Lung Stretch Receptors Research Articles

Treatment-emergent central sleep apnea: a unique sleep-disordered breathing.

Treatment-emergent central sleep apnea (TECSA) is a specific form of sleep-disordered breathing, characterized by the emergence or persistence of central apneas during treatment for obstructive sleep apnea. The purpose of this review was to summarize the definition, epidemiology, potential mechanisms, clinical characteristics, and treatment of TECSA. We searched for relevant articles up to January 31, 2020, in the PubMed database. The prevalence of TECSA varied widely in different studies. The potential mechanisms leading to TECSA included ventilatory control instability, low arousal threshold, activation of lung stretch receptors, and prolonged circulation time. TECSA may be a self-limited disorder in some patients and could be resolved spontaneously over time with ongoing treatment of continuous positive airway pressure (CPAP). However, central apneas persist even with the regular CPAP therapy in some patients, and new treatment approaches such as adaptive servo-ventilation may be necessary. We concluded that several questions regarding TECSA remain, despite the findings of many studies, and it is necessary to carry out large surveys with basic scientific design and clinical trials for TECSA to clarify these irregularities. Further, it will be vital to evaluate the baseline demographic and polysomnographic data of TECSA patients more carefully and comprehensively.

Respiratory modulation of human autonomic function on Earth.

We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05Hz breathing, however, breathing at usual frequencies (∼0.25Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R-R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long-term neuroplasticity in serial measurements made over 20 days during and following space travel?

Breath‐Holding: Simple Demonstrations of Complex Physiology

The complex interaction of chemical (i.e. chemoreceptors) and mechanical (i.e. lung‐stretch receptors) factors influences breath‐holding (BH). The aim of this project was to develop a simple set of procedures to be used as class‐room demonstrations or laboratory exercises to differentiate the roles of chemical and mechanical mechanisms in regulating BH.The increase in ventilation during rebreathing (plastic bag) was initially used to demonstrate the progressive increase in drive to breathe due to chemical factors. BH time (stopwatch) was also used as a quantifiable and intuitive metric of drive to breathe. Maximal BH's were conducted under the following conditions: 1) end‐expiratory BH (lung stretch receptor unloading), 2) end‐inspiratory BH (lung stretch receptor loading), 3) BH following 30s of hyperventilation (reduces pCO2 & isolates the influence of decreased pO2), and 4) BH following 5 breaths of pure oxygen (elevates pO2 & isolates the influence of increased pCO2). Using the end‐expiratory BH as the standard, students observed the increase in BH time with each of the other 3 maneuvers. An advanced critical thinking procedure was also introduced whereby students rebreathed in and out of a bag twice at the end of a maximal BH before attempting to hold their breath again. This procedure highlights the powerful suppression of drive to breathe by lung‐stretch receptors despite elevated chemical drive to breathe.These procedures represent a simple method to highlight complex physiological mechanisms which contribute to the drive to breathe. Such simple activities are suitable and adaptable for use across a range of physiology curricula and teaching settings.

Sex‐Specific Heart Rate Responses to Apneic Manipulations in Young Healthy Subjects

Contributions of lung stretch and chemoreflex stimulation to heart rate (HR) responses to apnea have not been elucidated independently in men and women. We tested the hypothesis that HR responses to apnea would be exaggerated in men relative to women. Relative changes in HR (ECG) were analyzed during 4 maximal apneic maneuvers: 1) end‐inspiratory (INSP), 2) end‐tidal expiratory (ETE), 3) INSP following hyperoxic breathing (HX), and 4) INSP following hyperventilation (HV). HR data from all apneas were analyzed in 10s bins. The first 5 bins (50s) of each apnea were compared between sexes in these analyses. INSP caused similar changes in HR between sexes (‐8 ± 11 and ‐7 ± 6 bpm, P=0.8), and the time courses of the changes in HR were also similar. Although the nadir bradycardic response to ETE (designed to unload lung stretch receptors) was similar between men and women (‐9 ± 7 and ‐9 ± 8 bpm, P=0.9) onset of bradycardia was delayed in women (30s bin) compared with men, in whom the bradycardia was immediate (10s bin). During HX (eliminating the influence of O2) and HV (eliminating the influence of CO2) both the time courses of the HR responses and the HR nadirs (HX: ‐17 ± 13 and ‐14 ± 11 bpm, P=0.6; HV: ‐33 ± 12 and ‐35 ± 17 bpm, P=0.9) were similar between men and women, respectively. These data suggest that sex differences in HR responses to apnea are not dependent on changes in O2 or CO2 but, rather, are unveiled during the unloading of lung stretch receptors. Supported by NSERC, AIHS, Mount Royal University Innovation Grant, and the University of Alberta Human Performance Scholarship Fund.

Control of breathing and blood pressure by parafacial neurons in conscious rats

The retrotrapezoid nucleus (RTN), located in the parafacial region, contains glutamatergic neurons that express the transcriptor factor Phox2b and that are suggested to be central respiratory chemoreceptors. Studies in anaesthetized animals or in vitro have suggested that RTN neurons are important in the control of breathing by influencing respiratory rate, inspiratory amplitude and active expiration. However, the contribution of these neurons to cardiorespiratory control in conscious rats is not clear. Male Holtzman rats (280-300 g, n = 6-8) with bilateral stainless-steel cannulae implanted into the RTN were used. In conscious rats, the microinjection of the ionotropic glutamatergic agonist NMDA (5 pmol in 50 nl) into the RTN increased respiratory frequency (by 42%), tidal volume (by 21%), ventilation (by 68%), peak expiratory flow (by 24%) and mean arterial pressure (MAP, increased by 16 ± 4, versus saline, 3 ± 2 mmHg). Bilateral inhibition of the RTN neurons with the GABA(A) agonist muscimol (100 pmol in 50 nl) reduced resting ventilation (52 ± 34, versus saline, 250 ± 56 ml min(-1) kg(-1) with absolute values) and attenuated the respiratory response to hypercapnia and hypoxia. Muscimol injected into the RTN slightly reduced resting MAP (decreased by 13 ± 7, versus saline, increased by 3 ± 2 mmHg), without changing the effects of hypercapnia or hypoxia on MAP and heart rate. The results suggest that RTN neurons activate facilitatory mechanisms important to the control of ventilation in resting, hypoxic or hypercapnic conditions in conscious rats.

Control of respiration in fish, amphibians and reptiles

Fish and amphibians utilise a suction/force pump to ventilate gills or lungs, with the respiratory muscles innervated by cranial nerves, while reptiles have a thoracic, aspiratory pump innervated by spinal nerves. However, fish can recruit a hypobranchial pump for active jaw occlusion during hypoxia, using feeding muscles innervated by anterior spinal nerves. This same pump is used to ventilate the air-breathing organ in air-breathing fishes. Some reptiles retain a buccal force pump for use during hypoxia or exercise. All vertebrates have respiratory rhythm generators (RRG) located in the brainstem. In cyclostomes and possibly jawed fishes, this may comprise elements of the trigeminal nucleus, though in the latter group RRG neurons have been located in the reticular formation. In air-breathing fishes and amphibians, there may be separate RRG for gill and lung ventilation. There is some evidence for multiple RRG in reptiles. Both amphibians and reptiles show episodic breathing patterns that may be centrally generated, though they do respond to changes in oxygen supply. Fish and larval amphibians have chemoreceptors sensitive to oxygen partial pressure located on the gills. Hypoxia induces increased ventilation and a reflex bradycardia and may trigger aquatic surface respiration or air-breathing, though these latter activities also respond to behavioural cues. Adult amphibians and reptiles have peripheral chemoreceptors located on the carotid arteries and central chemoreceptors sensitive to blood carbon dioxide levels. Lung perfusion may be regulated by cardiac shunting and lung ventilation stimulates lung stretch receptors.

What to do about apnea of prematurity?

apnea of prematurity and resultant intermittent hypoxic episodes are universal in preterm infants. These events range from presumably benign “periodic” breathing to clinically significant events that may require mechanical ventilation. Persistence of these events is a major factor in prolonging

The Prevalence and Natural History of Complex Sleep Apnea

Central sleep apnea (CSA) may occasionally occur in patients with obstructive sleep apnea during titration with a continuous positive airway pressure (CPAP) device. To determine the prevalence and the natural history of CPAP-emergent CSA. This is a retrospective study of 1286 patients with a diagnosis of OSAwho underwent titration with a positive airway device during a 1-year period. Patients were seen in consultation and underwent full-night attended polysomnography followed by full-night attended CPAP titration. Four weeks after CPAP therapy, patients returned to the clinic for follow-up, and objective adherence to CPAP was recorded. In patients who had CSA on CPAP, a second full-night attended CPAP titration was recommended. Eighty-four of the 1286 patients developed a central apnea index (CAI) of 5 or greater per hour while on CPAP. The incidence of CSA varied from 3% to 10% monthly, with an overall incidence of 6.5%. Forty-two of the 84 patients returned for a second CPAP titration. In 33 patients, CSA was eliminated. In each of the remaining 9 patients, the CAI remained at 5 or greater per hour, with an average of 13 per hour. These patients characteristically had the most severe OSA, and 5 had a CAI of 5 or more per hour at baseline. Two of the 9 patients were on opioids In this large retrospective study of 1286 patients with a diagnosis of OSA, 6.5% had CPAP-emergent or persistent CSA. However, CPAP-emergent CSA was generally transitory and was eliminated within 8 weeks after CPAP therapy. The prevalence of CPAP-persistent CSA was about 1.5%. Severity of OSA, a CAI of 5 or greater per hour, and use of opioids were potential risk factors.

Complex Sleep Apnea: It Isn't Really a Disease

Complex Sleep Apnea: It Isn't Really a Disease

Release of ATP and glutamate in the nucleus tractus solitarii mediate pulmonary stretch receptor (Breuer–Hering) reflex pathway

The Breuer–Hering inflation reflex is initiated by activation of the slowly adapting pulmonary stretch receptor afferents (SARs), which monosynaptically activate second-order relay neurones in the dorsal medullary nucleus of the solitary tract (NTS). Here we demonstrate that during lung inflation SARs release both ATP and glutamate from their central terminals to activate these NTS neurones. In anaesthetized and artificially ventilated rats, ATP- and glutamate-selective microelectrode biosensors placed in the NTS detected rhythmic release of both transmitters phase-locked to lung inflation. This release of ATP and glutamate was independent of the centrally generated respiratory rhythm and could be reversibly abolished during the blockade of the afferent transmission in the vagus nerve by topical application of local anaesthetic. Microionophoretic application of ATP increased the activity of all tested NTS second-order relay neurones which receive monosynaptic inputs from the SARs. Unilateral microinjection of ATP into the NTS site where pulmonary stretch receptor afferents terminate produced central apnoea, mimicking the effect of lung inflation. Application of P2 and glutamate receptor antagonists (pyridoxal-5′-phosphate-6-azophenyl-2′,4′-disulphonic acid, suramin and kynurenic acid) significantly decreased baseline lung inflation-induced firing of the second-order relay neurones. These data demonstrate that ATP and glutamate are released in the NTS from the central terminals of the lung stretch receptor afferents, activate the second-order relay neurones and hence mediate the key respiratory reflex — the Breuer—Hering inflation reflex.

Inhibitory input from slowly adapting lung stretch receptors to retrotrapezoid nucleus chemoreceptors

The retrotrapezoid nucleus (RTN) contains CO(2)-activated interneurons with properties consistent with central respiratory chemoreceptors. These neurons are glutamatergic and express the transcription factor Phox2b. Here we tested whether RTN neurons receive an input from slowly adapting pulmonary stretch receptors (SARs) in halothane-anaesthetized ventilated rats. In vagotomized rats, RTN neurons were inhibited to a variable extent by stimulating myelinated vagal afferents using the lowest intensity needed to inhibit the phrenic nerve discharge (PND). In rats with intact vagus nerves, RTN neurons were inhibited, also to a variable extent, by increasing positive end-expiratory pressure (PEEP; 2-6 cmH(2)O). The cells most sensitive to PEEP were inhibited during each lung inflation at rest and were instantly activated by stopping ventilation. Muscimol (GABA-A agonist) injection in or next to the solitary tract at area postrema level desynchronized PND from ventilation, eliminated the lung inflation-synchronous inhibition of RTN neurons and their steady inhibition by PEEP but did not change their CO(2) sensitivity. Muscimol injection into the rostral ventral respiratory group eliminated PND but did not change RTN neuron response to either lung inflation, PEEP increases, vagal stimulation or CO(2). Generalized glutamate receptor blockade with intracerebroventricular (i.c.v.) kynurenate eliminated PND and the response of RTN neurons to lung inflation but did not change their CO(2) sensitivity. PEEP-sensitive RTN neurons expressed Phox2b. In conclusion, RTN chemoreceptors receive an inhibitory input from myelinated lung stretch receptors, presumably SARs. The lung input to RTN may be di-synaptic with inhibitory pump cells as sole interneurons.

Zur Interaktion chemosensibler und vagaler Afferenzen auf die respiratorische Moto-Aktivität und die Atemarbeit

The central interaction of intracranial and arterial chemoreceptors plays an important role for the generation of respiratory motor activity. Whereas the inspiratory inhibitory effect of lung stretch receptors is largely described, relatively little is known about their influence on expiration and on the pathomechanisms of obstructive airway disease. In anaesthetised cats, electrical activity of inspiratory and expiratory muscles (IM, EM) has been studied along with tidal volume and the position of breathing in eupnoea and increased respiratory drive before and after bilateral vagotomy. In order to mimic slowly adapting lung stretch receptor activity (SAR), the distal ends of vagal nerves (VN) were stimulated electrically using a frequency modulated signal derived from the respiratory alterations in oesophageal pressure. With intact VN, electrical stimulation of carotid sinus nerves or inhalation of 5 % CO (2) in O (2) resulted in an increased activation of IM in inspiration and activation of EM in expiration. Elimination of lung stretch receptor activity during quiet breathing resulted in prolongation and increase in IM activity without much effecting EM, since expiration is passive in eupnoeic breathing. After bilateral vagotomy, the electrical activity of the expiratory muscles was effectively reduced and the activity of the inspiratory muscles was largely enhanced. The effects of vagotomy could be completely reversed by electrical VN stimulation. Simulating an increased tidal volume by increasing the end inspiratory stimulation frequency to more than 100 Hz resulted in a decrease in IM activity and tidal volume. On mimicking an increased end expiratory lung inflation by end expiratory frequencies up to 50 Hz, expiration was prolonged and expiratory muscles activated. In consequence the position of breathing shifted to below the functional residual capacity (FRC). The results of these acute investigations show, that besides terminating inspiration, lung stretch receptors cause a facilitation of expiration during increased respiratory drive and expiratory airflow limitation by activation of expiratory muscles.

Respiration-related afferents to parabrachial pontine regions

The dorsolateral pons around the parabrachial nucleus is an important participant in respiratory control. This area involves various respiration-related neurons, and their respiratory modulation is thought to arise from afferents from medullary respiratory neurons. Today, however, only a limited number of afferent sources have been identified. First, relatively well-characterized afferents to the pons are those originating from two types of the lung stretch receptors, slowly adapting and rapidly adapting receptors. That is, the majority of the second-order relay neurons of these receptors in the nucleus tractus solitarii project to the pons. Second, certain types of respiratory neurons of the medullary respiratory groups are either known to or presumed to project to the pons. For instance, major inhibitory neurons of the Botzinger complex, augmenting and decrementing expiratory neurons, send afferents to the pons. This article overviews such afferents and discusses their connectivity with pontine neurons.

Alveolar septal collapse in the transitional infant lung: a possible common mechanism in sudden unexpected death in infancy

Sudden unexpected death in infancy (SUDI) is a category used to represent the largest single group of infant deaths. Although there are several theories, the cause of SUDI remains unknown and the mechanism of co-sleeping associated deaths are also undetermined. We investigate a possible biomechanical mechanism which may be common in SUDI and may provide an explanation for the association of the known risk factors for SUDI such as co-sleeping, prematurity, prone sleeping position, overwrapping, overheating and maternal smoking. The neonatal lung has few, if any, true septa but from about four weeks of age, a period of rapid alveolarisation commences. The developing alveolar walls (septae) have little fibre support against surface tension forces as they grow but are supported by a double layer of capillaries. Until the elastin/collagen supporting network is laid down these nascent septal walls are vulnerable to collapse against sac or duct walls during this transitional period. We hypothesise that such collapse will prevent one side of the septa, and the wall it overlays, from alveolar gas exchange and a functional left–right shunt is formed which may result in hypoxia. Furthermore, lung stretch receptors in bronchi running through or adjacent to collapsed regions will be activated, falsely signalling lung inflation to the brain stem with resultant respiratory inhibition, so precipitating further collapse. The process will continue until lung volume falls below residual capacity, when normal tidal breathing efforts will no longer result in significant air flow, even if stretch receptor signals have not produced complete apnoea. Large inspiratory efforts are then required to break the surface tension seal, which damages capillaries to produce petechial haemorrhages. Many epidemiological risk factors for SUDI could influence such a mechanism, leading to the proposal that Alveolar Septal Collapse in Infancy (ASCI) is a core mechanism via which these factors act.

GABA, in some cases together with glycine, is used as the inhibitory transmitter by pump cells in the Hering-Breuer reflex pathway of the rat

The Hering-Breuer reflex is one of the fundamental respiratory reflexes and is mediated by second-order relay neurons of the slowly adapting lung stretch receptors. These neurons, which are called pump cells, are located in the nucleus tractus solitarii and include a population of inhibitory neurons. We aimed to determine which transmitter, GABA or glycine, the inhibitory pump cells use. In addition, we examined whether or not second-order relay neurons of the rapidly-adapting lung stretch receptors (RAR-cells), whose excitatory or inhibitory nature is not known, use these inhibitory neurotransmitters. In Nembutal-anesthetized, neuromuscularly blocked and artificially ventilated rats, we labeled pump cells ( n=33) and RAR-cells ( n=26) with Neurobiotin and processed the tissues for detection of mRNA encoding either glutamic acid decarboxylase isoform 67 (GAD67) or glycine transporter 2 (GLYT2) using in situ hybridization. The pump cells were located in the interstitial nucleus and its vicinity and the RAR-cells in the commissural subnucleus. The majority (64%) of the pump cells examined for GAD67 mRNA and many (26%) of the pump cells examined for GLYT2 mRNA expressed respective mRNAs. Of the eight pump cells in which both mRNAs were double-detected, three expressed both mRNAs and one expressed GAD67 mRNA but not GLYT2 mRNA, the other four expressing neither mRNAs. On the other hand, RAR-cells expressed neither GAD67 mRNA nor GLYT2 mRNA. The results suggest that the inhibitory pump cells are basically GABAergic and some of them may corelease GABA and glycine, and that RAR-cells are neither GABAergic nor glycinergic. These findings expand our understanding of the networks of lung receptor-mediated reflexes including the Hering-Breuer reflex.

Short-term autonomic control of cardiovascular function: a mini-review with the help of mathematical models.

In this work the main aspects of the short-term regulation of the cardiovascular system are reviewed and critically discussed, laying special emphasis on the role of the autonomic neural mechanisms involved, on their mutual interrelationships and complex integration. All these aspects are summarized with the help of mathematical models developed by the authors in past years. The main characteristics of the uncontrolled system (i.e., the heart and vessels) and of the efferent neural branches (sympathetic and vagal) working on it are first described. Then, the afferent pathways which participate in feedback mechanisms (baroreceptors, chemoreceptors, lung-stretch receptors, direct CNS response), and the feedforward mechanisms anticipating cardiovascular requirements are introduced, and their role discussed with reference to various cardiovascular perturbations (hemorrhage or posture changes, hypoxia, asphyxia, dynamic exercise). Analysis of physiological data via mathematical equations, and results of computer simulations, emphasize the great complexity, richness and variability of the autonomic cardiovascular control, including redundant mechanisms and antagonistic requirements. The use of mathematical models is essential to capture this richness, and to summarize apparent contradictory data into a coherent and comprehensive theoretical setting.

Respiratory control during postural changes in anesthetized cats

The effect of postural changes on respiration was investigated in ten anesthetized cats by applying body tilting during the inspiration phase while recording respiratory patterns, as given by the diaphragmatic EMG, together with either the lung volume or the air flow temperature. The results show that the head-up tilting during inspiration reduced the period of the inspiratory phase and increased the end-inspiratory lung volume. On the other hand, the head-down tilting during inspiration had opposite effects. These effects disappeared after transection of the vagus nerve. However, labyrinthectomy did not diminish the effects, probably because of functional suppression of the vestibular system due to the anesthetic. When correlating the activity of 15 vagal afferents presumably originating from the slowly adapting lung stretch receptors with lung volume changes during tilting, their maximum firing rate (87 +/- 15.7 Hz) was increased with an increase in the lung inflation volume and was attained earlier on head-up tilting and it was reduced with a decrease of the lung volume on head-down tilting (63 +/- 16.6 Hz) as compared with the value in the horizontal position (74 +/- 14.2 Hz). These results suggest that respiratory modulation during head-up or head-down tilting is consistent with the Hering-Breuer reflexes and minimizes the externally induced lung volume changes during postural changes.

Role of short-term cardiovascular regulation in heart period variability: a modeling study.

A mathematical model of short-term cardiovascular regulation is used to investigate how heart period variability reflects the action of the autonomic regulatory mechanisms (vagal and sympathetic). The model includes the pulsating heart, the systemic (splanchnic and extrasplanchnic) and pulmonary circulation, the mechanical effect of respiration on venous return, two groups of receptors (arterial baroreceptors and lung stretch receptors), the sympathetic and vagal efferent branches, and a very low-frequency (LF) vasomotor noise. All model parameters were given on the basis of physiological data from the literature. We used data from humans whenever possible, whereas parameters for the regulation loops are derived from dog experiments. The model, with basal parameter values, produces a heart period power spectrum with two distinct peaks [a high frequency (HF) peak at the respiratory rate and a LF peak at approximately 0.1 Hz]. Sensitivity analysis on the mechanism gains suggests that the HF peak is mainly affected by the vagal mechanism, whereas the LF peak is increased by a high sympathetic gain and reduced by a high vagal gain. Moreover, the LF peak depends significantly on the reactivity of resistance vessels and is affected by noise, amplified by the sympathetic control loop at its resonance frequency. The model may represent a new tool to study alterations in the heart period spectrum on the basis of quantitative physiological hypotheses.

A mathematical model of CO2 effect on cardiovascular regulation.

The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reflex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during artificial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreflex, peripheral chemoreflex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specific stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting.

Acute cardiovascular response to isocapnic hypoxia. II. Model validation.

The role of the different mechanisms involved in the cardiovascular response to hypoxia [chemoreceptors, baroreceptors, lung stretch receptors, and central nervous system (CNS) hypoxic response] is analyzed in different physiological conditions by means of a mathematical model. The results reveal the following: 1) The model is able to reproduce the cardiovascular response to hypoxia very well between 100 and 28 mmHg PO(2). 2) Sensitivity analysis of the impact of each individual mechanism underlines the role of the baroreflex in avoiding excessive derangement of systemic arterial pressure and cardiac output during severe hypoxia and suggests the existence of significant redundancy among the other regulatory factors. 3) Simulation of chronic sinoaortic denervation (i.e., simultaneous exclusion of baroreceptors, chemoreceptors, and lung stretch receptors) shows that the CNS hypoxic response alone is able to maintain quite normal cardiovascular adjustments to hypoxia; however, suppression of the CNS hypoxic response, as might occur during anesthesia, led to a significant arterial hypotension. 4) Simulations of experiments with controlled ventilation show a significant decrease in heart rate that can only partly be ascribed to inactivation of lung stretch receptors. 5) Simulations performed by maintaining constant cardiac output suggest that during severe hypoxia the chemoreflex can produce a significant decrease in systemic blood volume. In all the previous cases, model predictions exhibit a satisfactory agreement with physiological data.