Identifying novel drug targets in the carotid body for the future treatment of cardiorespiratory and metabolic disorders

Abstract

Treatment of non-communicable diseases is the principle challenge facing modern medicine. Aberrant sympathetic nerve activity is a hallmark of hypertension and diabetes that exacerbates cardiovascular risk in both conditions, yet clinically remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the carotid body - the primary site of peripheral chemoreception and a powerful activator of the sympathetic nervous system. This led the carotid body to emerge as a potential therapeutic target for the treatment of sympathetically mediated diseases. However, causes of the peripheral chemoreflex sensitisation in disease state are not understood. In this work a multi-pronged approach is used to gain insight into the mechanisms underlying carotid body sensitisation in experimental hypertension. This is done with the intent to identify molecular targets in the carotid body to ameliorate its aberrant activity. A hypothesis-free transcriptomic screen of carotid bodies from Spontaneously Hypertensive and normotensive Wistar-Kyoto rats controls indicated that the sensitised state is associated with altered humoral signaling linked to metabolic dysfunction. This led to the identification of the Glucagon-like peptide-1 receptor (GLP1R) in the carotid body of rats and humans where its activation was shown to attenuate chemoreflex-evoked blood pressure and sympathetic responses. Hyperglycaemia induced rises in sympathetic activity were also abated by stimulation of GLP1R in the carotid body. These data pinpoint GLP1R in the carotid body as a potential therapeutic target to ameliorate excessive sympathetic activity in the hypertensive-diabetic state.

Date of Award	21 Jun 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	David Murphy (Supervisor), Julian Paton (Supervisor) & I C G Campbell (Supervisor)