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At least four mechanisms have been proposed to elucidate how neurons in the retrotrapezoid (RTN) region sense changes in CO2/H+ to regulate breathing (i.e., function as respiratory chemosensors). These mechanisms include: (1) intrinsic neuronal sensitivity to H+ mediated by TASK‐2 and GPR4; (2) paracrine activation of RTN neurons by CO2‐responsive astrocytes (via a purinergic mechanism); (3) enhanced excitatory synaptic input or disinhibition; and (4) CO2‐induced vascular contraction. Although blood flow can influence tissue CO2/H+ levels, there is limited understanding of how control of vascular tone in central CO2 chemosensitive regions might contribute to respiratory output. In this review, we focus on recent evidence that CO2/H+‐induced purinergic‐dependent vasoconstriction in the ventral parafacial region near RTN neurons supports respiratory chemoreception. This mechanism appears to be unique to the ventral parafacial region and opposite to other brain regions, including medullary chemosensor regions, where CO2/H+ elicits vasodilatation. We speculate that this mechanism helps to maintain CO2/H+ levels in the vicinity of RTN neurons, thereby maintaining the drive to breathe. Important next steps include determining whether disruption of CO2/H+ vascular reactivity contributes to or can be targeted to improve breathing problems in disease states, such as Parkinson's disease. What is the topic of this review?The homeostatic mechanism that controls breathing in response to changes in CO2/H+ is exquisitely sensitive, with convergent roles proposed for chemosensory brainstem neurons in the retrotrapezoid nucleus (RTN), their supporting glial cells and the vasculature.What advances does it highlight?We focus on recent evidence that CO2/H+‐induced purinergic‐dependent vasoconstriction in the RTN region supports respiratory chemoreception. This mechanism appears to be unique to the RTN and opposite to other medullary chemosensor regions, where CO2/H+ elicits vasodilatation. We speculate that this mechanism helps to maintain CO2/H+ levels in the vicinity of RTN neurons, thereby maintaining the drive to breathe. [ABSTRACT FROM AUTHOR]

Endothelin‐1 (ET‐1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty‐four men (31 ± 5 years, 26 ± 3 kg/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05–0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 1.00). Bosentan increased plasma ET‐1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (−0.48 ± 0.38 to −0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve −93 ± 108 to −27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET‐1 in control of resting BP, possibly through a chemoreceptor‐mediated mechanism. [ABSTRACT FROM AUTHOR]

Abstract At least four mechanisms have been proposed to elucidate how neurons in the retrotrapezoid (RTN) region sense changes in CO2/H+ to regulate breathing (i.e., function as respiratory chemosensors). These mechanisms include: (1) intrinsic neuronal sensitivity to H+ mediated by TASK‐2 and GPR4; (2) paracrine activation of RTN neurons by CO2‐responsive astrocytes (via a purinergic mechanism); (3) enhanced excitatory synaptic input or disinhibition; and (4) CO2‐induced vascular contraction. Although blood flow can influence tissue CO2/H+ levels, there is limited understanding of how control of vascular tone in central CO2 chemosensitive regions might contribute to respiratory output. In this review, we focus on recent evidence that CO2/H+‐induced purinergic‐dependent vasoconstriction in the ventral parafacial region near RTN neurons supports respiratory chemoreception. This mechanism appears to be unique to the ventral parafacial region and opposite to other brain regions, including medullary chemosensor regions, where CO2/H+ elicits vasodilatation. We speculate that this mechanism helps to maintain CO2/H+ levels in the vicinity of RTN neurons, thereby maintaining the drive to breathe. Important next steps include determining whether disruption of CO2/H+ vascular reactivity contributes to or can be targeted to improve breathing problems in disease states, such as Parkinson's disease.

Introduction: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI. Methods: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0%CO2) and normoxic-hypercapnia (21%O2, 5%CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. Results: Therewere no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1mth post-bleo. However, at D7 post-bleo, themale rats exhibited a higher AHI than female rats. Bothmale and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes. Conclusion: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders. [ABSTRACT FROM AUTHOR]

The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure. [ABSTRACT FROM AUTHOR]

We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty‐six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (−19 ± 16 bpm) than normocapnic normoxic apneas (−11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (−19 ± 15 bpm; p = 0.999) and hypercapnic apneas (−14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (−11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (−9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia. [ABSTRACT FROM AUTHOR]

Abstract Endothelin‐1 (ET‐1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty‐four men (31 ± 5 years, 26 ± 3 kg/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05–0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 1.00). Bosentan increased plasma ET‐1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (−0.48 ± 0.38 to −0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve −93 ± 108 to −27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET‐1 in control of resting BP, possibly through a chemoreceptor‐mediated mechanism.

The article delves into the impact of disrupting the peripheral chemoreflex on brachial blood flow in individuals with treated hypertension. Researchers discovered that blocking the chemoreflex with low-dose dopamine led to increased blood flow and vascular conductance during exercise. The study suggests that those with hypertension may have heightened chemoreflex sensitivity affecting blood flow to muscles during exercise. Future research should address limitations like the absence of a healthy control group and the narrow focus on handgrip exercise to enhance the findings' generalizability. The article also discusses the effects of exercise pressor reflex and isocapnic hypoxia on brachial blood flow in individuals with hypertension, as well as the use of low-dose dopamine and rhythmic handgrip contraction to regulate blood flow. Additional information can be found in the online Supporting Information section of the article. [Extracted from the article]

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ~52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline. [ABSTRACT FROM AUTHOR]

IntroductionSex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI.MethodsALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point.ResultsThere were no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1 mth post-bleo. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats. Both male and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes.ConclusionA sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders.

Abstract We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty‐six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (−19 ± 16 bpm) than normocapnic normoxic apneas (−11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (−19 ± 15 bpm; p = 0.999) and hypercapnic apneas (−14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (−11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (−9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia.

The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure.

Swimmer athletes showed a decreased ventilatory response and reduced sympathetic activation during peripheral hypoxic chemoreflex stimulation. Based on these observations, we hypothesized that swimmers develop a diminished cardiorespiratory coupling due to their decreased hypoxic peripheral response. To resolve this hypothesis, we conducted a study using coherence time‐varying analysis to assess the cardiorespiratory coupling in swimmer athletes. We recruited 12 trained swimmers and 12 control subjects for our research. We employed wavelet time‐varying spectral coherence analysis to examine the relationship between the respiratory frequency (Rf) and the heart rate (HR) time series during normoxia and acute chemoreflex activation induced by five consecutive inhalations of 100% N2. Comparing swimmers to control subjects, we observed a significant reduction in the hypoxic ventilatory responses to N2 in swimmers (0.012 ± 0.001 vs. 0.015 ± 0.001 ΔVE/ΔVO2, and 0.365 ± 0.266 vs. 1.430 ± 0.961 ΔVE/ΔVCO2/ΔSpO2, both p < 0.001, swimmers vs. control, respectively). Furthermore, the coherence at the LF cutoff during hypoxia was significantly lower in swimmers compared to control subjects (20.118 ± 3.502 vs. 24.935 ± 3.832 area under curve [AUC], p < 0.012, respectively). Our findings strongly indicate that due to their diminished chemoreflex control, swimmers exhibited a substantial decrease in cardiorespiratory coupling during hypoxic stimulation. [ABSTRACT FROM AUTHOR]

Uncontrolled hypertension drives the global burden of increased cardiovascular disease (CVD) morbidity and mortality. Although high blood pressure (BP) is treatable and preventable, only half of the patients with hypertension undergoing treatment have their BP controlled. The failure of polypharmacy to attain adequate BP control may be due to a lack of physiological response, however, medication non-adherence and clinician inertia to increase treatment intensity are critical factors associated with poor hypertension management. The long-time medication titration, lifelong drug therapy, and often multi-drug treatment strategy are frustrating when the BP goal is not achieved, leading to increased CVD risk and a substantial burden on the healthcare system. Growing evidence indicates that neurohumoral activation is critical in initiating and maintaining elevated BP and its adverse consequences. Over the past decades, device-based therapies targeting the mechanisms underlying hypertension pathophysiology have been extensively studied. Among these, robust clinical experience for hypertension management exists for renal denervation (RDN) and baroreflex activation therapy (BAT), carotid body denervation (CBD), central arteriovenous anastomosis, and to a lesser extent, deep brain stimulation. Future studies are warranted to define the role of device-based approaches as an alternative or adjunctive treatment option to treat hypertension. Systemic hypertension is a growing contributor to global disease burden and premature cause of death worldwide. The percentage of patients achieving target BP levels remains largely inadequate. Hypertension is characterised by activation of the sympathetic nervous system, with the magnitude depending on age and the disease severity. Device-based interventions have been extensively studied to directly target the relevant sympathetic neural pathophysiological mechanisms involved in BP control. Modulation of the chronic sympathetic outflow with CBD or BAT shows promise for the treatment of poorly controlled hypertension in addition to antihypertensive medicines. The BP response to device-based therapies appears variable and cannot be predicted before the procedure. Until more robust evidence related to patient selection, procedural and technical aspects is available, chemoreflex and baroreflex neuromodulation therapy should be restricted to randomised sham-controlled trials performed in experienced centres. [ABSTRACT FROM AUTHOR]

Normobaric hyperoxia stimulates ventilation (V_ E) in a time- and dose-dependent manner. Whether this occurs via an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors remains unclear. We measured the ventilatory response to hyperoxic CO2 rebreathing with O2 clamped at increasingly higher pressures. We hypothesized that the V_ E versus PCO2 relationship is fixed and independent of PO2. On four occasions, 20 participants (10 F; mean ± SD age: 24 ± 4 yr) performed three repetitions of modified rebreathing in four, randomized, isoxic-hyperoxic conditions: mild: PO2=150 mmHg; moderate: PO2=200 mmHg; high: PO2=300 mmHg; and extreme: PO2-700 mmHg. Breath-by-breath V_ E, end-tidal CO2 (PETCO2), and O2 (PETO2) were measured by pneumotach and gas analyzer. For each rebreathing trial, the PETCO2 at which V_ E rose was identified as the ventilatory recruitment threshold (VRT, mmHg), data before VRT provided baseline V_ E (V_ EBSL, L·min-1) and the slope of the response above VRT gave central chemoreflex sensitivity (V_ ES, L·min-1·mmHg-1). For each condition, VRT, V_ EBSL, and V_ ES from liketrials were averaged, and repeated measures ANOVA assessed between-condition differences. There were no effects of PETO2 on V_ EBSL (mild: 7.4 ± 4.2 L·min-1; moderate: 6.9 ± 4.2 L·min-1; high: 6.5±3.7 L·min-1; extreme: 7.5 ± 2.7 L·min-1; P = 0.24), VRT (mild: 42.8 ± 3.2 mmHg; moderate: 42.5 ± 2.7 mmHg; high: 42.3 ± 2.7 mmHg; extreme: 41.8 ± 2.7 mmHg; P = 0.07), or V_ ES (mild: 4.88±2.6 L·min-1·mmHg-1; moderate: 4.76 ± 2.2 L·min-1·mmHg-1; high: 4.81±2.3 L·min-1·mmHg-1; extreme: 4.39 ± 1.9 L·min-1·mmHg-1; P = 0.41). The V_ E-PCO2 relationship is unaltered across a range of mild to extreme PO2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity. [ABSTRACT FROM AUTHOR]

Abstract Swimmer athletes showed a decreased ventilatory response and reduced sympathetic activation during peripheral hypoxic chemoreflex stimulation. Based on these observations, we hypothesized that swimmers develop a diminished cardiorespiratory coupling due to their decreased hypoxic peripheral response. To resolve this hypothesis, we conducted a study using coherence time‐varying analysis to assess the cardiorespiratory coupling in swimmer athletes. We recruited 12 trained swimmers and 12 control subjects for our research. We employed wavelet time‐varying spectral coherence analysis to examine the relationship between the respiratory frequency (Rf) and the heart rate (HR) time series during normoxia and acute chemoreflex activation induced by five consecutive inhalations of 100% N2. Comparing swimmers to control subjects, we observed a significant reduction in the hypoxic ventilatory responses to N2 in swimmers (0.012 ± 0.001 vs. 0.015 ± 0.001 ΔVE/ΔVO2, and 0.365 ± 0.266 vs. 1.430 ± 0.961 ΔVE/ΔVCO2/ΔSpO2, both p

Uncontrolled hypertension drives the global burden of increased cardiovascular disease (CVD) morbidity and mortality. Although high blood pressure (BP) is treatable and preventable, only half of the patients with hypertension undergoing treatment have their BP controlled. The failure of polypharmacy to attain adequate BP control may be due to a lack of physiological response, however, medication non-adherence and clinician inertia to increase treatment intensity are critical factors associated with poor hypertension management. The long-time medication titration, lifelong drug therapy, and often multi-drug treatment strategy are frustrating when the BP goal is not achieved, leading to increased CVD risk and a substantial burden on the healthcare system. Growing evidence indicates that neurohumoral activation is critical in initiating and maintaining elevated BP and its adverse consequences. Over the past decades, device-based therapies targeting the mechanisms underlying hypertension pathophysiology have been extensively studied. Among these, robust clinical experience for hypertension management exists for renal denervation (RDN) and baroreflex activation therapy (BAT), carotid body denervation (CBD), central arteriovenous anastomosis, and to a lesser extent, deep brain stimulation. Future studies are warranted to define the role of device-based approaches as an alternative or adjunctive treatment option to treat hypertension.

Rationale: Although sleep apnea occurs in over 50% of individuals with Alzheimer's Disease (AD) or related tauopathies, little is known concerning the potential role of tauopathy in the pathogenesis of sleep apnea. Here, we tested the hypotheses that, during presumptive sleep, a murine model of tauopathy (rTg4510) exhibits: 1) increased breathing instability; 2) impaired chemoreflex function; and 3) exacerbation of these effects with tauopathy progression. Methods: rTg4510 mice initially develop robust tauopathy in the hippocampus and cortex, and eventually progresses to the brainstem. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh, and hypopnea incidence weremeasured in young adult (5-6months; n = 10-14/group) and aged (13-15 months; n = 22-24/group) nontransgenic (nTg), monogenic control tetracycline transactivator, and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep (i.e., eyes closed, curled/laying posture, stable breathing for >200 breaths) while breathing room air (21% O2). Peripheral and central chemoreceptor sensitivity were assessed with transient exposures (5min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2 in 21% O2), respectively. Results: We report significant increases in Type I, II, and III apneas (all p < 0.001), sighs (p = 0.002) and hypopneas (p < 0.001) in aged rTg4510 mice, but only Type III apneas in young adult rTg4510 mice (p < 0.001) versus age-matched nTg controls. Aged rTg4510 mice exhibited profound chemoreflex impairment versus age matched nTg and tTA mice. In rTg4510 mice, breathing frequency, tidal volume and minute ventilation were not affected by hyperoxic or hypercapnic challenges, in striking contrast to controls. Histological examination revealed hyperphosphorylated tau in brainstem regions involved in the control of breathing (e.g., pons, medullary respiratory column, retrotrapezoid nucleus) in aged rTg4510 mice. Neither breathing instability nor hyperphosphorylated tau in brainstem tissues were observed in young adult rTg4510 mice. Conclusion: Older rTg4510 mice exhibit profound impairment in the neural control of breathing, with greater breathing instability and near absence of oxygen and carbon-dioxide chemoreflexes. Breathing impairments paralleled tauopathy progression into brainstem regions that control breathing. These findings are consistent with the idea that tauopathy per se undermines chemoreflexes and promotes breathing instability during sleep. [ABSTRACT FROM AUTHOR]

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv‐aCO2)] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv‐aCO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end‐tidal forcing (ETF) protocols (termed: ETF‐1 and ETF‐2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF‐1 (n = 11) and ETF‐2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv‐aCO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF‐1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF‐2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv‐aCO2 difference did not change during the rebreathing protocol (−0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF‐1 (−3.9 ± 1.1 mmHg; P < 0.001) and ETF‐2 (−3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv‐aCO2 difference during ETF (−0.095 ± 0.089 mmHg cm−1 s−1; P = 0.001) but not during rebreathing (−0.028 ± 0.045 mmHg · cm−1 · s−1; P = 0.067). These findings suggest that, although the Pjv‐aCO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2. Key points: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow.We assessed these assumptions by measuring arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end‐tidal forcing.The difference between arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end‐tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end‐tidal forcing but not rebreathing.These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings. [ABSTRACT FROM AUTHOR]

The cardiovascular response to exercise is largely determined by neurocirculatory control mechanisms that help to raise blood pressure and modulate vascular resistance which, in concert with regional vasodilatory mechanisms, promote blood flow to active muscle and organs. These neurocirculatory control mechanisms include a feedforward mechanism, known as central command, and three feedback mechanisms, namely, 1) the baroreflex, 2) the exercise pressor reflex, and 3) the arterial chemoreflex. The hemodynamic consequences of these control mechanisms result from their influence on the autonomic nervous system and subsequent alterations in cardiac output and vascular resistance. Although stimulation of the baroreflex inhibits sympathetic outflow and facilitates parasympathetic activity, central command, the exercise pressor reflex, and the arterial chemoreflex facilitate sympathetic activation and inhibit parasympathetic drive. Despite considerable understanding of the cardiovascular consequences of each of these mechanisms in isolation, the circulatory impact of their interaction, which occurs when various control systems are simultaneously activated (e.g., during exercise at altitude), has only recently been recognized. Although aging and cardiovascular disease (e.g., heart failure, hypertension) have both been recognized to alter the hemodynamic consequences of these regulatory systems, this review is limited to provide a brief overview on the action and interaction of neurocirculatory control mechanisms in health. [ABSTRACT FROM AUTHOR]

Rationale: Although sleep apnea occurs in over 50% of individuals with Alzheimer’s Disease (AD) or related tauopathies, little is known concerning the potential role of tauopathy in the pathogenesis of sleep apnea. Here, we tested the hypotheses that, during presumptive sleep, a murine model of tauopathy (rTg4510) exhibits: 1) increased breathing instability; 2) impaired chemoreflex function; and 3) exacerbation of these effects with tauopathy progression.Methods: rTg4510 mice initially develop robust tauopathy in the hippocampus and cortex, and eventually progresses to the brainstem. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh, and hypopnea incidence were measured in young adult (5–6 months; n = 10–14/group) and aged (13–15 months; n = 22–24/group) non-transgenic (nTg), monogenic control tetracycline transactivator, and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep (i.e., eyes closed, curled/laying posture, stable breathing for >200 breaths) while breathing room air (21% O2). Peripheral and central chemoreceptor sensitivity were assessed with transient exposures (5 min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2 in 21% O2), respectively.Results: We report significant increases in Type I, II, and III apneas (all p < 0.001), sighs (p = 0.002) and hypopneas (p < 0.001) in aged rTg4510 mice, but only Type III apneas in young adult rTg4510 mice (p < 0.001) versus age-matched nTg controls. Aged rTg4510 mice exhibited profound chemoreflex impairment versus age matched nTg and tTA mice. In rTg4510 mice, breathing frequency, tidal volume and minute ventilation were not affected by hyperoxic or hypercapnic challenges, in striking contrast to controls. Histological examination revealed hyperphosphorylated tau in brainstem regions involved in the control of breathing (e.g., pons, medullary respiratory column, retrotrapezoid nucleus) in aged rTg4510 mice. Neither breathing instability nor hyperphosphorylated tau in brainstem tissues were observed in young adult rTg4510 mice.Conclusion: Older rTg4510 mice exhibit profound impairment in the neural control of breathing, with greater breathing instability and near absence of oxygen and carbon-dioxide chemoreflexes. Breathing impairments paralleled tauopathy progression into brainstem regions that control breathing. These findings are consistent with the idea that tauopathy per se undermines chemoreflexes and promotes breathing instability during sleep.

Introduction: Sleep apnea (SA) is highly prevalent in patients with chronic kidney disease and may contribute to the development and/or progression of this condition. Previous studies suggest that dysregulation of renal hemodynamics and oxygen flux may play a key role in this process. The present study sought to determine how chronic intermittent hypoxia (CIH) associated with SA affects regulation of renal artery blood flow (RBF), renal microcirculatory perfusion (RP), glomerular filtration rate (GFR), and cortical and medullary tissue PO2 as well as expression of genes that could contribute to renal injury. We hypothesized that normoxic RBF and tissue PO2 would be reduced after CIH, but that GFR would be increased relative to baseline, and that RBF, RP, and tissue PO2 would be decreased to a greater extent in CIH vs. sham during exposure to intermittent asphyxia (IA, FiO2 0.10/FiCO2 0.03). Additionally, we hypothesized that gene programs promoting oxidative stress and fibrosis would be activated by CIH in renal tissue.Methods: All physiological variables were measured at baseline (FiO2 0.21) and during exposure to 10 episodes of IA (excluding GFR).Results: GFR was higher in CIH-conditioned vs. sham (p < 0.05), whereas normoxic RBF and renal tissue PO2 were significantly lower in CIH vs. sham (p < 0.05). Reductions in RBF, RP, and renal tissue PO2 during IA occurred in both groups but to a greater extent in CIH (p < 0.05). Pro-oxidative and pro-fibrotic gene programs were activated in renal tissue from CIH but not sham.Conclusion: CIH adversely affects renal hemodynamic regulation and oxygen flux during both normoxia and IA and results in changes in renal tissue gene expression. [ABSTRACT FROM AUTHOR]

The classic peripheral chemoreflex response is a critical homeostatic mechanism. In healthy individuals, appropriate chemoreflex responses are triggered by acute activation of the carotid body - the principal chemosensory organ in mammals. However, the aberrant chronic activation of the carotid body can drive the elevated sympathetic activity underlying cardio-respiratory diseases such as hypertension, diabetes and heart failure. Carotid body resection induces intolerable side effects and so understanding how to modulate carotid body output without removing it, and whilst maintaining the physiological chemoreflex response, represents the next logical next step in the development of effective clinical interventions. By definition, excessive carotid body output must result from altered intra-carotid body inter-cellular communication. Alongside the canonical synaptic transmission from glomus cells to petrosal afferents, many other modes of information exchange in the carotid body have been identified, for example bidirectional signalling between type I and type II cells via ATP-induced ATP release, as well as electrical communication via gap junctions. Thus, herein we review the carotid body as an integrated circuit, discussing a variety of different inter-cellular signalling mechanisms and highlighting those that are potentially relevant to its pathological hyperactivity in disease with the aim of identifying novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Introduction: Sleep apnea (SA) is highly prevalent in patients with chronic kidney disease and may contribute to the development and/or progression of this condition. Previous studies suggest that dysregulation of renal hemodynamics and oxygen flux may play a key role in this process. The present study sought to determine how chronic intermittent hypoxia (CIH) associated with SA affects regulation of renal artery blood flow (RBF), renal microcirculatory perfusion (RP), glomerular filtration rate (GFR), and cortical and medullary tissue PO2 as well as expression of genes that could contribute to renal injury. We hypothesized that normoxic RBF and tissue PO2 would be reduced after CIH, but that GFR would be increased relative to baseline, and that RBF, RP, and tissue PO2 would be decreased to a greater extent in CIH vs. sham during exposure to intermittent asphyxia (IA, FiO2 0.10/FiCO2 0.03). Additionally, we hypothesized that gene programs promoting oxidative stress and fibrosis would be activated by CIH in renal tissue.Methods: All physiological variables were measured at baseline (FiO2 0.21) and during exposure to 10 episodes of IA (excluding GFR).Results: GFR was higher in CIH-conditioned vs. sham (p < 0.05), whereas normoxic RBF and renal tissue PO2 were significantly lower in CIH vs. sham (p < 0.05). Reductions in RBF, RP, and renal tissue PO2 during IA occurred in both groups but to a greater extent in CIH (p < 0.05). Pro-oxidative and pro-fibrotic gene programs were activated in renal tissue from CIH but not sham.Conclusion: CIH adversely affects renal hemodynamic regulation and oxygen flux during both normoxia and IA and results in changes in renal tissue gene expression.

Noninvasive studies of the central respiratory control are of key importance to understanding the physiopathology of central apneas and periodic breathing. The study of the brainstem and cortical-subcortical centers may be achieved by using functional magnetic resonance imaging (fMRI) during gas challenges (hypercapnia). Nonetheless, disentangling specific from non-specific effects of hypercapnia in fMRI is a major methodological challenge, as CO2 vasodilatory effects and physiological noise do strongly impact the BOLD signal. This is particularly true in deep brainstem regions where chemoreceptors and rhythm pattern generators are located. One possibility to detect the true neural-related activation is given by the presence of a supralinear relation between CO2 changes and BOLD signal related to neurovascular coupling in overactive neural areas. Here, we test this hypothesis of a supralinear relationship between CO2 and BOLD signal, as a marker of specificity. We employed a group-masked Independent Component Analysis (mICA) approach and we compared activation levels across different mixtures of inspired CO2 using polynomial regression. Our results highlight key nodes of the central breathing control network, also including dorsal pontine and medullary regions. The suggested methodology allows a voxel-wise parametrization of the response, targeting an issue that affects many fMRI studies employing hypercapnic challenges. [ABSTRACT FROM AUTHOR]

Bioelectronic medicine is a novel field in modern medicine based on the specific neuronal stimulation to control organ function, cardiovascular, and immune homeostasis. However, most studies addressing neuromodulation of the immune system have been conducted on anesthetized animals, which can affect the nervous system and neuromodulation. Here, we review recent studies involving conscious experimental rodents (rats and mice) to better understand the functional organization of neural control of immune homeostasis. We highlight typical experimental models of cardiovascular regulation, such as electrical activation of the aortic depressor nerve or the carotid sinus nerve, bilateral carotid occlusion, the Bezold-Jarisch reflex, and intravenous administration of the bacterial endotoxin lipopolysaccharide. These models have been used to investigate the relationship between neuromodulation of the cardiovascular and immune systems in conscious rodents (rats and mice). These studies provide critical information about the neuromodulation of the immune system, particularly the role of the autonomic nervous system, i.e., the sympathetic and parasympathetic branches acting both centrally (hypothalamus, nucleus ambiguus, nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla), and peripherally (particularly spleen and adrenal medulla). Overall, the studies in conscious experimental models have certainly highlighted to the reader how the methodological approaches used to investigate cardiovascular reflexes in conscious rodents (rats and mice) can also be valuable for investigating the neural mechanisms involved in inflammatory responses. The reviewed studies have clinical implications for future therapeutic approaches of bioelectronic modulation of the nervous system to control organ function and physiological homeostasis in conscious physiology. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We assessed the test–retest variability of respiratory chemoreflex characterization by Duffin's modified rebreathing method and explored whether signal averaging of repeated trials improves confidence in parameter estimation.What is the main finding and its importance?Modified rebreathing is a reproducible method to characterize responses of central and peripheral respiratory chemoreflexes. Signal averaging of multiple repeated tests minimizes within‐ and between‐test variability, improves the confidence of chemoreflex characterization and reduces the minimal change in parameters required to establish an effect. Future experiments that apply this method might benefit from signal averaging to improve its discriminatory effect. We assessed the test–retest variability of central and peripheral respiratory chemoreflex characterization by Duffin's modified rebreathing method and explored whether signal averaging of repeated trials improves confidence in parameter estimation. Over four laboratory visits, 13 participants (mean ± SD age, 25 ± 5 years) performed six repetitions of modified rebreathing in isoxic–hypoxic conditions [end‐tidal PO2${P_{{{\rm{O}}_{\rm{2}}}}}$ (PET,O2${P_{{\rm{ET,}}{{\rm{O}}_{\rm{2}}}}}$) = 50 mmHg] and isoxic–hyperoxic conditions (PET,O2${P_{{\rm{ET,}}{{\rm{O}}_{\rm{2}}}}}$ = 150 mmHg). End‐tidal PCO2${P_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$ (PET,CO2${P_{{\rm{ET,C}}{{\rm{O}}_{\rm{2}}}}}$), PET,O2${P_{{\rm{ET,}}{{\rm{O}}_{\rm{2}}}}}$ and minute ventilation (V̇$\dot {\rm V}$E) were measured breath‐by‐breath, by gas analyser and pneumotachograph. The V̇$\dot {\rm V}$E versus PET,CO2${P_{{\rm{ET,C}}{{\rm{O}}_{\rm{2}}}}}$ relationships were fitted with a piecewise model to estimate the ventilatory recruitment threshold (VRT) and the slope above the VRT (V̇$\dot {\rm V}$ES). Breath‐by‐breath data from the three within‐ and between‐day trials were averaged using two approaches [simple average (fit then average) and ensemble average (average then fit)] and compared with a single‐trial fit. Variability was assessed by intraclass correlation (ICC) and coefficient of variance (CV), and the minimal detectable change was computed for each approach using two independent sets of three trials. Within days, the VRT and V̇$\dot {\rm V}$ES exhibited excellent test–retest variability in both hyperoxic conditions (VRT: ICC = 0.965, CV = 2.3%; V̇$\dot {\rm V}$ES: ICC = 0.932, CV = 15.5%) and hypoxic conditions (VRT: ICC = 0.970, CV = 2.9%; V̇$\dot {\rm V}$ES: ICC = 0.891, CV = 17.2%). Between‐day reproducibility was also excellent (hyperoxia, VRT: ICC = 0.930, CV = 2.2%; V̇$\dot {\rm V}$ES: ICC = 0.918, CV = 14.2%; and hypoxia, VRT: ICC = 0.940, CV = 3.0%; V̇$\dot {\rm V}$ES: ICC = 0.880, CV = 18.1%). Compared with a single‐trial fit, there were no differences in VRT or V̇$\dot {\rm V}$ES using the simple average or ensemble average approaches; however, ensemble averaging reduced the minimal detectable change for V̇$\dot {\rm V}$ES from 2.95 to 1.39 L min−1 mmHg−1 (hyperoxia) and from 3.64 to 1.82 L min−1 mmHg−1 (hypoxia). Single trials of modified rebreathing are reproducible; however, signal averaging of repeated trials improves confidence in parameter estimation. [ABSTRACT FROM AUTHOR]

Introduction: In the most recent recommendations of the International Federation of Gynecology and Obstetrics (FIGO), a chapter was dedicated to the physiological approach and to the description of fetal mechanisms developed to respond to hypoxia. Our objective was to classify the type of hypoxia in the case of metabolic acidemia and to describe the order of appearance of fetal heart rate abnormalities in cases of gradually evolving hypoxia. Material and methods: 132 neonates born between 2018 and 2020 with acidemia were included. We excluded preterm birth, fetuses with congenital anomaly and twin pregnancies. Intrapartum cardiotocography traces were assigned to one of these four types of labor hypoxia: acute, subacute, gradually evolving and chronic hypoxia. For gradually evolving hypoxia, fetal heart rate abnormalities were described according to the FIGO classification. Results: 36 cardiotocography traces (27.3%) were classified as acute hypoxia, 14 (10.6%) as subacute hypoxia, and 3 (3.2%) as chronic hypoxia; gradually evolving hypoxia occurred in 62 cases (47%). In 77.4% of cases of gradually evolving hypoxia, deceleration was the first anomaly to appear, with loss of variability and bradycardia appearing later. Increased fetal heart rate was observed immediately after late deceleration in 46.8% of cases and was followed by a loss of variability or saltatory rhythm in 37.1% of cases. Conclusions: In cases of metabolic acidemia at term, the most frequent situation observed was gradually evolving hypoxia, with an initial occurrence of decelerations. The sequence of fetal heart rate modifications was variable. [ABSTRACT FROM AUTHOR]

Background: Brief hypoxic exposures are increasingly applied as interventions for aging-related conditions. To optimize the therapeutic impact of hypoxia, knowledge of the sex-related differences in physiological responses to hypoxia is essential. This study compared hypoxia-induced hypoxemic responses in elderly men and women. Methods: Seven elderly men (70.3 ± 6.0 years old) and nine women (69.4 ± 5.5 years old) breathed 10% O2 for 5 min while arterial (SaO2; transcutaneous photoplethysmography) and cerebral tissue O2 saturation (ScO2; near-infrared spectroscopy), ventilatory frequency, tidal volume, minute-ventilation, and partial pressures of end-tidal O2 (PETO2) and CO2 (mass spectrometry) were continuously monitored. Cerebral tissue oxygen extraction fraction (OEF) equaled (SaO2–ScO2)/SaO2. Results: During 5 min hypoxia SaO2 fell from 97.0 ± 0.8% to 80.6 ± 4.6% in the men and from 96.3 ± 1.4% to 72.6 ± 4.0% in the women. The slope ΔSaO2/min was steeper in the women than the men (−4.71 ± 0.96 vs. −3.24 ± 0.76%/min; p = 0.005). Although SaO2 fell twice as sharply per unit decrease in PETO2 in the women than the men (−1.13 ± 0.11 vs. −0.54 ± 0.06%/mmHg; p = 0.003), minute-ventilation per unit hypoxemia increased less appreciably in the women (−0.092 ± 0.014 vs. −0.160 ± 0.021 L/min/%; p = 0.023). OEF fell with hypoxia duration in the women, but remained stable in the men. Conclusion: During 5 min hypoxic breathing, elderly women experience more intense hypoxemia and reduced chemoreflex sensitivity vs. their male counterparts, which may lower OEF stability in women despite augmented O2 dissociation from hemoglobin during hypoxia. These sex-related differences merit attention when implementing brief hypoxic exposures for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Aims: Intravenous iron therapy can improve symptoms in patients with heart failure, anaemia and iron deficiency. The mechanisms underlying such an improvement might involve chemoreflex sensing and nocturnal breathing patterns. Methods and results: Patients with heart failure, reduced left ventricular ejection fraction, anaemia (haemoglobin <13 g/dl in men; <12 g/dl in women) and iron deficiency (ferritin <100 or 100–299 μg/L with transferrin saturation <20%) were 2:1 randomized to patient‐tailored intravenous ferric carboxymaltose dose or placebo. Chemoreflex sensitivity cardiorespiratory sleep study, symptom assessment and cardiopulmonary exercise test were performed before and 2 weeks after the last treatment dose. Fifty‐eight patients (38 active arm/20 placebo arm) completed the study. Intravenous iron was associated with less severe symptoms, higher haemoglobin (12.5 ± 1.4 vs. 11.7 ± 1.0 mg/dl, p < 0.05) and improved haematinic parameters. Ferric carboxymaltose improved the central hypercapnic ventilatory response (−25.8%, p < 0.05 vs. placebo), without changes in peripheral chemosensitivity. In particular, the central hypercapnic ventilatory responses passed from 4.6 ± 6.5 to 2.9 ± 2.9 L/min/mmHg after ferric carboxymaltose and from 4.4 ± 4.6 to 4.6 ± 3.9 L/min/mmHg after placebo (ptreatment*condition = 0.046). In patients presenting with sleep‐related breathing disorder, apnoea–hypopnoea index was reduced with active treatment as compared to placebo (12 ± 11 vs. 19 ± 13 events/h, p < 0.05). After ferric carboxymaltose, but not after placebo, both peak oxygen uptake (VO2) increased (Δ1.1 ± 2.0 ml/kg/min, p < 0.05) and VO2/workload slope was steeper (Δ0.67 ± 1.7 L/min/W, p < 0.01). Conclusions: Intravenous ferric carboxymaltose improves the hypercapnic ventilatory response and sleep‐related breathing disorders in patients with heart failure, anaemia and iron deficiency. These newly described findings, along with improved oxygen delivery to exercising muscles, likely contribute to the favourable effects of ferric carboxymaltose in anaemic patients with heart failure. [ABSTRACT FROM AUTHOR]

In the rat, the activity of laryngeal adductor muscles, the crural diaphragm, and sympathetic vasomotor neurons is entrained to the post-inspiratory (post-I) phase of the respiratory cycle, a mechanism thought to enhance cardiorespiratory efficiency. The identity of the central neurons responsible for transmitting respiratory activity to these outputs remains unresolved. Here we explore the contribution of the Kölliker-Fuse/Parabrachial nuclei (KF-PBN) in the generation of post-I activity in vagal and sympathetic outputs under steady-state conditions and during acute hypoxemia, a condition that potently recruits post-I activity. In artificially ventilated, vagotomised and urethane-anesthetised rats, bilateral KF-PBN inhibition by microinjection of the GABA A receptor agonist isoguvacine evoked stereotypical responses on respiratory pattern, characterised by a reduction in phrenic nerve burst amplitude, a modest lengthening of inspiratory time, and an increase in breath-to-breath variability, while post-I vagal nerve activity was abolished and post-I sympathetic nerve activity diminished. During acute hypoxemia, KF-PBN inhibition attenuated tachypnoeic responses and completely abolished post-I vagal activity while preserving respiratory-sympathetic coupling. Furthermore, KF-PBN inhibition disrupted the decline in respiratory frequency that normally follows resumption of oxygenation. These findings suggest that the KF-PBN is a critical hub for the distribution of post-I activities to vagal and sympathetic outputs and is an important contributor to the dynamic adjustments to respiratory patterns that occur in response to acute hypoxia. While KF-PBN appears essential for post-I vagal activity, it only partially contributes to post-I sympathetic nerve activity, suggesting the contribution of multiple neural pathways to respiratory-sympathetic coupling.

Acute lung injury (ALI) induces inflammation that disrupts the normal alveolar-capillary endothelial barrier which impairs gas exchange to induce hypoxemia that reflexively increases respiration. The neural mechanisms underlying the respiratory dysfunction during ALI are not fully understood. The purpose of this study was to investigate the role of the chemoreflex in mediating abnormal ventilation during acute (early) and recovery (late) stages of ALI. We hypothesized that the increase in respiratory rate (fR) during post-ALI is mediated by a sensitized chemoreflex. ALI was induced in male Sprague-Dawley rats using a single intra-tracheal injection of bleomycin (Bleo: low-dose = 1.25 mg/Kg or high-dose = 2.5 mg/Kg) (day 1) and respiratory variables- fR, Vt (Tidal Volume), and VE (Minute Ventilation) in response to 10% hypoxia (10% O2, 0% CO2) and 5% hypercapnia/21% normoxia (21% O2, 5% CO2) were measured weekly from W0-W4 using whole-body plethysmography (WBP). Our data indicate sensitization (∆fR = 93 ± 31 bpm, p < 0.0001) of the chemoreflex at W1 post-ALI in response to hypoxic/hypercapnic gas challenge in the low-dose bleo (moderate ALI) group and a blunted chemoreflex (∆fR = −0.97 ± 42 bpm, p < 0.0001) at W1 post-ALI in the high-dose bleo (severe ALI) group. During recovery from ALI, at W3-W4, both low-dose and high-dose groups exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia. We then hypothesized that the blunted chemoreflex at W1 post-ALI in the high-dose bleo group could be due to near maximal tonic activation of chemoreceptors, called the “ceiling effect”. To test this possibility, 90% hyperoxia (90% O2, 0% CO2) was given to bleo treated rats to inhibit the chemoreflex. Our results showed no changes in fR, suggesting absence of the tonic chemoreflex activation in response to hypoxia at W1 post-ALI. These data suggest that during the acute stage of moderate (low-dose bleo) and severe (high-dose bleo) ALI, chemoreflex activity trends to be slightly sensitized and blunted, respectively while it becomes significantly sensitized during the recovery stage. Future studies are required to examine the molecular/cellular mechanisms underlying the time-course changes in chemoreflex sensitivity post-ALI.

From a physiological point of view, peripheral chemoreceptors (PCh) are the main sensors of hypoxia in mammals and are responsible for adaptation to hypoxic conditions. Their stimulation causes hyperventilation—to increase oxygen uptake and increases sympathetic output in order to counteract hypoxia-induced vasodilatation and redistribute the oxygenated blood to critical organs. While this reaction promotes survival in acute settings it may be devastating when long-lasting. The permanent overfunctionality of PCh is one of the etiologic factors and is responsible for the progression of sympathetically-mediated diseases. Thus, the deactivation of PCh has been proposed as a treatment method for these disorders. We review here physiological background and current knowledge regarding the influence of widely prescribed medications on PCh acute and tonic activities. [ABSTRACT FROM AUTHOR]

Heart failure with reduced ejection fraction is associated with increased exercise intolerance, morbidity, and mortality. Importantly, exercise intolerance in heart failure with reduced ejection fraction is a key factor limiting patient quality of life and survival. Exercise intolerance in heart failure with reduced ejection fraction stems from a multi-organ failure to maintain homeostasis at rest and during exercise, including the heart, skeletal muscle, and autonomic nervous system, lending itself to a system constantly trying to "catch-up". Hemodynamic control during exercise is regulated primarily by the autonomic nervous system, whose operation, in turn, is partly regulated via reflexive information from exercise-stimulated receptors throughout the body (e.g., arterial baroreflex, central and peripheral chemoreceptors, and the muscle metabo- and mechanoreflexes). Persons with heart failure with reduced ejection fraction exhibit malfunctioning autonomic reflexes, which lead to exaggerated sympathoexcitation and attenuated parasympathetic tone. Chronic elevation of sympathetic activity is associated with increased morbidity and mortality. In this review, we provide an overview of how each main exercise-related autonomic reflex is changed in heart failure with reduced ejection fraction, and the role of exercise training in attenuating or reversing the counterproductive changes. [ABSTRACT FROM AUTHOR]

Alessia Riglietti,1,&ast; Francesco Fanfulla,2,&ast; Massimo Pagani,3 Daniela Lucini,3,4 Mara Malacarne,3,4 Mauro Manconi,5– 7 Guido Ferretti,8,9 Fabio Esposito,10,11 Carlo W Cereda,12 Marco Pons1 1Department of Pulmonology, Regional Hospital of Lugano (EOC), Lugano, 6900, Switzerland; 2Respiratory Function and Sleep Unit – Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy; 3Exercise Medicine Unit, Istituto Auxologico Italiano, MIlan, 20133, Italy; 4University of Milan, BIOMETRA Department, Milan, Italy; 5Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Regional Hospital (EOC) of Lugano, Lugano, Switzerland; 6Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; 7Department of Neurology, University Hospital, Inselspital, Bern, Switzerland; 8Department APSI, University of Geneva, Geneva, Switzerland; 9Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; 10Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy; 11IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 12Stroke Center EOC, Department of Neurology, Neurocenter of Southern Switzerland Regional Hospital (EOC) of Lugano, Lugano, Switzerland&ast;These authors contributed equally to this workCorrespondence: Mauro ManconiRegional Hospital of Lugano, Via Tesserete, 46, Lugano, 6903, SwitzerlandTel +41-91-8116825Email mauro.manconi@eoc.chIntroduction: Sleep-related breathing disorders are highly prevalent in patients with ischemic stroke. Among sleep-disordered breathing disorders, obstructive sleep apnea is the most represented one, but central sleep apnea, isolated or in the context of a periodic breathing/Cheyne–Stokes respiration, is frequently reported in these patients. Altered baroreflex responses have been reported in the acute phases of a cerebral event.Methods: We conducted, in a group of patients with ischemic stroke (n=60), a prospective 3-month follow-up physiological study to describe the breathing pattern during sleep and baroreflex sensitivity in the acute phase and in the recovery phase.Results: In the acute phase, within 10 days from the onset of symptoms, 22.4% of patients had a normal breathing pattern, 40.3% had an obstructive pattern, 16.4% had a central pattern, and 29.9% showed a mixed pattern. Smaller variations in the Apnea–Hypopnea Index were found in normal breathing and obstructive groups (ΔAHI 2.1± 4.1 and − 2.8± 11.6, respectively) in comparison with central and mixed patterns (ΔAHI − 6.9± 15.1 and − 12.5± 13.1, respectively; ANOVA p=0.01). The obstructive pattern became the most frequent pattern, in 38.3% of patients at baseline and 61.7% of patients at follow-up. Modification of baroreflex sensitivity over time was influenced by the site of the lesion and by the sleep disorder pattern in the acute phase (MANOVA p=0.005).Conclusion: We suggest that a down-regulation of autonomic activity, possibly related to reduced vagal modulation, may help the recovery after stroke, or a transitory disconnection from the cortical node that participates in the regulation of sympathetic outflow.Keywords: sleep-disordered breathing, baroreflex, chemoreflex, brain lesion

From a physiological point of view, peripheral chemoreceptors (PCh) are the main sensors of hypoxia in mammals and are responsible for adaptation to hypoxic conditions. Their stimulation causes hyperventilation—to increase oxygen uptake and increases sympathetic output in order to counteract hypoxia-induced vasodilatation and redistribute the oxygenated blood to critical organs. While this reaction promotes survival in acute settings it may be devastating when long-lasting. The permanent overfunctionality of PCh is one of the etiologic factors and is responsible for the progression of sympathetically-mediated diseases. Thus, the deactivation of PCh has been proposed as a treatment method for these disorders. We review here physiological background and current knowledge regarding the influence of widely prescribed medications on PCh acute and tonic activities.

Postural orthostatic tachycardia syndrome (POTS) is a disorder epitomized by the story of the blind men and the elephant. Patients may see primary care internists or pediatricians due to fatigue, be referred to neurologists for “spells”, to cardiologists for evaluation of pre-syncope or chest pain, to gastroenterologists for nausea or dyspepsia, and even pulmonologists for dyspnea. Adoption of a more systematic approach to their evaluation and better characterization of patients has led to greater understanding of comorbidities, hypotheses prompting mechanistic investigations, and pharmacologic trials. Recent work has implicated disordered sympathetic nervous system activation in response to central (thoracic) hypovolemia. It is this pathway that leads one zero in on a putative focal point from which many of the clinical manifestations can be explained – specifically the carotid body. Despite heterogeneity in etiopathogenesis of a POTS phenotype, we propose that aberrant activation and response of the carotid body represents one potential common pathway in evolution. To understand this postulate, one must jettison isolationist or reductionist ideas of chemoreceptor and baroreceptor functions of the carotid body or sinus, respectively, and consider their interaction and interdependence both locally and centrally where some of its efferents merge. Doing so enables one to connect the dots and appreciate origins of diverse manifestations of POTS, including dyspnea for which the concept of neuro-mechanical uncoupling is wanting, thereby expanding our construct of this symptom. This perspective expounds our premise that POTS has a prominent respiratory component.

Background Central apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown. Methods and Results Consecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24‐hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter‐defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea‐hypopnea index (expressed as median [interquartile range]) at daytime (3 [0–9] versus 10 [3–20] events/hour) and nighttime (10 [3–21] versus 23 [11–36] events/hour) (all P0.05), also after matching women and men for possible confounders. Conclusions In chronic HF, CA are associated with a greater risk of adverse events in women than in men.

Obstructive sleep apnea is a frequent finding in clinical practice especially with the obesity epidemic and the growing awareness of sleep-disordered breathing as a potential and treatable risk factor for cardiovascular diseases. It frequently coexists undiagnosed activating pathophysiological mechanisms known to participate in development and progression of cardiovascular diseases and resistance to therapeutical strategies. The sympathetic activation and the baroreflex and chemoreflex impairment appear to be the main pathophysiological factors that activating several mechanisms elicit cardiac and vascular damage. Data from cross-sectional population-based studies, prospective studies and meta-analysis have clearly shown the implication of OSA in the development of the hypertensive state and the benefits obtained by continuous positive airway pressure on daytime blood pressure and cardiovascular risk. [ABSTRACT FROM AUTHOR]

Introduction: Parabrachial Kölliker-Fuse (KF) complex, located in dorsolateral part of the pons, is involved in the respiratory control, however, its role in the baroreflex and chemoreflex responses has not been established yet. This study was performed to test the contribution of the KF to chemoreflex and baroreflex and the effect of microinjection of a reversible synaptic blocker (Cocl2) into the KF in urethane anesthetized rats. Methods: Activation of chemoreflex was induced by systemic hypoxia caused by N2 breathing for 30 seconds "hypoxic- hypoxia methods" and baroreflex was evoked by intravenous injection (i.v.) of phenylephrine (Phe, 20 µg /kg/0.05–0.1 mL). N2 induced generalized vasodilatation followed by tachycardia reflex and Phe evoked vasoconstriction followed by bradycardia. Results: Microinjection of Cocl2 (5 mM/100 nL/side) produced no significant changes in the Phe-induced hypertension and bradycardia, whereas the cardiovascular effect of N2 was significantly attenuated by the injection of CoCl2 to the KF. Conclusion: The KF played no significant role in the baroreflex, but could account for cardiovascular chemoreflex in urethane anesthetized rats.