Professor Julian Paton

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Professor Julian Paton

E10 / E9,
University Walk, Bristol
BS8 1TD
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julian.f.r.paton@bristol.ac.uk

Telephone Number (0117) 331 2275
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Organisations

School of Physiology and Pharmacology

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Mechanisms of neurogenic hypertension

Research overview

Paton's group seeks to understand what changes within the central nervous system during the aetiology of neurogenic hypertension. Sympathetic nerve activity destined for the heart and arterioles is elevated prior to the onset of hypertension, which is suggestive of a causative role. In hypertension, cerebral vascular resistance is elevated causing brain hypoperfusion - a well known stimulant of sympathetic activity and hypertension. The microvasculature of the brainstem is also inflamed.

The hypothesis of elevated brainstem vascular resistance and inflammation as causative to hypertension is being explored in animal models and human patients. Transcriptomic analysis of brainstem genes altered in hypertension has led to exciting novel targets that are being validated with virally mediated transgenesis, stem cell transplantation, optogenetics and radio-telemetry in vivo.

The group's interest in mechanisms of central respiratory pattern generation has led to the observation that its modulation of sympathetic outflow is enhanced in hypertension. Additionally, data has shed light on plausible reasons for respiratory arrhythmias such as: sudden infant death and Rett syndromes. Data are being used to make mathematical models to assist in the further understanding of brainstem function as well as contributing to the Human Physiome project. A number of clinical translational studies driven by hypotheses gleaned from basic animal research are now underway in hypertensive patients.

Key words

Brainstem, autonomic nervous system, sympathetic activity, blood pressure, breathing, baroreceptor, chemoreceptor, reflexes, bladder

Key findings

  • 1995-1996: Invention of a “tour de force” integrative physiological in situ working heart- brainstem preparation. This allowed studies we could not have done previously.
  • 1998-2002: In collaboration with Professor Sergey Kasparov, we revealed that brainstem actions of angiotensin II, a peptide associated with hypertension, were mediated by liberation of nitric oxide from the endothelium leading to a novel form of brain signalling: vascular-neuronal signalling.
  • 2003: We provided unequivocal evidence that vascular-neuronal signalling in the brainstem contributed to high blood pressure levels in an animal model of hypertension.
  • 2006-present: Discovery that brainstem pacemaker activity was essential for gasping. This and other work dives our mathematical modelling which contributes to the Human Physiome Project.
  • 2007- present: In collaboration with Professor David Murphy, we identified unique genes within brain regions regulating arterial pressure thereby providing unique clues as to those that may generate neurogenic hypertension.
  • 2007: We discovered that the brainstem vasculature was inflamed in the hypertensive brain.
  • 2007: In collaboration with Professors Jeff Smith (NINDS, NIH) and Ilya Rybak (Drexel University), we revealed the precise compartments of the brainstem for generation of distinct respiratory patterns and the conditions and mechanisms for expression of these different rhythms.

2009: In collaboration with Dr Andrew Allen (Melbourne University) and Dr Anthony Pickering, we discovered that enhanced sympathetic activity precedes the onset of hypertension and is dependent on exacerbated modulation by the brainstem respiratory pattern generator.

Diseases related to this field of research

Hypertension, neurovascular disease, cerebral artery stenosis, SIDS, Rett syndrome, heart failure

Processes and functions relevant to this work

Autonomic nervous system function, homeostatic reflexes

Research group

Ana Abdala, Michael Greenwood, James Hewinson, Beihui Liu, Fiona McBryde, Jennifer Palmer, Prajni Sadananda, Lauren Salo, Annabel Simms, Peter Steed, Marie Toward

Techniques in routine use

Neurophysiology, patch clamp, imaging, fMRI, microneurography, in vivo gene transfer, lentivirus, adenovirus, stem cell

Equipment in routine use

Radio-telemetry, confocal microscopy, electrophysiology, fMRI,

Collaborations

Bristol:
Prof Raimondo Ascione (Bristol Heart Institute)
Dr Andreas Baumbach (Bristol Heart Institute)
Prof Alan Champneys (Mathematical Engineering)
Dr Kimberly Connor (Physiology & Pharmacology)
Dr David Cussans (Physics)
Prof S Kasparov (Physiology & Pharmacology)
Dr Patrick Kehoe (Frenchay - Bristol)
Dr Philip Langton (Physiology & Pharmacology)
Professor Seth Love (frenchay Hospital - Bristol)
Dr Angus Nightingale (Bristol Heart Institute)
Prof. D. Murphy (LINE - Bristol)
Prof David Newbold (Physics - Bristol)
Mr N Patel (Frenchay Hospital - Bristol - UK)
National
Dr G S Bewick - Department of Physiology - University of Aberdeen
Dr Mark Dewhurst - Pfizer UK - Kent
Dr M Dutschmann - Physiology - University of Leeds
International:
Dr A Allen - Department of Phjysiology - University of Melbourne - Melbourne, Australia
Prof John Bissonnette (Physiology - University of Oregon - USA)
Dr Derek Leishman - Lilly - USA
Prof B Machado - Univ Sao-Paulo - Riberao Preto - Brazil
Prof R McAllen - Howard Florey Institute - Melbourne - Australia
Dr D Mayorov

Teaching

  • Respiratory physiology to Veterinary, Medical and Science students.
  • Respiratory practical classes. 
  • Third year honours element organiser on the Cardiovascular System in Health and Disease.
  • Cardiovascular physiology to stage III honours physiology students
  • Molecular Neuroscience course
  • Lectures on cardiovascular physiology to students at the University of Oxford.

Public engagement

I have given a number of public lectures on my research and on the clinical problem of high blood pressure (‘Pumping up the Pressure! Why high blood pressure is bad for you’, and more general lectures on ‘Revealing Physiology’ and ‘Fizziology is Phun’. These have been to school pupils within schools as well as to the general public. I have been invited to make these lectures in the UK, Brazil and the United States of America. Some of the lectures are listed below:

 

  • 2000-2010 University Open Day lectures, University of Bristol
  • 2004, Lecture, Taunton School, Taunton, Somerset
  • 2004 L. Floyd Clarke Memorial Lecturer, Univ. Wyoming, Laramie, USA
  • 2005, Public Lecture, Physiological Society-FEPS, University of Bristol, Bristol.
  • 2006, Public Lecture, Brazilian Physiological Society, Ribeirao-Preto, Brazil.
  • 2006, University of the Third Age, Bath
  • 2006 Keynote Speaker, Research Appreciation Day, Univ. North Texas, Dallas, Texas, USA.
  • 2007, Seminars to VIth formers Taunton School, Taunton, Somerset
  • 2009 Key Note Speaker, Inaugural Undergraduate Physiological Symposium, University of Oxford


Key publications

  1. Paton, J, Wang, S, Polson, J & Kasparov, S 2008, ‘Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension’. Journal of Molecular Medicine, vol 86(6)., pp. 705 - 710
  2. Waki, H, Liu, B, Miyake, M, Katahira, K, Murphy, D, Kasparov, S & Paton, J 2007, ‘Junctional Adhesion Molecule-1 Is Upregulated in Spontaneously Hypertensive Rats: Evidence for a Prohypertensive Role Within the Brain Stem’. Hypertension, vol 49 (6)., pp. 1321 - 1327
  3. Qiu, J, Yao, S, Hindmarch, C, Antunes, V, Paton, J & Murphy, D 2007, ‘Transcription factor expression in the hypothalamo- neurohypophyseal system of the dehydrated rat: upregulation of Gonadotrophin inducible transcription factor 1 mRNA is mediated by cAMP-dependent protein kinase A’. Journal of Neuroscience, vol 27 (9)., pp. 2196 - 2203

Latest publications

  1. Greenwood, M, Bordieri, L, Greenwood, MP, Melo, MR, Colombari, DSA, Colombari, E, Paton, JFR & Murphy, D 2014, ‘Transcription Factor CREB3L1 Regulates Vasopressin Gene Expression in the Rat Hypothalamus’. The Journal of Neuroscience, vol 34., pp. 3810-20
  2. Niewinski, P, Janczak, D, Rucinski, A, Tubek, S, Engelman, ZJ, Jazwiec, P, Banasiak, W, Sobotka, PA, Hart, ECJ, Paton, JFR & Ponikowski, P 2014, ‘Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure’. Experimental Physiology, vol 99., pp. 552-61
  3. Niewinski, P, Tubek, S, Banasiak, W, Paton, JFR & Ponikowski, P 2014, ‘Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans’. Journal of Physiology, vol 592., pp. 1295-308
  4. Ruchaya, PJ, Antunes, VR, Paton, JFR, Murphy, D & Yao, ST 2014, ‘The cardiovascular actions of fractalkine/CX3CL1 in the hypothalamic paraventricular nucleus are attenuated in rats with heart failure’. Experimental Physiology, vol 99., pp. 111-22
  5. Geraldes, V, Gonçalves-Rosa, N, Liu, B, Paton, JFR & Rocha, I 2014, ‘Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats’. Experimental Physiology, vol 99., pp. 89-100
  6. McBryde, FD, Abdala, AP, Hendy, EB, Pijacka, W, Marvar, P, Moraes, DJA, Sobotka, PA & Paton, JFR 2013, ‘The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension’. Nature Communications, vol 4.
  7. Hart, EC, McBryde, FD, Burchell, AE, Ratcliffe, LEK, Stewart, LQ, Baumbach, A, Nightingale, A & Paton, JFR 2013, ‘Translational Examination of Changes in Baroreflex Function After Renal Denervation in Hypertensive Rats and Humans’. Hypertension.

Full publications list in the University of Bristol publications system

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