Chemoreflex Sensitivity Research Articles

Effect of Chronic Intermittent Hypoxia on Angiotensin II Receptors in the Central Nervous System

ABSTRACTChronic intermittent hypoxia (CIH) increases basal sympathetic nervous system activity, augments chemoreflex-induced sympathoexcitation, and raises blood pressure. All effects are attenuated by systemic or intracerebroventricular administration of angiotensin II type 1 receptor (AT1R) antagonists. This study aimed to quantify the effects of CIH on AT1R- and AT2R-like immunoreactivity in the rostroventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), central regions that are important components of the extended chemoreflex pathway. Eighteen Sprague-Dawley rats were exposed to intermittent hypoxia (FIO2 = 0.10, 1 min at 4-min intervals) for 10 hr/day for 1, 5, 10, or 21 days. After exposure, rats were deeply anesthetized and transcardially perfused with phosphate buffered saline (PBS) followed by 4% paraformaldehyde in PBS. Brains were removed and sectioned coronally into 50 µm slices. Immunohistochemistry was used to quantify AT1R and AT2R in the RVLM and the PVN. In the RVLM, CIH significantly increased the AT1R-like immunoreactivity, but did not alter AT2R immunoreactivity, thereby augmenting the AT1R:AT2R ratio in this nucleus. In the PVN, CIH had no effect on immunoreactivity of either receptor subtype. The current findings provide mechanistic insight into increased basal sympathetic outflow, enhanced chemoreflex sensitivity, and blood pressure elevation observed in rodents exposed to CIH.

Evaluation of Breath-Holding Test in Assessment of Peripheral Chemoreflex Sensitivity in Patients with Chronic Heart Failure.

Background:The sensitivity of peripheral chemoreflex is a marker of the severity of heart failure and the prognosis of the outcome in these patients. The assessment of chemosensitivity in these patients remains an actual problem.Objective:The aim of the study was to explore the relationship between a Breath-Holding Test (BHT) and single-breath carbon dioxide test and to evaluate the reliability of both tests in patients with Heart Failure (HF).Method:The study was performed in 43 patients with chronic heart failure. All subjects underwent BHT and single-breath carbon dioxide (CB-CO2), the evaluation of both tests was repeated a month later. Relationship of two test was evaluated by correlation analysis. Reliability was assessed with calculation of Standard Error of Measurement (SEM), Coefficient of Variation (CV) and Intraclass Correlation Coefficient (ICC).Results:The duration of the breath-holding was inversely correlated to the result of CB-CO2 test (r = -0.86 at first measurement and r = -0.79 after a month) The ICC was 0.87 (95%CI: 0.78–0.93) for SB-CO2 test and 0,93 (95%CI: 0.88–0.96) for BHT, the CV was 24% for SB-CO2 and 13% for BHT. SEM for SB-CO2 test was 0.04 L / min / mmHg and limits of variation was 0.11 L / min / mmHg; SEM for BHT was 3.6 sec and limits of variation was10 sec.Conclusion:Breath-holding test is a reliable and safe method for assessing the sensitivity of peripheral chemoreflex to carbon dioxide in patients with heart failure.

Voluntary breath-holding duration in healthy subjects with obesity: Role of peripheral chemosensitivity to carbon dioxide

ObjectiveThe present study aimed to explore the peripheral chemoreflex sensitivity in healthy subjects with high body mass index (BMI). MethodsWe studied 26 healthy men with obesity and 23 healthy men without obesity. All participants performed the breath-holding test in the morning, and the single-breath carbon dioxide (SB-CO2) test on the next day. ResultsThe sensitivity of peripheral chemoreceptors to CO2 did not differ between two groups (P = .47). In contrast, the duration of breath-holding was significantly lower in participants with elevated BMI (40.6 ± 10.5 s versus 47.2 ± 8.7 s; P < .05). In the multifactor regression model, only differences in waist-to-hip ratio (WHR) and SB-CO2 remained statistically significant (R2 for the model = 0.62, P < .001). ConclusionsThe sensitivity of peripheral chemoreflex to CO2 was preserved in healthy men with obesity. The higher sensitivity of peripheral chemoreflex to CO2 and higher WHR were associated with a decrease in the duration of voluntary apnea in subjects with obesity.

PACAP-(6-38) or kynurenate microinjections in the RVLM prevent the development of sympathetic long-term facilitation after acute intermittent hypoxia.

Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF). The role of PACAP in mediating sLTF in response to intermittent activation of the RVLM was investigated in urethane-anaesthetized and artificially ventilated rats ( n = 65, Sprague-Dawley). Bilateral RVLM microinjections of the PACAP type 1 receptor/vasoactive intestinal polypeptide receptor type 2 receptor antagonist PACAP-(6-38) [ n = 6, change (Δ): -16.4 ± 6.5%) or an ionotropic glutamate antagonist, kynurenate ( n = 6, Δ:-7.2 ± 2.3%), blocked the development of acute intermittent hypoxia-induced sLTF ( n = 6, Δ: 49.2 ± 14.2%). Intermittent RVLM microinjections of glutamate caused sLTF ( n = 5, Δ: 56.9 ± 14.7%) that was abolished by PACAP-(6-38) pretreatment ( n = 5, Δ:-1.2 ± 4.7%). Conversely, intermittent microinjections of PACAP in the RVLM did not elicit sLTF. Intermittent bilateral disinhibition of the RVLM by microinjection of γ-aminobutyric acid in the caudal ventrolateral medulla did not elicit sLTF. Direct activation of RVLM neurons is crucial for the development of sLTF. PACAP and glutamate act synergistically in the RVLM, with both being necessary for the sLTF response. We found that activation of glutamate but not PACAP receptors is necessary and sufficient to generate sLTF, even in the absence of intermittent hypoxia. Our results demonstrate that PACAP within the RVLM may contribute to the development of obstructive sleep apnea -induced hypertension. NEW & NOTEWORTHY Pharmacological blockade of either pituitary adenylate cyclase-activating polypeptide (PACAP) or ionotropic glutamate receptors in the rostral ventrolateral medulla prevents development of sympathetic long-term facilitation. PACAP receptor inhibition prevents the occurrence of hypoxia-induced peripheral chemoreflex sensitization. Thus, PACAP receptors may be a potential therapeutic target serving to reduce heightened sympathetic tone and hypersensitized cardiovascular reflexes.

Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter?

Heart failure (HF) is a global public health problem that, independent of its etiology [reduced (HFrEF) or preserved ejection fraction (HFpEF)], is characterized by functional impairments of cardiac function, chemoreflex hypersensitivity, baroreflex sensitivity (BRS) impairment, and abnormal autonomic regulation, all of which contribute to increased morbidity and mortality. Exercise training (ExT) has been identified as a nonpharmacological therapy capable of restoring normal autonomic function and improving survival in patients with HFrEF. Improvements in autonomic function after ExT are correlated with restoration of normal peripheral chemoreflex sensitivity and BRS in HFrEF. To date, few studies have addressed the effects of ExT on chemoreflex control, BRS, and cardiac autonomic control in HFpEF; however, there are some studies that have suggested that ExT has a beneficial effect on cardiac autonomic control. The beneficial effects of ExT on cardiac function and autonomic control in HF may have important implications for functional capacity in addition to their obvious importance to survival. Recent studies have suggested that the peripheral chemoreflex may also play an important role in attenuating exercise intolerance in HFrEF patients. The role of the central/peripheral chemoreflex, if any, in mediating exercise intolerance in HFpEF has not been investigated. The present review focuses on recent studies that address primary pathophysiological mechanisms of HF (HFrEF and HFpEF) and the potential avenues by which ExT exerts its beneficial effects.

KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure.

Enhanced carotid body chemoreflex activity contributes to development of disordered breathing patterns, autonomic dysregulation and increases in incidence of arrhythmia in animal models of reduced ejection fraction heart failure. Chronic reductions in carotid artery blood flow are associated with increased carotid body chemoreceptor activity. Krüppel-like Factor 2 (KLF2) is a shear stress-sensitive transcription factor that regulates the expression of enzymes which have previously been shown to play a role in increased chemoreflex sensitivity. We investigated the impact of restoring carotid body KLF2 expression on chemoreflex control of ventilation, sympathetic nerve activity, cardiac sympatho-vagal balance and arrhythmia incidence in an animal model of heart failure. The results indicate that restoring carotid body KLF2 in chronic heart failure reduces sympathetic nerve activity and arrhythmia incidence, and improves cardiac sympatho-vagal balance and breathing stability. Therapeutic approaches that increase KLF2 in the carotid bodies may be efficacious in the treatment of respiratory and autonomic dysfunction in heart failure. Oscillatory breathing and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid body chemoreflex (CBC) sensitivity plays a role in this process and can be precipitated by chronic blood flow reduction. We hypothesized that downregulation of a shear stress-sensitive transcription factor, Krüppel-like Factor 2 (KLF2), mediates increased CBC sensitivity in CHF and contributes to associated autonomic, respiratory and cardiac sequelae. Ventilation (Ve), renal SNA (RSNA) and ECG were measured at rest and during CBC activation in sham and CHF rabbits. Oscillatory breathing was quantified as the apnoea-hypopnoea index (AHI) and respiratory rate variability index (RRVI). AHI (control 6±1/h, CHF 25±1/h), RRVI (control 9±3/h, CHF 29±3/h), RSNA (control 22±2% max, CHF 43±5% max) and arrhythmia incidence (control 50±10/h, CHF 300±100/h) were increased in CHF at rest ( 21%), as were CBC responses (Ve, RSNA) to 10% (all P<0.05vs. control). In vivo adenoviral transfection of KLF2 to the carotid bodies in CHF rabbits restored KLF2 expression, and reduced AHI (7±2/h), RSNA (18±2% max) and arrhythmia incidence (46±13/h) as well as CBC responses to hypoxia (all P<0.05 vs. CHF empty virus). Conversely, lentiviral KLF2 siRNA in the carotid body decreased KLF2 expression, increased chemoreflex sensitivity, and increased AHI (6±2/h vs. 14±3/h), RRVI (5±3/h vs. 20±3/h) and RSNA (24±4% max vs. 34±5% max) relative to scrambled-siRNA rabbits. In conclusion, down-regulation of KLF2 in the carotid body increases CBC sensitivity, oscillatory breathing, RSNA and arrhythmia incidence during CHF.

Inorganic nitrate supplementation attenuates peripheral chemoreflex sensitivity but does not improve cardiovagal baroreflex sensitivity in older adults.

Aging is associated with increased peripheral chemoreceptor activity, reduced nitric oxide (NO) bioavailability, and attenuation of cardiovagal baroreflex sensitivity (BRS), collectively increasing the risk of cardiovascular disease. Evidence suggests that NO may attenuate peripheral chemoreflex sensitivity and increase BRS. Exogenous inorganic nitrate ([Formula: see text]) increases NO bioavailability via the [Formula: see text]-[Formula: see text]-NO pathway. Our hypothesis was that inorganic [Formula: see text] supplementation would attenuate peripheral chemoreflex sensitivity and enhance spontaneous cardiovagal BRS in older adults. We used a randomized, placebo-controlled crossover design in which 13 older (67 ± 3 yr old) adults ingested beetroot powder containing (BRA) or devoid of (BRP) [Formula: see text] and [Formula: see text] daily over 4 wk. Spontaneous cardiovagal BRS was assessed over 15 min of rest and was quantified using the sequence method. Chemoreflex sensitivity was assessed via ~5 min of hypoxia (10% fraction of inspired O2) and reported as the slope of the relationship between O2 saturation (%[Formula: see text]) and minute ventilation (in l/min) or heart rate (in beats/min). Ventilatory responsiveness to hypoxia was reduced after BRA (from -0.14 ± 0.04 to -0.05 ± 0.02 l·min-1·%[Formula: see text]-1, P = 0.01) versus BRP (from -0.10 ± 0.05 to -0.11 ± 0.05 l·min-1·%[Formula: see text]-1, P = 0.80), with no differences in heart rate responsiveness (BRA: from -0.47 ± 0.06 to -0.33 ± 0.04 beats·min-1·%[Formula: see text]-1, BRP: from -0.48 ± 0.07 to -0.42 ± 0.06 beats·min-1·%[Formula: see text]-1) between conditions (interaction effect, P = 0.41). Spontaneous cardiovagal BRS was unchanged after BRA and BRP (interaction effects, P = 0.69, 0.94, and 0.39 for all, up, and down sequences, respectively), despite a reduction in resting systolic and mean arterial blood pressure in the experimental (BRA) group ( P < 0.01 for both). These findings illustrate that inorganic [Formula: see text] supplementation attenuates peripheral chemoreflex sensitivity without concomitant change in spontaneous cardiovagal BRS in older adults. NEW & NOTEWORTHY Exogenous inorganic nitrate supplementation attenuates ventilatory, but not heart rate, responsiveness to abbreviated hypoxic exposure in older adults. Additionally, inorganic nitrate reduces systolic and mean arterial blood pressure without affecting spontaneous cardiovagal baroreflex sensitivity. These findings suggest that inorganic nitrate may attenuate sympathetically oriented pathologies associated with aging.

Intermittent low-level lead exposure causes anxiety and cardiorespiratory impairment

Aim: To characterize behavioural and cardiorespiratory changes in a new, intermittent low-level lead exposure animal model. Introduction: Lead (Pb) is a cumulative toxic metal affecting all body systems that are particularly vulnerable during developmental phase. Permanent lead exposure has been defined as a cause of behavioural changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, no studies have been performed to describe a new, intermittent low-level lead exposure profile, that has been increased in the past years. Methods: Foetuses were intermittently (PbI) exposed to water containing lead acetate (0.2%, w/v) throughout life until adulthood (28 weeks of age). A control group (without exposure, CTL), matching in age and sex was used. At 26 weeks, behavioural tests were performed for anxiety (Elevated Plus Maze Test) and locomotor activity (Open Field Test) assessment. Blood pressure (BP), electrocardiogram (ECG), heart rate (HR) and respiratory frequency (RF) rates were recorded at 28 weeks of age. Baroreflex gain (BRG) and chemoreflex sensitivity (ChS) were calculated. Student's T-test was used (significance p<0.05) for statistical analysis. Results: An intermittent lead exposure causes hypertension (increased diastolic and mean BP), increased RF, decreased baroreflex function and increased ChS, without significant changes in HR, when compared to CTL group. Regarding behavioral changes, the intermittent lead exposure model showed an anxiety-like behaviour without changes in locomotor activity. Conclusion: Intermittent low-level lead exposure induces changes on the cardiorespiratory profile characterized by hypertension, carotid chemosensitivity and baroreflex impairment. According to behavioural tests results, this study also shows that the exposure to lead during developmental phases causes anxiety in adult animals without locomotor activity impairment. In summary, this study brings new insights on the environmental factors that influence nervous and cardiovascular systems during development, which can help creating public policy strategies to prevent and control the adverse effects of Pb toxicity.

Acute fall and long-term rise in oxygen saturation in response to meditation.

The effects of meditation on arterial and tissue oxygenation are unknown and difficult to assess because respiration is often altered, directly or indirectly, during meditation practice. Thus, changes in respiration may affect cardiovascular responses independently from meditation. In this study, we aim to isolate the specific effect of meditation on arterial and tissue oxygenation and other cardiorespiratory indexes while systematically controlling for the role of respiration. Furthermore, we aim to clarify to what extent prior expertise in meditation practice is needed to observe reliable changes. Eighty participants, half with and half without prior meditation experience, were tested while pacing breathing at predetermined rates, in the presence or absence of mantra meditation instructions, and in a body scan meditation that did not involve controlled breathing. Continuous recordings were acquired for arterial and brain oxygenation, respiratory excursion, electrocardiogram, skin vasomotion, and blood pressure. In both groups, meditation acutely decreased arterial and cerebral oxygen saturation, reduced chemoreflex sensitivity, and prolonged the RR interval, independently of respiration. Conversely, slow breathing improved heart rate variability, independently of concurrent meditation. In addition to the immediate effects of meditation, the individuals with long-term practice of meditation had overall higher arterial and cerebral oxygen saturation, overall lower blood pressure, and slower baseline respiration. Meditation acutely lowers arterial and tissue oxygenation. A repeated exposure to this condition may lead to long-term adaptation and, through increased ventilatory efficiency and improved gas exchanges, to an increase in baseline oxygenation. Meditation induces favorable changes in cardiovascular and respiratory end points of clinical interest.

P2425Effects of intravenous iron therapy on chemoreflex sensitivity and sleep disordered breathing in chronic heart failure

P2425Effects of intravenous iron therapy on chemoreflex sensitivity and sleep disordered breathing in chronic heart failure

Increased circadian variations in chemoreflex sensitivity in chronic heart failure

Respiratory function follows a circadian pattern, and rhythmic changes in carotid body sensitivity to blood gases may contribute to these oscillations in ventilation. Recent studies have demonstrated that the isolated rat carotid body shows enhanced responses to hypoxic and hypercapnic stimulation in the presence of melatonin, a nocturnally released hormone. Carotid body dysfunction is known to occur in several pathological conditions, including chronic heart failure (CHF). CHF is characterized by tonic hyperactivity and exaggerated reactivity of the carotid bodies to hypoxia and hypercapnia. Thus, we've begun to examine circadian rhythms in chemoreflex breathing in CHF to determine if the already heightened hypoxic and hypercapnic responses in CHF are further augmented during the night. Male Sprague‐Dawley rats were divided into either control or CHF groups. Heart failure was induced via coronary ligation. Chemoreflex breathing was assessed during the day and then again 12 hours later during the night. Animals were exposed to room air (baseline), hypoxia (10 % O2) and hypercapnia (5 % CO2). Percent change in respiratory rate from day to night were similar between CHF (17.1 % increase) and control (16.9 % increase) rats when exposed to room air, but hypoxic and hypercapnic challenges induced large circadian differences in CHF (hypoxia: 20.9 % increase; hypercapnia: 23.9 % increase) but not in control (hypoxia: 8.2 % increase; hypercapnia: 13.9 % increase) rats. CHF rats also showed robust night time circadian differences in tidal volume when exposed to room air (31.6 % increase), hypoxia (27.9 % increase), and hypercapnia (43.8 %). In contrast, circadian variations in tidal volume were attenuated in control rats (room air: 11 % increase; hypoxia: 15.6 % increase; hypercapnia: 11.0 % increase). Minute ventilation showed similar differences between CHF and control rats with CHF significantly augmenting circadian variations. CHF rats showed a 53.1 % increase in minute ventilation during the night, and a 52.9 % increase and a 78.2 % increase in response to hypoxia and hypercapnia, respectively. Control rats, in contrast, showed only a 27.7 % increase in minute ventilation to room air, a 25.1 % increase in response to hypoxia, and a 26.9 % increase in response to hypercapnia. Therefore, the data suggest that circadian rhythms in ventilatory responses are amplified in CHF. Future research may directly assess the contribution of the carotid bodies to this phenomenon.

Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats.

Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho-vagal imbalance. Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood. We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre-sympathetic regions of the brainstem. Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho-vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF. Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho-vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague-Dawley rats (n=32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho-vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean±SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2±4.0 vs. 9.7±2.6eventsh-1 ), autonomic imbalance [0.6±0.2 vs. 0.2±0.1 low/high frequency heart rate variability (LF/HFHRV )] and cardiac arrhythmias (196.0±239.9 vs. 19.8±21.7eventsh-1 ). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6±43.2% vs. 296.0±43.9% LF/HFHRV , normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0±239.9 vs. 576.7±472.9eventsh-1 ) and diastolic dysfunction (0.008±0.004 vs. 0.027±0.027mmHgμl-1 ). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF.

The Influence of Age on Interaction between Breath-Holding Test and Single-Breath Carbon Dioxide Test.

Introduction. The aim of the study was to compare the breath-holding test and single-breath carbon dioxide test in evaluation of the peripheral chemoreflex sensitivity to carbon dioxide in healthy subjects of different age. Methods. The study involved 47 healthy volunteers between ages of 25 and 85 years. All participants were divided into 4 groups according to age: 25 to 44 years (n = 14), 45 to 60 years (n = 13), 60 to 75 years (n = 12), and older than 75 years (n = 8). Breath-holding test was performed in the morning before breakfast. The single-breath carbon dioxide (SB-CO2) test was performed the following day. Results. No correlation was found between age and duration of breath-holding (r = 0.13) and between age and peripheral chemoreflex sensitivity to CO2 (r = 0.07). In all age groups there were no significant differences in the mean values from the breath-holding test and peripheral chemoreflex sensitivity tests. In all groups there was a strong significant inverse correlation between breath-holding test and SB-CO2 test. Conclusion. A breath-holding test reflects the sensitivity of the peripheral chemoreflex to carbon dioxide in healthy elderly humans. Increasing age alone does not alter the peripheral ventilatory response to hypercapnia.

Endurance training attenuates the increase in peripheral chemoreflex sensitivity with intermittent hypoxia.

Patients with heart failure and sleep apnea have greater chemoreflex sensitivity, presumably due to intermittent hypoxia (IH), and this is predictive of mortality. We hypothesized that endurance training would attenuate the effect of IH on peripheral chemoreflex sensitivity in healthy humans. Fifteen young healthy subjects (9 female, 26 ± 1 yr) participated. Between visits, 11 subjects underwent 8 wk of endurance training that included running four times/wk at 80% predicted maximum heart rate and interval training, and four control subjects did not change activity. Chemoreflex sensitivity (the slope of ventilation responses to serial oxygen desaturations), blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were assessed before and after 30 min of IH. Endurance training decreased resting systolic blood pressure (119 ± 3 to 113 ± 3 mmHg; P = 0.027) and heart rate (67 ± 3 to 61 ± 2 beats/min; P = 0.004) but did not alter respiratory parameters at rest (P > 0.2). Endurance training attenuated the IH-induced increase in chemoreflex sensitivity (pretraining: Δ 0.045 ± 0.026 vs. posttraining: Δ -0.028 ± 0.040 l·min-1·% O2 desaturation-1; P = 0.045). Furthermore, IH increased mean blood pressure and MSNA burst rate before training (P < 0.05), but IH did not alter these measures after training (P > 0.2). All measurements were similar in the control subjects at both visits (P > 0.05). Endurance training attenuates chemoreflex sensitization to IH, which may partially explain the beneficial effects of exercise training in patients with cardiovascular disease.

Breath-holding test in evaluation of peripheral chemoreflex sensitivity in healthy subjects

The aim of the study was to determine the feasibility of using a breath-holding test in assessing the sensitivity of the peripheral chemoreflex compared with the single-breath carbon dioxide test.The study involved 48 healthy volunteers between the ages of 18–29 years. The breath-holding test was performed followed by the single-breath carbon dioxide test on the next day. A month after the first tests, these tests were repeated to evaluate their reproducibilityThe coefficient of variability in the single-breath carbon dioxide test ranged from 0 to 32% with a mean of 10±7%. The mean coefficient of variability of the breath-holding test was 6±4% (0–19%).A significant inverse correlation between the results of the two tests was noted following analysis (r=−0.82, p<0.05). ConclusionA breath-holding test after deep inspiration reflects the sensitivity of the peripheral chemoreflex as defined by the single-breath carbon dioxide test in healthy subjects.

Hypertension Editors' Picks: Hypertension and Sleep.

Hypertension Editors' Picks: Hypertension and Sleep.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension. The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n=9) or sham CSD (n=9) 5weeks after renal artery clipping, in comparison with normal Wistar rats (n=5). After 21days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98±4mmHg vs. 2K1C: 147±8mmHg; P<0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P<0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14±2mmHg by week 3 (P<0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension.

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

ISH NIA OS-04 P2X3 RECEPTOR ACTIVITY IN THE CAROTID BODY (CB) OF SPONTANEOUSLY HYPERTENSIVE (SH) RATS CONTRIBUTES TO INCREASED CHEMOREFLEX HYPERSENSITIVITY AND HYPERTENSION

Objective: Arterial hypertension is associated with increases in both peripheral chemoreceptor reflex sensitivity and sympathetic nerve activity (SNA). We have shown that CB resection in SH rats reduces arterial pressure (AP; McBryde et al. 2013). Since P2X3 receptors exist in the rat CB and P2X3 receptor activity is associated with afferent hyperreflexia (Ford et al. 2015), we hypothesized that P2X3 receptor would be upregulated in the CB of SH vs normotensive (Wistar) control rats and that a selective P2X3 receptor antagonist (AF-219) would reduce chemoreflex hypersensitivity, AP and SNA in SH rats. Design and Method: SH and Wistar rats were implanted with radio-telemetry devices to record AP and renal SNA (RSNA) in conscious animals. Animals were infused with AF-219 (8 mg/kg/h) or vehicle i.v. for 1 h. The CB was stimulated with sodium cyanide (120 μg/kg i.v.). Western blotting and immunohistochemistry revealed the level of expression and localisation of P2X3 receptor protein in the CB, respectively. Results: In the CB, P2X3 receptor protein was upregulated four fold in SH vs Wistar rat (P < 0.05). Glomus cells of SH rat (identified as expressing tyrosine hydroxylase) and afferent nerve fibres were immunopositive for P2X3 receptors. In contrast, in Wistar rats, glomus cells expressing P2X3 receptors were fewer and P2X3 was not detected in nerve fibres. Infusion of AF-219 reduced: CB hyperreflexia (P < 0.05); AP (systolic −28 ± 3mmHg; P < 0.001) and RSNA (34%; P < 0.01). No changes in chemoreflex sensitivity, AP or RSNA were detected after vehicle or AF-219 infusion in Wistar rats. Conclusions: We surmise that upregulation of P2X3 receptors in the CB of SH rats contributes to chemoreflex hypersensitivity. Further, antagonism of P2X3 receptors lowers both AP and RSNA substantially in SH rats. Thus, P2X3 receptor antagonists may provide a novel way to attenuate CB over-activity and offer a novel approach for controlling hypertension. Supported by: Afferent Pharmaceuticals

Spinal cord injury is associated with enhanced peripheral chemoreflex sensitivity.

Sleep‐disordered breathing (SDB) is prevalent in individuals with chronic spinal cord injury (SCI), but the exact mechanism is unknown. The aim of this study was to investigate whether peripheral chemoreceptors activity is enhanced in individuals with chronic SCI compared to abled‐bodied control subjects using CO 2 and O2 chemical tests. In protocol (1) 30 subjects (8 cervical [cSCI], 7 thoracic [tSCI] and 15 able‐bodied [AB]) were studied to determine the ventilatory response to hyperoxia during wakefulness in the supine position. In protocol (2) 24 subjects (6 cSCI, 6 tSCI, and 12 AB subjects) were studied to determine the ventilatory response to a single breath of CO 2 (SBCO 2). The chemoreflex response to SBCO 2 was calculated as ∆VE/∆CO 2 (L/min/mmHg). The ventilatory response to hyperoxia was defined as the % change in VT following acute hyperoxia compared to preceding baseline. During hyperoxia SCI subjects had a significant decrease in VT and VE (63.4 ± 21.7% and 63.1 ± 23.0% baseline, respectively, P < 0.05) compared to AB (VT: 87.1 ± 14.3% and VE: 91.38 ± 15.1% baseline, respectively, P < 0.05). There was no significant difference between cSCI and tSCI in the VT or VE during hyperoxia (P = NS). There was no significant correlation between AHI and VE% baseline (r = −0.28) in SCI and AB (n = 30). SCI participants had a greater ventilatory response to an SBCO 2 than AB (0.78 ± 0.42 L/min/mmHg vs. 0.26 ± 0.10 L/min/mmHg, respectively, P < 0.05). Peripheral ventilatory chemoresponsiveness is elevated in individuals with chronic SCI compared to able‐bodied individuals.