Sympathetic Modulation By Glucagon Like Peptide 1 And Melanocortin 4 Receptors In The Carotid Body Of Wistar Rats

Abstract

Diabetes is a chronic metabolic disorder that occurs when there is raised levels of glucose in the blood (hyperglycemia) caused by either insulin deficiency or an inadequate response to insulin. Globally, the clinical problem of diabetes and obesity is huge (8.5% of total population) and this is reflected in Aotearoa by 6% of the population. Diabetes increases the likelihood of stroke, heart attack, vascular and visual disorders. Such a clinical tsunami makes understanding mechanisms of glucose homeostasis more critical than ever. An area that remains unexplained are the mechanisms by which sympathetic nervous activity (SNA) is heightened in diabetes as this contributes substantially to blood hyperglycaemia. Given the influential role of the carotid body (CB) in regulating SNA together with its ability to sense blood glucose, insulin and adrenaline, we tested the hypothesis that two newly revealed receptors from transcriptomic sequencing - glucagon-like peptide-1 (GLP1R) and melanocortin-4 (MC4R) located within the CB play a significant role in controlling SNA. The working heart-brainstem preparation was used to evaluate functionally the cardiovascular (SNA, heart rate, arterial pressure) and respiratory (phrenic nerve) activity in Wistar rats. The specific agonists and antagonists of GLP1R (Exendin-4 and Exendin-3, respectively) and MC4R (THIQ and HS014, respectively) were injected into the internal carotid artery (ICA) which, via the carotid body artery, perfuses the CB. Data are expressed 10 min post injection. The CB was stimulated with low doses of sodium cyanide (i.a.). Immunocytochemistry detected GLP1 and MC4 receptors localised to distinct cell groups within the carotid body. Stimulation of GLP1R within the CB inhibited the chemoreflex evoked sympathetic response (p<0.05) whilst it was augmented powerfully by the MC4R agonist (p<0.05) compared to baseline. In contrast, heart rate, arterial pressure and phrenic activity were unaffected. GLP1Rs antagonist alone increased the chemoreflex evoked sympathetic response above basline (p<0.05) while antagonising MC4Rs was without effect. Injections of vehicle did not alter either the chemoreflex evoked or basal SNA. For the first time, stimulation of metabolism-linked receptors – GLP1 and MC4 within the CB modulate SNA differentially. Our data purport endogenous secretion of GLP-1 within the CB affecting sympathetic activity. Our study provides novel targets within the CB that might be pharmacologically probed to control metabolism via modulation of SNA; such data may provide the much needed guidance for controlling blood glucose in diabetes.