Cardiometabolic conflux at the carotid body

Background: Diabetes is the fastest-growing disease in New Zealand, and when combined with high blood pressure (hypertension), so-called sweet pressure (SP) is the leading cause of mortality. However, controlling SP remains challenging clinically. One target that remains unexploited is the sympathetic nervous system (SNA). As the carotid body (CB) has a pivotal role in regulating SNA, blood pressure and blood glucose, we searched for novel signalling pathways linking the CB with metabolism. Using RNA sequencing, we discovered melanocortin type-4 receptor (MC4R) expression was upregulated in the CB of spontaneously hypertensive rats (SHR) versus Wistar rats; these receptors have an essential role in regulating cardiovascular and energy homeostasis. Hypothesis: We hypothesised that blockade of MC4R within the CB would reduce SNA and alleviate SP. Methods: The SHR was used as a hypertensive-diabetic model as it has glucose intolerance. Using a novel in situ preparation, we recorded SNA activity while injecting an MC4R antagonist (HS014) into the CB via the internal carotid artery. Results: The upregulated MC4R expression in the CB of SHR versus Wistar rat was validated using qPCR and immunocytochemistry. Antagonising MC4R within the CB lowered SNA and prevented the SNA hyperactivation triggered by hyperglycaemia (high glucose). No such responses were found in control Wistar rats. Conclusion: MC4R signalling is a novel mechanism within the CB that depresses ongoing SNA and, importantly, the elevated SNA caused by hyperglycaemia; whether this reduces blood glucose awaits testing in vivo. These data provide a potential mechanism for controlling co-comorbidity of hypertension and blood glucose. Funding: HRC, Royal Society Te Apārangi and Sidney Taylor Trust funded this research. This is the full abstract presented at the American Physiology Summit 2023 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.