Julian F R Paton

University of Bristol, Bristol, England, United Kingdom

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Publications (309)1114.3 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronization but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPG) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPG). We discuss the limitations of present CPGs and appraise the advantages of analogue over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease.This article is protected by copyright. All rights reserved
    The Journal of Physiology 11/2014; · 4.38 Impact Factor
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    ABSTRACT: Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.
    Current Hypertension Reports 11/2014; 16(11):493. · 3.90 Impact Factor
  • Ana Paula Abdala, Julian F. R. Paton, Jeffrey C. Smith
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    ABSTRACT: Pharmacological and mathematical modelling studies support the view that synaptic inhibition in mammalian brainstem respiratory circuits is essential for generating normal and stable breathing movements. GABAergic and glycinergic neurones are known components of these circuits but their precise functional roles have not been established, especially within key microcircuits of the respiratory pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes involved in phasic control of respiratory pump and airway muscles. Here, we review briefly current concepts of relevant complexities of inhibitory synapses and the importance of synaptic inhibition in the operation of these microcircuits. We highlight results and limitations of classical pharmacological studies that have suggested critical functions of synaptic inhibition. We then explore the potential opportunities for optogenetic strategies that represent a promising new approach for interrogating function of inhibitory circuits, including a hypothetical wish list for optogenetic approaches to allow expedient application of this technology. We conclude that recent technical advances in optogenetics should provide a means to understand the role of functionally select and regionally confined subsets of inhibitory neurones in key respiratory circuits such as those in the pre-BötC and BötC.This article is protected by copyright. All rights reserved
    The Journal of Physiology 11/2014; · 4.38 Impact Factor
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    ABSTRACT: Background It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions which role on neurogenic hypertension remains unknown. Objective To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neurons activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). Methods In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP), heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex function were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. Results LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic,mean-BP and LF of systolicBP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Conclusion Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP- LF band. Our data are amongst the first to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy.
    Autonomic Neuroscience. 09/2014;
  • The Journal of Physiology 09/2014; 592(18). · 4.38 Impact Factor
  • The Journal of Physiology 09/2014; 592(18). · 4.38 Impact Factor
  • Alona Ben-Tal, Sophie S Shamailov, Julian F R Paton
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    ABSTRACT: A minimal model for the neural control of heart rate (HR) has been developed with the aim of better understanding respiratory sinus arrhythmia (RSA) - a modulation of HR at the frequency of breathing. This model consists of two differential equations and is integrated into a previously-published model of gas exchange. The heart period is assumed to be affected primarily by the parasympathetic signal, with the sympathetic signal taken as a parameter in the model. We include the baroreflex, mechanical stretch-receptor feedback from the lungs, and central modulation of the cardiac vagal tone by the respiratory drive. Our model mimics a range of experimental observations and provides several new insights. Most notably, the model mimics the growth in the amplitude of RSA with decreasing respiratory frequency up to 7 breaths per minute (for humans). Our model then mimics the decrease in the amplitude of RSA at frequencies below 7 breaths per minute and predicts that this decrease is due to the baroreflex (we show this both numerically and analytically with a linear baroreflex). Another new prediction of the model is that the gating of the baroreflex leads to the dependency of RSA on mean vagal tone. The new model was also used to test two previously-suggested hypotheses regarding the physiological function of RSA and supports the hypothesis that RSA minimizes the work done by the heart while maintaining physiological levels of arterial CO2. These and other new insights the model provides extend our understanding of the integrative nature of vagal control of the heart.
    Mathematical biosciences. 07/2014;
  • Tadachika Koganezawa, Julian F.R. Paton
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    ABSTRACT: Brainstem hypoperfusion is a major excitant of sympathetic activity triggering hypertension but the exact mechanisms involved remain incompletely understood. A major source of excitatory drive to preganglionic sympathetic neurons originates from the ongoing activity of premotor neurons in the rostral ventrolateral medulla (RVLM sympathetic premotor neurons). The chemosensitivity profile of physiologically characterized RVLM sympathetic premotor neurons during hypoxia and hypercapnia remains unclear. We examined whether physiologically characterized RVLM sympathetic premotor neurons can sense brainstem ischemia intrinsically. We addressed this issue in a unique in situ arterially perfused preparation before and after a complete blockade of fast excitatory and inhibitory synaptic transmission. During hypercapnic-hypoxia, respiratory modulation of RVLM sympathetic premotor neurons was lost but tonic firing of most RVLM sympathetic premotor neurons was elevated. After blockade of fast excitatory and inhibitory synaptic transmission, RVLM sympathetic premotor neurons continued to fire and exhibited an excitatory firing response to hypoxia but not hypercapnia. This study suggests that RVLM sympathetic premotor neurons can sustain high levels of neuronal discharge when oxygen is scarce. The intrinsic ability of RVLM sympathetic premotor neurons to maintain responsivity to brainstem hypoxia is an important mechanism ensuring adequate arterial pressure essential for maintaining cerebral perfusion in face of depressed ventilation and/or high cerebral vascular resistance.This article is protected by copyright. All rights reserved
    Experimental physiology 07/2014; · 3.17 Impact Factor
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    ABSTRACT: Background and purposeThe paraventricular nucleus (PVN) of the hypothalamus is an important integrative site of neuroendocrine control of the circulation. We investigate the role of oxytocin receptors (OTRs) in PVN in cardiovascular homeostasis.Experimental approachExperiments were performed in conscious male Wistar rats equipped with radiotelemetric device. The PVN was unilaterally co-transfected with an adenoviral vector (Ad) engineered to over-express OTRs along with an enhanced green fluorescent protein (eGFP) tag. Control groups were PVN transfected with an Ad expressing eGFP alone or untransfected, sham rats (Wt). Rats were recorded without and with selective blockade of OTRs (OTX), both under baseline and stressful conditions. Baro-receptor reflex sensitivity (BRS) and cardiovascular short-term variability were evaluated using the sequence method and spectral methodology, respectively.Key resultsUnder baseline conditions OTR rats exhibited enhanced BRS and reduced blood pressure (BP) variability in comparison to eGFP and Wt rats. Exposure to stress increased BP, BP variability and heart rate (HR) in all rats. In eGFP and Wt rats, but not in OTR rats, BRS decreased during exposure to stress. Pre-treatment of OTR rats with OTX reduced BRS and enhanced BP and HR variability under baseline and stressful conditions. In Wt rats pre-treated with OTX, BRS was decreased and BP variability was increased under baseline and stress while HR variability was increased only during stress.Conclusions and ImplicationsOTRs in PVN are involved in tonic neural control of BRS and cardiovascular short-term variability. The failure of this mechanism could critically contribute to autonomic deregulation in cardiovascular disease.
    British Journal of Pharmacology 05/2014; · 5.07 Impact Factor
  • Hypertension 04/2014; · 6.87 Impact Factor
  • Davi J A Moraes, Benedito H Machado, Julian F R Paton
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    ABSTRACT: A major aspect of hypertension is excessive sympathetic activity but the reasons for this remain elusive. Sympathetic tone is increased in the spontaneously hypertensive (SH) rat reflecting, in part, enhanced respiratory-sympathetic coupling. We aimed to identify which respiratory cells might have altered properties. Using the working heart-brain stem preparation, we monitored simultaneously sympathetic and respiratory nerve activity in combination with intracellular recordings of physiologically characterized medullary presympathetic or respiratory neurons. In SH rats, respiratory modulation of both inspiratory and postinspiratory phases of sympathetic activity was larger relative to Wistar rats. An additional burst of sympathetic activity in the preinspiratory phase was also present in SH rats. After synaptic isolation of rostral medullary presympathetic neurons, there was no difference in their excitability compared with neurons in Wistar rats. Rather, both pre-Bötzinger preinspiratory and Bötzinger postinspiratory neurons had increased neuronal excitability in SH rats relative to Wistar rats; this was attributed to higher input resistance/reduced leak current in preinspiratory neurons and reduced calcium activated potassium conductance in postinspiratory neurons. Thus, the respiratory network of the SH rat is reconfigured to a pattern dominated by heightened excitability of preinspiratory and postinspiratory neurons. These neurons both provide augmented excitatory synaptic drive to rostral medullary presympathetic neurons contributing to excessive sympathetic nerve activity associated with hypertension in the in situ SH rat. Our data indicate selective modulation of potassium conductances in 2 subsets of respiratory neurons contributing to neurogenic hypertension.
    Hypertension 03/2014; · 6.87 Impact Factor
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    ABSTRACT: Sympathetic preganglionic neurones (SPN) convey sympathetic activity flowing from the CNS to the periphery to reach the target organs. Although previous in vivo and in vitro cell recording studies have explored their electrophysiological characteristics it has not been possible to relate these characteristics to their roles in cardiorespiratory reflex integration. We used the working heart-brainstem preparation to make whole-cell patch clamp recordings from T3-4 SPN (n=98). These SPN were classified by their distinct responses to activation of the peripheral chemoreflex, diving response and arterial baroreflex allowing the discrimination of muscle vasoconstrictor-like (MVClike, 39%) from cutaneous vasoconstrictor-like (CVClike, 28%) SPN. The MVClike SPN have higher baseline firing frequencies (2.52±0.33 vs CVClike 1.34±0.17 Hz, p=0.007). The CVClike have longer AHPs (314±36 vs MVClike 191±13 ms, P<0.001) and lower input resistance (346±49 vs MVClike 496±41 MΩ, P<0.05). The MVClike firing was respiratory-modulated with peak discharge in the late inspiratory:early expiratory phase and this activity was generated by both a tonic and respiratory-modulated barrage of synaptic events that were blocked by intrathecal kynurenate. In contrast the activity of CVClike SPN was underpinned by rhythmical membrane potential oscillations suggestive of gap junctional coupling. Thus we have related the intrinsic electrophysiological properties of two classes of SPN in situ to their roles in cardiorespiratory reflex integration and have shown that they deploy different cellular mechanisms that are likely to influence how they integrate and shape the distinctive sympathetic outputs.
    The Journal of Physiology 03/2014; · 4.38 Impact Factor
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    ABSTRACT: Arginine vasopressin (AVP) is a neurohypophysial hormone regulating hydromineral homeostasis. Here we show that the mRNA encoding cAMP responsive element-binding protein-3 like-1 (CREB3L1), a transcription factor of the CREB/activating transcription factor (ATF) family, increases in expression in parallel with AVP expression in supraoptic nuclei (SONs) and paraventicular nuclei (PVNs) of dehydrated (DH) and salt-loaded (SL) rats, compared with euhydrated (EH) controls. In EH animals, CREB3L1 protein is expressed in glial cells, but only at a low level in SON and PVN neurons, whereas robust upregulation in AVP neurons accompanied DH and SL rats. Concomitantly, CREB3L1 is activated by cleavage, with the N-terminal domain translocating from the Golgi, via the cytosol, to the nucleus. We also show that CREB3L1 mRNA levels correlate with AVP transcription level in SONs and PVNs following sodium depletion, and as a consequence of diurnal rhythm in the suprachiasmatic nucleus. We tested the hypothesis that CREB3L1 activates AVP gene transcription. Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs, whereas a dominant-negative mutant reduces expression. Rat AVP promoter deletion constructs revealed that CRE-like and G-box sequences in the region between -170 and -120 bp are important for CREB3L1 actions. Direct binding of CREB3L1 to the AVP promoter was shown by chromatin immunoprecipitation both in vitro and in the SON itself. Injection of a lentiviral vector expressing CREB3L1CA into rat SONs and PVNs resulted in increased AVP biosynthesis. We thus identify CREB3L1 as a regulator of AVP transcription in the rat hypothalamus.
    Journal of Neuroscience 03/2014; 34(11):3810-20. · 6.91 Impact Factor
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    ABSTRACT: Sensory information arising from the upper neck is important in the reflex control of posture and eye position. It has also been linked to the autonomic control of the cardiovascular and respiratory systems. Whiplash associated disorders (WAD) and cervical dystonia, which involve disturbance to the neck region, can often present with abnormalities to the oromotor, respiratory and cardiovascular systems. We investigated the potential neural pathways underlying such symptoms. Simulating neck afferent activity by electrical stimulation of the second cervical nerve in a working heart brainstem preparation (WHBP) altered the pattern of central respiratory drive and increased perfusion pressure. Tracing central targets of these sensory afferents revealed projections to the intermedius nucleus of the medulla (InM). These anterogradely labelled afferents co-localised with parvalbumin and vesicular glutamate transporter 1 indicating that they are proprioceptive. Anterograde tracing from the InM identified projections to brain regions involved in respiratory, cardiovascular, postural and oro-facial behaviours-the neighbouring hypoglossal nucleus, facial and motor trigeminal nuclei, parabrachial nuclei, rostral and caudal ventrolateral medulla and nucleus ambiguus. In brain slices, electrical stimulation of afferent fibre tracts lateral to the cuneate nucleus monosynaptically excited InM neurones. Direct stimulation of the InM in the WHBP mimicked the response of second cervical nerve stimulation. These results provide evidence of pathways linking upper cervical sensory afferents with CNS areas involved in autonomic and oromotor control, via the InM. Disruption of these neuronal pathways could, therefore, explain the dysphagic and cardiorespiratory abnormalities which may accompany cervical dystonia and WAD.
    Brain Structure and Function 03/2014; · 7.84 Impact Factor
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    ABSTRACT: Astrocytes produce and release L-lactate as a potential source of energy for neurons. Here we present evidence that L-lactate, independently of its caloric value, serves as an astrocytic signalling molecule in the locus coeruleus (LC). The LC is the principal source of norepinephrine to the frontal brain and thus one of the most influential modulatory centers of the brain. Optogenetically activated astrocytes release L-lactate, which excites LC neurons and triggers release of norepinephrine. Exogenous L-lactate within the physiologically relevant concentration range mimics these effects. L-lactate effects are concentration-dependent, stereo-selective, independent of L-lactate uptake into neurons and involve a cAMP-mediated step. In vivo injections of L-lactate in the LC evokes arousal similar to the excitatory transmitter, L-glutamate. Our results imply the existence of an unknown receptor for this 'glio-transmitter'.
    Nature Communications 02/2014; 5:3284. · 10.74 Impact Factor
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    ABSTRACT: Our aim was to assess the timing and mechanisms of the sympathoexcitation that occurs immediately after coronary ligation. We recorded thoracic sympathetic (tSNA) and phrenic activities, heart rate (HR) and perfusion pressure in Wistar rats subjected to either ligation of the left anterior descending coronary artery (LAD) or Sham operated in the working heart-brainstem preparation. Thirty minutes after LAD ligation, tSNA had increased (basal: 2.5±0.2 µV, 30 min: 3.5±0.3 µV), being even higher at 60 min (5.2±0.5 µV, P<0.01); while no change was observed in Sham animals. HR increased significantly 45 min after LAD (P<0.01). Sixty minutes after LAD ligation, there was: (i) an augmented peripheral chemoreflex - greater sympathoexcitatory response (50, 45 and 27% of increase to 25, 50 and 75 µL injections of NaCN 0.03%, respectively, when compared to Sham, P<0.01); (ii) an elevated pressor response (32±1 versus 23±1 mmHg in Sham, P<0.01) and a reduced baroreflex sympathetic gain (1.3±0.1 versus Sham 2.0±0.1%.mmHg-1, P<0.01) to phenylephrine injection; (iii) an elevated cardiac sympathetic tone (ΔHR after atenolol: -108±8 versus -82±7 bpm in Sham, P<0.05). In contrast, no changes were observed in cardiac vagal tone and bradycardic response to both baroreflex and chemoreflex between LAD and Sham groups. The immediate sympathoexcitatory response in LAD rats was dependent on an excitatory spinal sympathetic cardiocardiac reflex, whereas at 3 h an angiotensin II type 1 receptor mechanism was essential since Losartan curbed the response by 34% relative to LAD rats administered saline (P<0.05). A spinal reflex appears key to the immediate sympathoexcitatory response after coronary ligation. Therefore, the sympathoexcitatory response seems to be maintained by an angiotensinergic mechanism and concomitant augmentation of sympathoexcitatory reflexes.
    PLoS ONE 01/2014; 9(7):e101886. · 3.53 Impact Factor
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    ABSTRACT: We evaluated the feasibility of imaging brain vasculature in a transgenic rat model (L7543) which expressed a construct carrying the eGFP under the control of CAG promoter (Popova et al., Transgen. Res. 2008) using fiber endomicroscopy (CellVizio, Mauna Kea Technologies). eGFP expression were first evaluated in cortical and brainstem slices from L7543 rat using confocal microscopy (Leica SP5). Expression of eGFP in the cortex and brainstem was largely restricted to endothelial cells, although astrocytes in younger rats (up to P35) were also fluorescent. Next, the brainstem and cortex were imaged, without a contrasting agent, in anaesthetized P21-P40 rats using a fiber probe-based confocal laser endomicroscopy. Pial microvessels of the ventral or dorsal brainstem, or cortex were imaged using S-1500 and Mini-Z probes (1.5 and 0.94 mm tip diameter, respectively). The vascular contractility was visualized after application of a thromboxane agonist U46619 and sodium nitroprusside. Arterioles and veins were identified based on the eGFP expression profile. In addition, beveled probes S-300/B and S-650/B (0.3 and 0.65 mm tip diameter, respectively) were used to visualize vascular tree in Z-dimension. Currently we are working to adapt this method for imaging in unanaesthetized rats. This approach should be useful to investigate changes in cerebral microcirculation in hypertension and other vascular pathologies.
    The FASEB Journal 01/2014; 28(1 Supplement). · 5.70 Impact Factor
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    ABSTRACT: Abstract Respiratory modulation seen in the sympathetic nerve activity (SNA) implies that the respiratory and sympathetic networks interact. During hypertension elicited by chronic intermittent hypoxia (CIH), the SNA displays an enhanced respiratory modulation reflecting strengthened interactions between the networks. In this chapter, we review a series of experimental and modeling studies that help elucidate possible mechanisms of sympatho-respiratory coupling. We conclude that this coupling significantly contributes to both the sympathetic baroreflex and the augmented sympathetic activity after exposure to CIH. This conclusion is based on the following findings. (1) Baroreceptor activation results in perturbation of the respiratory pattern via transient activation of postinspiratory neurons in the Bötzinger complex (BötC). The same BötC neurons are involved in the respiratory modulation of SNA, and hence provide an additional pathway for the sympathetic baroreflex. (2) Under hypercapnia, phasic activation of abdominal motor nerves (AbN) is accompanied by synchronous discharges in SNA due to the common source of this rhythmic activity in the retrotrapezoid nucleus (RTN). CIH conditioning increases the CO2 sensitivity of central chemoreceptors in the RTN which results in the emergence of AbN and SNA discharges under normocapnic conditions similar to those observed during hypercapnia in naïve animals. Thus, respiratory–sympathetic interactions play an important role in defining sympathetic output and significantly contribute to the sympathetic activity and hypertension under certain physiological or pathophysiological conditions, and the theoretical framework presented may be instrumental in understanding of malfunctioning control of sympathetic activity in a variety of disease states.
    Breathing, Emotion and Evolution, Edited by Gert Holstege, Caroline M. Beers and Hari H. Subramanian, 01/2014: pages 1 - 23; Elsevier.
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    ABSTRACT: Despite extensive use of the renovascular/Goldblatt model of hypertension–2 K-C, and the use of renal denervation to treat drug resistant hypertensive patients, autonomic mechanisms that underpin the maintenance of this hypertension are important yet remain unclear. Our aim was to analyse cardiovascular autonomic function by power spectral density analysis of both arterial pressure and pulse interval measured continuously by radio telemetry for 6 weeks after renal artery clipping. Mean arterial pressure increased from 106 ± 5 to 185 ± 2 mmHg during 5 weeks post clipping when it stabilized. A tachycardia developed during the 4th week, which plateaued between weeks 5 and 6. The gain of the cardiac vagal baroreflex decreased immediately after clipping and continued to do so until the 5th week when it plateaued (from − 2.4 ± 0.09 to − 0.8 ± 0.04 bpm/mmHg; P < 0.05). A similar time course of changes in the high frequency power spectral density of the pulse interval was observed (decrease from 13.4 ± 0.6 to 8.3 ± 0.01 ms2; P < 0.05). There was an increase in both the very low frequency and low frequency components of systolic blood pressure that occurred 3 and 4 weeks after clipping, respectively. Thus, we show for the first time the temporal profile of autonomic mechanisms underpinning the initiation, development and maintenance of renovascular hypertension including: an immediate depression of cardiac baroreflex gain followed by a delayed cardiac sympathetic predominance; elevated sympathetic vasomotor drive occurring after the initiation of the hypertension but coinciding during its mid-development and maintenance.
    Autonomic neuroscience: basic & clinical 01/2014; · 1.82 Impact Factor
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    ABSTRACT: Salt appetite, the primordial instinct to favorably ingest salty substances, represents a vital evolutionary important drive to successfully maintain body fluid and electrolyte homeostasis. This innate instinct was shown here in Sprague-Dawley rats by increased ingestion of isotonic saline (IS) over water in fluid intake tests. However, this appetitive stimulus was fundamentally transformed into a powerfully aversive one by increasing the salt content of drinking fluid from IS to hypertonic saline (2% w/v NaCl, HS) in intake tests. Rats ingested HS similar to IS when given no choice in one-bottle tests and previous studies have indicated that this may modify salt appetite. We thus investigated if a single 24 h experience of ingesting IS or HS, dehydration (DH) or 4% high salt food (HSD) altered salt preference. Here we show that 24 h of ingesting IS and HS solutions, but not DH or HSD, robustly transformed salt appetite in rats when tested 7 days and 35 days later. Using two-bottle tests rats previously exposed to IS preferred neither IS or water, whereas rats exposed to HS showed aversion to IS. Responses to sweet solutions (1% sucrose) were not different in two-bottle tests with water, suggesting that salt was the primary aversive taste pathway recruited in this model. Inducing thirst by subcutaneous administration of angiotensin II did not overcome this salt aversion. We hypothesised that this behavior results from altered gene expression in brain structures important in thirst and salt appetite. Thus we also report here lasting changes in mRNAs for markers of neuronal activity, peptide hormones and neuronal plasticity in supraoptic and paraventricular nuclei of the hypothalamus following rehydration after both DH and HS. These results indicate that a single experience of drinking HS is a memorable one, with long-term changes in gene expression accompanying this aversion to salty solutions.
    PLoS ONE 01/2014; 9(8):e104802. · 3.53 Impact Factor

Publication Stats

5k Citations
1,114.30 Total Impact Points

Institutions

  • 1996–2014
    • University of Bristol
      • • School of Physiology and Pharmacology
      • • The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology
      • • Medical School
      Bristol, England, United Kingdom
  • 2013
    • University Hospitals Bristol NHS Foundation Trust
      Bristol, England, United Kingdom
  • 2011–2013
    • University of Melbourne
      • Department of Physiology
      Melbourne, Victoria, Australia
    • University of Birmingham
      • School of Sport and Exercise Sciences
      Birmingham, ENG, United Kingdom
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • Thomas Jefferson University
      • Department of Pathology, Anatomy & Cell Biology
      Philadelphia, PA, United States
  • 2002–2013
    • Geisel School of Medicine at Dartmouth
      • Department of Physiology and Neurobiology
      Hanover, New Hampshire, United States
  • 2012
    • University of Bath
      • Department of Physics
      Bath, ENG, United Kingdom
    • Massey University
      • Institute of Information and Mathematical Sciences
      Palmerston North, Manawatu-Wanganui, New Zealand
  • 2008–2012
    • National Institutes of Health
      • Section on Cellular Neurobiology
      Bethesda, MD, United States
    • University of Occupational and Environmental Health
      Kitakyūshū, Fukuoka, Japan
  • 2008–2011
    • Wakayama Medical University
      • Department of Physiology
      Wakayama, Wakayama, Japan
  • 2007–2011
    • Drexel University College of Medicine
      • Department of Neurobiology & Anatomy
      Philadelphia, PA, United States
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
  • 2003–2011
    • McKnight Brain Institute
      Gainesville, Florida, United States
  • 2010
    • Hebei Medical University
      Chentow, Hebei, China
  • 2009
    • University of Newcastle
      • Department of Biological Sciences
      Newcastle, New South Wales, Australia
    • University of Florida
      • Department of Physiology and Functional Genomics
      Gainesville, FL, United States
    • Scuola Internazionale Superiore di Studi Avanzati di Trieste
      Trst, Friuli Venezia Giulia, Italy
  • 2008–2009
    • University of São Paulo
      • Faculdade de Medicina de Ribeirão Preto (FMRP)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2000–2009
    • University of Leeds
      • School of Biomedical Sciences
      Leeds, England, United Kingdom
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
    • University of Texas Southwestern Medical Center
      • Department of Physiology
      Dallas, TX, United States
  • 2001–2008
    • Case Western Reserve University
      • Department of Medicine (University Hospitals Case Medical Center)
      Cleveland, OH, United States
    • Drexel University
      • School of Biomedical Engineering, Science and Health Systems
      Philadelphia, PA, United States
  • 2006
    • University of Missouri
      • Department of Biomedical Sciences
      Columbia, MO, United States
  • 2005
    • Universitätsmedizin Göttingen
      • Department of Neuro- and Sensory Physiology
      Göttingen, Lower Saxony, Germany
    • Wayne State University
      • Department of Physiology
      Detroit, MI, United States
  • 2002–2003
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1994
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1991
    • Dupont
      Delaware, Ohio, United States