Carotid body: an emerging target for cardiometabolic co-morbidities.

NEW FINDINGS: What is the topic of this review? Regarding the global metabolic syndrome crisis, this review focuses on common mechanisms for high blood sugar and high blood pressure. Connections are made between the homeostatic regulation of blood pressure and blood sugar and their dysregulation to reveal signalling mechanisms converging on the carotid body. What advances does it highlight? The carotid body plays a major part in the generation of excessive sympathetic activity in diabetes and also underpins diabetic hypertension. As treatment of diabetic hypertension is notoriously difficult, we propose that novel receptors within the carotid body may provide a novel treatment strategy. ABSTRACT: The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti-diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co-exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter-regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel 'metabolic' receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB.

Combined Arterial Hypertension and Ischemic Stroke Exaggerate Anesthesia-Related Hypotension and Cerebral Oxygenation Deficits: A Preclinical Study.

BACKGROUND: Intraoperative arterial hypotension (IOH) is a common side effect of general anesthesia (GA), associated with poor outcomes in ischemic stroke. While IOH is more prevalent with hypertension, it is unknown whether IOH may differ when GA is induced during ischemic stroke, versus other clinical settings. This is important given that many stroke patients receive GA for endovascular thrombectomy. METHODS: We evaluate the cardiovascular responses to volatile GA (isoflurane in 100% o2 ) before and during middle cerebral artery occlusion stroke in rats instrumented to record blood pressure (BP) and cerebral tissue oxygenation (p o2 ) in the projected penumbra, in clinically relevant cohorts of normotensive (Wistar rat, n = 10), treated hypertensive (spontaneously hypertensive [SH] + enalapril, n = 12), and untreated hypertensive (SH rat, n = 12). RESULTS: During baseline induction of GA, IOH was similar in normotensive, treated hypertensive, and untreated hypertensive rats during the induction phase (first 10 minutes) (-24 ± 15 vs -28 ± 22 vs -48 ± 24 mm Hg; P > .05) and across the procedure (-24 ± 13 vs -30 ± 35 vs -39 ± 27 mm Hg; P > .05). Despite the BP reduction, cerebral p o2 increased by ~50% in all groups during the procedure. When inducing GA after 2 hours, all stroke groups showed a greater magnitude IOH compared to baseline GA induction, with larger falls in treated (-79 ± 24 mm Hg; P = .0202) and untreated(-105 ± 43 mm Hg; P < .001) hypertensive rats versus normotensives (-49 ± 21 mm Hg). This was accompanied by smaller increases in cerebral p o2 in normotensive rats (19% ± 32%; P = .0144 versus no-stroke); but a decrease in cerebral p o2 in treated (-11% ± 19%; P = .0048) and untreated (-12% ± 15%; P = .0003) hypertensive rats. Sham animals (normotensive and hypertensive) showed similar magnitude and pattern of IOH when induced with GA before and after sham procedure. CONCLUSIONS: Our findings are the first demonstration that ischemic stroke per se increases the severity of IOH, particularly when combined with a prior history of hypertension; this combination appears to compromise penumbral perfusion.

GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition.

BACKGROUND: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. METHODS: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. RESULTS: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. CONCLUSIONS: We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

Therapeutic Relevance of Elevated Blood Pressure After Ischemic Stroke in the Hypertensive Rats.

Over 80% of patients exhibit an acute increase in blood pressure (BP) following stroke. Current clinical guidelines make no distinction in BP management between patients with or without prior hypertension. Spontaneously hypertensive (SH) rats were preinstrumented with telemeters to record BP, intracranial pressure, and brain tissue oxygen in the predicted ischemic penumbra for 3 days before and 10 days after transient middle cerebral artery occlusion (n=8 per group) or sham (n=5). Before stroke, BP was either left untreated or chronically treated to a normotensive level (enalapril 10 mg/kg per day). Poststroke elevations in BP were either left uncontrolled, controlled (to the prestroke baseline level), or overcontrolled (to a normotensive level) via subcutaneous infusion of labetalol. Baseline values of intracranial pressure and brain tissue oxygen were similar between all groups, whereas BP was lower in treated SH rats (144±3 versus 115±5 mm Hg; P<0.001). Following middle cerebral artery occlusion, a similar rise in BP was observed in untreated (+16±2 mm Hg; P=0.005) and treated SH rats (+13±5 mm Hg; P=0.021). Intervening to prevent BP from increasing after stroke did not worsen outcome. However, reducing BP below prestroke baseline levels was associated with higher intracranial pressure (days 1-3; P<0.001), reduced cerebral perfusion pressure (days 2-4; P<0.001), higher mortality, slower functional recovery and larger infarct volumes. Although treating to maintain BP at the prestroke baseline level was not detrimental, our results suggest that when setting BP targets after stroke, consideration must be given to the potential negative impact of inadvertent excessive BP lowering in subjects with undiagnosed or poorly controlled hypertension.

Comparison of accelerometer-derived physical activity levels between individuals with and without cancer: a UK Biobank study.

Aim: To identify the difference in physical activity (PA) levels between individuals with and without cancer, and to estimate all-cause mortality associated with this difference. Methods: Current cancer, cancer survivor and cancer-free groups were identified from the UK Biobank. We used multivariate and Cox regression to estimate PA differences and association of PA with all-cause mortality. Results: Compared with the cancer-free individuals, participants in the two cancer groups had fewer minutes in moderate-to-vigorous PA per day in adjusted analyses. The PA difference was associated with higher mortality in the current cancer group. Conclusion: Patients with a history of cancer were less active than those without cancer, and PA is associated with increased mortality. PA improvement strategies in cancer patients must be explored.

Hypertensive Response to Ischemic Stroke in the Normotensive Wistar Rat.

Background and Purpose- Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure in the hours and days following ischemic stroke. Whether this poststroke hypertension is beneficial or harmful remains controversial and the underlying physiological basis is unclear. Methods- To investigate the dynamic cardiovascular response to stroke, adult Wistar rats (n=5-8 per group, 393±34 g) were instrumented with telemeters to blood pressure, intracranial pressure, renal sympathetic nerve activity, and brain tissue oxygen in the predicted penumbra (Po2). After 2 weeks of recovery, cardiovascular signals were recorded for a 3-day baseline period, then ischemic stroke was induced via transient middle cerebral artery occlusion, or sham surgery. Cardiovascular signals were then recorded for a further 10 days, and the functional sensorimotor recovery assessed using the cylinder and sticky dot tests. Results- Baseline values of all variables were similar between groups. Compared to sham, in the 2 days following stroke middle cerebral artery occlusion produced an immediate, transient rise above baseline in mean blood pressure (21±3 versus 2±4 mm Hg; P<0.001), renal sympathetic nerve activity (54±11% versus 7±4%; P=0.006), and cerebral perfusion pressure (12±5 versus 1±4; P≤0.001). Intracranial pressure increased more slowly, peaking 3 days after middle cerebral artery occlusion (14±6 versus -1±1 mm Hg; P<0.001). Treating with the antihypertensive agent nifedipine after stroke (1.5-0.75 mg/kg per hour SC) ameliorated poststroke hypertension (12±3 mm Hg on day 1; P=0.041), abolished the intracranial pressure increase (3±1; P<0.001) and reduced cerebral perfusion pressure (10±3 mm Hg; P=0.017). Preventing poststroke hypertension affected neither the recovery of sensorimotor function nor infarct size. Conclusions- These findings suggest that poststroke hypertension is immediate, temporally matched to an increase in sympathetic outflow, and elevates cerebral perfusion pressure for several days after stroke, which may enhance cerebral perfusion. Preventing poststroke hypertension does not appear to worsen prognosis after stroke in young, normotensive, and otherwise healthy rats. Visual Overview- An online visual overview is available for this article.