Rumen-protected arginine in ewe lambs: effects on circulating serum amino acids and carotid artery hemodynamics.

Sixty nonpregnant, nulliparous Rambouillet ewes (51 ± 1.4 kg initial body weight) were used in a completely randomized design to determine 1) if rumen-protected l-Arg (RP-ARG) supplementation would increase serum concentrations of amino acids resulting from Arg supplementation and metabolism, and decrease serum concentrations of amino acids that compete with Arg for transporters, 2) if RP-ARG supplementation would alter carotid artery hemodynamics, and 3) the most effective oral dose of RP-ARG to positively increase both circulating amino acids and improve peripheral tissue blood perfusion as measured by carotid hemodynamics. Ewes were penned individually in a temperature-controlled facility. Ewes were randomly assigned to one of four treatments: a control group that received no supplemental Arg (CON; 50 g of finely ground corn, only), or Arg-supplemented groups that received 90 (90), 180 (180), or 360 (360) mg RP-ARG·kg BW-1·d-1 mixed in 50 g of finely ground corn. Supplements were administered once daily for 14 d and fully consumed before the delivery of a total pelleted diet at 0630 and 1830 hours daily. Baseline and final blood samples were collected at days 0 (before treatment initiation) and 15, respectively. Doppler ultrasound was used to assess carotid arterial hemodynamics at 0600 hours on days 0 (before treatment initiation), 5, 8, 12, and 15. After 14 d of supplementation, ewes fed 180 had greater Arg (P = 0.05) and Orn (P = 0.05) and tended (P = 0.08) to have greater Asp in serum than ewes fed 90, and for these amino acids, ewes fed 180 were similar (P ≥ 0.16) compared with ewes fed 360. All supplemented ewes (90, 180, and 360) had a negative change (P = 0.02) from baseline when normalized to CON for the pulsatility and resistance indices, which indicate greater distal tissue blood perfusion and lower vascular resistance of blood flow, respectively. Additionally, there were quadratic responses for the pulsatility and resistance indices (P = 0.03 and 0.01, respectively) where ewes fed 180 had the greatest change from baseline when normalized to CON. Results indicate that Arg supplementation increased serum amino acid concentrations and improved peripheral tissue blood perfusion. The 180 mg·kg BW-1·d-1 RP-ARG dose was determined to be the optimal dose for nonpregnant, nulliparous Rambouillet ewes.

Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans.

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (r2=0.29, P<0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%, P<0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.

Effect of Equol on Vasocontractions in Rat Carotid Arteries Treated with High Insulin.

Previous research has indicated that high insulin affects vascular function. Equol is an active metabolite of daidzein, an isoflavone produced from soy by intestinal microbial flora, with beneficial effects on the vascular system. This study investigated whether equol was beneficial for vascular function under high insulin conditions. Using organ culture techniques, rat carotid arteries were treated for 23 ± 1 h with a vehicle, high insulin (100 nM), or equol (100 µM) plus high insulin (100 nM). Vascular isometric forces were measured by the organ bath technique. In each endothelium-intact ring, the contractions induced by high-K+, noradrenaline, or by serotonin (5-HT) were similar for the vehicle, insulin, and equol + insulin treatments. Contractions induced by a selective 5-HT2A receptor agonist (TCB2) increased with insulin treatment (vs. vehicle), but less so with equol + insulin. Under basal conditions, a selective 5-HT2B receptor agonist (BW723C86) did not induce contraction; following precontraction by a thromboxane analog, it induced contraction but not relaxation. These responses were similar across the three treatments. Acetylcholine-induced relaxations were also similar for the three treatments. In the endothelium-denuded preparations, 5-HT-induced contraction was augmented with insulin treatment (vs. vehicle) but less so by equol + insulin treatment. These differences in 5-HT-induced contractions were eliminated by iberiotoxin, a large-conductance calcium-activated K+ channel (BKCa) inhibitor. These results suggest that equol exerts a preventive effect on the enhancement of 5-HT-induced contraction by high insulin (possibly mediated by the 5-HT2A receptor), and that these effects may be attributed to the activation of BKCa channels in vascular smooth muscle.

The effects of aging on the distribution of cerebral blood flow with postural changes and mild hyperthermia.

PURPOSE: Cerebral blood flow (CBF) would be impaired with dual stresses of heat and orthostatic changes, even if those stresses are mild, in the elderly with declined cardio- and cerebrovascular functions with aging. To test the hypothesis, we compared the response of blood flow in the internal carotid artery (ICA) and vertebral artery (VA) to dual stresses of heat and orthostatic changes between the elderly and young individuals. METHODS: Nine elderly and eight young healthy men (71.3 ± 3.0 and 23.3 ± 3.1 years, mean ± SD, respectively) underwent measurements of blood flow in the ICA, VA and external carotid artery (ECA) via ultrasonography. The measurements were obtained in sitting and supine positions under normothermic (NT) and mildly hyperthermic (HT) conditions (ambient temperature 28 °C). Esophageal temperatures increased from NT (36.4 ± 0.2 °C, mean ± SE) to HT (37.4 ± 0.2 °C) with lower legs immersion in 42 °C water. RESULTS: With heat stress, ECA blood flow increased in both postures in both age groups (effect of heat, p < 0.001), whereas ICA blood flow remained unchanged. With postural changes from supine to sitting, ECA blood flow remained unchanged whereas ICA blood flow decreased (effect of posture, p = 0.027) by 18% in NT in the young and by 20% in HT in the elderly. VA blood flow remained unchanged under both heat stress and postural changes. CONCLUSIONS: The CBF is impaired under dual stresses of heat and orthostatic changes in healthy aged individuals, even if the levels of the stresses are mild.

Spatially structured cell populations process multiple sensory signals in parallel in intact vascular endothelium.

Blood flow, blood clotting, angiogenesis, vascular permeability, and vascular remodeling are each controlled by a large number of variable, noisy, and interacting chemical inputs to the vascular endothelium. The endothelium processes the entirety of the chemical composition to which the cardiovascular system is exposed, carrying out sophisticated computations that determine physiological output. Processing this enormous quantity of information is a major challenge facing the endothelium. We analyzed the responses of hundreds of endothelial cells to carbachol (CCh) and adenosine triphosphate (ATP) and found that the endothelium segregates the responses to these two distinct components of the chemical environment into separate streams of complementary information that are processed in parallel. Sensitivities to CCh and ATP mapped to different clusters of cells, and each agonist generated distinct signal patterns. The distinct signals were features of agonist activation rather than properties of the cells themselves. When there was more than one stimulus present, the cells communicated and combined inputs to generate new distinct signals that were nonlinear combinations of the inputs. Our results demonstrate that the endothelium is a structured, collaborative sensory network that simplifies the complex environment using separate cell clusters that are sensitive to distinct aspects of the overall biochemical environment and interactively compute signals from diverse but interrelated chemical inputs. These features enable the endothelium to selectively process separate signals and perform multiple computations in an environment that is noisy and variable.

First granted example of novel FDA trial design under Expedited Access Pathway for premarket approval: BeAT-HF.

BACKGROUND: The Food and Drug Administration (FDA) initiated the Expedited Access Pathway (EAP) to accelerate approval of novel therapies targeting unmet needs for life-threatening conditions. EAP allows for the possibility of initial FDA approval using intermediate end points with postapproval demonstration of improved outcomes. OBJECTIVE: Describe the EAP process using the BeAT-HF trial as a case study. METHODS: BeAT-HF will examine the safety and effectiveness of baroreflex activation therapy (BAT) in heart failure patients with reduced ejection fraction using an Expedited and Extended Phase design. In the Expedited Phase, BAT plus guideline-directed medical therapy (GDMT) will be compared at 6 months postimplant to GDMT alone using 3 intermediate end points: 6-minute hall walk distance, Minnesota Living with Heart Failure Questionnaire, and N-terminal pro-B-type natriuretic peptide. The rate of heart failure morbidity and cardiovascular mortality will be compared between the arms to evaluate early trending using predictive probability modeling. Sample size of 264 patients randomized 1:1 to BAT + GDMT versus GDMT alone provides 81% power for the Expedited Phase intermediate end points. For the Extended Phase, the heart failure morbidity and cardiovascular mortality end point is based on an expected event rate of 0.4 events/patient/year in the GDMT arm. With an adaptive sample size selection design for robustness to inaccurate assumptions, a sample size of 480-960 randomized patients followed ≥2 years allows detecting a 30% reduction in the primary end point with a power of 97.5%. CONCLUSION: Through a unique collaboration with FDA under the EAP, the BeAT-HF trial design allows for the possibility of approval of BAT, initially for symptom relief and subsequently for outcomes improvement.

Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction.

OBJECTIVE: To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction. DESIGN: We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe-/-) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed. RESULTS: ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe-/- mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation. CONCLUSIONS: We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.

Effect of ovariectomy and Sideritis euboea extract administration on large artery mechanics, morphology, and structure in middle-aged rats.

BACKGROUND: Arterial function is regulated by estrogen, but no consistent pattern of arterial mechanical remodeling in response to depleted estrogen levels is available. OBJECTIVE: To examine long-term effects of ovariectomy (OVX) on the mechanical properties, morphology, and histological structure of the carotid artery in middle-aged rats and a potentially protective effect of Sideritis euboea extract (SID), commonly consumed as "mountain tea". METHODS: 10-month-old female Wistar rats were allocated into control (sham-operated), OVX, OVX+SID, and OVX+MALT (maltodextrin; excipient used for dilution of SID) groups. They were sacrificed after 6 months and their carotid arteries were submitted to inflation/extension tests and to dimensional and histological evaluation. RESULTS: Remodeling in OVX rats was characterized by a decreased in situ axial extension ratio, along with increased opening angle, thickness, and area of the vessel wall and of its medial layer, but unchanged lumen diameter. Compositional changes involved increased elastin/collagen densities. Characterization by the "four-fiber" microstructure-motivated model revealed similar in situ biaxial response of carotid arteries in OVX and control rats. CONCLUSIONS: Carotid artery remodeling in OVX rats was largely consistent with hypertensive remodeling, despite the minor arterial pressure changes found, and was not altered by administration of SID, despite previous evidence of its osteo-protective effect.

Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans.

KEY POINTS: A recent 30 year prospective study showed that lifelong sauna use reduces cardiovascular-related and all-cause mortality; however, the specific cardiovascular adaptations that cause this chronic protection are currently unknown. We investigated the effects of 8 weeks of repeated hot water immersion ('heat therapy') on various biomarkers of cardiovascular health in young, sedentary humans. We showed that, relative to a sham group which participated in thermoneutral water immersion, heat therapy increased flow-mediated dilatation, reduced arterial stiffness, reduced mean arterial and diastolic blood pressure, and reduced carotid intima media thickness, with changes all on par or greater than what is typically observed in sedentary subjects with exercise training. Our results show for the first time that heat therapy has widespread and robust effects on vascular function, and as such, could be a viable treatment option for improving cardiovascular health in a variety of patient populations, particularly those with limited exercise tolerance and/or capabilities. ABSTRACT: The majority of cardiovascular diseases are characterized by disorders of the arteries, predominantly caused by endothelial dysfunction and arterial stiffening. Intermittent hot water immersion ('heat therapy') results in elevations in core temperature and changes in cardiovascular haemodynamics, such as cardiac output and vascular shear stress, that are similar to exercise, and thus may provide an alternative means of improving health which could be utilized by patients with low exercise tolerance and/or capabilities. We sought to comprehensively assess the effects of 8 weeks of heat therapy on biomarkers of vascular function in young, sedentary subjects. Twenty young, sedentary subjects were assigned to participate in 8 weeks (4-5 times per week) of heat therapy (n = 10; immersion in a 40.5°C bath sufficient to maintain rectal temperature ≥ 38.5°C for 60 min per session) or thermoneutral water immersion (n = 10; sham). Eight weeks of heat therapy increased flow-mediated dilatation from 5.6 ± 0.3 to 10.9 ± 1.0% (P < 0.01) and superficial femoral dynamic arterial compliance from 0.06 ± 0.01 to 0.09 ±0.01 mm(2)  mmHg(-1) (P = 0.03), and reduced (i.e. improved) aortic pulse wave velocity from 7.1 ± 0.3 to 6.1 ± 0.3 m s(-1) (P = 0.03), carotid intima media thickness from 0.43 ± 0.01 to 0.37 ± 0.01 mm (P < 0.001), and mean arterial blood pressure from 83 ± 1 to 78 ± 2 mmHg (P = 0.02). No changes were observed in the sham group or for carotid arterial compliance, superficial femoral intima media thickness or endothelium-independent dilatation. Heat therapy improved endothelium-dependent dilatation, arterial stiffness, intima media thickness and blood pressure, indicating improved cardiovascular health. These data suggest heat therapy may provide a simple and effective tool for improving cardiovascular health in various populations.

Effects of Omega-3 Fatty Acids on Erectile Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia.

The aim of this study was to investigate whether the omega-3 fatty acids help to improve erectile function in an atherosclerosis-induced erectile dysfunction rat model. A total of 20 male Sprague-Dawley rats at age 8 weeks were divided into three groups: Control group (n = 6, untreated sham operated rats), Pathologic group (n = 7, untreated rats with chronic pelvic ischemia [CPI]), and Treatment group (n = 7, CPI rats treated with omega-3 fatty acids). For the in vivo study, electrical stimulation of the cavernosal nerve was performed and erectile function was measured in all groups. Immunohistochemical antibody staining was performed for transforming growth factor beta-1 (TGF-ß1), endothelial nitric oxide synthase (eNOS), and hypoxia inducible factor 1-alpha (HIF-1α). In vivo measurement of erectile function in the Pathologic group showed significantly lower values than those in the Control group, whereas the Treatment group showed significantly improved values in comparison with those in the Pathologic group. The results of western blot analysis revealed that systemically administered omega-3 fatty acids ameliorated the cavernosal molecular environment. Our study suggests that omega-3 fatty acids improve intracavernosal pressure and have a beneficial role against pathophysiological consequences such as fibrosis or hypoxic damage on a CPI rat model, which represents a structural erectile dysfunction model.

Influencia de la manipulación de C1 sobre el flujo carotideo y el umbral de dolor a la presión en pacientes con cervicalgia / No disponible

Introducción: Si bien conocemos estudios que nos indican los efectos vasculares inmediatos de la realización de algunas técnicas manipulativas cervicales y de cómo afectan en el dolor y la movilidad, creemos necesario diseñar estudios que muestren la prevalencia de dichos efectos días, semanas o meses tras las intervenciones. Objetivos: Valorar el efecto de la aplicación de una técnica semidirecta en rotación de C1, con contacto indexial en los valores hemodinámicos carotideos y el umbral de dolor a la presión, en pacientes con cervicalgia y disfunción osteopática del atlas, en el periodo comprendido desde la manipulación hasta 7 días después. Material y métodos: A tres pacientes con historial previo de cervicalgia, (n=3, edad 26 ± 4,58 años) y test de flexión-rotación positivo se les aplicó la técnica manipulativa semidirecta en rotación para C1. Se realizó una medición previa de las variables, una «post1» inmediata tras la intervención, una «post2» tras 24h de la intervención, y una «post3» a los 7 días de la intervención. Resultados: El registro algométrico post-intervención mostró unos valores de 1,17 ± 0,72 kg/cm2, mientras que el registro doppler mostró unos valores de 0,05 ± 0,03 para el Índice de pulsatilidad y de 0,11 ± 0,05 para el Índice de resistividad. Conclusiones: Tras la manipulación, se produjo un aumento de la pulsatilidad y reducción de la resistividad en el flujo arterial, y un aumento del umbral nociceptivo

No disponible

The effect of physical activity on cardiometabolic health and inflammation in treated HIV infection.

BACKGROUND: In HIV-uninfected populations, physical activity decreases mortality and inflammation. Inflammation is a potential cause of comorbidities in HIV+ adults, the evidence examining the effect of physical activity on cardiometabolic health is limited. This analysis examines the relationship between physical activity, cardiometabolic health and inflammation. METHODS: We conducted a nested study within the SATURN-HIV trial in which 147 HIV+ adults were randomized to 10 mg daily rosuvastatin or placebo. Measures of physical activity, cardiometabolic health, inflammation and vascular disease (carotid artery intima media thickness and computed tomography-acquired measures pericardial fat volume) were assessed at baseline and through 96 weeks. Spearman correlations and multivariable analyses were used to explore relationships between physical activity, cardiometabolic health and inflammation. RESULTS: Median age (Q1, Q3) was 46 (40.4, 52.7) years, 80% were male, 69% were African American and 46% were on protease inhibitors. Baseline median physical activity was 44 min per week (0, 150), 24% of participants performed greater than 150 min per week. At baseline, physical activity correlated with several markers of cardiometabolic health and inflammation (all P≤0.05). Over all time points median physical activity was independently associated with carotid distensibility (ß=2.53; P=0.008), pericardial fat volume (ß=-6.13; P=0.001) and interleukin-6 (ß=-0.468; P<0.001). CONCLUSIONS: Physical activity is associated with vascular disease, endothelial function, and may be an adjuvant to decreasing comorbidities in HIV+ adults. Further studies should examine long-term effects of physical activity on cardiometabolic health and inflammation in this population. Clinicaltrials.gov NCT01218802.

Effects of Omega-3 Fatty Acids on Erectile Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia

The aim of this study was to investigate whether the omega-3 fatty acids help to improve erectile function in an atherosclerosis-induced erectile dysfunction rat model. A total of 20 male Sprague-Dawley rats at age 8 weeks were divided into three groups: Control group (n = 6, untreated sham operated rats), Pathologic group (n = 7, untreated rats with chronic pelvic ischemia [CPI]), and Treatment group (n = 7, CPI rats treated with omega-3 fatty acids). For the in vivo study, electrical stimulation of the cavernosal nerve was performed and erectile function was measured in all groups. Immunohistochemical antibody staining was performed for transforming growth factor beta-1 (TGF-β1), endothelial nitric oxide synthase (eNOS), and hypoxia inducible factor 1-alpha (HIF-1α). In vivo measurement of erectile function in the Pathologic group showed significantly lower values than those in the Control group, whereas the Treatment group showed significantly improved values in comparison with those in the Pathologic group. The results of western blot analysis revealed that systemically administered omega-3 fatty acids ameliorated the cavernosal molecular environment. Our study suggests that omega-3 fatty acids improve intracavernosal pressure and have a beneficial role against pathophysiological consequences such as fibrosis or hypoxic damage on a CPI rat model, which represents a structural erectile dysfunction model.

Carotid baroreflex activation therapy for resistant hypertension.

Arterial baroreceptors are mechanosensitive sensory nerve endings in the walls of the carotid sinuses and aortic arch that buffer the increases and decreases in arterial blood pressure. Electrical field stimulation of the carotid sinus, known as carotid baroreflex activation therapy, holds promise as a novel device-based intervention to supplement, but not replace, drug therapy for patients with resistant hypertension. Acute electrical field stimulation of even one carotid sinus can cause a sufficiently large reflex decrease in blood pressure to overcome offsetting reflexes from the contralateral carotid baroreceptors and aortic baroreceptors that are not paced. However, the initial phase III Rheos Pivotal Trial on continuous carotid baroreceptor pacing for resistant hypertension with the first-generation baroreceptor pacemaker yielded equivocal data on efficacy and adverse effects due to facial nerve injury during surgical implantation. A miniaturized second-generation pacing electrode has seemingly overcome the safety issue, and early results with the new device suggest efficacy of unilateral carotid sinus stimulation in heart failure. A phase III trial of this new device for resistant hypertension has been registered.

Effect of 5-HT(2A) receptor antagonists on blood flow in the carotid vessels upon elevation of serotonin level.

We studied the ability of predominantly 5-HT2A receptor antagonists to prevent a serotonin-induced change of blood flow in the carotid vessels of rats with experimental serotonin-induced spasm. Ritanserin, ketanserin, and 5-HT2A receptor antagonist RU-476 reduced the effect of serotonin on the blood fl ow velocity in the internal carotid artery by 2.3, 1.7, and 2.6 times, respectively.

γ-Tocopherol-rich supplementation additively improves vascular endothelial function during smoking cessation.

Oxidative stress and inflammation persist years after smoking cessation thereby limiting the restoration of vascular endothelial function (VEF). Although short-term smoking cessation improves VEF, no studies have examined co-therapy of antioxidants in combination with smoking cessation to improve VEF. We hypothesized that improvements in γ-tocopherol (γ-T) status during smoking cessation would improve VEF beyond that from smoking cessation alone by decreasing oxidative stress and proinflammatory responses. A randomized, double-blind, placebo-controlled study was conducted in otherwise healthy smokers (22 ± 1 years; mean ± SEM) who quit smoking for 7 days with placebo (n=14) or γ-T-rich supplementation (n=16; 500 mg γ-T/day). Brachial artery flow-mediated dilation (FMD), cotinine, and biomarkers of antioxidant status, oxidative stress, and inflammation were measured before and after 7 days of smoking cessation. Smoking cessation regardless of supplementation similarly decreased plasma cotinine, whereas γ-T-rich supplementation increased plasma γ-T by seven times and its urinary metabolite γ-carboxyethyl hydroxychroman by nine times (P<0.05). Smoking cessation with γ-T-rich supplementation increased FMD responses by 1.3% (P<0.05) beyond smoking cessation alone (4.1 ± 0.6% vs 2.8 ± 0.3%; mean ± SEM). Although plasma malondialdehyde decreased similarly in both groups (P<0.05), plasma oxidized LDL and urinary F2-isoprostanes were unaffected by smoking cessation or γ-T-rich supplementation. Plasma TNF-α and myeloperoxidase decreased (P<0.05) only in those receiving γ-T-rich supplements and these were inversely related to FMD (P<0.05; R=-0.46 and -0.37, respectively). These findings demonstrate that short-term γ-T-rich supplementation in combination with smoking cessation improved VEF beyond that from smoking cessation alone in young smokers, probably by decreasing the proinflammatory mediators TNF-α and myeloperoxidase.

Resistant hypertension: baroreflex stimulation as a new tool.

Uncontrolled hypertension remains a significant public health challenge. In recent years, a new baroreflex stimulator has been used to treat these patients. Initial observations suggest that the electrical field stimulation of carotid baroreceptors acutely attenuates sympathetic activation of the vasculature, heart and kidney while augmenting cardiac vagal regulation. During the long-term treatment an average blood pressure (BP) drop of 30-40/15-25 mmHg was observed with a responder rate (>10 mmHg reduction in BP) of up to 80% after 1 year of treatment. Some of this effect can be explained by a 'placebo' effect as suggested by the double-blind Pivotal Trial. The complication rate with the first generation device was 20-30%. With a second generation device, these problems have been reduced to <10%. Even though additional data from controlled clinical trials will be required before more widespread use can be recommended, this treatment option is now approved in Europe for the treatment of severe resistant hypertension and is performed in selected centres with experienced vascular surgeons and hypertension specialists.

Vasorelaxing effects of estetrol in rat arteries.

This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E(4)) vs 17ß-estradiol (E(2)) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E(4) and E(2) (0·1-100  µmol/l) were constructed. In all arteries tested, E(4) had lower potency than E(2), although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1  µmol/l) caused a significant rightward shift in the CRC to both E(4) and E(2), indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N(ω)-nitro-L-arginine methyl ester (L-NAME) blunted E(2)-mediated but not E(4)-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E(4) or E(2) in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E(4) compared with E(2) in uterine arteries. Endothelium denudation inhibited responses to both E(4) and E(2), while E(4) and E(2) concentration-dependently blocked smooth muscle cell Ca(2)(+) entry in K(+)-depolarized and Ca(2)(+)-depleted uterine arteries. In conclusion, E(4) relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E(4)-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca(2)(+) entry, but not NO synthases or endothelium-dependent hyperpolarization.

Tetrahydrobiopterin supplementation enhances carotid artery compliance in healthy older men: a pilot study.

BACKGROUND: We performed a pilot study to test the hypothesis that acute oral ingestion of tetrahydrobiopterin (BH(4)), a key cofactor modulating vascular nitric oxide (NO) synthase activity, improves large elastic artery stiffness with aging in men. METHODS: Healthy older (63 ± 2 years; n = 8) and young (age 25 ± 1 years; n = 6) men were studied 3 h after ingestion of BH(4) (10 mg·kg(-1) body weight) or placebo on separate days in a randomized, placebo-controlled, double-blind study. RESULTS: Baseline carotid artery compliance was 37% lower (0.17 ± 0.02 vs. 0.22 ± 0.02 mm/mm Hg·10(-1)) and ß-stiffness was 42% higher (7.3 ± 1.1 vs. 4.2 ± 0.5 AU) in the older men (both P < 0.05). BH(4) ingestion markedly increased circulating BH(4) concentrations in both groups (17-19-fold, P < 0.05), but increased compliance (+39% to 0.23 ± 0.02 mm/mm Hg·10(-1), P < 0.01) and decreased ß-stiffness index (-27% to 5.3 ± 0.7 AU, P < 0.01) only in the older men. BH(4) also reduced carotid systolic blood pressure (SBP) in the older men (P < 0.05). CONCLUSIONS: These preliminary results support the possibility that limited BH(4) bioavailability contributes to impaired carotid artery compliance in healthy older men. Further studies are needed to determine if increasing BH(4) bioavailability though oral BH(4) supplementation may have therapeutic efficacy for improving large elastic artery compliance and reducing central SBP with aging.