Pulmonary Vascular Responses to Chronic Intermittent Hypoxia in a Guinea Pig Model of Obstructive Sleep Apnea.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

Carotid body chemosensitivity is not attenuated during cold water diving.

Tonic carotid body (CB) activity is reduced during exposure to cold and hyperoxia. We tested the hypotheses that cold water diving lowers CB chemosensitivity and augments CO2 retention more than thermoneutral diving. Thirteen subjects [age: 26 ± 4 yr; body mass index (BMI): 26 ± 2 kg/m2) completed two 4-h head-out water immersion protocols in a hyperbaric chamber (1.6 ATA) in cold (15°C) and thermoneutral (25°C) water. CB chemosensitivity was assessed with brief hypercapnic ventilatory response ([Formula: see text]) and hypoxic ventilatory response ([Formula: see text]) tests before dive, 80 and 160 min into the dive (D80 and D160, respectively), and immediately after and 60 min after dive. Data are reported as an absolute mean (SD) change from predive. End-tidal CO2 pressure increased during both the thermoneutral water dive [D160: +2 (3) mmHg; P = 0.02] and the cold water dive [D160: +1 (2) mmHg; P = 0.03]. Ventilation increased during the cold water dive [D80: 4.13 (4.38) and D160: 7.75 (5.23) L·min-1; both P < 0.01] and was greater than the thermoneutral water dive at both time points (both P < 0.01). [Formula: see text] was unchanged during the dive (P = 0.24) and was not different between conditions (P = 0.23). [Formula: see text] decreased during the thermoneutral water dive [D80: -3.45 (3.61) and D160: -2.76 (4.04) L·min·mmHg-1; P < 0.01 and P = 0.03, respectively] but not the cold water dive. However, [Formula: see text] was not different between conditions (P = 0.17). In conclusion, CB chemosensitivity was not attenuated during the cold stress diving condition and does not appear to contribute to changes in ventilation or CO2 retention.

Role of olfactory receptor78 in carotid body-dependent sympathetic activation and hypertension in murine models of chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread breathing disorder. CIH-treated rodents exhibit activation of the sympathetic nervous system and hypertension. Heightened carotid body (CB) activity has been implicated in CIH-induced hypertension. CB expresses high abundance of olfactory receptor (Olfr) 78, a G-protein coupled receptor. Olfr 78 null mice exhibit impaired CB sensory nerve response to acute hypoxia. Present study examined whether Olfr78 participates in CB-dependent activation of the sympathetic nervous system and hypertension in CIH-treated mice and in hemeoxygenase (HO)-2 null mice experiencing CIH as a consequence of naturally occurring OSA. CIH-treated wild-type (WT) mice showed hypertension, biomarkers of sympathetic nerve activation, and enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), and these responses were absent in CIH-treated Olfr78 null mice. HO-2 null mice showed higher apnea index (AI) (58 ± 1.2 apneas/h) than WT mice (AI = 8 ± 0.8 apneas/h) and exhibited elevated blood pressure (BP), elevated plasma norepinephrine (NE) levels, and heightened CB sensory nerve response to hypoxia and sLTF. The magnitude of hypertension correlated with AI in HO-2 null mice. In contrast, HO-2/Olfr78 double null mice showed absence of elevated BP and plasma NE levels and augmented CB response to hypoxia and sLTF. These results demonstrate that Olfr78 participates in sympathetic nerve activation and hypertension and heightened CB activity in two murine models of CIH.NEW & NOTEWORTHY Carotid body (CB) sensory nerve activation is essential for sympathetic nerve excitation and hypertension in rodents treated with chronic intermittent hypoxia (CIH) simulating blood O2 profiles during obstructive sleep apnea (OSA). Here, we report that CIH-treated mice and hemeoxygenase (HO)-2-deficient mice, which show OSA phenotype, exhibit sympathetic excitation, hypertension, and CB activation. These effects are absent in Olfr78 null and Olfr78/HO-2 double null mice.

Relevance of carotid bodies in COVID-19: A hypothetical viewpoint.

We have considered some of the available evidence to account for the impact of SARS-CoV on the regulatory control of the autonomic nervous and respiratory systems. Apart from stimulating general interest in the subject, our hope was to provide putative explanations for some of the patients' symptoms based on described physiological and pathophysiological mechanisms seen in other diseases. Herein, we have focused on the carotid bodies. In this hypothetical viewpoint, we have discussed the plasticity of the carotid body chemoreflex and made a comparison between acute and chronic exposures to high altitude with COVID-19. From these discussions, we have postulated that the sensitivity of the hypoxic ventilatory response may well determine the outcome of disease severity and those that live at high altitude may be more resistant. We have provided insight into silent hypoxia and attempted to explain an absence of ventilatory drive and anxiety yet maintenance of consciousness. In an attempt to discover more about the mysteries of COVID-19, we conclude with questions and some hypothetical studies that may answer them.

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

[Figure: see text].

Simulated sleep apnea alters hydrogen sulfide regulation of blood flow and pressure.

In sleep apnea, airway obstruction causes intermittent hypoxia (IH). In animal studies, IH-dependent hypertension is associated with loss of vasodilator hydrogen sulfide (H2S), and increased H2S activation of sympathetic nervous system (SNS) activity in the carotid body. We previously reported that inhibiting cystathionine γ-lyase (CSE) to prevent H2S synthesis augments vascular resistance in control rats. The goal of this study was to evaluate the contribution of IH-induced changes in CSE signaling to increased blood pressure and vascular resistance. We hypothesized that chronic IH exposure eliminates CSE regulation of blood pressure (BP) and vascular resistance. In rats instrumented with venous catheters, arterial telemeters, and flow probes on the main mesenteric artery, the CSE inhibitor dl-propargylglycine (PAG, 50 mg/kg/day i.v. for 5 days) increased BP in Sham rats but decreased BP in IH rats [in mmHg, Sham (n = 11): 114 ± 4 to 131 ± 6; IH (n = 8): 131 ± 8 to 115 ± 7 mmHg, P < 0.05]. PAG treatment increased mesenteric vascular resistance in Sham rats but decreased it in IH rats (day 5/day 1: Sham: 1.50 ± 0.07; IH: 0.85 ± 0.19, P < 0.05). Administration of the ganglionic blocker hexamethonium (to evaluate SNS activity) decreased mesenteric resistance in PAG-treated Sham rats more than in saline-treated Sham rats or PAG-treated IH rats. CSE immunoreactivity in IH carotid bodies compared with those from Sham rats. However, CSE staining in small mesenteric arteries was less in arteries from IH than in Sham rats but not different in larger arteries (inner diameter > 200 µm). These results suggest endogenous H2S regulates blood pressure and vascular resistance, but this control is lost after IH exposure with decreased CSE expression in resistance size arteries. IH exposure concurrently increases carotid body CSE expression and relative SNS control of blood pressure, suggesting both vascular and carotid body H2S generation contribute to blood pressure regulation.NEW & NOTEWORTHY These results suggest that CSE's protective role in the vasculature is impaired by simulated sleep apnea, which also upregulates CSE in the carotid body. Thus, this enzyme system can exert both pro- and antihypertensive effects and may contribute to elevated SNS outflow in sleep apnea.

Role of the Carotid Body in an Ovine Model of Renovascular Hypertension.

The carotid body is implicated as an important mediator and potential treatment target for hypertension. The mechanisms driving increased carotid body tonicity in hypertension are incompletely understood. Using a large preclinical animal model, which is crucial for translation, we hypothesized that carotid sinus nerve denervation would chronically decrease blood pressure in a renovascular ovine model of hypertension in which hypertonicity of the carotid body is associated with reduced common carotid artery blood flow. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. Hypertension was accompanied by a significant reduction in common carotid blood flow but no change in renal blood flow. Carotid sinus nerve denervation significantly reduced blood pressure compared with sham. In both hypertensive and normotensive animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure and common carotid conductance but a reduction in renal vascular conductance. These responses were not different between the animal groups. Taken together, our findings indicate that (1) the carotid body is activated in renovascular hypertension, and this is associated with reduced blood flow (decreased vascular conductance) in the common carotid artery and (2) the carotid body can differentially regulate blood flow to the common carotid and renal arteries. We suggest that in the ovine renovascular model, carotid body hypertonicity may be a product of reduced common carotid artery blood flow and plays an amplifying role with the kidney in the development of hypertension.

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease.

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood and oxygen delivery to the brain and vital organs. However, in certain conditions, including obstructive sleep apnea, heart failure and essential/spontaneous hypertension, the CB becomes hyperactive, promoting neurogenic hypertension and arrhythmia. G-protein-coupled receptors (GPCRs) are very highly expressed in the CB and have key roles in mediating baseline CB activity and hypoxic sensitivity. Here, we provide a brief overview of the numerous GPCRs that are expressed in the CB, their mechanism of action and downstream effects. Furthermore, we will address how these GPCRs and signaling pathways may contribute to CB hyperactivity and cardiovascular and respiratory disease. GPCRs are a major target for drug discovery development. This information highlights specific GPCRs that could be targeted by novel or existing drugs to enable more personalized treatment of CB-mediated cardiovascular and respiratory disease.

Carotid Body and Metabolic Syndrome: Mechanisms and Potential Therapeutic Targets.

The carotid body (CB) is responsible for the peripheral chemoreflex by sensing blood gases and pH. The CB also appears to act as a peripheral sensor of metabolites and hormones, regulating the metabolism. CB malfunction induces aberrant chemosensory responses that culminate in the tonic overactivation of the sympathetic nervous system. The sympatho-excitation evoked by CB may contribute to the pathogenesis of metabolic syndrome, inducing systemic hypertension, insulin resistance and sleep-disordered breathing. Several molecular pathways are involved in the modulation of CB activity, and their pharmacological manipulation may lead to overall benefits for cardiometabolic diseases. In this review, we will discuss the role of the CB in the regulation of metabolism and in the pathogenesis of the metabolic dysfunction induced by CB overactivity. We will also explore the potential pharmacological targets in the CB for the treatment of metabolic syndrome.

Hypoxia-inducible factors and obstructive sleep apnea.

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.

Neuronal Networks in Hypertension: Recent Advances.

Neurogenic hypertension is associated with excessive sympathetic nerve activity to the kidneys and portions of the cardiovascular system. Here we examine the brain regions that cause heightened sympathetic nerve activity in animal models of neurogenic hypertension, and we discuss the triggers responsible for the changes in neuronal activity within these regions. We highlight the limitations of the evidence and, whenever possible, we briefly address the pertinence of the findings to human hypertension. The arterial baroreflex reduces arterial blood pressure variability and contributes to the arterial blood pressure set point. This set point can also be elevated by a newly described cerebral blood flow-dependent and astrocyte-mediated sympathetic reflex. Both reflexes converge on the presympathetic neurons of the rostral medulla oblongata, and both are plausible causes of neurogenic hypertension. Sensory afferent dysfunction (reduced baroreceptor activity, increased renal, or carotid body afferent) contributes to many forms of neurogenic hypertension. Neurogenic hypertension can also result from activation of brain nuclei or sensory afferents by excess circulating hormones (leptin, insulin, Ang II [angiotensin II]) or sodium. Leptin raises blood vessel sympathetic nerve activity by activating the carotid bodies and subsets of arcuate neurons. Ang II works in the lamina terminalis and probably throughout the brain stem and hypothalamus. Sodium is sensed primarily in the lamina terminalis. Regardless of its cause, the excess sympathetic nerve activity is mediated to some extent by activation of presympathetic neurons located in the rostral ventrolateral medulla or the paraventricular nucleus of the hypothalamus. Increased activity of the orexinergic neurons also contributes to hypertension in selected models.

Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans.

We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence (P < 0.01), AP incidence (P = 0.01), and AP content per burst (P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once (P < 0.01) and more than once (P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH (P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst (P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.

P2X3 receptor antagonism reduces the occurrence of apnoeas in newborn rats.

Hyperreflexia of the peripheral chemoreceptors is a potential contributor of apnoeas of prematurity (AoP). Recently, it was shown that elevated P2X3 receptor expression was associated with elevated carotid body afferent sensitivity. Therefore, we tested whether P2X3 receptor antagonism would reduce AoP known to occur in newborn rats. Unrestrained whole-body plethysmography was used to record breathing and from this the frequency of apnoeas at baseline and following administration of either a P2X3 receptor antagonist - AF-454 (5 mg/kg or 10 mg/kg s.c.) or vehicle was derived. In a separate group, we tested the effects of AF-454 (10 mg/kg) on the hypoxic ventilatory response (10 % FiO2). Ten but not 5 mg/kg AF-454 reduced the frequency of AoP and improved breathing regularity significantly compared to vehicle. Neither AF-454 (both 5 and 10 mg/kg) nor vehicle affected baseline respiration. However, P2X3 receptor antagonism (10 mg/kg) powerfully blunted hypoxic ventilatory response to 10 % FiO2. These data suggest that P2X3 receptors contribute to AoP and the hypoxic ventilatory response in newborn rats but play no role in the drive to breathe at rest.

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.

Baroreflex Amplification and Carotid Body Modulation for the Treatment of Resistant Hypertension.

PURPOSE OF REVIEW: Patients with true resistant hypertension (RH) are characterized by having high sympathetic activity and therefore potentially benefit from treatments such as baroreflex amplification (baroreflex activation therapy (BAT) or endovascular baroreflex amplification therapy (EVBA)) or carotid body (CB) modulation. This review aims at providing an up-to-date overview of the available evidence regarding these two therapies. RECENT FINDINGS: In recent years, increasing evidence has confirmed the potential of baroreflex amplification, either electrically (Barostim neo) or mechanically (MobiusHD), to improve blood pressure control on short- and long-term with only few side effects, in patients with RH. Two studies regarding unilateral CB resection did not show a significant change in blood pressure. Only limited studies regarding CB modulation showed promising results for transvenous CB ablation, but not for unilateral CB resection. Despite promising results from mostly uncontrolled studies, more evidence regarding the safety and efficacy from ongoing large randomized sham-controlled trials is needed before baroreflex amplification and CB modulation can be implemented in routine clinical practice.

Ventilatory and carotid body responses to acute hypoxia in rats exposed to chronic hypoxia during the first and second postnatal weeks.

Chronic hypoxia (CH) during postnatal development causes a blunted hypoxic ventilatory response (HVR) in neonatal mammals. The magnitude of the HVR generally increases with age, so CH could blunt the HVR by delaying this process. Accordingly, we predicted that CH would have different effects on the respiratory control of neonatal rats if initiated at birth versus initiated later in postnatal development (i.e., after the HVR has had time to mature). Rats had blunted ventilatory and carotid body responses to hypoxia whether CH (12 % O2) occurred for the first postnatal week (P0 to P7) or second postnatal week (P7 to P14). However, if initiated at P0, CH also caused the HVR to retain the "biphasic" shape characteristic of newborn mammals; CH during the second postnatal week did not result in a biphasic HVR. CH from birth delayed the transition from a biphasic HVR to a sustained HVR until at least P9-11, but the HVR attained a sustained (albeit blunted) phenotype by P13-15. Since delayed maturation of the HVR did not completely explain the blunted HVR, we tested the alternative hypothesis that the blunted HVR was caused by an inflammatory response to CH. Daily administration of the anti-inflammatory drug ibuprofen (4 mg kg-1, i.p.) did not alter the effects of CH on the HVR. Collectively, these data suggest that CH blunts the HVR in neonatal rats by impairing carotid body responses to hypoxia and by delaying (but not preventing) postnatal maturation of the biphasic HVR. The mechanisms underlying this plasticity require further investigation.

Contribution of the Retrotrapezoid Nucleus and Carotid Bodies to Hypercapnia- and Hypoxia-induced Arousal from Sleep.

The combination of hypoxia and hypercapnia during sleep produces arousal, which helps restore breathing and normalizes blood gases. Hypercapnia and hypoxia produce arousal in mammals by activating central (pH-sensitive) and peripheral (primarily O2-sensitive) chemoreceptors. The relevant chemoreceptors and the neuronal circuits responsible for arousal are largely unknown. Here we examined the contribution of two lower brainstem nuclei that could be implicated in CO2 and hypoxia-induced arousal: the retrotrapezoid nucleus (RTN), a CO2-responsive nucleus, which mediates the central respiratory chemoreflex; and the C1 neurons, which are hypoxia activated and produce arousal and blood pressure increases when directly stimulated. Additionally, we assessed the contribution of the carotid bodies (CBs), the main peripheral chemoreceptors in mammals, to hypoxia and CO2-induced arousal. In unanesthetized male rats, we tested whether ablation of the RTN, CBs, or C1 neurons affects arousal from sleep and respiratory responses to hypercapnia or hypoxia. The sleep-wake pattern was monitored by EEG and neck EMG recordings and breathing by whole-body plethysmography. The latency to arousal in response to hypoxia or hypercapnia was determined along with changes in ventilation coincident with the arousal. RTN lesions impaired CO2-induced arousal but had no effect on hypoxia-induced arousal. CB ablation impaired arousal to hypoxia and, to a lesser extent, hypercapnia. C1 neuron ablation had no effect on arousal. Thus, the RTN contributes to CO2-induced arousal, whereas the CBs contribute to both hypoxia and CO2-induced arousal. Asphyxia-induced arousal likely requires the combined activation of RTN, CBs and other central chemoreceptors.SIGNIFICANCE STATEMENT Hypercapnia and hypoxia during sleep elicit arousal, which facilitates airway clearing in the case of obstruction and reinstates normal breathing in the case of hypoventilation or apnea. Arousal can also be detrimental to health by interrupting sleep. We sought to clarify how CO2 and hypoxia cause arousal. We show that the retrotrapezoid nucleus, a brainstem nucleus that mediates the effect of brain acidification on breathing, also contributes to arousal elicited by CO2 but not hypoxia. We also show that the carotid bodies contribute predominantly to hypoxia-induced arousal. Lesions of the retrotrapezoid nucleus or carotid bodies attenuate, but do not eliminate, arousal to CO2 or hypoxia; therefore, we conclude that these structures are not the sole trigger of CO2 or hypoxia-induced arousal.

Potential Contribution of Carotid Body-Induced Sympathetic and Renin-Angiotensin System Overflow to Pulmonary Hypertension in Intermittent Hypoxia.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA), featured by chronic intermittent hypoxia (CIH), is an independent risk for systemic hypertension (HTN) and is associated with pulmonary hypertension (PH). The precise mechanisms underlying pulmonary vascular remodeling and PH in OSA are not fully understood. However, it has been suggested that lung tissue hypoxia, oxidative stress, and pro-inflammatory mediators following CIH exposure may contribute to PH. RECENT FINDINGS: New evidences obtained in preclinical OSA models support that an enhanced carotid body (CB) chemosensory reactiveness to oxygen elicits sympathetic and renin-angiotensin system (RAS) overflow, which contributes to HTN. Moreover, the ablation of the CBs abolished the sympathetic hyperactivity and HTN in rodents exposed to CIH. Accordingly, it is plausible that the enhanced CB chemosensory reactivity may contribute to the pulmonary vascular remodeling and PH through the overactivation of the sympathetic-RAS axis. This hypothesis is supported by the facts that (i) CB stimulation increases pulmonary arterial pressure, (ii) denervation of sympathetic fibers in pulmonary arteries reduces pulmonary remodeling and pulmonary arterial hypertension (PAH) in humans, and (iii) administration of angiotensin-converting enzyme (ACE) or blockers of Ang II type 1 receptor (ATR1) ameliorates pulmonary remodeling and PH in animal models. In this review, we will discuss the supporting evidence for a plausible contribution of the CB-induced sympathetic-RAS axis overflow on pulmonary vascular remodeling and PH induced by CIH, the main characteristic of OSA.

Maternal physical activity prevents the overexpression of hypoxia-inducible factor 1-α and cardiorespiratory dysfunction in protein malnourished rats.

Maternal physical activity attenuates cardiorespiratory dysfunctions and transcriptional alterations presented by the carotid body (CB) of rats. Rats performed physical activity and were classified as inactive/active. During gestation and lactation, mothers received either normoprotein (NP-17% protein) or low-protein diet (LP-8% protein). In offspring, biochemical serum levels, respiratory parameters, cardiovascular parameters and the mRNA expression of hypoxia-inducible factor 1-alpha (HIF-1α), tyrosine hydroxylase (TH) and purinergic receptors were evaluate. LP-inactive pups presented lower RF from 1st to 14th days old, and higher RF at 30 days than did NP-inactive and NP-active pups. LP-inactive pups presented with reduced serum protein, albumin, cholesterol and triglycerides levels and an increased fasting glucose level compared to those of NP-inactive and NP-active groups. LP and LP-inactive animals showed an increase in the cardiac variability at the Low-Frequency bands, suggesting a major influence of sympathetic nervous activity. In mRNA analyses, LP-inactive animals showed increased HIF-1α expression and similar expression of TH and purinergic receptors in the CB compared to those of NP groups. All these changes observed in LP-inactive pups were reversed in the pups of active mothers (LP-active). Maternal physical activity is able to attenuate the metabolic, cardiorespiratory and HIF-1α transcription changes induced by protein malnutrition.

Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body.

RATIONALE: Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel. OBJECTIVE: To examine if leptin induces hypertension acting on the CB Trpm7. METHODS AND RESULTS: C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Leprb overexpression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension. CONCLUSIONS: We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.