Peripheral Chemoreflex Sensitivity Research Articles

Circulatory Effects of Peripheral Chemoreflex Inhibition During Exercise in Treated Hypertension

The sensitization of the peripheral (carotid) chemoreflex can cause a sympathetically mediated restraint of blood flow to the exercising muscles in some disease states (e.g., heart failure, COPD). Such impairments in nutritive blood flow have the potential to impair exercise tolerance and raise exercising blood pressure (BP). Increased peripheral chemoreflex sensitivity and pronounced exercise-induced surges in BP have been reported in hypertension. Herein, we tested the hypothesis that suppressing peripheral chemoreflex sensitivity improves skeletal muscle blood flow during exercise in hypertension. Fourteen patients with treated hypertension (age 69±11 years, systolic BP 136±12 mmHg, diastolic BP 80±11 mmHg; mean ± SD) performed a resting baseline (3 min), an isocapnic hypoxia rebreathing test and rhythmic handgrip exercise (3 min at 50% of maximal voluntary contraction, 1 s contraction and 2 s relaxation) with either intravenous 0.9% saline (control) or low-dose dopamine (2 mcg·kg−1·min−1) to inhibit the peripheral chemoreflex. BP (finger plethysmography), heart rate (HR; electrocardiogram) and ventilation (V̇E; heated pneumotachometer) were recorded throughout. Brachial artery blood flow was monitored (duplex Doppler ultrasound) at rest (1 min average) and during handgrip (15 s averages), and vascular conductance calculated as brachial blood flow/mean BP. Dopamine blunted the peak (last 15 s) increase in V̇E during isocapnic hypoxic rebreathing compared to saline infusion (Δ6±6 vs. Δ9±5 L·min−1, P=0.026), while also attenuating peak mean BP (Δ3±4 vs. Δ8±6 mmHg, P=0.007). Dopamine did not change resting mean BP (95±10 vs. 98±10 mmHg, P=0.155) and HR (68±7 vs. 66±8 beats·min−1, P=0.100). However, dopamine increased resting brachial blood flow (59±20 vs. 48±16 mL·min−1, P=0.030) and vascular conductance (0.565±0.246 vs. 0.483±0.160 mL·min−1·mmHg−1, P=0.039) and decreased resting V̇E (10.5±3.2 vs. 11.5±3.1 L·min−1, P=0.036) versus saline. Handgrip increased brachial artery blood flow (p<0.05 vs. rest after 45 s), vascular conductance (p<0.05 vs. rest after 45 s) in both saline and dopamine trials, while mean BP, HR and V̇E were unchanged (main effect of time P=0.829, P=0.954 and P=0.255, respectively). Notably, brachial artery blood flow (e.g., Δ76±54 vs. Δ60±43 mL·min−1 at 60 s) and vascular conductance (e.g., Δ0.730±0.440 vs. Δ0.570±0.424 mL·min−1·mmHg−1 at 60 s) responses to handgrip were greater with dopamine than saline (main effect of condition both p<0.0001). Collectively, these findings indicate that the use of low-dose dopamine to suppress peripheral chemoreflex sensitivity improves skeletal muscle blood flow during rhythmic handgrip exercise in patients with treated hypertension. Funding support provided by the Health Research Council of New Zealand (19/687) and the Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Orexin 1 Receptors in The Paraventricular Nucleus of The Hypothalamus (PVN) Facilitate The Peripheral Chemoreflex

Increased sensitivity of the peripheral chemoreflex (PCR) to hypoxia is associated with cardiovascular-related diseases such as hypertension and heart failure. We previously showed that systemic blockade of both orexin 1 (Ox1R) and orexin 2 receptors reduced the PCR-mediated hypoxic ventilatory response (HVR), and that hypoxia activates PVN-projecting orexin neurons. The effect of OxR blockade on the HVR was strongest in the active phase of the circadian cycle and was associated with decreased numbers of activated neurons in the nucleus of the solitary tract (nTS) and nTS-projecting corticotropin-releasing neurons in the PVN. While the projection from the PVN to the nTS contributes to the PCR, the neuronal mechanism(s) activating this projection are unclear. We hypothesized that orexin acting at Ox1R in the PVN facilitates the PCR. To test this hypothesis, we first performed IHC to confirm the expression of Ox1R in the PVN. We then assessed the degree to which specific Ox1R blockade reduced the HVR (n=6; tested first with vehicle (100% DMSO), then Ox1R antagonist SB-334867, 1 mg/kg, i.p). To assess the contribution of PVN Ox1Rs to the PCR as well as the associated activation of neurons in the PVN and nTS, we specifically knocked down Ox1R expression in the PVN via nanoinjection of an Ox1R shRNA-GFP expressing AAV vector. Rats were exposed to graded hypoxia during the active phase, with inspired O2 taken from 21% to 11% over a ~5 min period. Rats were kept near-isocapnic by slightly increasing the inspired CO2. Subsets of rats were exposed to hypoxia to assess the effects of Ox1R on neuronal activation using c-Fos expression as a surrogate marker. Systemic Ox1R blockade significantly reduced the HVR compared to the control response (by ~30%; p=0.0027). Knockdown of Ox1R in the PVN also reduced the HVR (by ~20%; p=0.049) and reduced the number of c-Fos expressing PVN neurons in response to hypoxia (p=0.0232). More specifically, hypoxia induced c-Fos expression in fewer PVN neurons transfected with Ox1R shRNA (confirmed by GFP expression) than neurons from control rats transfected with scrambled RNA (p=0.0083). Ox1R knockdown in the PVN also significantly reduced the hypoxia-induced increase in number of c-Fos expressing tyrosine-hydroxylase (TH) nTS neurons (p=0.0303), suggesting that PVN Ox1Rs mediate hypoxia-induced activation of TH neurons in the nTS. These findings suggest that in the PVN, orexin acting at Ox1Rs mediate the facilitation of the PCR and the associated activation of the PVN and nTS neurons. Ox1R in the PVN could be a novel target to treat diseases associated with increased PCR sensitivity. Grants: 5R01HL098602 (to DK, EH and KC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A test of the interaction between central and peripheral respiratory chemoreflexes in humans.

How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured the peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic CO2 tensions ( ) to determine the form of the relationship between PChS and central . Twenty participants (10F) completed three repetitions of modified rebreathing tests with end-tidal ( ) clamped at 150, 70, 60 and 45mmHg. End-tidal ( ), , ventilation ( E ) and calculated oxygen saturation (SC O2 ) were measured breath-by-breath by gas-analyser and pneumotach. The E - relationship of repeat-trials were linear-interpolated, combined, averaged into 1mmHg bins, and fitted with a double-linear function ( E S, L min-1 mmHg-1 ). PChS was computed at intervals of 1mmHg of as follows: the difference in E between the three hypoxic profiles and the hyperoxic profile (∆ E ) was calculated; three ∆ E values were plotted against corresponding SC O2 ; and linear regression determined PChS (Lmin-1 mmHg-1 %SC O2 -1 ). These processing steps were repeated at each to produce the PChS vs. isocapnic relationship. These were fitted with linear and polynomial functions, and Akaike information criterion identified the best-fit model. One-way repeated measures analysis of variance assessed between-condition differences. E S increased (P<0.0001) with isoxic from 3.7±1.5 L min-1 mmHg-1 at 150mmHg to 4.4±1.8, 5.0±1.6 and 6.0±2.2 Lmin-1 mmHg-1 at 70, 60 and 45mmHg, respectively. Mean SC O2 fell progressively (99.3±0%, 93.7±0.1%, 90.4±0.1% and 80.5±0.1%; P<0.0001). In all individuals, PChS increased with , and this relationship was best described by a linear model in 75%. Despite increasing central chemoreflex activation, PChS increased linearly with indicative of an additive central-peripheral chemoreflex response. KEY POINTS: How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic carbon dioxide tensions ( ) to determine the form of the relationship between PChS and central . Participants performed three repetitions of modified rebreathing with end-tidal fixed at 150, 70, 60 and 45mmHg. PChS was computed at intervals of 1mmHg of end-tidal ( ) as follows: the difference in E between the three hypoxic profiles and the hyperoxic profile (∆ E ) was calculated; three ∆ E values were plotted against corresponding calculated oxygen saturation (SC O2 ); and linear regression determined PChS (Lmin-1 mmHg-1 %SC O2 -1 ). In all individuals, PChS increased with , and this relationship was best described by a linear (rather than polynomial) model in 15 of 20. Most participants did not exhibit a hypo- or hyper-additive effect of central chemoreceptors on the peripheral chemoreflex indicating that the interaction was additive.

The effect of acute oral pyridoxine supplementation on peripheral chemoreflex sensitivity in human hypertension

ATP has been identified as an important signalling molecule in the carotid body. Animal models of hypertension have uncovered that ATP transmission via purinergic (P2) receptors increases carotid body tonicity and sensitivity, which drives sympathetic outflow and elevates blood pressure. A naturally occurring metabolite of pyridoxine (Vitamin B6), namely pyridoxal-5-phosphate, is a non-selective P2X receptor antagonist. In this study we tested the hypothesis that oral administration of pyridoxine reduces peripheral chemoreflex sensitivity and blood pressure in human hypertension. 14 treated hypertensive patients (4 men, 71±5 yr, 27±6 kg·m -2 , 156±19/83±8 mmHg) completed a double-blind placebo-controlled crossover study with either oral pyridoxine (600 mg) or placebo. Two-hours later, minute ventilation (V̇ E ), end-tidal partial pressures of oxygen and carbon dioxide (P ET O 2 and P ET CO 2 ), mean arterial pressure (MAP), and heart rate (HR) were recorded during an isocapnic hypoxic rebreathing protocol (target P ET O 2 45mmHg). Cardiorespiratory responses were taken as the change from baseline to peak rebreathing (final 15s). Arterial oxygen saturation (S a O 2 ) was calculated from P ET O 2 using the Severinghaus equation, and peripheral chemoreflex sensitivity taken as ΔV̇ E divided by ΔS a O 2 . Baseline V̇ E (13.02±3.26 vs. 12.68±4.13 L·min -1 , P=0.616), MAP (109±11 vs. 104±10 mmHg, P=0.058), and HR (63±11 vs. 62±8 BPM, P=0.463), were not different between pyridoxine and placebo conditions, respectively. The ΔV̇ E response to isocapnic hypoxia tended to be blunted with pyridoxine compared to placebo (6.88±3.94 vs. 9.87±7.69 L·min -1 ; P=0.188), but this did not reach statistical significance. Similarly, peripheral chemoreflex sensitivity was not different with pyridoxine compared to placebo (-0.46±0.31 vs. -0.64±0.49 L·min -1 ·% -1 , P=0.148). However, individuals with a higher peripheral chemoreflex sensitivity in the placebo condition, displayed a more marked reduction in peripheral chemoreflex sensitivity following pyridoxine (R 2 =0.63, P=0.005). While HR and MAP increased during isocapnic hypoxia (both P&lt;0.001), the magnitude of this response did not differ with pyridoxine or placebo administration. In this preliminary study, oral pyridoxine lowered neither blood pressure nor peripheral chemoreflex sensitivity in human hypertension. However, oral pyridoxine did lower peripheral chemoreflex sensitivity in those hypertension patients in whom baseline peripheral chemoreflex sensitivity (i.e., placebo condition) was highest. It is possible that oral pyridoxine supplementation may be beneficial for those hypertensive patients who exhibit overactivation of their peripheral chemoreflex. Health Research Council of New Zealand (Ref# 19/687), the University of Auckland Faculty Research Development Fund, and the New Zealand Lottery Grants Board (R-LHR-2021-153114). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Arterial stiffness and peripheral chemoreflex responsiveness in electronic cigarette users

Electronic cigarettes (e-cigarettes) are marketed as less harmful alternatives to tobacco smoking, but the short- and long-term health consequences are unclear. Raised arterial stiffness and increased peripheral chemoreflex sensitivity are pathogenic features of several clinical conditions and associated with adverse outcomes. The aim of this study was to determine if regular e-cigarettes use is associated with increased arterial stiffness and elevated peripheral chemoreflex responsiveness.Eight healthy e-cigarettes users (E-cig; &gt;12 months, 6 women, 27±5yr, 26.0±4.5kg/m2 mean±SD) and 13 healthy non-e-cigarettes user controls (HC; 8 women, 26±4yr, 22.4±3.4kg/m2,) were studied under 3 conditions (each for 5min) in the following order: room-air, isocapnic hyperoxia (1.0 fraction of inspired oxygen [FiO2]; peripheral chemoreflex deactivation) and isocapnic hypoxia (0.1 FiO2; peripheral chemoreflex activation). In each condition, arterial stiffness was evaluated by the aortic augmentation index (AIx) and aortic pulse wave velocity (PWV) (SphygmoCor), while heart rate (HR), mean arterial pressure (MAP), and minute ventilation (V̇E) were monitored.In room air, AIx was higher in E-cig compared to HC (18.4±3.4 vs. 8.1±2.5%, P=0.023), while PWV (5.7±0.3 vs. 5.8±0.8m/sec, P=0.731), HR (68±6 vs. 70±9beats/min, P=0.616), MAP (83±4 vs. 83±7mmHg/min, P=0.920), and V̇E (12.7±2.2 vs. 13.9±3.1L/min, P=0.515) were not different. During isocapnic hyperoxia, AIx was unchanged in both E-cig (21.9±11.2%, P=0.327) and HC (9.2±7.9%, P=1.000) versus room air, with AIx remaining higher in E-cig (P=0.006). There were no changes from isocapnic hyperoxia to room air in both E-cig and HC in aortic PWV (Δ0.1±0.1 and Δ0.1±0.2m/sec, P=0.894), HR (Δ-3±3 and Δ-2±3beats/min, P=0.482), MAP (Δ0.3±2.2 and Δ-0.9±2.1mmHg/min, P=0.528) and V̇E (Δ1.1±2.0 vs. Δ1.2±4.6L/min, P=0.124). During isocapnic hypoxia, AIx was unchanged in E-cig (14.7±9.5%, P=0.288) versus room air, but was decreased in HC (2.8±9.4%, P=0.006), such that AIx remained higher in E-cig than HC (P=0.009). HR increased similarly during isocapnic hypoxia in both E-cig (77±7beats/min, P&lt;0.001) and HC (82±7beats/min, P&lt;0.001) compared to room air. In E-cig and HC no change was observed in aortic PWV (Δ0.4±0.4 and Δ0.2±1.4m/sec, P=0.254), MAP (Δ-0.2±2.0 and Δ0.3±2.3mmHg/min, P=0.609) and V̇E (Δ 1.4±1.0 vs. Δ1.1±1.4L/min, P=0.638) during isocapnic hypoxia relative to room air.These preliminary findings suggest that arterial stiffness is higher in young e-cigarettes users, and that the normal hypoxia-induced reduction in arterial stiffness in young non-e-cigarette users is absent in e-cigarettes users. Future studies are needed to determine if the altered effects of hypoxia on arterial stiffness in young e-cigarettes users is associated with exaggerated peripheral chemoreflex mediated sympatho-excitation and/or local endothelial/vascular smooth muscle mechanisms, and if it is reversible on cessation of e-cigarette use. Health Research Council of New Zealand (Ref# 19/687. JPF, JFRP), and the Sidney Taylor Trust (JFRP). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reflex regulation and the functional assessment possibility of the cardiorespiratory system in pregnancy: a systematic review

INTRODUCTION: Anesthesia planning for cesarean section requires knowledge of physiological and functional features a pregnant patient has in her gestational age. Proper planning reduced the perioperative critical incidents risk. OBJECTIVE: Search for data on the methods and results of assessing the cardiorespiratory status of pregnant women using methods that involve such key mechanisms of arterial baroreflex (ABR) and peripheral chemoreflex (PCR) mechanisms. MATERIAL AND METHODS: We performed a systematic review of the literature in accordance with the PRISMA guidelines. The bibliographic search was performed in December 2022 in the Medline (Pubmed), RSCI (eLibrary.ru) and Cochrane Library databases. The search keywords were: “pregnancy breath holding test”, “pregnancy chemoreflex”, “pregnancy baroreflex”, “Valsalva test pregnancy”. RESULTS: 110 documents were found, after deleting 68 papers for various reasons 42 full-text sources were analyzed, including a detailed comparative analysis of 8 sources that met totally the inclusion criteria. The design, objectives, methods, data availability, and outcomes of the studies were heterogeneous, so a meta-analysis was not performed. Were extracted and summarized data on functional changes in the work of cardiorespiratory system during pregnancy and changes in the sensitivity of the baroreflex and chemoreflex. CONCLUSIONS: The sensitivity of PCR in pregnant women can be assessed by inhalation of hyperoxic, hypercapnic and isooxic-hypercapnic gas mixtures (rebreathing test). The sensitivity of ABR in pregnant can be assessed by phenylephrine test, Valsalva test, orthostatic test, and spectral analysis of the sequences of blood pressure values and the R-R interval. The sensitivity of PCR in full-term pregnancy increases. The sensitivity of ABR in pregnant progressively decreases from the beginning of pregnancy to the end of the second trimester and increases in the postpartum period to initial level; in the third trimester of pregnancy, changes in ABR sensitivity are individual and do not have a single trend.

Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68±5years; mean±SD) and 13 normotensives (NT; 65±6years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150mmHg (isoxic hyperoxia; central chemoreflex activation) or 50mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( vs. slope) and sympathetic (MSNA vs. slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48±1.33 vs. 1.58±0.42Lmin-1 mmHg-1 , P=0.030: 3.32±1.90 vs. 1.77±0.62a.u.mmHg-1 , P=0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for (R2 =0.666, P<0.0001) and MSNA (R2 =0.698, P=0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

The Relationship Between Central and Peripheral Chemoreflex Sensitivities and V̇E‐V̇CO2 Slope Below and Above the Respiratory Compensation Point of Incremental Exercise

During incremental exercise, the ventilation (V̇E) versus carbon dioxide production (V̇CO2) relationship exhibits a double‐linear response with an inflection of slope at the transition from hyperpnea to hyperventilation (i.e., respiratory compensation point (RCP)). Whether peripheral or central chemoreflexes contribute to the hyperventilatory response to incremental exercise remains undetermined. This study tested the hypothesis that peripheral and not central chemoreflex sensitivity would relate to the magnitude of the V̇E‐V̇CO2 slope above RCP and that neither would relate to the sub‐RCP V̇E‐V̇CO2 slope. Seven healthy, caffeine‐free males (age: 27±5 years) performed a ramp‐incremental test to exhaustion on a cycle ergometer, during which ventilation and gas exchange were measured by metabolic cart. The V̇E‐V̇CO2 slope above and below RCP were determined by linear regression from the estimated lactate threshold to RCP, and from RCP to end‐exercise, respectively. On four separate days, 12 modified rebreathing tests were performed: six in isoxic‐hyperoxia (PO2=150 mmHg) and six in isoxic‐hypoxia (PO2=50 mmHg). Using ensemble‐average data, central chemoreflex sensitivity was measured as the mean hyperoxic V̇E versus end‐tidal partial pressure of carbon dioxide (PETCO2) slope (in L∙min‐1∙mmHgPETCO2‐1) and the peripheral chemoreflex sensitivity was determined from the difference of hypoxic and hyperoxic slopes. The mean V̇E‐V̇CO2 slopes above and below RCP were 35.0+3.7 (range: 28.3‐39.9) and 61.8+9.2 (range: 51.9‐78.3), respectively. Mean peripheral and central chemoreflex sensitivities were 1.6±1.3 L∙min‐1∙mmHgPETCO2‐1 (range: 0.1‐3.7) and 4.1±2.1 L∙min‐1∙mmHgPETCO2‐1 (range: 2.3‐8.4), respectively. Peripheral chemoreflex sensitivity did not relate to V̇E‐V̇CO2 slope below (r=0.44, p=0.32) or above (r=‐0.02, p=0.96) RCP. No relationships were found between central chemoreflex sensitivity and V̇E‐V̇CO2 slope below (r=0.06, p=0.90) or above (r=0.04, p=0.93) RCP. These preliminary observations suggest that neither central nor peripheral chemoreflex sensitivity factor into the magnitude of the hyperpneic or hyperventilatory response to incremental exercise.

A Strategy to Enhance Confidence in Respiratory Chemoreflex Characterization by Modified Rebreathing

Modelling breath‐by‐breath ventilation (V̇E) in response to carbon dioxide rebreathing in hyperoxic and hypoxic conditions (modified rebreathing) is used to characterize the central and peripheral respiratory chemoreflexes in humans. However, breath‐to‐breath variability produces uncertainty in the estimation of model parameters. We explored whether signal‐averaging of repeated rebreathing trials would improve chemoreflex sensitivity parameter estimation and confidence. Seven healthy males (age: 27±5 years) performed 6 repetitions of modified rebreathing tests in isoxic‐hypoxic (end‐tidal PO2 (PETO2)=50 mmHg) and ‐hyperoxic conditions (PETO2=150 mmHg) over the course of 4 days. End‐tidal PCO2 (PETCO2), PETO2 and V̇E were measured breath‐by‐breath by dual gas analyser and pneumotach. The slope of the V̇E vs PETCO2 relationship above the PETCO2 threshold in the hyperoxic test gave the central chemoreflex sensitivity (L∙min‐1∙mmHg‐1) and the difference in hypoxic versus hyperoxic test slopes provided peripheral chemoreflex sensitivity. Chemoreflex slopes modelled from a single trial versus ensemble‐average of 6 trials were compared by paired t‐test and effect size (Cohen’s d). Breath‐by‐breath data from the 6 trials were aligned to the same starting PETCO2, linearly interpolated to 0.1 mmHg of PETCO2, ensemble‐averaged, and averaged into 0.2 mmHg bins. Central chemoreflex sensitivity did not differ (p=0.94) between single (4.10±2.98 L∙min‐1∙mmHg‐1, 95%CI: 3.82–4.39) versus ensemble‐averaged data (4.13±2.14 L∙min‐1∙mmHg‐1, 95%CI: 3.99–4.27) but the 95%CI was reduced (p=0.031) by 0.29 L∙min‐1∙mmHg‐1 (effect size=1.5) with the ensemble‐averaged approach. Similarly, peripheral chemoreflex sensitivity did not differ (p=0.83) between single (1.69±1.14 L∙min‐1∙mmHg‐1, 95%CI: 1.54–1.84) versus ensemble‐averaged data (1.58±1.32 L∙min‐1∙mmHg‐1, 95%CI: 1.5 –1.66); 95%CI of the ensemble‐averaged data was 0.15 L∙min‐1∙mmHg‐1 lower than a single trial but this was not different (p=0.38; effect size=0.5). Signal averaging of multiple modified rebreathing trials reduces the confidence interval of respiratory chemoreflex sensitivity. This strategy could enhance the ability to detect differences in respiratory chemoreflex control in comparative or interventional studies where modified rebreathing is used.

Peripheral Chemoreflex Sensitivity is Augmented in Human Type 2 Diabetes

IntroductionThe peripheral chemoreceptors have been implicated in the pathogenesis of type 2 diabetes. Our main objective was to examine peripheral chemosensitivity in individuals with type 2 diabetes, as well as the contribution of the peripheral chemoreceptors to basal cardiovascular control. We hypothesized individuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity to hypoxia compared to healthy, non‐diabetic controls. We further hypothesized the peripheral chemoreceptors contribute to cardiovascular dysfunction in type 2 diabetes.MethodsEight adults with diagnosed type 2 diabetes (3M/5F, 54±3 yrs, HbA1c 8.1±0.6%) and nineteen healthy controls (8M/11F, 50±3 yrs, HbA1c 5.3±0.1%) participated (IRB #2010295 and #2018486). Ventilatory and hemodynamic responses to acute hypoxia were assessed to determine peripheral chemosensitivity [i.e., hypoxic ventilatory (HVR), heart rate (HHRR) and blood pressure (HBPR) response]. Separately, heart rate, blood pressure and forearm blood flow (Doppler ultrasound) were measured while breathing normoxic or hyperoxic air (100% O2; Modified Dejours test) to acutely attenuate peripheral chemoreceptor activity. Forearm blood flow was normalized for mean arterial blood pressure for measures of vascular resistance.ResultsPeripheral chemosensitivity was augmented in adults with type 2 diabetes compared to control as assessed via the HVR (‐1.10±0.16 vs ‐0.50±0.10 L/min/%, p&lt;0.01) and HBPR (‐0.92±0.17 vs ‐0.42±0.19 mmHg/%, p=0.06), with no differences in HHRR (‐0.68±0.22 vs ‐0.56±0.12 beats/min/%, p=0.64). Higher HVR and HBPR were associated with higher fasting insulin (R=‐0.58, p&lt;0.01 and R=‐0.38, p=0.06) and HbA1c (R=‐0.60, p&lt;0.01 and R=‐0.39, p=0.05). Attenuation of peripheral chemoreceptor activity with acute hyperoxia decreased heart rate (p&lt;0.01) and blood pressure (p=0.02), with no effect on forearm vascular resistance (p=0.55); any effect of hyperoxia did not differ between adults with type 2 diabetes and controls (p&gt;0.05).ConclusionIndividuals with type 2 diabetes exhibit exaggerated peripheral chemoreflex sensitivity which is associated with disease severity (i.e., HbA1c). In contrast, the contribution of the peripheral chemoreceptors to basal cardiovascular function in type 2 diabetes does not differ from non‐diabetic controls. Results advance our understanding of the pathogenesis of type 2 diabetes and related complications.

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

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

Low ventilatory responsiveness to transient hypoxia or breath-holding predicts fast marathon performance in healthy middle-aged and older men

The aim of this study was to test the utility of haemodynamic and autonomic variables (e.g. peripheral chemoreflex sensitivity [PCheS], blood pressure variability [BPV]) for the prediction of individual performance (marathon time and VO2max) in older men. The post-competition vasodilation and sympathetic vasomotor tone predict the marathon performance in younger men, but their prognostic relevance in older men remains unknown. The peripheral chemoreflex restrains exercise-induced vasodilation via sympathetically-mediated mechanism, what makes it a plausible candidate for the individual performance marker. 23 men aged ≥ 50 year competing in the Wroclaw Marathon underwent an evaluation of: resting haemodynamic parameters, PCheS with two methods: transient hypoxia and breath-holding test (BHT), cardiac barosensitivity, heart rate variability (HRV) and BPV, plasma renin and aldosterone, VO2max in a cardiopulmonary exercise test (CPET). All tests were conducted twice: before and after the race, except for transient hypoxia and CPET which were performed once, before the race. Fast marathon performance and high VO2max were correlated with: low ventilatory responsiveness to hypoxia (r = − 0.53, r = 0.67, respectively) and pre-race BHT (r = − 0.47, r = 0.51, respectively), (1) greater SD of beat-to-beat SBP (all p < 0.05). Fast performance was related with an enhanced pre-race vascular response to BHT (r = − 0.59, p = 0.005). The variables found by other studies to predict the marathon performance in younger men: post-competition vasodilation, sympathetic vasomotor tone (LF-BPV) and HRV were not associated with the individual performance in our population. The results suggest that PCheS (ventilatory response) predicts individual performance (marathon time and VO2max) in men aged ≥ 50 yeat. Although cause-effect relationship including the role of peripheral chemoreceptors in restraining the post-competition vasodilation via the sympathetic vasoconstrictor outflow may be hypothesized to underline these findings, the lack of correlation between individual performance and both, the post-competition vasodilation and the sympathetic vasomotor tone argues against such explanation. Vascular responsiveness to breath-holding appears to be of certain value for predicting individual performance in this population, however.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Measuring Peripheral Chemoreflex Hypersensitivity in Heart Failure.

Heart failure with reduced ejection fraction (HFrEF) induces chronic sympathetic activation. This disturbance is a consequence of both compensatory reflex disinhibition in response to lower cardiac output and patient-specific activation of one or more excitatory stimuli. The result is the net adrenergic output that exceeds homeostatic need, which compromises cardiac, renal, and vascular function and foreshortens lifespan. One such sympatho-excitatory mechanism, evident in ~40–45% of those with HFrEF, is the augmentation of carotid (peripheral) chemoreflex ventilatory and sympathetic responsiveness to reductions in arterial oxygen tension and acidosis. Recognition of the contribution of increased chemoreflex gain to the pathophysiology of HFrEF and to patients’ prognosis has focused attention on targeting the carotid body to attenuate sympathetic drive, alleviate heart failure symptoms, and prolong life. The current challenge is to identify those patients most likely to benefit from such interventions. Two assumptions underlying contemporary test protocols are that the ventilatory response to acute hypoxic exposure quantifies accurately peripheral chemoreflex sensitivity and that the unmeasured sympathetic response mirrors the determined ventilatory response. This Perspective questions both assumptions, illustrates the limitations of conventional transient hypoxic tests for assessing peripheral chemoreflex sensitivity and demonstrates how a modified rebreathing test capable of comprehensively quantifying both the ventilatory and sympathoneural efferent responses to peripheral chemoreflex perturbation, including their sensitivities and recruitment thresholds, can better identify individuals most likely to benefit from carotid body intervention.

Acute inorganic nitrate supplementation and the hypoxic ventilatory response in patients with obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) have increased cardiovascular disease risk largely attributable to hypertension. Heightened peripheral chemoreflex sensitivity (i.e., exaggerated responsiveness to hypoxia) facilitates hypertension in these patients. Nitric oxide blunts the peripheral chemoreflex, and patients with OSA have reduced nitric oxide bioavailability. We therefore investigated the dose-dependent effects of acute inorganic nitrate supplementation (beetroot juice), an exogenous nitric oxide source, on blood pressure and cardiopulmonary responses to hypoxia in patients with OSA using a randomized, double-blind, placebo-controlled crossover design. Fourteen patients with OSA (53 ± 10 yr, 29.2 ± 5.8 kg/m2, apnea-hypopnea index = 17.8 ± 8.1, 43%F) completed three visits. Resting brachial blood pressure and cardiopulmonary responses to inspiratory hypoxia were measured before, and 2 h after, acute inorganic nitrate supplementation [∼0.10 mmol (placebo), 4.03 mmol (low dose), and 8.06 mmol (high dose)]. Placebo increased neither plasma [nitrate] (30 ± 52 to 52 ± 23 μM, P = 0.26) nor [nitrite] (266 ± 153 to 277 ± 164 nM, P = 0.21); however, both increased following low (29 ± 17 to 175 ± 42 μM, 220 ± 137 to 514 ± 352 nM) and high doses (26 ± 11 to 292 ± 90 μM, 248 ± 155 to 738 ± 427 nM, respectively, P < 0.01 for all). Following placebo, systolic blood pressure increased (120 ± 9 to 128 ± 10 mmHg, P < 0.05), whereas no changes were observed following low (121 ± 11 to 123 ± 8 mmHg, P = 0.19) or high doses (124 ± 13 to 124 ± 9 mmHg, P = 0.96). The peak ventilatory response to hypoxia increased following placebo (3.1 ± 1.2 to 4.4 ± 2.6 L/min, P < 0.01) but not low (4.4 ± 2.4 to 5.4 ± 3.4 L/min, P = 0.11) or high doses (4.3 ± 2.3 to 4.8 ± 2.7 L/min, P = 0.42). Inorganic nitrate did not change the heart rate responses to hypoxia (beverage-by-time P = 0.64). Acute inorganic nitrate supplementation appears to blunt an early-morning rise in systolic blood pressure potentially through suppression of peripheral chemoreflex sensitivity in patients with OSA.NEW & NOTEWORTHY The present study is the first to examine the acute effects of inorganic nitrate supplementation on resting blood pressure and cardiopulmonary responses to hypoxia (e.g., peripheral chemoreflex sensitivity) in patients with obstructive sleep apnea (OSA). Our data indicate inorganic nitrate supplementation attenuates an early-morning rise in systolic blood pressure potentially attributable to blunted peripheral chemoreflex sensitivity. These data show proof-of-concept that inorganic nitrate supplementation could reduce the risk of cardiovascular disease in patients with OSA.

Prediction of the Effectiveness of Spontaneous Breathing in Patients with Brain Damage of Various Etiologies.

The aim of the study was to develop an informative method for assessing chemoreflex sensitivity and to evaluate its prognostic capacity for restoring spontaneous breathing in patients with brain damage of various etiologies. The study included 16 healthy volunteers and 38 patients on prolonged mechanical ventilation (VE) after a traumatic brain injury, anoxic brain damage, and cerebrovascular events. The external respiration variables were assessed from the initial level to the development of the first episode of desaturation with spO2 in the range of 90–80% against the background of normobaric hypoxia as indicators reflecting the development of adaptive ventilatory response and characterizing the state of peripheral chemoreflex sensitivity (PCS). The peripheral chemoreflex sensitivity index (PCSI) was calculated using the equation: PCSI = [RR(e) : RR(i)] × [Vt(e) : Vt(i)] × [VE(e) : VE(i)] × Vt(e) × VE(e), where PCSI is the peripheral chemoreflex sensitivity index in L2/min; RR(i) and RR(e); Vt(i) and Vt(e); VE(i) and VE(e) are the respiratory rate, tidal volume, minute ventilation initially (i), before a functional stress test, and during a functional test of normobaric hypoxia with spO2 in the range of 90–80% (e). With the PCSI values ≥15.6 L2/min, successful weaning from ventilators and recovery of spontaneous breathing are predicted. The sensitivity and specificity of PCSI were 78.57 [95% CI: 49.2–95.26] and 83.3% [95% CI: 62.6–95.26], respectively. The sensitivity and specificity of the traditional indicator of the success rate of weaning from ventilators and recovery of spontaneous breathing, Rapid Shallow Breathing Index (RSBI), in this cohort of patients was 69.23 [95% CI: 38.6–90.9] and 28.0% [95% CI: 12.03–49.3], respectively. A predictor of the patient’s weaning from mechanical ventilation is the assessment of peripheral chemoreflex sensitivity, which can be measured by a simple non-invasive bedside test based on measuring the difference in external ventilation parameters before and during a functional normobaric hypoxic trial.

Effects of maternal protein restriction on central and peripheral renin-angiotensin systems in male rat offspring

AimsWe investigated the involvement of the renin angiotensin system (RAS) on the cardiorespiratory control in rats from dams fed with a low-protein diet. Main methodsMale offspring were obtained from dams fed a normoprotein diet (NP, 17% casein) and low-protein diet (LP, 8% casein) during pregnancy and lactation. Direct measurements of arterial pressure (AP), heart rate (HR) and respiratory frequency (RF) were recorded in awake 90-day-old at resting and after losartan potassium through either intracerebroventricular (ICV) microinjections or intravenous (IV) administration. Cardiovascular variability was evaluated by spectral analysis. Peripheral chemoreflex sensitivity was assessed through the potassium cyanide (KCN; 40 μg/0.1 ml/rat, IV). Gene expression was evaluated by qPCR, and MAPK (Mitogen Activated Protein Kinase) expression was evaluated by western blot. Key findingsThe LP offspring had higher mean AP (MAP) and RF than NP offspring. In the spectral analysis, the LP rats also showed higher low frequency of systolic AP (NP: 2.7 ± 0.3 vs. LP: 5.0 ± 1.0 mmHg). After ICV losartan, MAP and RF in LP rats remained higher than those in NP rats, but without changes in HR. The peripheral chemoreflex was similar between the groups. LP group had lower gene expression of Rac1 (Ras-related C3 botulinum toxin substrate 1) (NP: 1.13 ± 0.06 vs. LP: 0.88 ± 0.08). Peripherally, LP rats had larger delta of MAP after IV losartan (NP: −9.8 ± 2 vs. LP: −23 ± 6 mmHg), without changes in HR and RF. SignificanceIn rats, the RAS participates peripherally, but not centrally, in the maintenance of arterial hypertension in male offspring induced by maternal protein restriction.

Autonomic innervation of the carotid body as a determinant of its sensitivity: implications for cardiovascular physiology and pathology.

The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Blood Pressure is Positively Associated with Glycosylated Hemoglobin but not the Hypoxic Ventilatory Response in Obstructive Sleep Apnea Patients

Study ObjectiveThe hypoxic ventilatory response (HVR) is considered an index of peripheral chemoreflex sensitivity. Previous work has suggested that an increase in the HVR is responsible for acute nocturnal blood pressure surges that ultimately lead to chronic elevations in blood pressure. Previous results have also indicated that glycosylation of hemoglobin (HbA1C) impairs nitric oxide (NO) relaxation of vascular smooth muscle leading to chronic elevations in blood pressure. Given these findings, we hypothesized that the HVR and HbA1C would be positively associated with blood pressure during sleep before and 3 weeks after treatment with mild intermittent hypoxia (MIH) in humans with obstructive sleep apnea (OSA).MethodsEight hypertensive participants with OSA were exposed to twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute normoxic intervals during wakefulness for 15 days over 3 weeks. PETCO2 was sustained at 2 mmHg above baseline during MIH administration. HbA1C was measured prior to completion of the protocol on Day 1 and 15. Moreover, blood pressure was measured over a period of 24 hours, before and after completion of the MIH protocol.ResultsOn Day 1, the HVR was negatively associated with HbA1C (−0.74, p &lt; 0.04) and systolic (SBP) (R = −0.73, p &lt; 0.05), diastolic (DBP) (R = −0.69, p &lt; 0.05) and mean arterial blood pressure (MAP) (R = −0.71, p &lt; 0.05) recorded during the sleep period of a 24 hour cycle. In contrast, HbA1C was positively associated with measures of SBP (R = 0.82, p &lt; 0.01), DBP (R = 0.81, p &lt; 0.01) and MAP (R = 0.86, p &lt; 0.01) during sleep. Following treatment with MIH, blood pressure during sleep decreased (Before vs. After MIH: SBP 131.9 ± 4.1 vs. 122.9 ± 3.1, DBP 77.8 ± 3.9 vs. 72.8 ± 3.9, MAP 95.8 ± 3.8 vs. 89.5 ± 3.4, P &lt; 0.02). The change (Δ) in SBP during sleep following MIH was correlated to the Δ HbA1C (R = 0.85, p ≤ 0.01). Moreover, the degree to which SBP dipped before vs. after MIH was also correlated to Δ HbA1C (R = 0.87, p ≤ 0.01). In contrast, Δ HVR was not correlated to the Δ in blood pressure parameters.ConclusionAlthough peripheral chemoreflex sensitivity may be responsible for acute surges in blood pressure, this factor does not appear to be a strong predictor of chronic changes in blood pressure. In contrast, modifications in local signaling molecules may ultimately have the greatest impact on chronic modifications in blood pressure. Indeed, our findings lend support to previous results which suggest that increases in blood pressure may be coupled to the impairment of nitric oxide in response to glycosylated hemoglobin. This relationship may exist in the presence of a blunted HVR.Support or Funding InformationDepartment of Veterans Affairs (I01CX000125 &amp; 15SRCS003 JHM, 1IK1RX002945 GSP), and NIH (R56HL142757 &amp; R01HL142757 JHM).

Histochemical and immunohistochemical localization of nitrergic structures in the carotid body of spontaneously hypertensive rats

The carotid body (CB) is a multipurpose metabolic sensor that acts to initiate cardiorespiratory reflex adjustments to maintain homeostasis of blood-borne chemicals. Emerging evidence suggests that nitric oxide increases the CB chemosensory activity and this enhanced peripheral chemoreflex sensitivity contributes to sympathoexcitation and consequent pathology. The aim of this study was to examine by means of NADPH-diaphorase histochemistry and nitric oxide synthase (NOS) immunohistochemistry the presence and distribution of nitrergic structures in the CB of spontaneously hypertensive rats (SHRs) and to compare their expression patterns to that of age-matched normotensive Wistar rats (NWRs). Histochemistry revealed that the chemosensory glomus cells were NADPH-d-negative but were encircled by fine positive varicosities, which were also dispersed in the stroma around the glomeruli. The NADPH-d-reactive fibers showed the same distributional pattern in the CB of SHRs, however their staining activity was weaker when compared with NWRs. Thin periglomerular, intraglomerular and perivascular varicose fibers, but not glomus or sustentacular cells in the hypertensive CB, constitutively expressed two isoforms of NOS, nNOS and eNOS. In addition, clusters of glomus cells and blood vessels in the CB of SHRs exhibited moderate immunoreactivity for the third known NOS isoenzyme, iNOS. The present study demonstrates that in the hypertensive CB nNOS and eNOS protein expression shows statistically significant down-regulation whereas iNOS expression is up-regulated in the glomic tissue compared to normotensive controls. Our results suggest that impaired NO synthesis could contribute to elevated blood pressure in rats via an increase in chemoexcitation and sympathetic nerve activity in the CB.