The Accelerator and Brake Modulatory System of Carotid Body Sensitivity

The carotid body (CB) is the primary sensor of arterial gases in the human body that through reflex pathways maintains cardiovascular homeostasis. It is known that CB chemosensitivity increases upon repeated stimulation as well as disease states; however, the molecular basis for this remains elusive. Objectives: To investigate the effect of excitatory and inhibitory amino acids in mediating CB afferent activity. Hypothesis: We hypothesised that glutamate and γ-aminobutyric acid (GABA) act to modulate CB sensitivity. Methods: Electrophysiological recordings of carotid sinus nerve (CSN) afferent discharge were made from an ex vivo arterially perfused common carotid artery bifurcation preparation. Effects of agents on CB sensitivity were assessed from responses evoked by cyanide (CN−) (1.23 μmol bolus). Results: The CSN response to CN− consisted of a rapid high amplitude discharge that was quenched abruptly, leading to a low amplitude tail. Glutamate administration augmented the CSN response to CN− by 2-fold compared to baseline ( p=0.0005). In contrast, GABA administration suppressed the CN− response by 2-fold ( p = 3.71 x 10−5). An N-methyl-D-aspartic acid (NMDA) receptor antagonist (MK801; 100 μM) increased the response amplitude resulting in one single high amplitude discharge (160% increase from baseline), abolishing the low amplitude tail. Such an effect was also observed following GABAA receptor blockade with bicuculline (500 μM), when an 80% increase was observed. The CN− response was blocked by PPADS (a P2X receptor antagonist; 100 μM) (242 ± 154 vs 4.82 ± 2.23 % change from baseline; p=0.03), suggesting it to be solely mediated by purinergic transmission. Summary of the data: We propose that CN-evoked excitation of CB chemosensory cells leads to the co-release of ATP and glutamate. ATP activates directly P2X receptors on petrosal chemosensory afferents, while glutamate acting via NMDA receptors on chemosensory cells leads to activity-induced potentiation of ATP release and co-release of GABA to quench ATP-mediated CSN discharge in a time-controlled manner. This is supported by our finding that blockade of either excitatory (NMDAR) or inhibitory (GABAA) receptors both heighten the CN− evoked CB response. A statement of the conclusions: Our results suggest an intrinsic ‘accelerator and brake’ paracrine mechanism within the CB involving glutamate and GABA controlling CB afferent sensitivity. Research was supported by the Health Research Council of New Zealand and the Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.