidal activity and multiple activities against a broad spectrum of bacterial pathogens. Three synthetic antimicrobial peptides (AMPs), AMP72, AMP126, and also AMP2041, designed by using ad hoc screening software developed in house, were synthesized and tested against nine reference strains. The peptides showed a partial ß-sheet structure in 10-mM phosphate buffer. Low cytolytic activity towards both human cell lines (epithelial, endothelial, and fibroblast) and sheep erythrocytes was observed for all peptides. The antimicrobial activity was dose dependent with a minimum bactericidal concentration (MBC) ranging from 0.17 to 10.12 µM (0.4-18.5 µg/ml) for Gram-negative and 0.94 to 20.65 µM (1.72-46.5 µg/ml) for Gram-positive bacteria. Interestingly, in high-salt environment, the antibacterial activity was generally maintained for Gram-negative bacteria. All peptides achieved complete bacterial killing in 20 min or less against Gram-negative bacteria. A linear time-dependent membrane permeabilization was observed for the tested peptides at 12.5 µg/ml. In a medium containing Mg²âº and Ca²âº, the peptide combination with EDTA restores the antimicrobial activity particularly for AMP2041. Moreover, in combination with anti-infective agents (quinolones or aminoglycosides) known to bind divalent cation, AMP126 and AMP2041 showed additive activity in comparison with colistin. Our results suggest the following: (i) there is excellent activity against Gram-negative bacteria, (ii) there is low cytolytic activity, (iii) the presence of a chelating agent restores the antimicrobial activity in a medium containing Mg²âº and Ca²âº, and (iv) the MBC value of the combination AMPs-conventional antibiotics was lower than the MBC of single agents alone.

Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls.

AIM: To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. DESIGN: Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 µg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). METHODS: In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. RESULTS: In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. CONCLUSIONS: The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.

Type 2 diabetes mellitus worsens arterial stiffness in hypertensive patients through endothelial dysfunction.

AIMS/HYPOTHESIS: Endothelium-derived factors are thought to be physiological modulators of large artery stiffness. The aim of the study was to investigate whether endothelial function could be a determinant of arterial stiffness in essential hypertensive patients, in relation with the concomitant presence of type 2 diabetes mellitus. METHODS: The study included 341 participants (84 hypertensive patients with and 175 without type 2 diabetes mellitus, 82 matched controls). Brachial artery endothelium-dependent flow-mediated dilation (FMD) was determined by high-resolution ultrasound and computerised edge detection system. Applanation tonometry was used to measure carotid-femoral pulse wave velocity (PWV). RESULTS: Hypertensive patients with diabetes had higher PWV (10.1 ± 2.3 m/s vs 8.6 ± 1.4 m/s, p < 0.001) and lower FMD (3.51 ± 2.07 vs 5.16 ± 2.96%, p < 0.001) than non-diabetic hypertensive patients, who showed impaired vascular function when compared with healthy participants (7.9 ± 1.6 m/s and 6.68 ± 3.67%). FMD was significantly and negatively correlated to PWV only in hypertensive diabetic patients (r = -0.456, p < 0.001), but not in hypertensive normoglycaemic patients (r = -0.088, p = 0.248) or in healthy participants (r = 0.008, p = 0.946). Multivariate analysis demonstrated that, in the diabetic group, FMD remained an independent predictor of PWV after adjustment for confounders (r(2) = 0.083, p = 0.003). Subgroup analysis performed in non-diabetic hypertensive patients revealed that neither obesity nor the metabolic syndrome affected the relationship between FMD and PWV. CONCLUSIONS/INTERPRETATION: Endothelial dysfunction is a determinant of aortic stiffness in hypertensive diabetic patients but not in hypertensive patients without diabetes. These results suggest that type 2 diabetes mellitus on top of hypertension might worsen arterial compliance by endothelium-related mechanisms.

High serum levels of CXC (CXCL10) and CC (CCL2) chemokines in untreated essential hypertension.

Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.

Cardiovascular changes in patients with primary aldosteronism after surgical or medical treatment.

BACKGROUND: Data on the cardiovascular middle-term follow-up of patients with primary aldosteronism (PA) are scanty. AIM: To detect the cardiovascular effects of surgery in patients with aldosterone (ALD)-producing adenoma (APA) and of pharmacotherapy in those with bilateral adrenal hyperplasia (BAH), a prospective study involving 60 consecutive patients with PA was performed. MATERIAL/ METHODS: Clinical, biochemical, and cardiovascular assessment was obtained before and after (31.5±4.4 months) surgery or proper medical treatment (32.1±5.0 months) in 19 and 41 patients, respectively. RESULTS: As expected, plasma ALD normalized in all operated patients, while in the other group it did not change. Systolic and diastolic blood pressure decreased (p<0.001) after both treatments. However, absolute and percentage reduction was significantly more pronounced (p<0.01) in operated than in non-operated patients. Left ventricular (LV) mass showed significant reduction after surgery (LV mass g/m(2), p<0.0007; LV mass g/m(2.7), p<0.01), but no change after medical treatment, so that the differences between absolute and percentage values at follow- up were statistically significant (p<0.01) between groups. Basal LV mass/m(2.7) was positively associated with age (p<0.009), body mass index (p<0.0008), drug number (p<0.03), and ALD/plasma renin activity ratio (p<0.01). Allocating the patients according to plasma ALD and cardiac parameters, patients who presented ALD reduction during the study also had a decrement in cardiac mass (p<0.04). CONCLUSIONS: Our data indicate that in patients with PA the removal of ALD excess by surgery in APA is effective in reducing blood pressure and in improving cardiac parameters, while anti-hypertensive therapy in BAH shows less positive impact on cardiovascular system.

Predictors of type 2 diabetes relapse after Roux-en-Y Gastric Bypass: A ten-year follow-up study.

AIMS: To assess the impact of bariatric surgery on remission and relapse of type 2 diabetes mellitus (T2DM) at 10 years of follow-up and analyze predictive factors. MATERIALS AND METHODS: Eighty-eight obese subjects undergoing Roux-en-Y gastric bypass (RYGB) and 25 subjects assigned to medical therapy (MT) were evaluated every year for 10 years. T2DM remission was defined by the American Diabetes Association criteria. RESULTS: Body mass index (BMI), fasting glucose, and haemoglobin A1c (HbA1c) improved more markedly in RYGB than MT patients throughout the 10-year period. Post-surgery remission rates were 74% and 53% at 1 and 10 years, respectively, while remission did not occur in MT patients. One-year post-surgery, BMI decreased more in subjects with remission than in those without, but no further decrease was observed thereafter. By partial-least-squares analysis, T2DM duration, baseline HbA1c, and ensuing insulin therapy were the strongest predictors of remission. Remission was achieved at one year in 91% of patients with T2DM duration < 4 years, and 79% of them remained in remission at 10 years. On the contrary only 42% of patients with T2DM duration ≥ 4 years achieved remission, which was maintained only in 6% at the end of 10 years. By survival analysis, patients with T2DM duration < 4 years had higher remission rates than those with duration ≥ 4 years (hazards ratio (HR) 3.1 [95%CI 1.8-5.7]). Relapse did not occur before two years post-surgery and was much less frequent in patients with < 4- vs ≥ 4-year duration (HR 11.8 [4.9-29.4]). CONCLUSIONS: Short T2DM duration and good glycemic control before RYGB surgery were the best requisites for a long-lasting T2DM remission, whereas weight loss had no impact on the long-term relapse of T2DM.

Dynamic evaluation of renal resistive index in normoalbuminuric patients with newly diagnosed hypertension or type 2 diabetes.

AIM/HYPOTHESIS: Renal resistive index is a useful measure for quantifying alterations in renal blood flow. In the present study we evaluated resistive index at baseline and after vasodilation induced by nitroglycerine in normoalbuminuric patients with type 2 diabetes or essential hypertension, relating the values to indices of systemic vascular dysfunction. METHODS: Newly diagnosed treatment-naïve type 2 diabetic (n = 32) and hypertensive patients (n = 49) were compared with 27 age- and sex-matched healthy controls. Renal resistive index was obtained by duplex ultrasound at baseline and after 25 µg sublingual nitroglycerine. Endothelium-dependent (flow-mediated dilation) and -independent (response to nitroglycerine) vasodilation in the brachial artery was assessed by computerised edge detection system. Carotid-femoral pulse-wave velocity and augmentation index were assessed by applanation tonometry. Nitrotyrosine levels, an index of oxidative stress, were also measured. RESULTS: Resistive index was higher in diabetic than in hypertensive patients and controls (p < 0.001), while changes in resistive index induced by nitroglycerine were lower in hypertensive patients compared with controls (p < 0.01), and were further reduced in type 2 diabetic patients. Hypertensive and diabetic patients showed significantly increased arterial stiffness, nitrotyrosine levels and reduced endothelial function than controls (p < 0.05). Changes in resistive index induced by nitroglycerine were independently related to serum glucose, reactive hyperaemia and aortic pulse-wave velocity in the overall population. CONCLUSIONS/INTERPRETATION: These results support the dynamic evaluation of renal resistive index as an early detector of renal vascular alterations in the presence of type 2 diabetes and hypertension, even before the onset of microalbuminuria.

Blood pressure through aging and menopause.

Together with the aging process, hypertension is the main risk factor contributing to the increase in cardiovascular morbidity and mortality in postmenopausal women, with a prevalence of around 60% in women older than 65 years. Considering that hypertension is a modifiable risk factor, the understanding of its epidemiology and pathophysiology and the development of appropriate therapeutic strategies are conceivably crucial in reducing cardiovascular risk. The high prevalence of hypertension in older women is largely due to the progressive stiffening of the arterial structure which accompanies the aging process in both sexes. However, the abrupt fall in circulating estrogen levels might independently contribute to the rise in blood pressure, through partly unknown mechanisms, such as a direct effect on the arterial wall, the activation of the renin-angiotensin system and of the sympathetic nervous system. Postmenopausal hypertension fosters the development of left ventricular hypertrophy and is the main factor contributing to coronary artery disease, chronic heart failure and stroke in older women. Recent analysis demonstrates that men and women receive a similar benefit from antihypertensive therapy in terms of reduction of cardiovascular morbidity and mortality and, considering that generally the response to different drugs is not different between the sexes, currently there is no need to use specific antihypertensive drug classes after menopause. Finally, although observational studies have shown that hormone replacement therapy is associated with lower cardiovascular risk and lower blood pressure values, randomized clinical trials have conversely denied this benefit and demonstrated rather that this therapeutical approach increases the risk of cardiovascular events.

Clinical and methodological aspects of endothelial function in patients with systemic autoimmune diseases.

The endothelium is not merely a barrier but it plays a key role in the maintenance of vascular homeostasis. An alteration of the endothelial function (EF) is an early marker of atherosclerosis, also contributing to the development of atherosclerotic lesions and later clinical complications. Systemic autoimmune diseases are characterized by the occurrence of premature atherosclerosis and cardiovascular disease. In view of the prognostic significance of EF for the development of atherosclerotic disease, many studies have evaluated the endothelium in systemic autoimmune diseases, using different techniques. The aim of the present paper is to review the different available techniques to study EF, their advantages and limitations and the data available on the study of EF in systemic autoimmune diseases. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. Several techniques were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries). Studies assessing microvasculature in systemic autoimmune diseases have shown the presence of reduced endothelium dependent vasodilation, while no agreement exists on the presence of endothelium independent alterations. Flow mediated dilation (FMD) has been widely used to evaluate endothelium-dependent vasodilation in peripheral macrocirculation. The majority of studies in systemic autoimmune diseases have shown a decreased brachial artery FMD, whereas endothelium-independent response appears unaffected by the disease in this district. These data strongly underline the different information that could be obtained by different techniques and suggests their combined use in prospective cohorts. Circulating markers of EF include direct products of endothelial cells that change when the endothelium is activated, such as measures of NO biology, inflammatory cytokines, adhesion molecules, as well as markers of endothelial damage and repair. Many of these circulating markers are difficult to measure and quite expensive, and currently are only used in research settings. In view of the complexities in the evaluation of EF, results represent the interaction of several endothelial pathways. No single test currently available is specific for the vascular district tested or the risk factor/diseases considered, and a panel of several tests is therefore needed to characterize the multiple aspects of endothelial biology.

Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia.

INTRODUCTION AND AIM: Dopamine agonists have been reported to increase the risk of cardiac valve regurgitation in patients with Parkinson's disease. However, it is unknown whether these drugs might be harmful for patients with hyperprolactinaemia (HyperPRL). The aim of the study was to evaluate whether HyperPRL patients treated with dopamine agonists had a higher prevalence of cardiac valves regurgitation than that of general population. METHODS AND PATIENTS: One hundred consecutive patients (79 women, 21 men, mean age 41 +/- 13 years) with HyperPRL during treatment with cabergoline were enrolled in an observational case-control study and compared with 100 matched normal subjects (controls). Valve regurgitation was assessed by echocardiography according to the American Society of Echocardiography recommendations. RESULTS: Seven HyperPRL patients (7%) and six controls (6%) had moderate (grade 3) regurgitation in any valve (p = 0.980). All were asymptomatic and had no signs of cardiac disease. Mean duration of cabergoline treatment was 67 +/- 39 months (range: 3-199 months). Mean cumulative dose of cabergoline was 279 +/- 301 mg (range: 15-1327 mg). Moderate valve regurgitation was not associated with the duration of treatment (p = 0.359), with cumulative dose of cabergoline (p = 0.173), with age (p = 0.281), with previous treatment with bromocriptine (p = 0.673) or previous adenomectomy (p = 0.497) in patients with HyperPRL. DISCUSSION: In conclusion, treatment with cabergoline was not associated with increased prevalence of cardiac valves regurgitation in patients with HyperPRL. Mean cumulative dose of cabergoline was lower in patients with HyperPRL than that reported to be deleterious for patients with Parkinson's disease: hence, longer follow-up is necessary, particularly in patients receiving weekly doses > 3 mg.

Analysis of risk factors for early hepatic artery thrombosis after liver transplantation. Possible contribution of reperfusion in the early morning.

BACKGROUND: Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. METHODS: The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis (<30 days from transplantation), several medical and surgical parameters were taken into consideration. Arterial reperfusion was considered to have taken place at a time of high coagulability when occurred between 6.00 a.m. and 10.00 a.m. on the basis of previous reports. RESULTS: Logistic regression identified donor age (OR for age >60: P=0.017), bench reconstruction of the artery (OR: 5.06, P=0.013) and time of high coagulability at reperfusion (OR 2.93, P=0.087), as independently associated with early hepatic artery thrombosis. CONCLUSIONS: The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

Systemic Inflammation after Third Molar Removal: A Case-Control Study.

Third molar extraction is one of the most frequent interventions in dentistry. Nevertheless, there is scarce evidence on the host response of individuals with impacted or semi-impacted third molars and the possible effects of surgical removal. A case-control study of 40 patients was designed to evaluate 1) the differences in biomarkers of systemic inflammation, vascular function, and metabolism (high-sensitive C-reactive protein, lipids, fibrinogen, oxidative stress, and endothelial function analysis) and 2) the acute and short-term effects of surgical removal in patients with bilateral impacted or semi-impacted third molars compared to controls with no third molars. Patients undergoing third molar extraction exhibited greater levels of systemic inflammation, oxidative stress, and triglycerides than controls. Raised white blood cell counts as well as peaks of serum levels of C-reactive protein and fibrinogen were noticed in the first postoperative week. Three months after the extraction, all markers returned to baseline values. Malondialdehyde, an indicator of oxidative stress indicator, was significantly reduced after third molar removal. Semi-impacted or impacted third molars are associated with higher systemic inflammation, and their removal may represent a useful human model to study acute inflammation and determine beneficial systemic effects ( ClinicalTrials.gov NCT03048175).

Ambulatory blood pressure monitoring and endothelium-dependent vasodilation in the elderly athletes.

AIM: Regular exercise is a key component of cardiovascular risk prevention strategies, because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events. Endothelium plays an important role in the local regulation of vascular tone and structure, mainly by nitric oxide (NO) synthesis and action. Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure (BP) and on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery. METHODS: The study population included 30 male subjects (mean age 65.6+/-5.6 years), who had practiced endurance running at a competitive level for at least 40 years, and 28 age- and sex-matched subjects (mean age 64.5+/-4.5 years) with sedentary lifestyle and free of cardiovascular disease. Athletes and control subjects underwent standard 12-lead ECG, clinic BP, 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, in the brachial artery by high-resolution ultrasonography. RESULTS: Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes, than in the controls (P<0.001, respectively). Systolic and diastolic 24-h BP variability, when assessed either by the standard deviation (S.D.), or by the coefficient of variation (CV), were also significantly lower in the athletes (P<0.01). The athletes also had a lower 24-h, day-time and night-time heart rate (HR) (P<0.01), as well as a lower HR variability (P<0.01). As regards circadian BP change, the %Delta was statistically significant greater in athletes (P<0.05). Elderly athletes showed higher FMD than elderly sedentary subjects (P<0.001), whereas no differences were shown in the response to GTN. CONCLUSIONS: Our results, suggest that long-term physical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging, preserving the capacity of the endothelium-dependent vasodilation and reduces BP values improving arterial pressure control.

Endothelial function in young subjects with vaso-vagal syncope.

BACKGROUND: The aim of this study was to determine whether endothelial function and inappropriate peripheral vasomotion have a significant role in the pathogenesis of neurally mediated syncope. METHODS: In 16 patients (mean age 28.2+/-5.8 years) with previous vaso-vagal syncope and in matched healthy subjects, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent response to glyceryl trinitrate (GTN), 25 mug, were measured in the brachial artery from high-resolution ultrasonography. Heart rate variability (HRV) analysis at rest and during tilt test was compared between two groups. RESULTS: In the subjects with positive tilt test, all HRV parameters were significant higher respect to subjects with negative tilt test (P<0.001). The patients with positive tilt test, showed persistent, marked variability of heart rate (HR), due to increased vagal activity with withdrawal sympathetic tone and consequently reduction of blood pressure (BP) (-30.4+/-4.2 mmHg, P<0.001) accompanied by a decrease in HR (-24.3+/-4.5 beats/min, P<0.001) compared to negative tilt test subjects. These findings prove the real presence of vagal hypertone in patients with syncope. In our study, HR reached values lower than 40 beats/min. FMD in patients with neurally mediated syncope were significantly greater than those in controls (respectively, 9.2+/-2.8% vs. 4.6+/-1.4%, P<0.01) whereas no differences were shown in the response to GTN (18.4+/-4.4% vs. 16.1+/-4.2%, n.s.). CONCLUSIONS: The augmented endothelial function and the abnormal vasodilation of peripheral arteries in association with bradycardia play an important role in the development of vaso-vagal syncope in young subjects.

[Chronic inflammation and endothelial dysfunction: analysis of a cohort of patients with SLE and UCTD]. / Flogosi cronica e disfunzione endoteliale: analisi di una coorte di pazienti affetti da LES e UCTD.

OBJECTIVE: Cardiovascular complications, mainly caused by an accelerated atherosclerosis, are one of the leading causes of death and disability in patients with systemic autoimmune diseases. Endothelial dysfunction is considered the earliest and reversible step of atherogenesis. Aim of the present study is to investigate endothelial function (EF) in patients with systemic lupus erythematosus (SLE), undifferentiated connective tissue diseases (UCTD) and correlate the results with clinical and laboratory variables. METHODS: EF was assessed on the peripheral microcirculation by the perfused forearm technique that can estimate both endothelium- dependent and endothelium- independent vasodilatation. The same evaluation has been repeated in two patients after the administration of 20 mg of 6-metilprednisolone. RESULTS: Twenty-three female patients with SLE or UCTD, with a follow up of at least 1 year have been studied and compared with 8 healthy controls matched for epidemiological variables and traditional risk factors for cardiovascular disease. A significant reduction both in endothelium dependent than endothelium independent vasodilatation was observed in both patients groups compared with controls. In addition, UCTD patients demonstrated a significant reduction in the nitric oxide pathway compared with controls and SLE patients. Finally, steroid administration induced an improvement of vascular reactivity. CONCLUSIONS: Despite the well documented side effects of chronic corticosteroid therapy, our data might suggest a role for antinflammatory and immunosuppressive therapy in the prevention of premature atherosclerosis in patients with systemic autoimmune diseases.

Role of cysteine residues of rat A2a adenosine receptors in agonist binding.

In the present study, we investigated the role of disulfide bridges and sulfhydryl groups in A2a adenosine receptor binding of the agonist 2-p-(2-carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosi ne (CGS 21680). To evaluate the presence of essential disulfide bridges, rat striatal membranes were incubated with [3H]CGS 21680 in the presence of dithiothreitol and binding of the agonist to membranes was measured. The amount of [3H]CGS 21680 which specifically bound, decreased progressively upon pretreatment of membranes with increasing concentrations of dithiothreitol. Pretreatment of rat striatal membranes with 12.5 mM dithiothreitol for 15 min at 25 degrees C resulted in a 2-fold decrease of A2a adenosine receptor affinity for [3H]CGS 21680, and a reduction in the maximal number of binding sites. The presence of agonist or antagonist ligands protected the A2a adenosine receptor sites from the effect of dithiothreitol. We also examined the susceptibility of A2a adenosine receptors to inactivation by the sulfhydryl alkylating reagent, N-ethylmaleimide. When rat striatal membranes were pretreated with N-ethylmaleimide for 30 minutes at 37 degrees C, a decrease in specific [3H]CGS 21680 binding was observed. Pretreatment of membranes with 1 mM N-ethylmaleimide also resulted in a 2-fold reduction of A2a adenosine receptor affinity for [3H]CGS 21680, as well as a slight decrease in the maximal number of binding sites. Neither agonist nor antagonist ligands were effective in protecting the receptor sites from inactivation by N-ethylmaleimide. In contrast, addition of 100 microM guanosine-5'-O-(3-thiotriphosphate) or 5'-guanylylimidodiphosphate were both effective in protecting the receptor sites from inactivation by N-ethylmaleimide. This protective effect was significant but not complete. Our data suggest that disulfide bridges play a role in the structural integrity of the A2a adenosine receptor, furthermore, reduced sulfhydryl groups appear to be important but we do not yet know if they are on the receptor or on the Gs alpha subunit.

Vasodilation to bradykinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients.

BACKGROUND: In essential hypertension, endothelium-dependent vasodilation is impaired because of reduced nitric oxide (NO) availability, which is mainly caused by oxidative stress. The present study was designed to identify the mechanism(s) responsible for NO-independent vasodilation to bradykinin in patients with essential hypertension. METHODS AND RESULTS: In 16 healthy subjects (49.5+/-5.8 years; 118.6+/-3.5/78.9+/-2.9 mm Hg) and 16 patients with essential hypertension (47.9+/-4.8 years; 154.6+/-4.5/102.9+/-3.2 mm Hg), we measured modifications in forearm blood flow (strain-gauge plethysmography) during intrabrachial infusion of bradykinin (5, 15, or 50 ng/100 mL of forearm tissue per minute) in the presence of saline, N(omega)-monomethyl-L-arginine (L-NMMA; used to inhibit NO synthase; 100 microg/100 mL of forearm tissue per minute), and ouabain (to block Na(+)K(+)/ATPase and prevent hyperpolarization; 0.7 microg/100 mL of forearm tissue per minute). In healthy subjects, vasodilatation to bradykinin was significantly blunted by L-NMMA and unaffected by ouabain. In hypertensive patients, vasodilatation to bradykinin was not modified by L-NMMA, but it was significantly reduced by ouabain. In an adjunctive group of 8 hypertensive patients (49.9+/-3.8 years; 155.9+/-5.5/103.7+/-3.9 mm Hg), the response to bradykinin was repeated during the administration of intrabrachial vitamin C (a scavenger for oxygen free radicals; 8 mg/100 mL of forearm tissue per minute). In these patients, L-NMMA-induced inhibition of vasodilation to bradykinin was restored, and ouabain was no longer effective. In a final group of 6 normotensive controls (45.9+/-4.1 years; 115.1+/-2.9/79.3+/-2.1 mm Hg), vasodilation to bradykinin residual to L-NMMA blockade was further inhibited by simultaneous ouabain infusion. CONCLUSIONS: Vasodilation to bradykinin is impaired in essential hypertensive patients because of an NO-system alteration caused by oxidative stress, and it is mediated by an alternative pathway, possibly involving endothelium-dependent hyperpolarization.