Vascular smooth muscle cell-derived nerve growth factor regulates sympathetic collateral branching to innervate blood vessels in embryonic skin.

Blood vessels serve as intermediate conduits for the extension of sympathetic axons towards target tissues, while also acting as crucial targets for their homeostatic processes encompassing the regulation of temperature, blood pressure, and oxygen availability. How sympathetic axons innervate not only blood vessels but also a wide array of target tissues is not clear. Here we show that in embryonic skin, after the establishment of co-branching between sensory nerves and blood vessels, sympathetic axons invade the skin alongside these sensory nerves and extend their branches towards these blood vessels covered by vascular smooth muscle cells (VSMCs). Our mosaic labeling technique for sympathetic axons shows that collateral branching predominantly mediates the innervation of VSMC-covered blood vessels by sympathetic axons. The expression of nerve growth factor (NGF), previously known to induce collateral axon branching in culture, can be detected in the vascular smooth muscle cell (VSMC)-covered blood vessels, as well as sensory nerves. Indeed, VSMC-specific Ngf knockout leads to a significant decrease of collateral branching of sympathetic axons innervating VSMC-covered blood vessels. These data suggest that VSMC-derived NGF serves as an inductive signal for collateral branching of sympathetic axons innervating blood vessels in the embryonic skin.

Vascular sympathetic neurotransmission and its serotonergic regulation are modified by chronic fluoxetine treatment.

Given the interconnection between depressive and cardiovascular disorders, we investigated whether antidepressant treatment (fluoxetine) modifies the serotonergic influence on rat vascular noradrenergic outflow. Twelve-week-old male Wistar rats received fluoxetine treatment (10 mg/kg/day; p.o.) for 14 days; then, they were pithed and prepared for sympathetic stimulation. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1, 0.5, 1, and 5 Hz) or i.v. noradrenaline (NA; 0.01, 0.05, 0.1, and 0.5 µg/kg). In fluoxetine-treated group, the electrical-induced vasoconstrictions were lower compared to non-treated rats. Intravenous infusion of 5-HT (10 µg/kg/min) inhibited the sympathetically-induced vasoconstrictions. Only 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) mimicked 5-HT-induced inhibition, while α-methyl-5-HT (5-HT2 agonist) increased the vasopressor responses. The inhibitory effect of 5-HT was: a) no modified by SB269970 (5-HT7 antagonist); b) abolished by WAY-100,635 (5-HT1A antagonist) plus LY310762 (5-HT1D antagonist); and c) potentiated by ritanserin (5-HT2A receptor antagonist). The vasoconstrictions induced by exogenous NA were not modified by 5-CT but were increased by α-methyl-5-HT. Our results suggest that fluoxetine treatment decreases NA release at vascular level and changes 5-HT modulation on rat vascular noradrenergic neurotransmission, inducing sympatho-inhibition via prejunctional 5-HT1A/1D receptors, and sympatho-potentiation via pre and/or postjunctional 5-HT2A receptors.

Revisiting the evaluation of central versus peripheral thermoregulatory control in humans.

Human thermoregulatory control is often evaluated through the relationship between thermoeffector output and core or mean body temperature. In addition to providing a general indication of whether a variable of interest alters thermoregulatory control, this relationship is often used to determine how this alteration may occur. This latter interpretation relies upon two parameters of the thermoeffector output-body temperature relationship: the onset threshold and thermosensitivity. Traditionally, changes in the onset threshold and thermosensitivity are interpreted as "central" or "peripheral" modulation of thermoregulatory control, respectively. This mini-review revisits the origins of the thermoeffector output-body temperature relationship and its use to interpret "central" or "peripheral" modulation of thermoregulatory control. Against this background, we discuss the strengths and weaknesses of this approach and highlight that "central" thermoregulatory control reflects the neural control of body temperature whereas "peripheral" thermoregulatory control reflects properties specific to the thermoeffector organs. We highlight studies that employed more direct approaches to investigate the neural control of body temperature and peripheral properties of thermoeffector organs. We conclude by encouraging future investigations interested in studying thermoregulatory control to more directly investigate the component of the thermoeffector loop under investigation.heat; human; skin blood flow; sweat; thermoregulatory.

Effects of ambient particulate matter on vascular tissue: a review.

Fine and ultra-fine particulate matter (PM) are major constituents of urban air pollution and recognized risk factors for cardiovascular diseases. This review examined the effects of PM exposure on vascular tissue. Specific mechanisms by which PM affects the vasculature include inflammation, oxidative stress, actions on vascular tone and vasomotor responses, as well as atherosclerotic plaque formation. Further, there appears to be a greater PM exposure effect on susceptible individuals with pre-existing cardiovascular conditions.

Role of the neurovascular unit in the process of cerebral ischemic injury.

Cerebral ischemic injury exhibits both high morbidity and mortality worldwide. Traditional research of the pathogenesis of cerebral ischemic injury has focused on separate analyses of the involved cell types. In recent years, the neurovascular unit (NVU) mechanism of cerebral ischemic injury has been proposed in modern medicine. Hence, more effective strategies for the treatment of cerebral ischemic injury may be provided through comprehensive analysis of brain cells and the extracellular matrix. However, recent studies that have investigated the function of the NVU in cerebral ischemic injury have been insufficient. In addition, the metabolism and energy conversion of the NVU depend on interactions among multiple cell types, which make it difficult to identify the unique contribution of each cell type. Therefore, in the present review, we comprehensively summarize the regulatory effects and recovery mechanisms of four major cell types (i.e., astrocytes, microglia, brain-microvascular endothelial cells, and neurons) in the NVU under cerebral ischemic injury, as well as discuss the interactions among these cell types in the NVU. Furthermore, we discuss the common signaling pathways and signaling factors that mediate cerebral ischemic injury in the NVU, which may help to provide a theoretical basis for the comprehensive elucidation of cerebral ischemic injury.

Sensory nerve-mediated and nitric oxide-dependent cutaneous vasodilation in normotensive and prehypertensive non-Hispanic blacks and whites.

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black (n = 16) or non-Hispanic white (n = 16). Within each group, participants were subdivided as either normotensive (n = 8 per group) or prehypertensive (n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1) control (lactated Ringer's), 2) 5% lidocaine (sensory nerve inhibition), 3) 20 mM Nω-nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites.NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.

Adrenergic Innervation of the thyroid Gland, Blood and Lymph Vessels, and Lymph Nodes in Hypothyroidism.

Adrenergic innervation in the tissue of the thyroid gland, blood vessels of the thyroid gland, cervical lymphatic vessel, and lymph nodes in rats with hypothyroidism was studied by using a specific histochemical fluorescent-microscopic method of visualization of catecholamines. The presence of adrenergic innervation in the blood and lymph vessels and nodes was demonstrated. In hypothyroidism, diffusion of norepinephrine from nerve fibers and varicose thickenings was observed in the wall of the upper and lower thyroid arteries and adjacent cervical lymphatic vessels and nodes.

Sympathetic baroreflex sensitivity is inversely related to vascular transduction in men but not women.

Sympathetic baroreflex sensitivity (BRS) is a measure of how effectively the baroreflex buffers beat-to-beat changes in blood pressure through the modulation of muscle sympathetic nerve activity (MSNA). However, current methods of assessment do not take into account the transduction of sympathetic nerve activity at the level of the vasculature, which is known to vary between individuals. In this study we tested the hypothesis that there is an inverse relationship between sympathetic BRS and vascular transduction. In 38 (18 men) healthy adults, continuous measurements of blood pressure, MSNA and superficial femoral artery diameter and blood flow (Doppler ultrasound) were recorded during 10 min of rest. Spontaneous sympathetic BRS was quantified as the relationship between diastolic pressure and MSNA burst incidence. Vascular transduction was quantified by plotting the changes in leg vascular conductance for 10 cardiac cycles following each burst of MSNA, and taking the nadir. In men, sympathetic BRS was inversely related to vascular transduction (r = -0.49; P = 0.04). However, this relationship was not present in women (r = -0.17; P = 0.47). To conclude, an interaction exists between sympathetic BRS and vascular transduction in healthy men, such that men with high sympathetic BRS have low vascular transduction and vice versa. This may be to ensure that blood pressure is regulated effectively, although further research is needed to explore what mechanisms are involved and examine why this relationship was not apparent in women.NEW & NOTEWORTHY Evidence suggests that compensatory interactions exist between factors involved in cardiovascular control. This study was the first to demonstrate an inverse relationship between sympathetic BRS and beat-to-beat vascular transduction. Those with low sympathetic BRS had high vascular transduction and vice versa. However, this interaction was present in young men but not women.

Sympathectomy-induced blood pressure reduction in adult normotensive and hypertensive rats is counteracted by enhanced cardiovascular sensitivity to vasoconstrictors.

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

Asynchronous action potential discharge in human muscle sympathetic nerve activity.

What strategies are employed by the sympathetic system to communicate with the circulation? Muscle sympathetic nerve activity (MSNA) occurs in bursts of synchronous action potential (AP) discharge, yet whether between-burst asynchronous AP firing exists remains unknown. Using multiunit microneurography and a continuous wavelet transform to isolate APs, we studied AP synchronicity within human MSNA. Asynchronous APs were defined as those which occurred between bursts. Experiment 1 quantified AP synchronicity in eight individuals at baseline (BSL), -10 mmHg lower body negative pressure (LBNP), -40 mmHg LBNP, and end-expiratory apnea (APN). At BSL, 33 ± 12% of total AP activity was asynchronous. Asynchronous discharge was unchanged from BSL (67 ± 37 AP/min) to -10 mmHg LBNP (69 ± 33 AP/min), -40 mmHg LBNP (83 ± 68 AP/min), or APN (62 ± 39 AP/min). Across all conditions, asynchronous AP probability and frequency decreased with increasing AP size. Experiment 2 examined the impact of the ganglia on AP synchronicity by using nicotinic blockade (trimethaphan). The largest asynchronous APs were derecruited from BSL (11 ± 4 asynchronous AP clusters) to the last minute of the trimethaphan infusion with visible bursts (7 ± 2 asynchronous AP clusters). However, the 6 ± 2 smallest asynchronous AP clusters could not be blocked by trimethaphan and persisted to fire 100 ± 0% asynchronously without forming bursts. Nonnicotinic ganglionic mechanisms affect some, but not all, asynchronous activity. The fundamental behavior of human MSNA contains between-burst asynchronous AP discharge, which accounts for a considerable amount of BSL activity.NEW & NOTEWORTHY Historically, sympathetic nerve activity destined for the blood vessels supplying skeletal muscle (MSNA) has been characterized by spontaneous bursts formed by synchronous action potential (AP) discharge. However, this study found a considerable amount (~30% during baseline) of sympathetic AP discharge to fire asynchronously between bursts of human MSNA. Trimethaphan infusion revealed that nonnicotinic ganglionic mechanisms contribute to some, but not all, asynchronous discharge. Asynchronous sympathetic AP discharge represents a fundamental behavior of MSNA.

Exercise Prevents Hypertension and Disrupts the Correlation Between Vascular Sympathetic Activity and Age-Related Increase in Blood Pressure in SHRs.

BACKGROUND: Hypertension usually accompanies the elevated sympathetic activity and sleep interruption. Few researches explored the dynamic changes and possible correlations in cardiovascular functions and sleep patterns during the development of hypertension. In contrast, exercise training provides several benefits on cardiovascular and sleep function in hypertensive subjects. However, controlling various factors during a long period of exercise training is difficult in hypertensive subjects, an animal model may be essential. This study aimed to explore dynamic changes in cardiovascular functions and sleep patterns during the development period of hypertension (10-20 weeks old) in spontaneously hypertensive rats (SHRs) and effects of exercise intervention. METHODS: We used the treadmill exercise model for 8 weeks and started when SHRs were 12 weeks old. Electroencephalogram, electromyogram, electrocardiogram, and blood pressure (BP) were recorded simultaneously for 24 hours once a week over 11 weeks. RESULTS: Untrained SHRs revealed the age-related increments in BP, and the significant increasing slopes of differences on BP and vascular sympathetic activity were observed during the development period of hypertension. Compared with untrained rats, age-related increases in BP and vascular sympathetic activity were significantly suppressed in trained SHRs. Nevertheless, trained SHRs showed more quiet sleep time at partial weeks. The positive correlation between the differences from 10 weeks of vascular sympathetic activity and BP was disappeared in trained SHRs. CONCLUSIONS: There existed the significant correlation between the dynamic changes of vascular sympathetic activity and age-related elevation of BP during the development period of hypertension; however, exercise prevented hypertension and disrupted this correlation.

Nerve growth factor (NGF) has an anti-tumor effects through perivascular innervation of neovessels in HT1080 fibrosarcoma and HepG2 hepatitis tumor in nude mice.

This study investigated whether NGF prevents tumor growth by promoting neuronal regulation of tumor blood flow. HT1080 fibrosarcoma cells or HepG2 hepatitis cells were subcutaneously implanted into nude mice. On Day 21 after the implantation of tumor cells, human NGF (40 or 80 ng/h for 14 days) was administered using a micro-osmotic pump. Growth rates of both tumors were significantly inhibited by the treatment of NGF, and the survival rate was also extended. Significant suppression of HT1080 tumor growth lasted after withdrawing NGF. NGF markedly increased the density of α-smooth muscle actin (α-SMA)-immunoreactive (ir) cells without changing neovessel density in HT1080 tumor tissues. Double immunostaining demonstrated protein gene product (PGP) 9.5-ir nerves around α-SMA-ir cells were found in HT1080 tumor tissue treated with NGF. The blood flow in HepG2 tumors treated with saline was significantly higher than in the non-tumor control area, but the tumor blood flow was markedly reduced by NGF treatment. In in vitro studies, NGF significantly accelerated migration of aortic smooth muscle cells but not endothelial cells, whereas NGF had no cytotoxic action on both cells. NGF inhibits tumor growth via indirect action, probably through innervation and maturation of tumor neovasculature, which regulates blood flow into tumor tissues.

Minimizing thermal damage to vascular nerves while drilling of calcified plaque.

OBJECTIVE: Drilling of calcified plaque (DCP) inside the artery is a method for removing calcified plaques. This study investigated the effect of drill. To validate the maximum temperature calculated by computer simulation, this value was also measured by an experimental on a phantom model. RESULTS: Increasing drill bit diameter during drilling would increase the temperature in vascular nerves. In a drill bit with a diameter of 4 mm, the risk of thermal necrosis in vascular nerves of the artery wall decreased by 8.57% by changing the drill from WC to NT. The same value for a drill bit with a diameter of 6 mm was 10.17%. However, the trend of the generated temperature in the vascular nerves did not change significantly with change of the material and diameter of the drill bit. The results showed that for DCP with the least risk of thermal necrosis in vascular nerves and subsequently the lowest risk of restenosis, coagulation and thermal stroke of the patient, the best option is to use a drill bit with a diameter of 4 mm and NT material for drilling.

Upward resetting of the vascular sympathetic baroreflex in middle-aged male runners.

This study focused on the influence of habitual endurance exercise training (i.e., committed runner or nonrunner) on the regulation of muscle sympathetic nerve activity (MSNA) and arterial pressure in middle-aged (50 to 63 yr, n = 23) and younger (19 to 30 yr; n = 23) normotensive men. Hemodynamic and neurophysiological assessments were performed at rest. Indices of vascular sympathetic baroreflex function were determined from the relationship between spontaneous changes in diastolic blood pressure (DBP) and MSNA. Large vessel arterial stiffness and left ventricular stroke volume also were measured. Paired comparisons were performed within each age category. Mean arterial pressure and basal MSNA bursts/min were not different between age-matched runners and nonrunners. However, MSNA bursts/100 heartbeats, an index of baroreflex regulation of MSNA (vascular sympathetic baroreflex operating point), was higher for middle-aged runners (P = 0.006), whereas this was not different between young runners and nonrunners. The slope of the DBP-MSNA relationship (vascular sympathetic baroreflex gain) was not different between groups in either age category. Aortic pulse wave velocity was lower for runners of both age categories (P < 0.03), although carotid ß-stiffness was lower only for middle-aged runners (P = 0.04). For runners of both age categories, stroke volume was larger, whereas heart rate was lower (both P < 0.01). In conclusion, we suggest that neural remodeling and upward setting of the vascular sympathetic baroreflex compensates for cardiovascular adaptations after many years committed to endurance exercise training, presumably to maintain arterial blood pressure stability. NEW & NOTEWORTHY Exercise training reduces muscle sympathetic burst activity in disease; this is often extrapolated to infer a similar effect in health. We demonstrate that burst frequency of middle-aged and younger men committed to endurance training is not different compared with age-matched casual exercisers. Notably, well-trained, middle-aged runners display similar arterial pressure but higher sympathetic burst occurrence than untrained peers. We suggest that homeostatic plasticity and upward setting of the vascular sympathetic baroreflex maintains arterial pressure stability following years of training.

Astrocytic endfeet re-cover blood vessels after removal by laser ablation.

The astrocyte, one of the glial cells, plays many functional roles. These include provision of nutrients from blood vessels to neurons, supply of neurotransmitters and support of blood-brain barrier (BBB) integrity. Astrocytes are known to support the integrity of BBB through maintenance of the tight junction between endothelial cells of blood vessels. However, evidence of its direct contribution to BBB is lacking owing to technical limitations. In this study, astrocytic endfeet covering blood vessels were removed by the laser ablation method with two photon laser scanning microscopy in in vivo mouse brain, and the re-covering of blood vessels with the astrocytic endfeet was observed in about half of the cases. Blood vessels kept their integrity without astrocytic endfoot covers: leakage of plasma marker dyes, Evans Blue or dextran-conjugated fluorescein, was not observed from stripped blood vessels, while ablation of vascular walls induced extravasation of Evans Blue. These results suggest that the astrocytic endfeet covering blood vessels do not contribute to the immediate BBB barrier.

Docosahexaenoic acid reduces resting blood pressure but increases muscle sympathetic outflow compared with eicosapentaenoic acid in healthy men and women.

Supplementation with monounsaturated or ω-3 polyunsaturated fatty acids ( n-3 PUFA) can lower resting blood pressure (BP) and reduce the risk of cardiovascular events. The independent contributions of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP, and the mechanisms responsible, are unclear. We tested whether EPA, DHA, and olive oil (OO), a source of monounsaturated fat, differentially affect resting hemodynamics and muscle sympathetic nerve activity (MSNA). Eighty-six healthy young men and women were recruited to participate in a 12-wk, randomized, double-blind trial examining the effects of orally supplementing ~3 g/day of EPA ( n = 28), DHA ( n = 28), or OO ( n = 30) on resting hemodynamics; MSNA was examined in a subset of participants ( n = 31). Both EPA and DHA supplements increased the ω-3 index ( P < 0.01). Reductions in systolic BP were greater [adjusted intergroup mean difference (95% confidence interval)] after DHA [-3.4 mmHg (-0.9, -5.9), P = 0.008] and OO [-3.0 mmHg (-0.5, -5.4), P = 0.01] compared with EPA, with no difference between DHA and OO ( P = 0.74). Reductions in diastolic BP were greater following DHA [-3.4 mmHg (-1.3,-5.6), P = 0.002] and OO [-2.2 mmHg (0.08,-4.3), P = 0.04] compared with EPA. EPA increased heart rate compared with DHA [4.2 beats/min (-0.009, 8.4), P = 0.05] and OO [4.2 beats/min, (0.08, 8.3), P = 0.04]. MSNA burst frequency was higher after DHA [4 bursts/min (0.5, 8.3), P = 0.02] but not OO [-3 bursts/min (-6, 0.6), P = 0.2] compared with EPA. Overall, DHA and OO evoked similar responses in resting BP; however, DHA, but not OO, increased peripheral vasoconstrictor outflow. These findings may have implications for fatty acid supplementation in clinical populations characterized by chronic high BP and sympathetic overactivation. NEW & NOTEWORTHY We studied the effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and olive oil supplementation on blood pressure (BP) and muscle sympathetic nerve activity (MSNA). After 12 wk of 3 g/day supplementation, DHA and olive oil were associated with lower resting systolic and diastolic BPs than EPA. However, DHA increased MSNA compared with EPA. The reductions in BP with DHA likely occur via a vascular mechanism and evoke a baroreflex-mediated increase in sympathetic activity.

Functional sympatholysis is impaired in end-stage renal disease.

Patients with end-stage renal disease (ESRD) have decreased exercise capacity and exercise intolerance that contribute to cardiovascular risk. One potential mechanism underlying exercise intolerance in ESRD is impaired ability to oppose sympathetically mediated vasoconstriction within exercising skeletal muscle (i.e., functional sympatholysis, FS). We hypothesized that ESRD patients have impaired FS compared with healthy (CON) and hypertensive (HTN) controls and that impaired FS is related to circulating levels of the uremic toxin asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide synthase inhibitor. Near-infrared spectroscopy-derived oxygen tissue saturation index (TSI) of the forearm muscle was measured continuously in 33 participants (9 CON, 14 HTN, 10 ESRD) at rest and during low-dose (-20 mmHg) lower body negative pressure (LBNP), moderate rhythmic handgrip exercise, and LBNP with concomitant handgrip exercise (LBNP+handgrip). Resting muscle TSI was lower in ESRD than in CON and HTN groups (CON = 67.8 ± 1.9%, HTN = 67.2 ± 1.1%, ESRD = 62.7 ± 1.5%, P = 0.03). Whereas CON and HTN groups had an attenuation in sympathetically mediated reduction in TSI during LBNP + handgrip compared with LBNP alone (P ≤ 0.05), this response was not present in ESRD (P = 0.71), suggesting impaired FS. There was no difference in plasma [ADMA] between groups (CON = 0.47 ± 0.05 µmol/l, HTN = 0.42 ± 0.06 µmol/l, ESRD = 0.63 ± 0.14 µmol/l, P = 0.106) and no correlation between plasma [ADMA] and resting muscle TSI (P = 0.84) or FS (P = 0.75). Collectively, these findings suggest that ESRD patients have lower muscle perfusion at rest and impaired FS but that these derangements are not related to circulating [ADMA].

Angiotensin II and vascular damage in hypertension: Role of oxidative stress and sympathetic activation.

Reactive oxygen species (ROS) are oxygen derivates and play an active role in vascular biology. These compounds are generated within the vascular wall, at the level of endothelial and vascular smooth muscle cells, as well as by adventitial fibroblasts. Physiologically, ROS generation is counteracted effectively by the rate of elimination. In hypertension, a ROS excess occurs, which is not counterbalanced by the endogenous antioxidant mechanisms, leading to a state of oxidative stress. Angiotensin II, the active peptide of the renin-angiotensin-system (RAS), is a significant stimulus for ROS generation within the vasculature. It was also documented that at the level of subfornical cerebral regions an inappropriate RAS stimulation may lead to an increased vascular sympathetic activity. More recently, in conditions of fetal undernutrition, it was also proposed an increased vascular sympathetic activity secondary to inappropriate RAS activation, leading to the development of hypertension in adult life. The present review will discuss the complex interaction between RAS activation, vascular ROS generation and increased sympathetic outflow in hypertension.

Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches.

In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders.

Nasal high flow, but not supplemental O2, reduces peripheral vascular sympathetic activity during sleep in COPD patients.

INTRODUCTION: Patients with COPD have increased respiratory loads and altered blood gases, both of which affect vascular function and sympathetic activity. Sleep, particularly rapid eye movement (REM) sleep, is known to exacerbate hypoxia and respiratory loads. Therefore, we hypothesize that nasal high flow (NHF), which lowers ventilatory loads, reduces sympathetic activity during sleep and that this effect depends on COPD severity. METHODS: We performed full polysomnography in COPD patients (n=17; FEV1, 1.6±0.6 L) and in matched controls (n=8). Participants received room air (RA) at baseline and single night treatment with O2 (2 L/min) and NHF (20 L/min) in a random order. Finger pulse wave amplitude (PWA), a measure of vascular sympathetic tone, was assessed by photoplethysmography. Autonomic activation (AA) events were defined as PWA attenuation ≥30% and indexed per hour for sleep stages (AA index [AAI]) at RA, NHF, and O2). RESULTS: In COPD, sleep apnea improved following O2 (REM-apnea hypopnea index [AHI] with RA, O2, and NHF: 18.6±20.9, 12.7±18.1, and 14.4±19.8, respectively; P=0.04 for O2 and P=0.06 for NHF). REM-AAI was reduced only following NHF in COPD patients (AAI-RA, 21.5±18.4 n/h and AAI-NHF, 9.9±6.8 n/h, P=0.02) without changes following O2 (NHF-O2 difference, P=0.01). REM-AAI reduction was associated with lung function expressed as FEV1 and FVC (FEV1: r=-0.59, P=0.001; FEV1/FVC: r=-0.52 and P=0.007). CONCLUSION: NHF but not elevated oxygenation reduces peripheral vascular sympathetic activity in COPD patients during REM sleep. Sympathetic off-loading by NHF, possibly related to improved breathing mechanics, showed a strong association with COPD severity.