Acute adenosine increases cardiac vagal and reduces sympathetic efferent nerve activities in rats

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. In 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 mu g kg-1). The effects of adenosine were also assessed in isolated perfused hearts (n= 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 +/- 56%, P < 0.01; +275 +/- 120%, P < 0.01; and +372 +/- 78%, P < 0.01, for the three doses, respectively; n= 7). Muscarinic blockade by atropine (5 mg kg-1, i.v.) significantly blunted the adenosine-induced bradycardia (-56.0 +/- 4.5%, P < 0.05; -86.2 +/- 10.5%, P < 0.01; and -34.3 +/- 9.7%, P < 0.01, respectively). Likewise, adenosine-induced bradycardia was markedly less in isolated heart preparations. Previous barodenervation did not modify the effects of adenosine on VNA. On the SNA side, adenosine administration was associated with a dose-dependent biphasic response, including overactivation in the first few seconds followed by a later profound SNA reduction. Earliest sympathetic activation was abolished by barodenervation, while subsequent sympathetic withdrawal was affected neither by baro- nor by chemodenervation. This is the first demonstration that acute adenosine is able to activate cardiac VNA, possibly through a central action. This increase in vagal outflow could make an important contribution to the antiarrhythmic action of this substance.

Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands

Salivary gland function is regulated by both the sympathetic and parasympathetic nervous systems. Previously we showed that the basal sympathetic outflow to the salivary glands (SNA(SG)) was higher in hypertensive compared to normotensive rats and that diabetes reduced SNA(SG) discharge at both strains. In the present study we sought to investigate how SNA(SG) might be modulated by acute changes in the arterial pressure and whether baroreceptors play a functional role upon this modulation. To this end, we measured blood pressure and SNA(SG) discharge in Wistar-Kyoto rats (WRY-intact) and in WRY submitted to sinoaortic denervation (WRY-SAD). We made the following three major observations: (i) in WRY-intact rats, baroreceptor loading in response to intravenous infusion of the phenylephrine evoked an increase in SNA(SG) spike frequency (81%, p<0.01) accompanying the increase mean arterial pressure ((sic)MAP: +77 +/- 14 mmHg); (ii) baroreceptor unloading with sodium nitroprusside infusion elicited a decrease in SNA(SG) spike frequency (17%, p<0.01) in parallel with the fall in arterial blood pressure ((sic)MAP: 30 3 mmHg) in WRY-intact rats; iii) in the WRY-SAD rats, phenylephrine-evoked rises in the arterial pressure ((sic)MAP: +56 +/- 6 mmHg) failed to produce significant changes in the SNA(SG) spike frequency. Taken together, these data show that SNA(SG) increases in parallel with pharmacological-induced pressor response in a baroreceptor dependent way in anaesthetised rats. Considering the key role of SNA(SG) in salivary secretion, this mechanism, which differs from the classic cardiac baroreflex feedback loop, strongly suggests that baroreceptor signalling plays a decisive role in the regulation of salivary gland function. (C) 2012 Elsevier Inc. All rights reserved.

Comparison of child self-reports and parent proxy-reports on quality of life of children with attention deficit hyperactivity disorder

Abstract Background Attention deficit hyperactivity disorder (ADHD) is a neurobiological condition that affects 3%–7% of the pediatric population and significantly compromises the quality of life (QoL) of these individuals. The aim of the current study was to compare child self-reports and parent proxy reports on the QoL of children with ADHD. Methods Forty-five children with ADHD, combined type, aged 8–12 years without comorbidities, were compared with 43 typically developing children. PedsQL™ 4.0 (Pediatric QoL Inventory™) Generic Core Scales (physical, emotional, social, and school functioning) were completed by families and children self-reporting their health-related QoL. Results Children with ADHD reported themselves significantly lowered their PedsQL™ scores on all dimensions in comparison to typically developing children. Statistically significant differences were observed in social functioning (p = 0.010), school functioning (p <0.001), psychosocial health (p <0.001), and total score (p = 0.002). The physical functioning and emotional functioning dimensions did not differ significantly between groups, with p = 0.841 and p = 0.070, respectively. Parents of children with ADHD also reported lower PedsQL™ scores, with statistically significant differences in all dimensions. The relationship between child self-reports and parent proxy reports indicated that there is greater agreement among children with ADHD, except for the school functioning. Conclusions This suggests that children with the disorder and their parents have a perception of the functional limitations the disorder brings. It is therefore important to undertake studies to verify the QoL in children with ADHD that aim to provide and measure the scope of the well-being of these children.

Purinergic and glutamatergic interactions in the hypothalamic paraventricular nucleus modulate sympathetic outflow

P2X receptors are expressed on ventrolateral medulla projecting paraventricular nucleus (PVN) neurons. Here, we investigate the role of adenosine 5′-triphosphate (ATP) in modulating sympathetic nerve activity (SNA) at the level of the PVN. We used an in situ arterially perfused rat preparation to determine the effect of P2 receptor activation and the putative interaction between purinergic and glutamatergic neurotransmitter systems within the PVN on lumbar SNA (LSNA). Unilateral microinjection of ATP into the PVN induced a dose-related increase in the LSNA (1 nmol: 38 ± 6 %, 2.5 nmol: 72 ± 7 %, 5 nmol: 96 ± 13 %). This increase was significantly attenuated by blockade of P2 receptors (pyridoxalphosphate-6-azophenyl-20,40-disulphonic acid, PPADS) and glutamate receptors (kynurenic acid, KYN) or a combination of both. The increase in LSNA elicited by L-glutamate microinjection into the PVN was not affected by a previous injection of PPADS. Selective blockade of non-N-methyl-D-aspartate receptors (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt, CNQX), but not N-methyl-D-aspartate receptors (NMDA) receptors (DL-2-amino-5-phosphonopentanoic acid, AP5), attenuated the ATP-induced sympathoexcitatory effects at the PVN level. Taken together, our data show that purinergic neurotransmission within the PVN is involved in the control of SNA via P2 receptor activation. Moreover, we show an interaction between P2 receptors and non-NMDA glutamate receptors in the PVN suggesting that these functional interactions might be important in the regulation of sympathetic outflow

P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure

Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Overactivation of this reflex is thought to contribute to increased sympathetic activity and hypertension; however, molecular mechanisms linking peripheral chemoreceptor drive to hypertension remain poorly understood. We have recently determined that activation of P2Y1 receptors in the RVLM mimicked effects of peripheral chemoreceptor activation. Therefore, we hypothesize that P2Y1 receptors regulate peripheral chemoreceptor drive in this region. Here, we determine whether P2Y1 receptors are expressed by C1 neurons in the RVLM and contribute to peripheral chemoreceptor control of breathing, sympathetic activity, and blood pressure. We found that injection of a specific P2Y1 receptor agonist (MRS2365) into the RVLM of anesthetized adult rats increased phrenic nerve activity (≈55%), sympathetic nerve activity (38±6%), and blood pressure (23±1 mm Hg), whereas application of a specific P2Y1 receptor antagonist (MRS2179) decreased peripheral chemoreceptor–mediated activation of phrenic nerve activity, sympathetic nerve activity, and blood pressure. To establish that P2Y1 receptors are expressed by C1 cells, we determine in the brain slice preparation using cell-attached recording techniques that cells responsive to MRS2365 are immunoreactive for tyrosine hydroxylase (a marker of C1 cells), and we determine in vivo that C1-lesioned animals do not respond to RVLM injection of MRS2365. These data identify P2Y1 receptors as key determinants of peripheral chemoreceptor regulation of breathing, sympathetic nerve activity, and blood pressure.

Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans

[EN] Chronic hypoxia is associated with elevated sympathetic activity and hypertension in patients with chronic pulmonary obstructive disease. However, the effect of chronic hypoxia on systemic and regional sympathetic activity in healthy humans remains unknown. To determine if chronic hypoxia in healthy humans is associated with hyperactivity of the sympathetic system, we measured intra-arterial blood pressure, arterial blood gases, systemic and skeletal muscle noradrenaline (norepinephrine) spillover and vascular conductances in nine Danish lowlanders at sea level and after 9 weeks of exposure at 5260 m. Mean blood pressure was 28 % higher at altitude (P < 0.01) due to increases in both systolic (18 % higher, P < 0.05) and diastolic (41 % higher, P < 0.001) blood pressures. Cardiac output and leg blood flow were not altered by chronic hypoxia, but systemic vascular conductance was reduced by 30 % (P < 0.05). Plasma arterial noradrenaline (NA) and adrenaline concentrations were 3.7- and 2.4-fold higher at altitude, respectively (P < 0.05). The elevation of plasma arterial NA concentration was caused by a 3.8-fold higher whole-body NA release (P < 0.001) since whole-body noradrenaline clearance was similar in both conditions. Leg NA spillover was increased similarly (x 3.2, P < 0.05). These changes occurred despite the fact that systemic O2 delivery was greater after altitude acclimatisation than at sea level, due to 37 % higher blood haemoglobin concentration. In summary, this study shows that chronic hypoxia causes marked activation of the sympathetic nervous system in healthy humans and increased systemic arterial pressure, despite normalisation of the arterial O2 content with acclimatisation.

Preparation of cold Mg + ion clouds for sympathetic cooling of highly charged ions at SPECTRAP

Die Elektronen in wasserstoff- und lithium-ähnlichen schweren Ionen sind den extrem starken elektrischen und magnetischen Feldern in der Umgebung des Kerns ausgesetzt. Die Laserspektroskopie der Hyperfeinaufspaltung im Grundzustand des Ions erlaubt daher einen sensitiven Test der Quantenelektrodynamik in starken Feldern insbesondere im magnetischen Sektor. Frühere Messungen an wasserstoffähnlichen Systemen die an einer Elektronenstrahl-Ionenfalle (EBIT) und am Experimentierspeicherring (ESR) der GSI Darmstadt durchgeführt wurden, waren in ihrer Genauigkeit durch zu geringe Statistik, einer starken Dopplerverbreiterung und der großen Unsicherheit in der Ionenenergie limitiert. Das ganze Potential des QED-Tests kann nur dann ausgeschöpft werden, wenn es gelingt sowohl wasserstoff- als auch lithium-ähnliche schwere Ionen mit einer um 2-3 Größenordnung gesteigerten Genauigkeit zu spektroskopieren. Um dies zu erreichen, wird gegenwärtig das neue Penningfallensystem SPECTRAP an der GSI aufgebaut und in Betrieb genommen. Es ist speziell für die Laserspektroskopie an gespeicherten hochgeladenen Ionen optimiert und wird in Zukunft von HITRAP mit nierderenergetischen hochgeladenen Ionen versorgt werden.rnrnSPECTRAP ist eine zylindrische Penningfalle mit axialem Zugang für die Injektion von Ionen und die Einkopplung eines Laserstrahls sowie einem radialen optischen Zugang für die Detektion der Fluoreszenz. Um letzteres zu realisieren ist der supraleitende Magnet als Helmholtz-Spulenpaar ausgelegt. Um die gewünschte Genauigkeit bei der Laserspektroskopie zu erreichen, muss ein effizienter und schneller Kühlprozess für die injizierten hochegeladenen Ionen realisiert werden. Dies kann mittels sympathetischer Kühlung in einer lasergekühlten Wolke leichter Ionen realisiert werden. Im Rahmen dieser Arbeit wurde ein Lasersystem und eine Ionenquelle für die Produktion einer solchen 24Mg+ Ionenwolke aufgebaut und erfolgreich an SPECTRAP in Betrieb genommen. Dazu wurde ein Festkörperlasersystem für die Erzeugung von Licht bei 279.6 nm entworfen und aufgebaut. Es besteht aus einem Faserlaser bei 1118 nm der in zwei aufeinanderfolgenden Frequenzverdopplungsstufen frequenzvervierfacht wird. Die Verdopplerstufen sind als aktiv stabilisierte Resonantoren mit nichtlinearen Kristallen ausgelegt. Das Lasersystem liefert unter optimalen Bedingeungen bis zu 15 mW bei der ultravioletten Wellenlänge und erwies sich während der Teststrahlzeiten an SPECTRAP als ausgesprochen zuverlässig. Desweiteren wurde eine Ionequelle für die gepulste Injektion von Mg+ Ionen in die SPECTRAP Falle entwickelt. Diese basiert auf der Elektronenstoßionisation eines thermischen Mg-Atomstrahls und liefert in der gepulsten Extraktion Ionenbündel mit einer kleinen Impuls- und Energieverteilung. Unter Nutzung des Lasersystems konnten damit an SPECTRAP erstmals Ionenwolken mit bis zu 2600 lasergekühlten Mg Ionen erzeugt werden. Der Nachweis erfolgte sowohl mittels Fluoreszenz als auch mit der FFT-ICR Technik. Aus der Analyse des Fluoreszenz-Linienprofils lässt sich sowohl die Sensitivität auf einzelne gespeicherte Ionen als auch eine erreichte Endtemperatur in der Größenordnung von ≈ 100 mK nach wenigen Sekunden Kühlzeit belegen.

Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention

In contrast to studies of depression and psychosis, the first part of this study showed no major differences in serum levels of cytokines and tryptophan metabolites between healthy children and those with attention-deficit/hyperactivity disorder of the combined type (ADHD). Yet, small decreases of potentially toxic kynurenine metabolites and increases of cytokines were evident in subgroups. Therefore we examined predictions of biochemical associations with the major symptom clusters, measures of attention and response variability.

Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism--effects of medication

Children with attention-deficit/hyperactivity disorder (ADHD) show a marked temporal variability in their display of symptoms and neuropsychological performance. This could be explained in terms of an impaired glial supply of energy to support neuronal activity.

Social cognition in attention-deficit hyperactivity disorder (ADHD)

Attention-deficit hyperactivity disorder (ADHD) is associated with a range of cognitive deficits and social cognition impairments, which might be interpreted in the context of fronto-striatal dysfunction. So far only few studies have addressed the issue of social cognition deficits in ADHD.