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The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e., the mechanism by which brain PCO2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of congenital central hypoventilation syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine, through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation. [ABSTRACT FROM AUTHOR]

The Kölliker-Fuse (KF) region, located in the dorsolateral pons, projects to several brainstem areas involved in respiratory regulation, including the chemoreceptor neurons within the retrotrapezoid nucleus (RTN). Several lines of evidence indicate that the pontine KF region plays an important role in the control of the upper airways for the maintenance of appropriate airflow to and from the lungs. Specifically, we hypothesized that the KF region is involved in mediating the response of the hypoglossal motor activity to central respiratory chemoreflex activation and to stimulation of the chemoreceptor neurons within the RTN region. To test this hypothesis, we combined immunohistochemistry and physiological experiments. We found that in the KF, the majority of biotinylated dextran amine (BDA)-labeled axonal varicosities contained detectable levels of vesicular glutamate transporter-2 (VGLUT2), but few contained glutamic acid decarboxylase-67 (GAD67). The majority of the RTN neurons that were FluorGold (FG)-immunoreactive (i.e., projected to the KF) contained hypercapnia-induced Fos, but did not express tyrosine hydroxylase. In urethane-anesthetized sino-aortic denervated and vagotomized male Wistar rats, hypercapnia (10% CO 2 ) or N-methyl- d -aspartate (NMDA) injection (0.1 mM) in the RTN increased diaphragm (Dia EMG ) and genioglossus muscle (GG EMG ) activities and elicited abdominal (Abd EMG ) activity. Bilateral injection of muscimol (GABA-A agonist; 2 mM) into the KF region reduced the increase in Dia EMG and GG EMG produced by hypercapnia or NMDA into the RTN. Our data suggest that activation of chemoreceptor neurons in the RTN produces a significant increase in the genioglossus muscle activity and the excitatory pathway is dependent on the neurons located in the dorsolateral pontine KF region. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the degree of sympathetic postganglionic neuronal loss required to impair cardiovascular-related sympathetic activity. To produce neuronal loss separate groups of rats were treated daily with guanethidine for either 5 days or 11 days, followed by a recovery period. Sympathetic activity was measured by renal sympathetic nerve activity (RSNA). Stereology of thoracic (T13) ganglia was performed to determine neuronal loss. Despite loss of more than two thirds of neurons in T13 ganglia in both treated groups no effect on resting blood pressure (BP) or heart rate (HR) was detected. Basal RSNA in rats treated for 5 days (0.61 ± 0.10 μV ∗ s) and 11 days (0.37 ± 0.08 μV ∗ s) was significantly less than vehicle-treated rats (0.99 ± 0.13 μV ∗ s, p < 0.05). Increases in RSNA by baroreceptor unloading were significantly lower in 5-day (1.09 ± 0.19 μV ∗ s) and 11-day treated rats (0.59 ± 0.11 μV ∗ s) compared with vehicle-treated rats (1.82 ± 0.19 μV ∗ s, p < 0.05). Increases in RSNA to chemoreceptor stimulation were significantly lower in 5-day treated rats (1.54 ± 0.25 μV ∗ s) compared with vehicle-treated rats (2.69 ± 0.23 μV ∗ s, p < 0.05). Increases in RSNA in 11-day treated rats were significantly lower (0.75 ± 0.15 μV ∗ s, p < 0.05) compared with both vehicle-treated and 5-day treated rats. A positive correlation of neurons to sympathetic responsiveness but not basal activity was detected. These data suggest that diminished capacity for reflex sympathetic responsiveness rather than basal activity alone must be assessed for complete detection of neurophysiological cardiovascular impairment. [ABSTRACT FROM AUTHOR]

The rostroventrolateral medulla contains two functional neuronal populations: (1) the parafacial respiratory group (pFRG) neurons and (2) the chemosensitive retrotrapezoid nucleus (RTN) neurons. Using anatomical and physiological techniques, we investigated the role of the RTN/pFRG in CO 2 -induced active expiration (AE) in urethane-anesthetized rats. Anterograde tracing using biotinylated dextran amine (BDA) revealed dense neuronal projections emanating from the RTN/pFRG to the caudal ventral respiratory group (cVRG), 60% of which contained vesicular glutamate transporter-2. The minority (16%) of the RTN projections to the cVRG emanated from Phox2b positive neurons. Hypercapnia (10% CO 2 ) increased Dia EMG and elicited Abd EMG activity. Bilateral injections of muscimol (2 mM) into the RTN/pFRG reduced the activation of Dia EMG (23 ± 4%) and abolished AE-induced by chemoreflex stimulation. Taken together, these results support the presence of direct excitatory projections from RTN/pFRG neurons to cVRG expiratory premotor neurons, playing a role in the generation/modulation of AE. [ABSTRACT FROM AUTHOR]

Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1 G93A Taconic rat groups (an ALS model). Meta-analysis results indicate: (1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; (2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ∼1.0; and (3) consistently reduced activity in end-stage SOD1 G93A rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease. [ABSTRACT FROM AUTHOR]

Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DATph2-/-) rats. DATph2-/- rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (~50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DATph2-/- rats. Body temperature was also maintained in adult DATph2-/- rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DATph2-/- rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. [ABSTRACT FROM AUTHOR]

Short-term and long-term blood pressure (BP) regulation and its maintenance at levels adequate to perfuse tissue organs involve an integrated action of multiple neural, cardiovascular, renal, endocrine and local tissue control systems. In the recent year, there has been a growing interest in the understanding of neural pathways key to BP control. For instance, through major advances in studies using both anesthetized and conscious animals, our knowledge of the essential neural mechanisms that subserve the baroreceptor, cardiopulmonary and chemoreceptor reflexes, and those evoked by the activation of stress pathways has dramatically increased. While the importance of these neural pathways in the maintenance of cardiovascular homeostasis is well established, the recognition of the central processing nuclei that integrate various afferent inputs to produce synchronous adjustments of autonomic outflows is still progressively expanding. Based on the literature provided thus far, the present review provides an overview in relation to the important neural determinants of BP control and later offers a concise description of major neuronal pathways that control autonomic outflows to the cardiovascular system in the short and long term. [ABSTRACT FROM AUTHOR]

Human studies use varying levels of low-dose (1-4 µg·kg-1·min-1) dopamine to examine peripheral chemosensitivity, based on its known ability to blunt carotid body responsiveness to hypoxia. However, the effect of dopamine on the ventilatory responses to hypoxia is highly variable between individuals. Thus we sought to determine 1) the dose response relationship between dopamine and peripheral chemosensitivity as assessed by the ventilatory response to hypoxia in a cohort of healthy adults, and 2) potential confounding cardiovascular responses at variable low doses of dopamine. Young, healthy adults (n = 30, age = 32 ± 1, 24 male/6 female) were given intravenous (iv) saline and a range of iv dopamine doses (1-4 µg·kg-1·min-1) prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects initially received iv saline, and after each HVR the dopamine infusion rate was increased by 1 µg·kg-1·min-1. Tidal volume, respiratory rate, heart rate, blood pressure, and oxygen saturation were continuously measured. Dopamine significantly reduced HVR at all doses (P > 0.05). When subjects were divided into high (n = 13) and low (n = 17) baseline chemosensitivity, dopamine infusion (when assessed by dose) reduced HVR in the high group only (P < 0.01), with no effect of dopamine on HVR in the low group (P > 0.05). Dopamine infusion also resulted in a reduction in blood pressure (3 µg·kg-1·min-1) and total peripheral resistance (1-4 µg·kg-1·min-1), driven primarily by subjects with low baseline chemosensitivity. In conclusion, we did not find a single dose of dopamine that elicited a nadir HVR in all subjects. Additionally, potential confounding cardiovascular responses occur with dopamine infusion, which may limit its usage. [ABSTRACT FROM AUTHOR]

Background Pulmonary artery hypertension (PH), associated with increased left ventricular (LV) diastolic pressure and pulmonary vasoconstriction, is frequently observed in heart failure (HF), where it holds prognostic significance. We hypothesized that Cheyne–Stokes respiration (CSR) may contribute to increased pulmonary arterartery pressure (PAP) and right ventricular (RV) remodeling in HF, via hypoxia/hypercapnia cycles and adrenergic activation by the chemoreflex stimulation. Methods Seventy-two HF patients(57 males, aged 65.1 SD 12.3 years, LV ejection fraction < 50%, 33.2 SD 7.5%), on guideline recommended pharmacological/device treatment underwent thorough clinical, echocardiographic and neurohormonal assessment, 24-hour cardiorespiratory screening for arrhythmias and CSR, and chemoreflex test for hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses. Results Twenty patients (28%) showed significant CSR (24-hour apnea–hypopnea index, AHI ≥ 15). Patients with CSR presented with: a) higher systolic pulmonary artery pressure (sPAP: 42.8 standard deviation—SD 10.1 vs 32.3 SD 5.7 mmHg, p < 0.001), despite similar LV systolic and diastolic function; b) indexes of right chamber remodeling (all p < 0.05); c) enhanced HVR (median 0.78, interquartile range—IR 0.46–1.22 vs 0.42, IR 0.18–0.67 L/min/%, p = 0.01) and HCVR (1.17, IR 0.97–1.29 vs 0.72, IR 0.47–0.93 L/min/mmHg, p = 0.02); d) increased plasma norepinephrine levels (690, IR 477–868 vs 366, IR 226–508 ng/L, p < 0.001). Univariate predictors of sPAP > 35 mmHg were AHI, HVR, HCVR; only AHI maintained its predictive value at multivariate analysis (p = 0.017). Conclusions CSR may contribute to increased pulmonary artery pressure and right chamber remodeling in HF, independently of the severity of LV systolic and diastolic dysfunction, likely via recurrent hypoxia/hypercapnia cycles and chemoreflex mediated adrenergic discharge. [ABSTRACT FROM AUTHOR]

This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume ( SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective. [ABSTRACT FROM AUTHOR]

In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 µg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 µg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (227%, P < 0.019) and integrated (↓48%, P < 0.004) pressor components of the reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the effect of amiodarone on mean arterial pressure (MAP), heart rate (HR), baroreflex, Bezold-Jarisch, and peripheral chemoreflex in normotensive and chronic one-kidney, one-clip (1K1C) hypertensive rats (N = 9 to 11 rats in each group). Amiodarone (50 mg/kg, iv) elicited hypotension and bradycardia in normotensive (-10 ± 1 mmHg, -57 ± 6 bpm) and hypertensive rats (-37 ± 7 mmHg, -39 ± 19 bpm). The baroreflex index (deltaHR/deltaMAP) was significantly attenuated by amiodarone in both normotensive (-0.61 ± 0.12 vs -1.47 ± 0.14 bpm/mmHg for reflex bradycardia and -1.15 ± 0.19 vs -2.63 ± 0.26 bpm/mmHg for reflex tachycardia) and hypertensive rats (-0.26 ± 0.05 vs -0.72 ± 0.16 bpm/mmHg for reflex bradycardia and -0.92 ± 0.19 vs -1.51 ± 0.19 bpm/mmHg for reflex tachycardia). The slope of linear regression from deltapulse interval/deltaMAP was attenuated for both reflex bradycardia and tachycardia in normotensive rats (-0.47 ± 0.13 vs -0.94 ± 0.19 ms/mmHg and -0.80 ± 0.13 vs -1.11 ± 0.13 ms/mmHg), but only for reflex bradycardia in hypertensive rats (-0.15 ± 0.02 vs -0.23 ± 0.3 ms/mmHg). In addition, the MAP and HR responses to the Bezold-Jarisch reflex were 20-30% smaller in amiodarone-treated normotensive or hypertensive rats. The bradycardic response to peripheral chemoreflex activation with intravenous potassium cyanide was also attenuated by amiodarone in both normotensive (-30 ± 6 vs -49 ± 8 bpm) and hypertensive rats (-34 ± 13 vs -42 ± 10 bpm). On the basis of the well-known electrophysiological effects of amiodarone, the sinus node might be the responsible for the attenuation of the cardiovascular reflexes found in the present study.

Several studies have reported impairment in cardiovascular function and control in diabetes. The studies cited in this review were carried out from a few days up to 3 months after streptozotocin administration and were concerned with the control of the circulation. We observed that early changes (5 days) in blood pressure control by different peripheral receptors were maintained for several months. Moreover, the impairment of reflex responses observed after baroreceptor and chemoreceptor stimulation was probably related to changes in the efferent limb of the reflex arc (sympathetic and parasympathetic), but changes also in the central nervous system could not be excluded. Changes in renal sympathetic nerve activity during volume expansion were blunted in streptozotocin-treated rats, indicating an adaptive natriuretic and diuretic response in the diabetic state. The improvement of diabetic cardiovascular dysfunction induced by exercise training seems to be related to changes in the autonomic nervous system. Complementary studies about the complex interaction between circulation control systems are clearly needed to adequately address the management of pathophysiological changes associated with diabetes.

It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders.

Brainstem catecholamine neurons modulate sensory information and participate in control of cardiorespiratory function. These neurons have multiple projections, including to the paraventricular nucleus (PVN), which contributes to cardiorespiratory and neuroendocrine responses to hypoxia. We have shown that PVN-projecting catecholaminergic neurons are activated by hypoxia, but the function of these neurons is not known. To test the hypothesis that PVN-projecting catecholamine neurons participate in responses to respiratory challenges, we injected IgG saporin (control; n = 6) or anti-dopamine β-hydroxylase saporin (DSAP; n = 6) into the PVN to retrogradely lesion catecholamine neurons projecting to the PVN. After 2 wk, respiratory measurements (plethysmography) were made in awake rats during normoxia, increasing intensities of hypoxia (12, 10, and 8% O2) and hypercapnia (5% CO2-95% O2). DSAP decreased the number of tyrosine hydroxylase- immunoreactive terminals in PVN and cells counted in ventrolateral medulla (VLM; --37%) and nucleus tractus solitarii (nTS; --36%). DSAP produced a small but significant decrease in respiratory rate at baseline (during normoxia) and at all intensities of hypoxia. Tidal volume and minute ventilation (VE) index also were impaired at higher hypoxic intensities (10-8% O2; e.g., VE at 8% O2: IgG = 181 ± 22, DSAP = 91 ± 4 arbitrary units). Depressed ventilation in DSAP rats was associated with significantly lower arterial O2 saturation at all hypoxic intensities. PVN DSAP also reduced ventilatory responses to 5% CO2 (VE: IgG = 176 ± 21 and DSAP = 84 ± 5 arbitrary units). Data indicate that catecholamine neurons projecting to the PVN are important for peripheral and central chemoreflex respiratory responses and for maintenance of arterial oxygen levels during hypoxic stimuli. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that neural coding patterns exist within the autonomic nervous system. We investigated sympathetic axonal recruitment strategies in humans during chemoreflex- and baroreflexmediated sympathoexcitation using a novel action potential (AP) analysis technique. Muscle sympathetic nerve activity (microneurography) was collected in 11 young individuals (6 females) during baseline and two subsequent protocols: 1) severe chemoreflex stimulation (maximal end-inspiratory apnea following rebreathe), and 2) severe baroreceptor unloading (-80 mmHg lower body negative pressure; LBNP). When compared with each respective baseline, apnea and LBNP increased AP frequency and mean AP content per sympathetic burst (all P < 0.01). When APs were binned according to peak-to-peak amplitude (i.e., into "clusters"), total clusters detected increased during both apnea (Δ7 ± 5; P = 0.0009) and LBNP (Δ11 ± 8; P = 0.0012) compared with baseline. This was concomitant to an increased number of active clusters per burst during apnea (Δ3 ± 1; P < 0.0001) and LBNP (Δ3 ± 3; P = 0.0076). At baseline and during apnea (R² = 0.98; P < 0.0001) and LBNP (R² = 0.95; P < 0.0001), a pattern emerged whereby AP cluster latency decreased as cluster size increased. Furthermore, the AP cluster latency profile was shifted downward during apnea (~53 ms) and upward during LBNP (~31 ms). The data indicate that variations in synaptic delays and latent subpopulations of larger axons exist as recruitment strategies for sympathetic outflow. The synaptic delay component appears to express reflex specificity, whereas latent subpopulation recruitment demonstrates sensitivity to stress severity. [ABSTRACT FROM AUTHOR]

Aim The peripheral chemoreflex is augmented in heart failure, and it may contribute to sympathoexcitation. This study aimed to investigate both the chemoreflex and the cardiac sympathetic nerve activity in the acute-stage post-myocardial infarction. Methods Myocardial infarction was induced in male adult Sprague-Dawley rats by permanent ligation of the left anterior descending coronary artery. Within-animal repeated measure assessment of normoxic and hypoxic ventilation patterns was determined with whole-body plethysmography and compared to sham-operated controls. Cardiac function, morphology and cardiac sympathetic nerve activity were determined 14 days later. Results Infarction induced increases in normoxic ventilation through increases in tidal volume within 3 days. At the same time points, the hypoxic ventilatory response to short durations (10 min) of hypoxia (8, 10 and 12% inspired O2) was blunted. At the end of the experiment (D14), increases in nerve activity, specifically through increased firing rate, and significant cardiac dysfunction (ejection fraction 43%) were observed in myocardial infarction ( MI) group. Conclusions An augmentation of normoxic ventilation caused by myocardial infarction occurs before the amplification of the hypoxic ventilatory response. It occurs much earlier following myocardial injury than previously demonstrated and may have a role in initiating cardiac sympathoexcitation. The difference in the augmentation of hypoxic response between early and late stages post-myocardial infarction suggest that the initial change in the chemoreflex is an alteration to the operating point of chemoreflex. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of blockade of the excitatory amino acid (EAA) receptors in the dorsomedial hypothalamic (DMH) area on the ventilatory and cardiovascular responses of the chemoreflex activation in conscious rats. Bilateral microinjection of kynurenic acid (2.7 nmol, n = 6) into the DMH area reduced the tachypneic (+264 ± 13 versus +204 ± 14 cpm, P < 0.05) and pressor (+52 ± 5 versus +31 ± 6 mmHg, P < 0.05) components of chemoreflex but had no effect on the bradycardic component (−214 ± 7 versus −244 ± 17 bpm) of the chemoreflex. The magnitudes of the reduction in pressor and tachypneic chemoreflex responses were not significantly correlated ( r = 0.308, P = 0.330). These data indicate that neurons located in the DMH area are activated by chemoreflex; that this activation is mediated via EAA receptors; and that it is essential for the full expression of the respiratory component of the chemoreflex. [ABSTRACT FROM AUTHOR]

Removal of carotid body (CB) improves animal models of hypertension (HTN) and heart failure, via withdrawal of chemoreflex-induced sympathetic activation. Effect of CB tumor (CBT) resection on blood pressure (BP) in subjects with HTN is unknown. A retrospective analysis of 20 subjects with HTN (BP≥140/90 mmHg or anti-hypertensives use) out of 134 with CBT resection. Short-term (30 days from surgery) and long-term (slope of regressions on time over the entire follow-up) changes in BP and heart rate were adjusted for covariates (interval between readings, total follow-up, number of readings and changes in therapy). Age and duration of HTN were 56±4 and 9±5 years. Adjusted short-term decreases in systolic (SBP: -9.9±3.1, p<0.001) and pulse pressures (PP: -7.9±2.7, p<0.002) were significant and correlated with their respective long-term changes (SBP: r=0.47, p=0.047; PP: r=0.54, p=0.019). There was a strong relationship between adjusted short-term changes in SBP and PP (r=0.64, p<0.004). Six (50% of responders or 33% of the total) had short-term falls of SBP ≥10 mmHg and of PP ≥ 5mmHg. First study to show that unilateral CBT resection is associated with sustained reduction of BP in hypertensive patients. Targeted CB chemoreflex removal could play a role in the therapy of human HTN. [ABSTRACT FROM AUTHOR]

Leptin, a peptide hormone produced by adipose tissue, acts in brain centers that control critical physiological functions such as metabolism, breathing and cardiovascular regulation. The importance of leptin for respiratory control is evident by the fact that leptin deficient mice exhibit impaired ventilatory responses to carbon dioxide (CO 2 ), which can be corrected by intracerebroventricular leptin replacement therapy. Leptin is also recognized as an important link between obesity and hypertension. Humans and animal models lacking either leptin or functional leptin receptors exhibit many characteristics of the metabolic syndrome, including hyperinsulinemia, insulin resistance, hyperglycemia, dyslipidemia and visceral adiposity, but do not exhibit increased sympathetic nerve activity (SNA) and have normal to lower blood pressure (BP) compared to lean controls. Even though previous studies have extensively focused on the brain sites and intracellular signaling pathways involved in leptin effects on food intake and energy balance, the mechanisms that mediate the actions of leptin on breathing and cardiovascular function are only beginning to be elucidated. This mini-review summarizes recent advances on the effects of leptin on cardiovascular and respiratory control with emphasis on the neural control of respiratory function and autonomic activity. [ABSTRACT FROM AUTHOR]

Chemoreceptor activation increases phrenic nerve activity (PNA) and sympathetic nerve activity (SNA). The dorsolateral pontine neurons, including the parabrachial nucleus and the Kölliker-Fuse (KF) region project to several brainstem areas involved in autonomic and respiratory regulation. Here the objective was to further test the hypothesis that the KF region could contribute to central and peripheral sympathetic chemoreflex activation. In urethane-anesthetized sino-aortic denervated or intact and vagotomized male Wistar rats ( N = 7-8/group), hypercapnia (end-expiratory CO from 5 to 10 %) or KCN increased mean arterial pressure (MAP), splanchnic SNA, and PNA frequency and amplitude. Bilateral injection of muscimol (GABA-A agonist; 2 mM-50 nl) into the KF region increased resting PNA amplitude and reduced resting PNA frequency, without significant changes in resting MAP and SNA. Bilateral blockade of the KF region reduced the rise in MAP, sSNA, and PNA frequency and amplitude produced by hypercapnia or hypoxia. Our data suggest that the KF neurons could integrate and modulate breathing and sympathetic outflow during chemoreceptor activation. [ABSTRACT FROM AUTHOR]

Background Pulmonary Arterial Hypertension (PAH) is a disease associated with increased arteriolar resistance in the lungs. Due to hypoxemia, some physiological mechanisms can be posteriorly affected, including respiratory and cardiovascular reflexes, but this has not yet been fully investigated. This study aimed to evaluate how these mechanisms were affected by monocrotaline (MCT)-induced PAH and the possible therapeutic role of angiotensin converting enzyme inhibitor (ACEi), captopril, in reversing this remodeling process. Methods and results Groups of Wistar rats received MCT injections (60 mg kg −1 ). Three weeks later, they received captopril (CPT, 100 mg kg −1 ) in their drinking water (MCT + CPT) or water alone (MCT) for 2 weeks. As control, saline-treated animals received captopril in their drinking water (CPT) or water alone (CON), also for 2 weeks. Results showed that PAH was fully induced in the MCT group, evidenced by a high pulmonary index. Gasometrical and respiratory analyses showed hypoxemia and compensatory hyperventilation. CPT treatment brought these parameters to similar values to those observed in the CON group. We observed that autonomic dysfunction in the MCT group was suppressed by CPT. Finally, cardiovascular reflexes analysis showed increased chemoreflex responses in the MCT group, while baroreflex sensibility was decreased. Surprisingly, CPT normalized these reflex responses to values similar to the CON group. Conclusions The present study demonstrates that MCT-induced PAH induces compensatory respiratory responses, dysautonomia, and baroreflex dysfunction and increases chemoreflex responses. The data also indicate that CPT was effective in reversing these cardio-respiratory disorders, suggesting that ACEi could be a potential therapeutic target for PAH. [ABSTRACT FROM AUTHOR]

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (ΔfR) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔVT) followed the same trend. The effect of hypoxia on ΔfR was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide;3%FiCO2). ΔfR was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion,RTNneurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN. [ABSTRACT FROM AUTHOR]

The control of breathing is commonly viewed as being a “brainstem affair”. As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, “non-brainstem” structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease. There is a clear link between respiration and anxiety and key theories of the psychopathology of anxiety (including panic disorders; PD) focus on respiratory control and related CO 2 monitoring system. With that in mind, we briefly present the respiratory manifestations of panic disorder and discuss the role of the dorso-medial/perifornical hypothalamus, the amygdalar complex, and the periaqueductal gray in respiratory control. We then present recent advances in basic research indicating how adult rodent previously subjected to neonatal stress may provide a very good model to investigate the pathophysiology of PD. [ABSTRACT FROM AUTHOR]

Hypertension is a disease common in adults, with many risk factors and potentially life-threatening outcomes. Blood pressure is controlled by receptors that inform the brain about the amount of pressure inside the arteries, and the amount of oxygen and carbon dioxide in the blood, respectively. Research has revealed that baroreflex sensitivity (BRS) decreases with increasing age and that there is a high correlation between hypertension and low BRS. However, various studies with differing results have indicated that high blood pressure is what causes BRS to decline, and vice versa. Several studies have shown very conflicting results on the correlation between chemoreflex and age; there have been indications of chemoreflex having a positive, negative, and zero correlation with age. In several experiments, the surgical removal of the chemoreceptors of hypertensive rats was followed by a decrease in blood pressure. These animal experiments, and an additional noninvasive human experiment in which the chemoreceptors were temporarily "shut off," are reasons why more attention should be given to chemoreceptors as a route of alleviating hypertension., Competing Interests: Conflict of Interest None declared., (International College of Angiology. This article is published by Thieme.)

This study aimed to evaluate the cardiovascular component of the arterial chemoreflex in rats recovered from low protein diet. Male Fischer rats were randomly divided into control and recovered (R-PR) groups after weaning. R-PR rats were fed with low protein diet for 35 days and recovered under normal protein diet for 70 days. Control rats received normal protein diet for 105 days. Arterial chemoreflex was elicited by intravenous injection of KCN. Results showed that pressor response of the chemoreflex was increased in R-PR. Data suggest that protein restriction may alter cardiovascular response to chemical activation of the chemoreflex after recovery. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) is extensively applied to challenge cardiovascular and respiratory function, and to induce physiological acclimatization. The purpose of this study was to test the hypothesis that oxyhemoglobin equilibrium and tachycardiac responses during hypoxemia were enhanced after 14-day IH exposures. Normobaric-poikilocapnic hypoxia was induced with inhalation of 10% O2 for 5-6 min interspersed with 4 min recovery on eight nonsmokers. Heart rate (HR), arterial O2 saturation (SaO2), and end-tidal O2 (PETO2) were continuously monitored during cyclic normoxia and hypoxia. These variables were compared during the first and fifth hypoxic bouts between day 1 and day 14. There was a rightward shift in the oxyhemoglobin equilibrium response following 14-day IH exposures, as indicated by the greater PETO2 (an index of arterial PO2) at 50% of SaO2 on day 14 compared with day 1 [33.9 ± 1.5 vs. 28.2 ± 1.3 mmHg (P = 0.005) during the first hypoxic bout and 39.4 ± 2.4 vs. 31.4 ± 1.5 mmHg (P = 0.006) during the fifth hypoxic bout] and by the augmented gains of ΔSaO2/ΔPETO2 (i.e., deoxygenation) during PETO2 from 65 to 40 mmHg in the first (1.12 ± 0.08 vs. 0.80 ± 0.02%/mmHg, P = 0.001) and the fifth (1.76 ± 0.31 vs. 1.05 ± 0.06%/mmHg, P = 0.024) hypoxic bouts. Repetitive IH exposures attenuated (P = 0.049) the tachycardiac response to hypoxia while significantly enhancing normoxic R-R interval variability in low-frequency and high-frequency spectra without changes in arterial blood pressure at rest or during hypoxia. We conclude that 14-day IH exposures enhance arterial O2 delivery and improve vagal control of HR during hypoxic hypoxemia. [ABSTRACT FROM AUTHOR]

Non-invasive assessment of ventilatory control stability or loop gain (which is a key contributor in a number of sleep-related breathing disorders) has proven to be cumbersome. We present a novel multivariate autoregressive model that we hypothesize will enable us to make time-varying measurements of loop gain using nothing more than spontaneous fluctuations in ventilation and CO2. The model is adaptive to changes in the feedback control loop and therefore can account for system non-stationarities (e.g. changes in sleep state) and it is resistant to artifacts by using a signal quality measure. We tested this method by assessing its ability to detect a known increase in loop gain induced by proportional assist ventilation (PAV). Subjects were studied during sleep while breathing on continuous positive airway pressure (CPAP) alone (to stabilize the airway) or on CPAP+PAV. We show that the method tracked the PAV-induced increase in loop gain, demonstrating its time-varying capabilities, and it remained accurate in the face of measurement related artifacts. The model was able to detect a statistically significant increase in loop gain from 0.14±10 on CPAP alone to 0.21±0.13 on CPAP+PAV (p<0.05). Furthermore, our method correctly detected that the PAV-induced increase in loop gain was predominantly driven by an increase in controller gain. Taken together, these data provide compelling evidence for the validity of this technique. [ABSTRACT FROM AUTHOR]

Aims To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. Methods The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia ( FI O2 = 0.11) and hyperoxia ( FI O2 = 1); and at altitude ( FI O2 = 0.21 and 1). Skeletal muscle P2 Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. Results At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level ( P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FIO2. The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively ( P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2 Y2 receptor expression remained unchanged with altitude residence. Conclusions Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP. [ABSTRACT FROM AUTHOR]

In response to hypoxia, a net vasodilation occurs in the limb vasculature in young healthy humans and this is referred to as 'hypoxia-induced vasodilation'. We performed two separate experiments to determine (1) if hypoxia-induced forearm vasodilation is impaired in older men ( n = 8) compared to young men ( n = 7) and (2) if acute systemic infusion of ascorbic acid would enhance hypoxia-induced vasodilation in older men ( n = 8). Heart rate, mean arterial pressure, oxygen saturation, minute ventilation, forearm vascular conductance ( FVC, Doppler ultrasound), and cutaneous vascular conductance ( CVC, laser Doppler flowmetry) were recorded continuously while subjects breathed 10% oxygen for 5 min. Changes from baseline were compared between groups and between treatments. The older adults had a significantly attenuated increase in FBF (13 ± 4 vs. 30 ± 7%) and FVC (16 ± 4 vs. 30 ± 7%) in response to 5 min of hypoxia. However, skin blood flow responses were comparable between groups (young: 35 ± 9, older: 30 ± 6%). In Experiment 2, FVC responses to 5 min of breathing 10% oxygen were not significantly different following saline (3 ± 10%) and ascorbic acid (8 ± 10%) in the older men. Ascorbic acid also had no physiological effects in the young men. These findings advance our basic understanding of how aging influences vascular responses to hypoxia and suggest that, in healthy humans, hypoxia-induced vasodilation is not restrained by reactive oxygen species. [ABSTRACT FROM AUTHOR]

Abstract: The chemoreflexes exert significant control over respiration and sympathetic outflow. Abnormalities in chemoreflex function may contribute to various disease processes. Based on prior animal studies, we developed the hypothesis that acutely elevating circulating angiotensin II levels into the pathophysiological range increases chemoreflex responsiveness in healthy humans. Eighteen adults were studied before (Pre) and during (Post) low (protocol 1; 2ng/kg/min; n=9) or high (protocol 2; 5ng/kg/min; n=9) dose angiotensin II infusion (study day 1). Chemoreflex responses were quantified by the pure nitrogen breathing method [slope of the minute ventilation vs. arterial oxygen saturation plot generated during a series (n=10) of 100% inspired nitrogen exposures (1–8 breaths)] and by measuring responses to hypercapnia (7% inspired carbon dioxide). Responses to a non-chemoreflex stimulus were also determined (cold pressor test). Measurements were repeated on a subsequent day (study day 2) before and during infusion of a control vasoconstrictor (phenylephrine) infused at a dose (0.6–1.2μg/kg/min) sufficient to increase blood pressure to the same degree as that achieved during angiotensin II infusion. We found that despite increasing plasma angiotensin II levels to pathophysiological levels responses to pure nitrogen breathing, hypercapnia, and the cold pressor test were unchanged by low (2ng/kg/min) and high dose (5ng/kg/min) angiotensin II infusion (protocols 1 and 2). Similarly, responses measured during phenylephrine infusion (Post) were unchanged (from Pre). These findings indicate that acutely increasing plasma angiotensin II levels to levels observed in disease states, such as human heart failure, do not increase chemoreflex responsiveness in healthy humans. [Copyright &y& Elsevier]

Enhanced peripheral chemosensitivity (PChS) is a common finding in congestive heart failure (CHF). Although initially it may be regarded as a compensatory mechanism to maintain adequate oxygenation and tissue perfusion, importantly it also contributes to disease progression. The magnitude of PChS is related to the severity of CHF but does not depend on its etiology. Numerous methodologies have been developed to assess PChS reliably; however, only two methods based on acute hypoxia have proven to be clinically and prognostically useful. The pathophysiology behind increased PChS is complex and involves disturbances in regional blood flow, gaseous neurotransmission, redox processes, and angiotensin signaling. Augmented PChS is believed to translate into sympathetic overactivity, decreased barosensitivity, reduced exercise tolerance, more arrhythmic events, and poor outcomes. In this review, we present current knowledge regarding the pathophysiology of peripheral chemoreflex, available methods for assessment, and clinical significance of increased PChS. [ABSTRACT FROM AUTHOR]

It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders. [ABSTRACT FROM AUTHOR]

Clinical evidence indicates that obstructive sleep apnea is more common and more severe in men compared with women. Sex differences in the vasoconstrictor response to hypoxemia-induced sympathetic activation might contribute to this clinical observation. In the current laboratory study, we determined sex differences in the acute physiological responses to maximal voluntary end-expiratory apnea (MVEEA) during wakefulness in healthy young men and women (26 ± 1 yr) as well as healthy older men and women (64 ± 2 yr). Mean arterial pressure (MAP), heart rate (HR), brachial artery blood flow velocity (BBFV, Doppler ultrasound), and cutaneous vascular conductance (CVC, laser Doppler flowmetry) were measured, and changes in physiological parameters from baseline were compared between groups. The breath-hold duration and oxygen-saturation nadir were similar between groups. In response to MVEEA, young women had significantly less forearm vasoconstriction compared with young men (ΔBBFV: 2 ± 7 vs. -25 ± 6% and ΔCVC: -5 ± 4 vs. -31 ± 4%), whereas ΔMAP (12 ± 2 vs. 16 ± 3 mmHg) and ΔHR (4 ± 2 vs. 6 ± 3 bpm) were comparable between groups. The attenuated forearm vasoconstriction in young women was not observed in postmenopausal women (ΔBBFV -21 ± 5%). We concluded that young women have blunted forearm vasoconstriction in response to MVEEA compared with young men, and this effect is not evident in older postmenopausal women. These data suggest that female sex hormones dampen neurogenic vasoconstriction in response to apnea-induced hypoxemia. [ABSTRACT FROM AUTHOR]

In this study, we sought to determine the effects produced by cecal ligation and perforation (CLP) on the autonomic responses to the activation of peripheral chemoreflexes in conscious rats. The peripheral chemoreflex was activated with potassium cyanide (KCN; 40 μg·(0.1 mL)−1; intravenous injection (i.v.)) in male Wistar rats 3, 6, 12, and 24 h after CLP or sham surgery. The mean arterial pressure (MAP), heart rate (HR), and respiratory frequency ( fR) were recorded simultaneously. CLP surgery reduced the baseline MAP when compared with the sham animals. In the animals of the sham group, the autonomic responses to KCN produced increases in MAP and fR as well as a decrease in HR. However, 12 and 24 h after CLP surgery, the autonomic responses to KCN were attenuated. The restoration of MAP by i.v. injected l-NAME or phenylephrine did not restore the autonomic response to KCN in rats subjected to CLP. These data show that septic shock induced by CLP compromised the autonomic responses to peripheral chemoreflex activation in conscious rats, suggesting that an important regulatory mechanism is impaired during the course of this condition. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rabbits exposed to chronic (14d) normobaric (P B ≈719mmHg) hypoxia ( ). [•] Chronic normobaric hypoxia (CNH) increased hematocrit but stagnated body weight. [•] Carotid nerve responses to ACh and ATP applied to the petrosal ganglion after CNH. [•] ATP and ACh increased carotid nerve discharge frequency in a dose-dependent manner. [•] ACh- and ATP-induced responses significantly increased their duration after CNH. [Copyright &y& Elsevier]