Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

CBmeter study: protocol for assessing the predictive value of peripheral chemoreceptor overactivation for metabolic diseases

IntroductionEarly screening of metabolic diseases is crucial since continued undiagnostic places an ever-increasing burden on healthcare systems. Recent studies suggest a link between overactivated carotid bodies (CB) and the genesis of type 2 diabetes mellitus. The non-invasive assessment of CB activity by measuring ventilatory, cardiac and metabolic responses to challenge tests may have predictive value for metabolic diseases; however, there are no commercially available devices that assess CB activity. The findings of the CBmeter study will clarify the role of the CBs in the genesis of—metabolic diseases and guide the development of new therapeutic approaches for early intervention in metabolic disturbances. Results may also contribute to patient classification and stratification for future CB modulatory interventions.MethodsThis is a non-randomised, multicentric, controlled clinical study. Forty participants (20 control and 20 diabetics) will be recruited from secondary and primary healthcare settings. The primary objective is to establish a new model of early diagnosis of metabolic diseases based on the respiratory and metabolic responses to transient 100% oxygen administration and ingestion of a standardised mixed meal.AnalysisRaw data acquired with the CBmeter will be endorsed against gold standard techniques for heart rate, respiratory rate, oxygen saturation and interstitial glucose quantification and analysed a multivariate analysis software developed specifically for the CBmeter study (CBview). Data will be analysed using clustering analysis and artificial intelligence methods based on unsupervised learning algorithms, to establish the predictive value of diabetes diagnosis.EthicsThe study was approved by the Ethics Committee of the Leiria Hospital Centre. Patients will be asked for written informed consent and data will be coded to ensure the anonymity of data.DisseminationResults will be disseminated through publication in peer-reviewed journals and relevant medical and health conferences.

Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat

Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo intact CB nerve activity and in vivo whole body ventilatory responses to hypoxia were modified by alterations in succinate metabolism and mitochondrial ROS (mitoROS) generation in the rat. Application of diethyl succinate (DESucc) caused concentration-dependent increases in chemoafferent frequency measuring approximately 10–30% of that induced by severe hypoxia. Inhibition of mitochondrial succinate metabolism by dimethyl malonate (DMM) evoked basal excitation and attenuated the rise in chemoafferent activity in hypoxia. However, approximately 50% of the response to hypoxia was preserved. MitoTEMPO (MitoT) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1) (mitochondrial antioxidants) decreased chemoafferent activity in hypoxia by approximately 20–50%. In awake animals, MitoT and SKQ1 attenuated the rise in respiratory frequency during hypoxia, and SKQ1 also significantly blunted the overall hypoxic ventilatory response (HVR) by approximately 20%. Thus, whilst the data support a role for succinate and mitoROS in CB and whole body O2-sensing in the rat, they are not the sole mediators. Treatment of the CB with mitochondrial selective antioxidants may offer a new approach for treating CB-related cardiovascular–respiratory disorders.

Medullary and Hypothalamic Functional Magnetic Imaging During Acute Hypoxia in Tracing Human Peripheral Chemoreflex Responses

Hypoxia-sensitive peripheral carotid chemoreceptors, which regulate sympathetic outflow from the brain stem, are promising antihypertensive treatment targets. However, the central nervous pathways integrating human peripheral chemoreflexes are poorly understood. We combined high-resolution functional magnetic resonance imaging with physiological profiling to elucidate hypothalamic and medullary responses to acute hypoxia. We exposed 12 healthy men (29.7±6.6 years) to 5 hypoxic episodes each by breathing 10% oxygen for 180 seconds followed by 90 seconds of normoxia during high-resolution subcortical functional magnetic resonance imaging. We recorded beat-by-beat finger blood pressure, ECG, and peripheral oxygen saturation (Sp o 2 ). We analyzed functional magnetic resonance imaging data through independent component analysis, correlation with systolic blood pressure and Sp o 2 , and functional connectivity analysis by dual regression. On average Sp o 2 decreased by 12±3% ( P <0.01) during hypoxia while heart rate increased by 3±7 bpm ( P <0.01). Systolic blood pressure was unchanged. Brain stem-centered analyses revealed 5 distinct hypoxia-responsive regions around the nucleus of the solitary tract, nucleus ambiguus/intermediate reticular nucleus, dorsal motor nucleus of the vagal nerve, spinal trigeminal nucleus, and inferior olivary nucleus. Hypothalamus-centered analysis revealed 3 such regions around the arcuate nucleus, anterior hypothalamic area/lateral hypothalamic area, and paraventricular nucleus. During hypoxia, these regions showed altered functional connectivity with various medullary and hypothalamic areas. We conclude that high-resolution functional magnetic resonance imaging reveals subcortical systems engaged by acute hypoxia, which likely correspond to the peripheral chemoreceptor pathway. Our methodology may have utility in studying peripheral chemoreflex contributions to cardiovascular disease and responses to peripheral chemoreceptor modulation. Registration: URL: https://www.drks.de/ . Unique identifier: DRKS00013101.

Carotid Body Chemoreceptors: Physiology, Pathology, and Implications for Health and Disease

The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2 and CO2, and pH, eliciting reflex ventilatory, cardiovascular and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiologic responses, and its role in maintaining health and potentiating disease. Emphasis will be placed on: i) Transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ionic channels; ii) Synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; iii) Integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and iv) The contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension and metabolic diseases, and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.

Carotid body chemosensitivity: early biomarker of dysmetabolism in humans

Objective The carotid bodies (CBs) are peripheral chemoreceptor organs classically described as being O2 sensors, which are increasingly emerging as core players in metabolic control. Herein we evaluated CB activity in prediabetes patients and determined its correlation with dysmetabolism clinical features. Design and methods Prediabetes patients were recruited at the Cardiology Service, Hospital Santa Marta, Centro Hospitalar Lisboa Central, EPE (CHLC-EPE). The study was approved by CHLC-EPE and NOVA Medical School Ethics Committee. Thirty-three prediabetic and 14 age-matched, non-prediabetic, volunteers had their peripheral chemosensitivity evaluated by the Dejours test. Serum biomarkers of metabolic disease, insulin sensitivity (HOMA-IR), blood pressure, carotid intima-media thickness (cIMT) and glucose tolerance were assessed. Results CB chemosensitivity was significantly increased in prediabetic group (P < 0.01). Fasting blood, glucose intolerance, fasting insulin and HOMA-IR were significantly higher in prediabetes patients. Insulin resistance correlated both with peripheral chemosensitivity, assessed by the Dejours test (P < 0.05) and with abdominal circumference (P < 0.01). HbA1c correlated with HOMA-IR (P < 0.05) and left cIMT (P < 0.05) in prediabetes patients. Conclusions We conclude that CB is overactive in prediabetes subjects and that peripheral chemosensitivity correlates with fasting insulin and insulin resistance representing a novel non-invasive functional biomarker to forecast early metabolic disease.

Losartan may attenuate altitude-related sleep disturbance

IntroductionSleep disturbance is common at high altitude and likely driven by an exaggerated peripheral chemoreceptor response which leads to apnoeic episodes and arousal. We hypothesised that this heightened response is in part mediated through angiotensin II receptors in the carotid body. To examine this link, we studied the effect of angiotensin II receptor blocker on sleep disturbance.MethodsTwenty participants paired by age, gender and ACE phenotype ascended to the Whymper Hut (5000 m) on Chimborazo in the Ecuadorean Andes as part of a double-blinded randomised placebo-controlled study of physiological mechanisms. Subjects were randomised to either losartan 100 mg daily or placebo. The primary outcome of sleep efficiency was measured using wrist-mounted actigraphs. One pair was excluded from analysis after descending before the end of the study due to acute mountain sickness.ResultsThere was a significantly different response to altitude between the two groups (F=3.274, p=0.029), as a decline in sleep efficiency in the placebo group (F=10.259, p<0.001) was not replicated in the angiotensin II receptor blocker group (F=0.459, p=0.713).ConclusionThe absence of any significant sleep disturbance in the intervention group suggests that peripheral chemoreceptor hypersensitivity is largely mediated by angiotensin II receptor activation. However, further research is needed to confirm our findings and to study the potential mechanisms of action.