The seminar will advocate that sensitization of visceral afferents triggers malfunctional plasticity in downstream neural circuits causing autonomic dysfunction compounding cardiovascular and respiratory disease.
The afferent system considered is the peripheral arterial chemoreceptor. The fundamental mechanisms determining its set-point sensitivity will be demonstrated via a novel “accelerator-brake” hypothesis involving glutamate-NMDA receptor signaling. Proof of concept studies in animals and humans that identified the carotid bodies as a novel target for the treatment of cardiovascular-respiratory diseases will be reviewed. Understanding the molecular mechanisms of carotid body dysfunction led to the identification of a potent therapeutic – Gefapixant (Lyfnua), a selective purinergic P2X3 receptor antagonist that has been approved by the European Medicines Agency for the treatment of chronic cough allowing opportunities for repurposing for cardiorespiratory diseases. Interestingly, this antagonist: (i) arrests the pathological hyperexcitability but preserves the physiological signaling of the carotid body; (ii) targets only the chemoreflex-sympathetic reflex pathway, which led to a new hypothesis that carotid body afferents driving different reflex motor outputs are phenotypically distinct based on neurochemical content.
The multi-modal property of the carotid body is exemplified by its detection of oxygen, carbon dioxide, low pH but we have extended this to the discovery of sensitivity to metabolic agents such as glucose and glucagon-like-1 peptide. This has led to the notion that the carotid body offers a potential nodal point for intervention in cardiovascular-respiratory diseases where diabetes is a co-morbidity. Translational studies will be presented to demonstrate our recent studies supporting ways by which modulation of carotid body can offer novel therapeutic advances for hypertension, heart failure and licit and illicit opioid induced respiratory depression.
References
Lataro R, Moraes, DM, Salgado H, Paton JFR (2023). P2X3 receptor antagonism attenuates the progression of heart failure. Nature Communications, 14, 1725.
Pauza AG, Thakkar P, Tasic T, Felippe I, Bishop P, Greenwood MP, Ast J, Broichhagen J, Hodson DJ, Salgado HC, Pauza DH, Japundzic-Zigon N, Murphy D & Paton JFR. (2022). GLP1R attenuates sympathetic response to glucose via carotid body inhibition. Circulation Research 130, 694-707.
Pijacka, W., Moraes, D.J.A., Ratcliffe, L.E.K., Nightingale, A.K., Hart, E.C., da Silva, M.P., Machado, B.H., McBryde, F.D., Abdala, A.P., Ford, A.P. & Paton, J.F.R. (2016). Purinergic receptors in the carotid body as a novel target for controlling hypertension. Nature Medicine 22, 1151-1159.
SPEAKER BIOGRAPHY
Julian is an integrative physiologist translating novel findings from animal models to humans. He was educated at the University of Birmingham (BSc (Hons) 1984) and University of London (PhD, 1987). Subsequently, between 1989-1994, he was a fellow at EI DuPont, Wilmington and University Washington, Seattle, US, and an Alexander von Humboldt Fellow (University of Göttingen, Germany). In 1994, he was awarded a British Heart Foundation Fellowship at the University of Bristol, UK. In 2017, he transferred to the University of Auckland, New Zealand, where he is Director of Manaaki Manawa (established 2019) – the Centre of Heart Research, and Co-Director of Pūtahi Manawa – Healthy Hearts of Aotearoa New Zealand (established 2021), which is the first national Centre of Research Excellence addressing equity in heart health through community-led research. His research focuses on the neural coupling between the cardiovascular and respiratory systems. His novel fundamental discoveries have resulted in first-in-human trials for treating neurogenic hypertension, sleep apnoea and heart failure. He is founder member and Chief Scientific Officer for Ceryx Medical Ltd. designing a novel bionic pacemaker for heart failure. He has 440 publications, ~24,500 citations and an h-index of 84. He was made Fellow of the Royal Society of New Zealand in 2021.
