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Professor Julian Paton

Mechanisms of neurogenic hypertension

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.

Research keywords

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

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

Equipment relevant to this work

  • Radio-telemetry
  • confocal microscopy
  • electrophysiology
  • fMRI

Research 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.

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