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Cortical control of the autonomic nervous system

01 February 2014
New Findings

  • What is the topic of this review?

    The pathways in the brain by which visceral information, in particular cardiopulmonary afferents, ascend to the cerebral cortex have been delineated in animal models. Studies using functional magnetic resonance imaging in humans have confirmed what was known from the animal studies and established the critical sites in the cerebral cortex of humans for autonomic control and the significance of these sites for cognitive emotional function.

  • What advances does it highlight?

    Stimulation of cardiopulmonary afferents in humans has consistently resulted in activation in the insular cortex and the anterior cingulate cortex. It has been shown that individuals who are characterized as cardiovascular responders to mental stress have a different pattern of activity in the cortex related to the cardiac changes.

  • A number of animal studies in the rat and cat have been particularly useful for determining the pathways and the sites in the forebrain and cortex that are responsible for autonomic control. For example, these experiments have demonstrated that there is a viscerotopically organized pathway, with the first site of termination in the nucleus of the solitary tract and with subsequent relays in the parabrachial nucleus and the ventroposterior parvocellular nucleus of the thalamus before final visceral afferent inputs in the insular cortex. Several neuroimaging studies in humans, using cardiopulmonary manipulations, have confirmed the importance of the insular cortex as a site of for visceral afferent inputs. The anterior cingulate cortex has also been implicated in cardiopulmonary control. Both the insular cortex and the infralimbic cortex have been shown to be involved in descending control of the cardiovascular system. Neuroimaging with functional magnetic resonance imaging has demonstrated that the cortical autonomic control pathways are different in individuals who are characterized as cardiovascular reactors to mental stress. There is evidence that this alteration in pathways in the cortex may be due to past experiences, including childhood trauma.

    The paraventricular nucleus and heart failure

    01 February 2014
    New Findings

  • What is the topic of this review?

    This review gives an update on the cellular and molecular mechanisms within the autonomic nervous system involved in non-pathological and pathological cardiovascular regulation.

  • What advances does it highlight?

    For cardiovascular homeostasis in non-pathological conditions to be maintained, discrete neural networks using specified signalling mechanisms at both cellular and molecular levels are required. In heart failure, the cell signalling protein partners CAPON and PIN decrease the bioavailability of nitric oxide by inhibiting neuronal nitric oxide synthase activity, leading to the removal of tonic neuronal inhibition. Following a myocardial infarction, pro-inflammatory cytokines in the paraventricular nucleus and the subsequent generation of reactive oxygen species, via angiotensin II activation of the angiotensin II type 1 receptor, increase neuronal excitability further, leading to sympathetic excitation.

  • A pathological feature of heart failure is abnormal control of the sympathetic nervous system. The paraventricular nucleus of the hypothalamus (PVN) is one of the most important central sites involved in regulating sympathetic tone and is, in part, responsible for the dysregulation of the sympathetic nervous system evident in heart failure. Generation of sympathetic tone in response to fluctuations in cardiovascular regulation uses discrete anatomical pathways and neurochemical modulators. Direct and indirect projections from the PVN pre-autonomic neurons innervate the sympathetic preganglionic neurons in the spinal cord, which in turn innervate sympathetic ganglia that give rise to the sympathetic nerves. Pre-autonomic neurons of the PVN themselves receive an afferent input arising from the nucleus tractus solitarii, and viscerosensory receptors convey cardiovascular fluctuations to the nucleus tractus solitarii. The PVN contains excitatory and inhibitory neurons, whose balance determines the sympathetic tone. In non-pathological conditions, the tonic inhibition of the PVN pre-autonomic neurons is mediated by GABA- and NO-releasing neurons. In heart failure, the pre-autonomic neurons are disinhibited by the actions of the excitatory neurotransmitters glutamate and angiotensin II, leading to increased sympathetic activity. A key feature of the disinhibition is a reduction in the bioavailability of NO as a consequence of disrupted CAPON and PIN signalling mechanisms within the neuron. Another critical feature that contributes to increased neuronal excitation within the PVN is the production of pro-inflammatory cytokines immediately following a myocardial infarction, the activation of the angiotensin II type 1 receptor and the production of reactive oxygen species. By examining the changes associated with the sympathetic nervous system pathway, we will progress our understanding of sympathetic regulation in heart failure, identify gaps in our knowledge and suggest new therapeutic strategies.

    Differential effect of sympathetic activation on tissue oxygenation in gastrocnemius and soleus muscles during exercise in humans

    01 February 2014
    New Findings

  • What is the central question of this study?

    The normal ability of sympathetic nerves to cause vasoconstriction is blunted in exercising skeletal muscle, a phenomenon termed ‘functional sympatholysis’. Animal studies suggest that functional sympatholysis appears to occur preferentially in fast-twitch type II glycolytic compared with slow-twitch type I oxidative skeletal muscle. We asked whether these findings can be extended to humans.

  • What is the main finding and its importance?

    We show that skeletal muscles composed largely of fast-twitch type II fibres may also be more sensitive to functional sympatholysis in humans, particularly at lower exercise intensities. Additionally, independent of muscle fibre type composition, the magnitude of sympatholysis is strongly related to exercise-induced increases in metabolic demand.

  • Animal studies suggest that functional sympatholysis appears to occur preferentially in glycolytic (largely type II) compared with oxidative (largely type I) skeletal muscle. Whether these findings can be extended to humans currently remains unclear. In 12 healthy male subjects, vasoconstrictor responses in gastrocnemius (i.e. primarily type II) and soleus muscles (i.e. primarily type I) were measured using near-infrared spectroscopy to detect decreases in muscle oxygenation (HbO2) in response to sympathetic activation evoked by a cold pressor test (CPT). The HbO2 responses to a CPT at rest were compared with responses during steady-state plantar flexion exercise (30 repetitions min–1) performed at 10, 20 and 40% maximal voluntary contraction (MVC) for 6 min. In resting conditions, HbO2 at the gastrocnemius (–14 ± 1%) and soleus muscles (–16 ± 1%) decreased significantly during CPT, with no differences between muscles. During planter flexion at 20% MVC, the change in HbO2 in response to the CPT was blunted in gastrocnemius but not soleus, whereas during 40% MVC both muscles exhibited a significant attenuation to sympathetic activation. The decreases in HbO2 in response to the CPT during exercise were significantly correlated with the metabolic demands of exercise (the decreases in HbO2 in response to steady-state plantar flexion) in both gastrocnemius and soleus muscles. Collectively, these results suggest that skeletal muscles composed mainly of glycolytic type II fibres are more sensitive to functional sympatholysis, particularly at lower intensities of exercise. Moreover, the blunting of sympathetic vasoconstriction during exercise is strongly related to metabolic demand; an effect that appears independent of fibre type composition.

    Differential visceral pain sensitivity and colonic morphology in four common laboratory rat strains

    01 February 2014
    New Findings

  • What is the central question of this study?

    Does stress sensitivity and susceptibility to inflammation innate to certain rat strains make them vulnerable to bowel dysfunction?

  • What is the main finding and its importance?

    Of four different rat strains, the Lewis rat, which displays both susceptibility to gastrointestinal inflammation and sensitivity to stress, exhibits the most aberrant gastrointestinal morphology and visceral pain sensitivity. Given the similarities to human functional bowel disorders, such as irritable bowel syndrome, this may make it a good model of this disease.

  • Irritable bowel syndrome is a common, debilitating gastrointestinal (GI) disorder characterized by episodic exacerbations of symptoms such as abdominal pain, bloating and altered bowel habit. Contributory factors for the development of irritable bowel syndrome include genetics, childhood trauma and prior GI infection leading to chronic low-grade inflammation or immune activation. Additional considerations in comprehending the chronic relapsing pattern that typifies irritable bowel syndrome symptoms are the effects of both psychosocial and infection-related stresses. Background stress and immune profiles can influence gut permeability and visceral pain sensitivity. This study examined whether innate susceptibility to inflammation and stress sensitivity in four rat strains is associated with bowel dysfunction. The pain threshold to colorectal distension was assessed in Lewis, Fischer (F344) and spontaneously hypertensive rats and compared with Sprague–Dawley control animals. Colons were subsequently excised and morphologically assessed for total length, goblet cell hyperplasia and muscle and mucosal thickness. Lewis rats displayed visceral hypersensitivity compared with other strains. At a morphological level, the gastrointestinal tract from these rats displayed mucosal goblet cell hyperplasia and alterations in muscle layer thickness. The Lewis rat strain, which is reported to have increased susceptibility to GI inflammation in addition to stress sensitivity, had the most prominent features of physiological and morphological GI dysfunction. These data support the hypothesis that background strain is a key factor in the development and exacerbation of bowel dysfunction in rodent models.

    Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects

    01 February 2014
    New Findings

  • What is the central question of this study?

    Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked?

  • What is the main finding and its importance?

    Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot.

  • The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

    Noradrenaline and neuropeptide Y contribute to initial, but not sustained, vasodilatation in response to local skin warming in humans

    01 February 2014
    New Findings

  • What is the central question of this study?

    Previous work has produced the counterintuitive finding that the vasoconstrictor neurotransmitters noradrenaline and neuropeptide Y are involved in vasodilatation. We aimed to discover whether sympathetic neurotransmitters are required for the sustained vasodilatation in response to local skin warming, as has been previously suggested, and to determine whether noradrenaline and neuropeptide Y are ‘mediating’ the sustained vasodilator response directly or acting to ‘prime’ (or kick-start) it.

  • What is the main finding and its importance?

    We have found that noradrenaline and neuropeptide Y are required at the initiation of vasodilatation in response to local skin warming, if a complete vasodilator response is to be achieved; however, they are not required once vasodilatation has begun.

  • In a three-part study, we examined whether noradrenaline, neuropeptide Y (NPY) and endothelial nitric oxide synthase (eNOS) were involved in the sustained vasodilatation in response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local skin heaters and laser-Doppler flow probes. Local skin temperature (Tloc) was increased from 34 to 42°C at a rate of 0.5°C (10 s)–1. Laser-Doppler flow was expressed as cutaneous vascular conductance (CVC; laser-Doppler flow/mean arterial pressure). In part 1, three skin sites were prepared; two were treated with the study vehicle (lactated Ringer solution), while the third site was treated with yohimbine and propranolol to antagonize α- and β-receptors, and 10 min of baseline data were record at a Tloc of 34°C. Receptor antagonism was confirmed via infusion of clonidine. The Tloc was increased to 42°C at all sites. Once CVC had stabilized, site 2 was treated with yohimbine and propranolol to examine the effect of adrenergic receptor blockade on sustained vasodilatation of the skin. Receptor antagonism was again confirmed via infusion of clonidine. All sites were treated with sodium nitroprusside, and Tloc was increased to 43°C to elicit maximal vasodilatation. In parts 2 and 3, the general protocol was the same, except that BIBP-3226 was used to antagonize Y1-receptors, NPY to test the efficacy of the antagonism, NG-amino-l-arginine to inhibit eNOS and ACh to test the adequacy of inhibition. Compared with control conditions, antagonism of α- and β-receptors, Y1-receptors and eNOS before local skin warming reduced the initial and sustained vasodilatation in response to increased Tloc. However, treatment with yohimbine and propranolol or BIBP-3226 after local skin warming did not affect the sustained vasodilatation [CVC, 90 ± 3 versus 89 ± 3%max (control vs. yohimbine and propranolol) and 88 ± 5 versus 87 ± 4%max (control vs. BIBP-3226); P > 0.05]. NG-Amino-l-arginine perfusion caused a large reduction in CVC during this phase (89 ± 5 versus 35 ± 4%max; P < 0.05). These data indicate that if their actions are antagonized after local warming and cutaneous vasodilatation has occurred, noradrenaline and NPY play little, if any, role in the sustained vasodilatation in response to local skin warming. However, eNOS contributes markedly to the sustained vasodilatation regardless of when it is inhibited.

    Extracellular calcium chelation and attenuation of calcium entry decrease in vivo cholinergic-induced eccrine sweating sensitivity in humans

    01 February 2014
    New Findings

  • What is the central question of this study?

    Calcium is an important second messenger in eccrine sweating; however, whether modulation of extracellular Ca2+ and Ca2+ entry has the capacity to modulate sweat rate in non-glabrous human skin has not been explored.

  • What is the main finding and its importance?

    Acetylcholine to sweat rate dose–response relationships identify that local in vivo Ca2+ chelation and L-type Ca2+ channel antagonism have the capacity to attenuate the cholinergic sensitivity of eccrine sweat glands. Importantly, these data translate previous glabrous in vitro animal studies into non-glabrous in vivo human skin.

  • Calcium is an important second messenger in eccrine sweating, with both internal and external sources being identified in vitro. It is unclear whether in vivo modulation of extracellular Ca2+ levels or influx has the capacity to modulate sweat rate in non-glabrous human skin. To test the hypothesis that lowering interstitial Ca2+ levels would decrease the sensitivity of the ACh to sweat rate (via capacitance hygrometry) dose–response relationship, nine healthy subjects received six ACh doses (1 x 10–5 to 1 x 100 m in 10-fold increments) with and without a Ca2+ chelator (12.5 mg ml–1 EDTA) via forearm intradermal microdialysis (protocol 1). To test the hypothesis that attenuating Ca2+ influx via L-type Ca2+ channels would also decrease the sensitivity of the ACh to sweat rate dose–response relationship, 10 healthy subjects received similar ACh doses with and without a phenylalkylamine Ca2+ channel blocker (1 mm verapamil; protocol 2). Non-linear regression curve fitting identified a right-shifted ED50 in EDTA-treated sites compared with ACh alone (–1.0 ± 0.1 and –1.5 ± 0.1 logm, respectively; P < 0.05), but unchanged maximal sweat rate (0.60 ± 0.07 and 0.58 ± 0.11 mg cm–2 min–1, respectively; P > 0.05) in protocol 1. Protocol 2 also resulted in a right-shifted ED50 (verapamil, –0.9 ± 0.1 logm; ACh alone, –1.6 ± 0.2 logm; P < 0.05), with unchanged maximal sweat rate (verapamil, 0.45 ± 0.08 mg cm–2 min–1; ACh alone, 0.35 ± 0.06 mg cm–2 min–1; P > 0.05). Thus, local in vivo Ca2+ chelation and L-type Ca2+ channel antagonism have the capacity to attenuate in vivo cholinergic sensitivity of eccrine sweat glands. These data suggest that interstitial Ca2+ and its influx via Ca2+ channels play a functional role in eccrine sweating in intact non-glabrous human skin.

    Exercise training effects on hypoxic and hypercapnic ventilatory responses in mice selected for increased voluntary wheel running

    01 February 2014
    New Findings

  • What is the central question of this study?

    We used experimental evolution to determine how selective breeding for high voluntary wheel running and exercise training (7–11 weeks) affect ventilatory chemoreflexes of laboratory mice at rest.

  • What is the main finding and its importance?

    Selective breeding, although significantly affecting some traits, did not systematically alter ventilation across gas concentrations. As with most human studies, our findings support the idea that endurance training attenuates resting ventilation. However, little evidence was found for a correlation between ventilatory chemoreflexes and the amount of individual voluntary wheel running. We conclude that exercise ‘training’ alters respiratory behaviours, but these changes may not be necessary to achieve high levels of wheel running.

  • Ventilatory control is affected by genetics, the environment and gene–environment and gene–gene interactions. Here, we used an experimental evolution approach to test whether 37 generations of selective breeding for high voluntary wheel running (genetic effects) and/or long-term (7–11 weeks) wheel access (training effects) alter acute respiratory behaviour of mice resting in normoxic, hypoxic and hypercapnic conditions. As the four replicate high-runner (HR) lines run much more than the four non-selected control (C) lines, we also examined whether the amount of exercise among individual mice was a quantitative predictor of ventilatory chemoreflexes at rest. Selective breeding and/or wheel access significantly affected several traits. In normoxia, HR mice tended to have lower mass-adjusted rates of oxygen consumption and carbon dioxide production. Chronic wheel access increased oxygen consumption and carbon dioxide production in both HR and C mice during hypercapnia. Breathing frequency and minute ventilation were significantly reduced by chronic wheel access in both HR and C mice during hypoxia. Selection history, while significantly affecting some traits, did not systematically alter ventilation across all gas concentrations. As with most human studies, our findings support the idea that endurance training (access to wheel running) attenuates resting ventilation. However, little evidence was found for a correlation at the level of the individual variation between ventilatory chemoreflexes and performance (amount of individual voluntary wheel running). We tentatively conclude that exercise ‘training’ alters respiratory behaviours, but these changes may not be necessary to achieve high levels of wheel running.

    Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure

    01 February 2014
    New Findings

  • What is the central question of this study?

    Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients.

  • What is the main finding and its importance?

    Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients.

  • Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P aCO 2) and a decrease in oxygen (P aO 2; P < 0.05 for both) at rest. The control subjects demonstrated no change in P aCO 2, P aO 2, ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min–1, P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min–1, P < 0.05). The reduced ventilation resulted in lower P aO 2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P aCO 2 (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.

    Physiological mechanisms of sex differences in exertional dyspnoea: role of neural respiratory motor drive

    01 February 2014
    New Findings

  • What is the central question of this study?

    Does the combination of a higher neural respiratory drive and greater dynamic mechanical ventilatory constraints during exercise in healthy women versus men form the mechanistic basis of sex differences in activity-related dyspnoea?

  • What is the main finding and its importance?

    Sex differences in activity-related dyspnoea in health primarily reflected the awareness of a higher neural respiratory drive needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical ventilatory constraints in women. These findings may have implications for our understanding of the mechanisms of sex differences in exertional dyspnoea in variants of health (e.g. the elderly) and in patients with cardiorespiratory disease.

  • The purpose of this study was to elucidate the physiological mechanisms of sex differences in exertional dyspnoea. We compared detailed measures of neural respiratory motor drive [diaphragmatic EMG (EMGdi) expressed as a percentage of maximal EMGdi (EMGdi%max)], breathing pattern, operating lung volumes, dynamic respiratory mechanics [tidal oesophageal (Poes,tidal%peak) and transdiaphragmatic pressure swings (Pdi,tidal%peak) expressed as a percentage of their respective peak values] and sensory intensity and unpleasantness ratings of dyspnoea during symptom-limited incremental cycle exercise in healthy young women (n = 25) and men (n = 25). The tidal volume to forced vital capacity ratio (VT%FVC), breathing frequency, EMGdi%max, Poes,tidal%peak, Pdi,tidal%peak and sensory intensity and unpleasantness ratings of dyspnoea were higher, while dynamic inspiratory capacity and inspiratory reserve volume were lower at a standardized absolute ventilation of 55 l min–1 during submaximal exercise in women versus men (all P < 0.05). In contrast, sex had no demonstrable effect on the inter-relationships between exercise-induced increases in VT%FVC, EMGdi%max and sensory intensity and unpleasantness ratings of dyspnoea. The results of this study suggest that sex differences in the intensity and unpleasantness of exertional dyspnoea in health are likely to reflect the awareness of a relatively higher neural respiratory motor drive (or EMGdi%max) needed to achieve any given ventilation during exercise in the setting of relatively greater dynamic mechanical constraints on VT expansion in women.

    Centrally administered angiotensin-(1-7) increases the survival of stroke-prone spontaneously hypertensive rats

    01 February 2014
    New Findings

  • What is the central question of this study?

    Activation of angiotensin-converting enzyme 2, resulting in production of angiotensin-(1–7) and stimulation of its receptor, Mas, exerts beneficial actions in a number cardiovascular diseases, including ischaemic stroke. A potential beneficial role for angiotensin-(1–7) in haemorrhagic stroke has not previously been reported.

  • What is the main finding and its importance?

    Central administration of angiotensin-(1–7) into stroke-prone spontaneously hypertensive rats, a model of haemorrhagic stroke, increases lifespan and improves the neurological status of these rats, as well as decreasing microglial numbers in the striatum (implying attenuation of cerebral inflammation). These actions of angiotensin-(1–7) have not previously been reported and identify this peptide as a potential new therapeutic target in haemorrhagic stroke.

  • Angiotensin-(1–7) [Ang-(1–7)] exerts cerebroprotective effects in ischaemic stroke, and this action is associated with a blunting of intracerebral inflammatory processes and microglial activation. Given that intracerebral inflammation and microglial activation play key roles in the mechanism of injury and brain damage in both ischaemic and haemorrhagic stroke, we have investigated the potential beneficial actions of Ang-(1–7) in stroke-prone spontaneously hypertensive rats (spSHRs), an established animal model of hypertension-induced haemorrhagic stroke. Angiotensin-(1–7) was administered by continuous infusion via the intracerebroventricular route for 6 weeks into spSHRs fed a high-sodium (4%) diet, starting at 49 days of age. This treatment resulted in a significant increase in survival of the spSHRs. Median survival was 108 days in control, artificial cerebrospinal fluid-infused spSHRs and 154 days in Ang-(1–7)-treated spSHRs. This effect was partly reversed by intracerebroventricular infusion of the Mas receptor blocker, A779. This Ang-(1–7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site. Importantly, infusions of Ang-(1–7) had no effect on kidney pathology, heart pathology, body weight, serum corticosterone levels or blood pressure. This study is the first to demonstrate the cerebroprotective actions of Ang-(1–7), including increased survival time, in spSHRs. As such, these data reveal a potential therapeutic target for haemorrhagic stroke.

    Exercise training and vascular cell phenotype in a swine model of familial hypercholesterolaemia: conduit arteries and veins

    01 February 2014
    New Findings

  • What is the central question of this study?

    Does endurance exercise training cause anti-atherogenic effects on the endothelium in a swine model of familial hypercholesterolaemia (FH), and how are these effects distributed across veins, arteries and multiple vascular territories within each system?

  • What is the main finding and its importance?

    Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control animals, and exercise training did not change vasomotor function within FH. In systemic conduit arteries and veins, few effects of FH on endothelial cell protein expression were noted, including both pro- and anti-atherogenic changes. These findings suggest that exercise training does not produce a consistently improved endothelial cell phenotype in either coronary or systemic conduit vessels in this swine model of FH.

  • Exercise training has emerged as an intervention for the primary and secondary prevention of coronary artery disease, but the mechanisms through which training reduces relative risk are not completely understood. The goal of this study was to investigate the impact of endurance exercise training on vasomotor function and vascular cell phenotype in coronary arteries and systemic conduit arteries and veins against a background of advanced atherosclerosis. We tested the hypothesis that exercise training restores endothelial vasomotor function and produces an anti-atherogenic endothelial and smooth muscle cell phenotype in familial hypercholesterolaemic (FH) swine. The study included 30 FH (15 exercised and 15 sedentary) and 13 non-FH control male castrated swine. The exercise-training intervention consisted of treadmill running 5 days per week for 16–20 weeks. Tissues sampled at sacrifice included vascular rings from the coronary circulation for vasomotor function experiments (dose-dependent bradykinin-induced vasorelaxation) and endothelial cells (ECs) from isolated segments of the thoracic aorta, the carotid, brachial, femoral and renal arteries, as well as each corresponding regionally associated vein, and from the abdominal vena cava, the right coronary and internal mammary arteries. Smooth muscle cells were sampled from the right coronary artery only. Vascular cell phenotype was assessed by immunoblotting for a host of both pro- and anti-atherogenic markers [e.g. endothelial nitric oxide synthase, p67phox, superoxide dismutase 1 (SOD1)]. Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control pigs, and exercise training did not change vasomotor function within FH. In contrast, only scattered effects of FH on EC phenotype were noted across the vasculature, which included both pro- and anti-atherogenic changes in EC protein expression (e.g. increased endothelial nitric oxide synthase in carotid artery ECs, decreased p67phox in brachial artery ECs, but decreased expression of the antioxidant protein SOD1 in thoracic vena cava; all P < 0.05). In thoracic vena cava ECs, this deficit was corrected by exercise training, while no other effects of exercise were observed in conduit vessel EC phenotype. Thus, while exercise training abrogated the adverse effect of hypercholesterolaemia on thoracic vena cava SOD1 expression, it appears that exercise training does not produce a consistently improved EC phenotype in either coronary or systemic conduit vessels in this FH swine model.

    Editorial Board

    03 January 2014