Carotid body chemoreceptors: physiology, pathology, and implications for health and disease

Abstract

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 physiological responses, and its role in maintaining health and potentiating disease. Emphasis is placed on 1) 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 ion channels; 2) 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; 3) 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 4) 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.

Keywords: autonomic system; carotid body; hypoxia.

Graphical abstract

FIGURE 1.

Interactions between cellular elements in the carotid body. A: carotid bifurcation and location of the carotid body. B: schematic representation of a carotid body glomerulus. Chemosensory and chemoproliferative synapses are indicated. C: schematic representation of the tripartite synapse. AR, adenosine receptor; DR, dopamine receptor; Panx-1, pannexin-1 channel; P2XR, purinergic 2X ionotropic receptor; P2YR, purinergic 2Y metabotropic receptor. (Reprinted from Ref. , with permission from Annual Review of Physiology.)

FIGURE 2.

Excitability and transduction mechanism components in type I cells. Type I cells are endowed with several voltage-dependent Na⁺ (VDNC), Ca²⁺ (VDCC), and K⁺ channels that render these cells excitable and capable of firing action potentials. Several K⁺ channels [oxygen sensitive (${\mathrm{K}}_{{\mathrm{O}}_2}$), large conductance (BK), TASK] have been shown to be directly or indirectly modulated by chemosensory stimuli (Po₂, pH, Pco₂). Thus, ${\mathrm{K}}_{{\mathrm{O}}_2}$ and BK channels appear to be directly modulated by Po₂, as indicated by the reduction of channel activity by hypoxia in excised patches. On the other hand, TASK channel activity is reduced directly by extracellular pH and indirectly by hypoxia, through reductions of intracellular ATP or the activation of AMP-activated protein kinase (AMPK) by the reduction of mitochondrial ATP production or [ATP]-to-[ADP] [P_i] ratio. This reduction of K⁺ currents leads to cell depolarization, recruitment of voltage-dependent Na⁺ and Ca²⁺ channels that further depolarize the cell, and increased intracellular Ca²⁺ concentration ([Ca²⁺]_i), a key element for the exocytotic release of the neurotransmitter(s) (NT). The latter one(s) will generate or modify afferent activity by activation of nerve terminals but also could modify type I cell properties acting on presynaptic receptors. Modification of type I cells by transmitter receptors may increase activity of phospholipase C (PLC) and protein kinase C (PKC) that can modify the activity of both transduction and voltage-dependent channels, thus enabling temporal modulation of sensory responses. Extracellular pH can also act on acid-sensing ion channels (ASICs) present in type I cells, depolarizing them and contributing to the sensory response. Finally, both transient receptor potential (TRP) channels and nonspecific cationic channels may also participate in the responses to hypoxia, both directly or indirectly through reactive oxygen species (ROS) produced during hypoxic challenges. ACh, acetylcholine; mAChR, muscarinic cholinergic receptor.

FIGURE 3.

Model for acute O₂ sensing by type I cells. Schematic representation of the mitochondrial-to-membrane signaling model of phototransduction in carotid body (CB) type I cells. Mitochondrial complex (MC)IV is the oxygen sensor, MCI is the effector, and NADH and reactive oxygen species (ROS) are signaling molecules that modulate ion channels in the plasma membrane. The size of MCIV relative to others is enlarged to facilitate explanation of the model. COX412, cytochrome-c oxidase subunit isoform 2; COX8B, cytochrome oxidase subunit VIIIbIMS, intermembrane space; QH2, reduced ubiquinone; FMN, flavin mononucleotide. (Reprinted from Ref. , with permission from Science Signaling.)

FIGURE 4.

Illustration of the widespread, multiorgan system effects mediated by stimulation of peripheral arterial chemoreceptors: schematic representation of most of the reflex responses that can be evoked by stimulating the carotid body chemoreceptors in a number of mammalian species. These include hematological, renal, gastrointestinal, endocrine, metabolic, and behavioral effects. BAT, brown adipose tissue; GFR, glomerular filtration rate; GI, gastrointestinal. (Reprinted from Ref. , with permission from Physiology).

FIGURE 5.

Influence of ventilation on autonomic and cardiovascular responses to chemoreceptor stimulation. Left: under conditions when breathing (ventilation) is decreased or absent, activation of chemoreceptors evokes powerful parasympathetic-mediated bradycardia accompanied by sympathetic-mediated vasoconstriction. Right: in contrast, during exposure to hypoxia (e.g., at high altitude), the large increase in ventilation reflexively inhibits both parasympathetic and sympathetic activity. Neurogenic-induced vasoconstriction is opposed by direct vasodilator effects of hypoxemia. Art, arterial; SNA, sympathetic nerve activity; TPVR, total peripheral vascular resistance.

FIGURE 6.

Hypoxia-induced vagal withdrawal and tachycardia are independent of the hypoxic ventilatory response in young healthy men. Exposure to hypoxia (10.5% O₂) increased heart rate (HR) despite volitional suppression of the ventilatory [minute ventilation ($\dot{\text{V}}\text{E}$)] response. Hypoxia decreased total peripheral resistance (TPR) and did not change mean arterial pressure (MAP). Sympathetic-mediated increases in HR were blocked by prior iv administration of the β-adrenergic receptor blocker propranolol. Reprinted from Ref. , with permission from Journal of Applied Physiology.

FIGURE 7.

Chemoreflex interactions with arterial baroreceptor, cardiopulmonary vagal, cardiac sympathetic spinal, exercise pressor, and chemosensitive renal afferent reflexes are illustrated. Afferent pathways in blue and green are sympathoinhibitory and sympathoexcitatory, respectively. See text for description of the interactions. DRG, dorsal root ganglion; HR, heart rate; SNA, sympathetic nerve activity.

FIGURE 8.

A and B: arterial pressure (AP) and sympathetic nerve activity (SNA) responses to acute intermittent hypoxia (AIH) in saline-treated (A) and losartan-treated (B) rats. C: group data for the percent change in SNA measured 60 min post-AIH minus SNA measured just before implementing AIH. D and E: acute hypoxia (10% O₂ for 45 s) induced increases in SNA measured pre-AIH and 60 min post-AIH in a saline-pretreated rat and a losartan-pretreated rat (D), with group data shown in E. The hypoxia-induced increase in SNA [area under the curve (AUC)] was normalized to the baseline response. ****P < 0.0001 vs. time control. ††††P < 0.0001 vs. AIH + saline. Reprinted from Ref. , with permission from Journal of Physiology.

FIGURE 9.

A: sympathetic nerve activity (SNA) responses to acute intermittent hypoxia (AIH) in control rats (vehicle injected), subfornical organ (SFO)-inhibited rats (SFOiso), carotid body-denervated (CBD) rats, and rats subjected to both CBD and SFOiso. B and C: group data for changes in SNA 60 min post-AIH in sham-operated and CBD rats, and rats treated with vehicle or isoguvacine (iso) injected into SFO, and CBD rats injected with isoguvacine. ***P < 0.001 vs. AIH + sham. ****P < 0.0001. †††P < 0.001. ‡‡P < 0.01. D and E: acute hypoxia induced increases in SNA measured pre- and post-AIH in rats previously injected with vehicle or isoguvacine into SFO (D), with group data shown in E. Reprinted from Ref. , with permission from Journal of Physiology.

FIGURE 10.

Contribution of the carotid body to the pathological effects mediated by sympathetic hyperactivation in human diseases. Diagram showing the pivotal role played by the carotid body in the pathological effects mediated by sympathetic hyperactivation in heart failure, obstructive sleep apnea, hypertension, and cardiometabolic diseases. Oxidative stress and inflammation are associated with carotid body chemosensory potentiation, leading to an increase in sympathetic nervous system activity, which promotes autonomic dysfunction, ventilatory instability, baroreflex alterations, hypertension, fibrosis, and insulin resistance. ET-1, endothelin 1; NO, nitric oxide; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla. (Reprinted from Ref. , with permission from Journal of Physiology.)

FIGURE 11.

Effects of carotid body (CB) ablation or carotid sinus nerve denervation in preclinical models of sympathetic-related diseases. Spontaneous hypertension: Prevents increases in blood pressure (BP) in young spontaneously hypertensive rats (SHRs). Reduces increased BP and sympathetic activation and improves baroreflex sensitivity (BRS) in adult SHRs (521). Congestive heart failure: Normalizes autonomic and BRS alterations, reduces apnea and arrhythmias. Attenuates myocardial deterioration and increases rat survival rate (367). Reduces enhanced renal sympathetic discharges, reduces respiratory instability and arrhythmia incidence in rabbit (509). Hypertensive and natriuretic responses to sodium load: reduced enhanced BP response and natriuresis induced by hypertonic NaCl infusion (542). Renovascular hypertension: Reduces increased BP, improves BRS and autonomic balance in rats (522). Intermittent hypoxia [obstructive sleep apnea (OSA)]: Normalizes increased BP after 21 days of chronic intermittent hypoxia (CIH) in rats. Restores autonomic balance and BRS and reduces arrhythmia incidence (469). Prevents hyperglycemia and high hepatic glucose output in mice. Reduces increased levels of catecholamines in plasma (427). High-fat and -carbohydrate diets: Normalizes sympathetic overflow and increased BP. Decreases weight gain, normalizes plasma glucose and insulin levels. Improves endothelial function (423). Protein-malnourished diets: Normalizes increased BP in offspring of protein-restricted rats (527). Heart failure—Dahl salt-sensitive hypertension: Reduces increased BP and 24-h urinary norepinephrine levels, improves myocardial function and rat survival rate (513).

FIGURE 12.

Main effects of carotid body ablation (CBA) in humans with resistant hypertension or congestive heart failure. Resistant hypertension: First-in-man study to test the safety and feasibility of unilateral CBA in 15 patients with drug-resistant hypertension. No overall reduction in blood pressure (BP) was found. However, 8 patients showed transient reductions in mean BP for 6 mo and decreases in sympathetic nerve activity to muscle (MSNA) (545). Resistant hypertension: Preliminary data from 15 patients. Transvenous catheter-based unilateral right CBA. At 6 mo systolic and diastolic mean BP were reduced by 10 ± 15 and 4 ± 7 mmHg, respectively (546). Preliminary data from 10 patients. The 24-h ambulatory BP 152 ± 11/89 ± 12 mmHg (systolic/diastolic) was reduced by 9 ± 9/4 ± 6 mmHg at 1 mo after CBA. Ambulatory BP continued reduced at 6 mo by 10 ± 15/4 ± 7 mmHg (547). Congestive heart failure: First-in-man study to test the safety and feasibility of unilateral right-sided CBA in 4 patients and bilateral CBA (BCBA) in 6 patients with CHF. At 1 mo, both MSNA and ventilatory chemoreflexes to hypoxia were reduced. Quality of life and fatigue scores showed transient improvement at 1–2 mo (35).

FIGURE 13.

Modulation of carotid body (CB) chemosensory responsiveness to oxygen to restore autonomic, cardiorespiratory, and metabolic balance in sympathetic-related diseases. Nonsurgical modulation of enhanced CB chemosensory discharge is a possible alternative to CB ablation or carotid sinus neurotomy to restore autonomic balance and normalize chemoreflex and baroreflex function, arterial blood pressure, endothelial function, and metabolism (see Refs. 32, 423, 441, 443, 469, 507, 543, 544, 553).