Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneously breathing adult rats.

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats.

Control of breathing in invertebrate model systems.

The invertebrates have adopted a myriad of breathing strategies to facilitate the extraction of adequate quantities of oxygen from their surrounding environments. Their respiratory structures can take a wide variety of forms, including integumentary surfaces, lungs, gills, tracheal systems, and even parallel combinations of these same gas exchange structures. Like their vertebrate counterparts, the invertebrates have evolved elaborate control strategies to regulate their breathing activity.

Augmented breaths ('sighs') are suppressed by morphine in a dose-dependent fashion via naloxone-sensitive pathways in adult rats.

Morphine treatment can eliminate augmented breaths (ABs; 'sighs') during spontaneous breathing. In the present study, unanesthetized rats were studied to: (1) determine the involvement of naloxone-sensitive receptor pathways, and (2) establish the dose-response relationship of this side effect. At a dosage of 5mg/kg (2-10mg/kg is recommended range for analgesia) morphine eliminated ABs from the breathing rhythm across nearly 100 min post-administration (vs.

The "other" respiratory effect of opioids: suppression of spontaneous augmented ("sigh") breaths.

The purpose of this study was to examine the effects of a clinically relevant opioid on the production of augmented breaths (ABs) in unanesthetized animals breathing normal room air, using a dosage which does not depress breathing. To do this we monitored breathing noninvasively, in unrestrained animals before and after subcutaneous injection of either morphine, or a saline control. The effect of ketamine/xylazine was also studied to determine the potential effect of an alternative sedative agent.

Breathing patterns during cardiac arrest.

The absence of respiratory movements is a major criterion recommended for use by bystanders for recognizing an out-of-hospital cardiac arrest (CA), as the persistence of eupneic breathing is considered to be incompatible with CA. The basis for CA-related apnea is, however, uncertain, since brain stem Po(2) is not expected to drop immediately to the critical level where anoxic apnea occurs. It is therefore essential on both clinical and physiological grounds to determine whether and when breathing stops after the onset of CA.

Respiratory effects of changing the volume load imposed on the peripheral venous system.

This study was designed to determine if acute distension of the hindlimb venous circulation stimulates breathing, thereby contributing to the respiratory responses to rapid changes in total blood volume. In 10 spontaneously breathing anesthetized sheep, we withdrew 15 ml kg(-1) of blood from a femoral vein over approximately 1-2 min. We then compared the respiratory effects of infusing this venous blood back into the femoral veins across two conditions: the inferior vena cava (IVC) was either unobstructed or obstructed by a balloon-tipped catheter.

The hypoxia-induced facilitation of augmented breaths is suppressed by the common effect of carbonic anhydrase inhibition.

The typical respiratory response to hypoxia includes a dramatic facilitation of augmented breaths (ABs) or 'sighs' in the breathing rhythm. We recently found that when acetazolamide treatment is used to promote CO(2) retention and counteract alkalosis during exposure to hypoxia, then the hypoxia-induced facilitation of ABs is effectively prevented. These results indicate that hyperventilation-induced hypocapnia/alkalosis is an essential factor involved in the hypoxia-induced facilitation of augmented breaths.

Control of breathing during acute change in cardiac preload in a patient with partial cardiopulmonary bypass.

We recently had the opportunity to investigate the ventilatory effects of changing the rate of venous return to the heart (and thus pulmonary gas exchange) in a patient equipped with a venous-arterial oxygenated shunt (extracorporeal membrane oxygenation (ECMO) support). The presence of the ECMO support provided a condition wherein venous return to the right heart could be increased or decreased while maintaining total aortic blood flow and arterial blood pressure (ABP) constant. The patient, who had received a heart transplant 12 years ago, was admitted for acute cardiac failure related to graft rejection.

Comparison of the metabolic and ventilatory response to hypoxia and H2S in unsedated mice and rats.

Hypoxia alters the control of breathing and metabolism by increasing ventilation through the arterial chemoreflex, an effect which, in small-sized animals, is offset by a centrally mediated reduction in metabolism and respiration. We tested the hypothesis that hydrogen sulfide (H(2)S) is involved in transducing these effects in mammals. The rationale for this hypothesis is twofold.

Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia.

Augmented breaths, or "sighs," commonly destabilize respiratory rhythm, precipitating apneas and variability in the depth and rate of breathing, which may then exacerbate sleep-disordered breathing in vulnerable individuals. We previously demonstrated that hypocapnia is a unique condition associated with a high prevalence of augmented breaths during exposure to hypoxia; the prevalence of augmented breaths during hypoxia can be returned to normal simply by the addition of CO(2) to the inspired air. We hypothesized that counteracting the effect of respiratory alkalosis during hypocapnic hypoxia by blocking carbonic anhydrase would yield a similar effect.

Hypoxia-induced modulation of the respiratory CPG.

Despite recent advances in our understanding of the neural control of breathing, the precise cellular, synaptic, and molecular mechanisms underlying the generation and modulation of respiratory rhythm remain largely unknown. This lack of fundamental knowledge in the field of neural control of respiration is likely due to the complexity of the mammalian brain where synaptic connectivity between central respiratory neurons, motor neurons and their peripheral counterparts cannot be mapped reliably. We have therefore developed an invertebrate model system wherein the essential elements of the central pattern generator (CPG), the motor neurons and the peripheral chemosensory cells involved in respiratory control have been worked out both in vivo and in vitro.

Control of breathing and volitional respiratory rhythm in humans.

When breathing frequency (f) is imperceptibly increased during a volitionally paced respiratory rhythm imposed by an auditory signal, tidal volume (Vt) decreases such that minute ventilation (Ve) rises according to f-induced dead-space ventilation changes (18). As a result, significant change in alveolar ventilation and Pco(2) are prevented as f varies. The present study was performed to determine what regulatory properties are retained by the respiratory control system, wherein the spontaneous automatic rhythmic activity is replaced by a volitionally paced rhythm.

Hypocapnia increases the prevalence of hypoxia-induced augmented breaths.

Augmented breaths promote respiratory instability and have been implicated in triggering periods of sleep-disordered breathing. Since respiratory instability is well known to be exacerbated by hypocapnia, we asked whether one of the destabilizing effects of hypocapnia might be related to an increased prevalence of augmented breaths. With this question in mind, we first sought to determine whether hypoxia-induced augmented breaths are more prevalent when hypocapnia is also present.

A peripheral oxygen sensor provides direct activation of an identified respiratory CPG neuron in Lymnaea.

The mechanisms by which peripheral, hypoxia-sensitive chemosensory cells modulate the output from the respiratory central pattern generator (CPG) remain largely unknown. In order to study this topic at a fundamental level, we have developed a simple invertebrate model system, Lymnaea stagnalis wherein we have identified peripheral chemoreceptor cells (PCRCs) that relay hypoxia-sensitive chemosensory information to a known respiratory CPG neuron, right pedal dorsal 1 (RPeD1). Significance of this chemosensory drive was confirmed via denervation of the peripheral sensory organ containing the PCRCs, and subsequent behavioral observation.

Peripheral oxygen-sensing cells directly modulate the output of an identified respiratory central pattern generating neuron.

Breathing is an essential homeostatic behavior regulated by central neuronal networks, often called central pattern generators (CPGs). Despite ongoing advances in our understanding of the neural control of breathing, the basic mechanisms by which peripheral input modulates the activities of the central respiratory CPG remain elusive. This lack of fundamental knowledge vis-à-vis the role of peripheral influences in the control of the respiratory CPG is due in large part to the complexity of mammalian respiratory control centres.

Respiratory control at exercise onset: an integrated systems perspective.

The near-immediate increase in breathing that accompanies the onset of constant load, dynamic exercise has remained a topic of interest to respiratory physiologists for the better part of a century. During this time, several theories have been proposed and tested in an attempt to explain what has been called the phase I response of exercise hyperpnoea, or the fast neural drive to breathe, and much controversy still remains as to what mediates this response. 'Central motor command' and 'afferent feedback' mechanisms, as described in animal models, have been centre stage in the debate, with much supportive evidence for their involvement.

Rapid increases in ventilation accompany the transition from passive to active movement.

We used a novel movement transition technique to look for evidence of a rapid onset drive to breathe related to the active component of exercise in humans. Ten volunteers performed the following transitions in a specially designed tandem exercise chair apparatus: rest to passive movement, passive to active movement, and rest to active movement. The transition from rest to active exercise was accompanied by an immediate increase in ventilation, as was the transition from rest to passive leg movement (Delta = 6.

The initial phase of exercise hyperpnoea in humans is depressed during a cognitive task.

Increased wakefulness is known to suppress the initial ventilatory response to passive movement and the steady-state ventilatory response to exercise. However, the effect of increased wakefulness upon the integrated ventilatory response at the onset of exercise is not known. We hypothesized that increasing wakefulness via a cognitive task would attenuate the initial ventilatory response to exercise, and so we examined the response to active leg extensions under two conditions: with and without concurrently solving a puzzle.

Respiratory response to passive limb movement is suppressed by a cognitive task.

Feedback from muscles stimulates ventilation at the onset of passive movement. We hypothesized that central neural activity via a cognitive task source would interact with afferent feedback, and we tested this hypothesis by examining the fast changes in ventilation at the transition from rest to passive leg movement, under two conditions: 1) no task and 2) solving a computer-based puzzle. Resting breathing was greater in condition 2 than in condition 1, evidenced by an increase in mean +/- SE breathing frequency (18.

CO2 does not affect passive exercise ventilatory decline.

Breathing increases abruptly at the start of passive exercise, stimulated by afferent feedback from the moving limbs, and declines toward a steady-state hyperpnea as exercise continues. This decline has been attributed to decreased arterial CO2 levels and adaptation in afferent feedback; however, the relative importance of these two mechanisms is unknown. To address this issue, we compared ventilatory responses to 5 min of passive leg extension exercise performed on 10 awake human subjects (6 men and 4 women) in isocapnic and poikilocapnic conditions.

The respiratory effects of two modes of passive exercise.

We monitored gas exchange and muscle activity during two commonly used modes of passive leg exercise as a means of assessing the degree of passivity associated with these techniques. Additionally, we measured the rapid changes in ventilation at the start and end of the passive exercise to assess changes that occur in the fast exercise drive to breathe during passive exercise. We monitored seven subjects at rest and during 5 min of passive exercise using (1) cycling movements performed on a tandem bicycle and (2) leg extension movements performed in a chair apparatus.