Faculty of Medical and Health Sciences

Translational Cardio-Respiratory Research Laboratory

Principle Investigator

Purinergic (P2X3) receptors encapsulate the glomus cells within the carotid body of a hypertensive rat (left) and human (middle). These are now being targeted in a new first-in-human clinical trial. On the right shows the exaggerated electrical voltage response of a single carotid body afferent neurone recorded from a hypertensive (Htn) versus a normotensive (Ntn) rat. Data from Pijacka et al. (Nature Med. 22: 1151-1159, 2016).

Summary of Research

In animal models and human patients I am exploring how the regulation of the cardiovascular and respiratory systems are coupled by the peripheral and central nervous systems and why these mechanisms fail in disease resulting in autonomic imbalance.

We are testing the hypothesis that organs sense blood flow/oxygen delivery via their sensory afferent nerves. In disease, these sensory afferents become highly sensitised, triggering exaggerated responses in blood pressure, sympathetic activity causing intense vasoconstriction that reduces organ blood flow leading to tissue ischaemia. Using novel pharmacological, electronic and optical devices, we are targeting the peripheral nervous system (sensory and motor) with the aim of reinstating organ blood flow homeostasis, thereby alleviating cardiac and vascular diseases. Based on our findings in animals, clinical trials are being devised with pharmaceutical and device companies that may provide potential novel solutions to unmet clinical need in hypertension, sleep apnoea and heart failure.

Current Research Questions

The carotid bodies have the greatest blood flow per unit mass in the body. Shown here is a corrosion cast of the dense capillary network of the carotid body located at the bifurcation of the common carotid artery in a rat. Data unpublished (P Langton & JFR Paton).

Will targeting the carotid body using a novel purinergic (P2X3) receptor antagonist reduce sympathetic activity in animal models and humans with heart failure, improve cardiac pump function and alleviate sleep apnoea?
Is the hypersensitivity of skeletal muscle afferents in hypertension due to activation of a purinergic receptor subtype and will its blockade reduce blood pressure and improve exercise tolerance in animals and humans?
Will reinstating respiratory sinus arrhythmia (a naturally occurring mechanism that causes heart rate variability) in heart failure (where RSA is lost) improve coronary artery blood flow and cardiac output?
In animal models and humans with hypertension, will improving brainstem blood flow reduce both sympathetic activity and arterial pressure?

Selected Publications

Many patients with hypertension have congenital defects in their vertebral arteries. Images are of two magnetic resonance angiograms of the cerebral arteries in healthy individuals (A,B, left side) and those with hypertension (A, B. right side). In A, a hypertensive patient has vertebral artery hypoplasia (VAH; very small right vertebral artery) and in B, a patient with no posterior communicating arteries (pCoA). We believe such deficits in brain blood flow lead to high blood pressure. From Warnert et al (2016; Circ. Res., 119, e140-e151).

Original

Pijacka, W., Katayama, P.L. Salgado, H.C., Lincevicius, G.S., Campos, R.R., McBryde, F.D. & Paton JFR. (2018). Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats. Journal of Physiology(online).
Moraes DJA, Bonagamba LGH, da Silva MP, Paton JFR, Machado BH. (2017). Role of ventral medullary catecholaminergic neurons for respiratory modulation of sympathetic outflow in rats. Scientific Reports (accepted)
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 Medicine22: 1151-1159.
Warnert, EAH, Rodrigues, JCL, Burchell AE, Neumann, S Ratcliffe, LEK, Manghat, N, Harris, AD, Adams, Z,. Nightingale AK, Wise R, Paton, JFR, & Hart EC. (2016). Is high blood pressure self-protection for the brain? Circulation Research 119:e140-e151.
Narkiewicz, K., Ratcliffe, L.E., Hart, E.J., Briant, L., Chrostowska, M., Wolf, J., Szyndler, A., Hering, D., Abdala, A.P., Manghat, N., Burchell, A., Durant, C., Lobo, M., Patel, N.J., Leiter, J.C., Engelman, Z.J., Nightingale, A. & Paton J.F.R. (2016). Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial. JACC : basic to translational, 1, 313-324.
O'Callaghan, EL, Chauhan, AS, Zhao, L, Lataro, RM, Salgado, HC, Nogaret, A, & Paton, JFR. (2016). Utility of a novel biofeedback device for within-breath modulation of heart rate in rats: a quantitative comparison of vagus nerve versus right atrial pacing. Frontiers in Physiology; 7: 27.
Briant, L.J.B., O'Callaghan, E.L., Champneys, A.R. & Paton, J.F.R. (2015). Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance? Journal of Physiology, 593: 5341-60.
Marina N, Ang R, Machhada A, Kasymov V, Karagiannis A, Hosford PS, Mosienko V, Teschemacher AG, Vihko P, Paton JF, Kasparov S, Gourine AV. (2015). Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat. Hypertension, 65, 775-783.
Moraes, DJA, Machado,BH & Paton, J.F.R. (2014). Specific respiratory neuron types have increased excitability that drive pre-sympathetic neurones in neurogenic hypertension. Hypertension 63, 1309-1318.
Cates, M.J., Steed, P.J., Abdala, A.P.L., Langton, P.D. & Paton, J.F.R. (2011). Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats. Journal of Applied Physiology, 111, 149-156.

In a human patient with heart failure sympathetic vasoconstrictor activity to arterioles in skeletal muscle was reduced after removal of a carotid body (bottom trace). Data from Niewinski et al. (Eur J Heart Fail., 19: 391-400, 2017).

Reviews

McBryde FD, Malpas SC, Paton JFR. (2016). Intra-cranial mechanisms for preserving brain blood flow in health and disease. Acta Physiol (Oxf). doi: 10.1111/apha.12706
Koeners, MP, Lewis, KE, Ford, AP & Paton, JFR^.(2016). Hypertension: A problem of organ blood flow supply-demand mismatch. Future Cardiology 12, 339-49.
Abdala, A.P., Paton, J.F.R. & Smith, J.C. (2015). Defining Inhibitory Neurone Function in Respiratory Circuits:Opportunities with Optogenetics?" Journal of Physiology, 593, 3033-46.
Paton, J.F.R. Sobotka, PA, Fudim, M., Engelman, ZJ, Hart, ECJ, McBryde, FD, Abdala, AP, Marina, N., Gourine, AV, Lobo, M., Patel, N, Burchell, A., Ratcliffe, L., Nightingale, A. (2013). The carotid body as a therapeutic target for treatment of sympathetically mediated diseases. Hypertension. 61, 5-13.
Smith, J.S., Rybak, I.A., Borgmann, A., Abdala, A.P., Paton J.F.R. (2013). Brainstem respiratory networks: building blocks and microcircuits. Trends in Neuroscience, 36:152-162.