Chemoreceptor Output Research Articles

Motor Adaptive Remodeling Speeds Up Bacterial Chemotactic Adaptation

Bacterial chemotaxis is a canonical system for the study of signal transduction. One of the hallmarks of this system is its robust adaptive behavior. However, how fast the system adapts remains controversial. The adaptation time measured at the level of the kinase activity was tens of seconds, whereas that measured at the level of the flagellar motor was <10 s. The flagellar motor was recently shown to exhibit adaptive remodeling, its main physiological function being to provide a robust match between the chemoreceptor output and the motor input, whereas its adaptation timescale was thought to be too slow to contribute much to the overall adaptation timescale of the chemotaxis system. Here, through theoretical modeling of the motor adaptive remodeling and experimental tests, we show that this motor adaptation contributes significantly to speeding up the overall chemotactic adaptation, thereby resolving the previous inconsistency.

Response to letter from Teppema and Berendsen concerning Fan et al. (2012): ‘Acetazolamide and cerebrovascular function at high altitude’

In their recent Letter to the Editor Teppema and Berendsen (2012) address a recent article by Fan et al. (2012) and raise two questions concerning the use of my modified rebreathing method at altitude. The authors state the first question as follows: ‘One of the features of Duffin's modified rebreathing is the initial hyperventilation lasting 5 min. At sea level this resulted in a mean and of 22 and 135 mmHg, respectively; at 5050 m these values were 17 and 63 mmHg (see Fan et al. 2010). In other words, in contrast to sea level, modified rebreathing at high altitude started with a sudden transient from a hypoxic to a hyperoxic condition. Despite the low , does this lead to a sudden reduction in carotid body output (and central chemoreceptor output if there is a crosstalk between them as recently suggested)? Note that in acclimatized subjects carotid body sensitivity is greatly enhanced (references in Teppema & Dahan, 2010) raising the question if hyperventilation down to a of 17 mmHg simply eliminates carotid body activity in these ‘sensitized’ subjects.’ The possibility of ‘crosstalk’ or central–peripheral interaction has been addressed in the past (St Croix et al. 1996) and was also examined using a new technique in a recent paper (Cui et al. 2011), and shown to be absent in humans, although present in animals (Blain et al. 2010; Tin et al. 2012). With respect to hyperventilation to a of 17 mmHg eliminating carotid body activity, this is indeed the purpose of the hyperventilation phase to lower the below chemoreceptor thresholds (Mohan & Duffin, 1997; Duffin et al. 2000), which are reduced during altitude acclimatisation (Somogyi et al. 2005; Fan et al. 2012). The second question is stated as follows: ‘During the course of modified rebreathing both the and ventilation rise. A crucial assumption underlying the Duffin type of rebreathing is that, due to the hyperventilation, the in all tissues decreases, which is followed by an equilibration of the arterial and central chemoreceptor during the rebreathing. Brain tissue () is closely linked to , but if cerebral blood flow (CBF) reaches saturation at a of 40–45 mmHg (a consistent observation by Battisti-Charbonney et al. 2011), the slope of the – relationship must change because the further rise is now solely dictated by the tissue CO2 buffering capacity. Does this lead to an altered ventilation– relationship?’ The second question is based on a misreading of Battisti-Charbonney et al. (2011); CBF reaches a vasodilatation threshold of about 50 mmHg as rises in hyperoxia, but continues to rise above that due to increasing perfusion pressure. This point is well illustrated in Zhang et al. (2011). Nevertheless, the question of whether the CBF response to affects the ventilation– relationship or more accurately the ventilation–brain tissue relationship is one that often arises when explaining the rebreathing approach. There is a general misconception that during rebreathing, brain tissue is driven by the rise in as it is in steady-state experiments. However, during rebreathing brain tissue rises due to the metabolic production of CO2, not due to the rising ; the latter is driven by the rise in tissue , not the reverse. Thus, rebreathing avoids the effect of CBF on the central arterial gradient, a problem that affects steady-state methods (Duffin, 2011). A caveat to these considerations is the recognition that the central chemoreceptors monitor [H+] (Gourine & Kasparov, 2011) and so changes in the relationship between and [H+] will affect the ventilation– relationship (Duffin, 2005).

Acetazolamide and cerebrovascular function at high altitude

In a recent issue of The Journal of Physiology, Fan and colleagues (Fan et al. 2012) studied the effect of intravenous acetazolamide (AZ) on cerebrovascular and ventilatory O2 and CO2 sensitivity at sea level and after acclimatization to 5050 m. In a previous study (Fan et al. 2010), resting middle cerebral artery blood flow velocity values were reported that were higher at 5050 m than at sea level by about 30%, but in their recent paper there was no significant difference although blood gases and stage of acclimatization were similar. Likewise, in the previous study hyperoxic ventilatory CO2 sensitivity rose by ∼ 42% at 5050 m, but in their last study there was no significant difference with sea level. What causes these variable results? May modified rebreathing perhaps introduce variations from unknown sources? One of the features of Duffin's modified rebreathing is the initial hyperventilation lasting 5 min. At sea level this resulted in a mean and of 22 and 135 mmHg, respectively; at 5050 m these values were 17 and 63 mmHg (see Fan et al. 2010). In other words, in contrast to sea level, modified rebreathing at high altitude started with a sudden transient from a hypoxic to a hyperoxic condition. Despite the low , does this lead to a sudden reduction in carotid body output (and central chemoreceptor output if there is a crosstalk between them as recently suggested)? Note that in acclimatized subjects carotid body sensitivity is greatly enhanced (references in Teppema & Dahan, 2010) raising the question if hyperventilation down to a of 17 mmHg simply eliminates carotid body activity in these ‘sensitized’ subjects. During the course of modified rebreathing both the and ventilation rise. A crucial assumption underlying the Duffin type of rebreathing is that, due to the hyperventilation, the in all tissues decreases, which is followed by an equilibration of the arterial and central chemoreceptor during the rebreathing. Brain tissue () is closely linked to , but if cerebral blood flow (CBF) reaches saturation at a of 40–45 mmHg (a consistent observation by Battisti-Charbonney et al. 2011), the slope of the – relationship must change because the further rise in is now solely dictated by the tissue CO2 buffering capacity. Does this lead to an altered ventilation– relationship? Fan and colleagues analysed the isocapnic hypoxic ventilatory response with a first-order polynomial function with the curvature representing hypoxic sensitivity and the hyperoxic ventilation as the y asymptote (Fan et al. 2012).The subjects rebreathed from a 6 l bag in which previously exhaled ambient air at rest was collected. So at 5050 m the subjects started to inhale air that contained much less oxygen than at sea level (mean resting values were 46 and 97 mmHg, respectively). The non-linear relationship between ventilation and predicts that curve fitting on data within a lower range will yield a greater hypoxic sensitivity, so the reported higher hypoxic sensitivity at 5050 m is not surprising. Hypoxic sensitivities between treatments cannot be compared unless data are sampled within the same range. In addition, how can curve fitting be applied without isocapnic hyperoxic ventilation data? To examine the influence of the acute direct effect of acetazolamide (AZ) on CBF without the ‘major confounding effects of changes in acid–base balance following oral administration’ the authors used the i.v. route. This is remarkable since chronic (oral) AZ is known to decrease the loop gain and stabilise the respiratory control system by lowering the plant gain without changing ventilatory CO2 or O2 sensitivity (Kiwull-Schone et al. 2006; Teppema & Dahan, 1999; Teppema et al. 2010; Edwards et al. 2012). The AZ-induced metabolic acidosis leads to a rise in ventilation and a decrease in , which has an independent stabilising influence on ventilatory control (Manisty et al. 2006). The metabolic acidosis induced by oral AZ is thought to play a crucial role in the prevention of acute mountain sickness and improvement of periodic breathing during sleep at high altitude (Swenson et al. 1991). Another disadvantage of a high intravenous dose of AZ is the ensuing chemical disequilibrium in vivo, as discussed by the authors. This leads to a smaller change in induced by a given change in and a reduced ventilatory CO2 sensitivity (Teppema et al. 1995) but, according to the data of Fan and colleagues (Fan et al. 2012), not to a diminished cerebrovascular CO2 sensitivity, indicating that the vascular response to CO2 may indeed be initiated at the arterial side of the blood–brain barrier.

Effects of Elevated Body Temperature on Control of Breathing

Effects of Elevated Body Temperature on Control of Breathing Changes in body temperature can be evoked mainly by alterations in the peripheral temperature, or modified by shifts in the central body temperature. Two conditions can lead to abnormal elevation of body temperature: hyperthermia or fever. As regards respiratory system, exposure to heat stress is accompanied by marked alterations in breathing, especially by an increase in ventilation. Ventilation rises due to an increase in central output from hypothalamus or brainstem, an increase in peripheral output via skin temperature receptors, an increase in central or/and peripheral chemoreceptor output or sensitivity and can be also mediated through changes in thermoregulatory mechanisms. This review summarizes results of previous studies as well as of experiments done in our laboratory in order to elucidate the mechanisms included in respiratory changes under heat stress.

Excess Ventilation during Exercise and Prognosis in Chronic Heart Failure

Excess ventilation during exercise with accompanying dyspnea is characteristic of chronic heart failure (CHF), and these patients often exhibit increased Ve relative to the Vco(2) compared with normal subjects. This can be measured in several ways, including using such variables as the slope of Ve versus Vco(2), the lowest ratio of Ve/Vco(2), and the ratio of Ve/Vco(2) at the lactic acidosis threshold or peak exercise. There is now considerable evidence that the degree of excess ventilation during exercise in patients with CHF is a robust predictor of outcome and identifies higher-risk patients requiring aggressive treatment, including heart transplantation. The mechanism of excess ventilation in patients with CHF during exercise is not completely understood. It may be related to enhanced output of chemoreceptors or peripheral muscle ergoreceptors, increased dead space/Vt ratio due to increased contribution of high ventilation-perfusion lung regions or rapid shallow breathing caused by earlier onset of lactic acidosis, or likely resulting from a combination of these causes.

Blood pressure long term regulation: A neural network model of the set point development

BackgroundThe notion of the nucleus tractus solitarius (NTS) as a comparator evaluating the error signal between its rostral neural structures (RNS) and the cardiovascular receptor afferents into it has been recently presented. From this perspective, stress can cause hypertension via set point changes, so offering an answer to an old question. Even though the local blood flow to tissues is influenced by circulating vasoactive hormones and also by local factors, there is yet significant sympathetic control. It is well established that the state of maturation of sympathetic innervation of blood vessels at birth varies across animal species and it takes place mostly during the postnatal period. During ontogeny, chemoreceptors are functional; they discharge when the partial pressures of oxygen and carbon dioxide in the arterial blood are not normal.MethodsThe model is a simple biological plausible adaptative neural network to simulate the development of the sympathetic nervous control. It is hypothesized that during ontogeny, from the RNS afferents to the NTS, the optimal level of each sympathetic efferent discharge is learned through the chemoreceptors' feedback. Its mean discharge leads to normal oxygen and carbon dioxide levels in each tissue. Thus, the sympathetic efferent discharge sets at the optimal level if, despite maximal drift, the local blood flow is compensated for by autoregulation. Such optimal level produces minimum chemoreceptor output, which must be maintained by the nervous system. Since blood flow is controlled by arterial blood pressure, the long-term mean level is stabilized to regulate oxygen and carbon dioxide levels. After development, the cardiopulmonary reflexes play an important role in controlling efferent sympathetic nerve activity to the kidneys and modulating sodium and water excretion.ResultsStarting from fixed RNS afferents to the NTS and random synaptic weight values, the sympathetic efferents converged to the optimal values. When learning was completed, the output from the chemoreceptors became zero because the sympathetic efferents led to normal partial pressures of oxygen and carbon dioxide.ConclusionsWe introduce here a simple simulating computational theory to study, from a neurophysiologic point of view, the sympathetic development of cardiovascular regulation due to feedback signals sent off by cardiovascular receptors. The model simulates, too, how the NTS, as emergent property, acts as a comparator and how its rostral afferents behave as set point.

Expression and function of presynaptic neurotransmitter receptors in the chemoafferent pathway of the rat carotid body.

Hypoxic chemotransmission in the carotid body (CB) is mediated by the release of neurotransmitters (NTs) from type I cells onto adjacent sensory (petrosal) nerve endings (Gonzalez et al. 1994; Urena et al. 1994). In the rat, there is strong evidence of a role for the co-release of fast-acting neurotransmitters, including acetylcholine (ACh) and ATP (Zhang et al. 2000), in chemosensory signalling. In contrast, little is known about the roles of NTs in mediating autoreceptor feedback mechanisms which are thought to play a role in modulating chemoreceptor output from the CB. Here, we present evidence for the involvement of two distinct NTs, ¦Ã-aminobutyric acid (GABA) and serotonin (5-HT), in mediating autoreceptor feedback onto type I cells during hypoxia. Although their actions are directly opposite, activation of receptors for either transmitter appears to regulate the activity of O2-sensitive K+ channels, such as the background K+ channel Kcnk3 (Buckler et al. 2000). 5-HT receptor activation also regulates the activity of the O2-sensitive large-conductance Ca2+-activated K+ channel (Peers, 1990). These results demonstrate the roles of NTs in regulating secretion from type I cells, by converging signals from different sources onto the same K+ channels involved in O2 sensing and control of the receptor potential.KeywordsCarotid BodyChemosensory SignallingPresynaptic DepolarisationCarotid Body TypeDepolarise Receptor PotentialThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Altered expression of vascular endothelial growth factor and FLK-1 receptor in chronically hypoxic rat carotid body.

The mammalian carotid body maintains a high level of chemoreceptor output and provides support for increased ventilatory drive over an extended period in animals chronically exposed to a low O2 environment (i.e., chronic hypoxia, CH; Bisgard, 2000). Important features of carotid body adaptation to CH include hypertrophy and hyperplasia of (O2-sensitive type I cells, and marked dilation of surrounding microvascular elements (McGregor et al 1984; Laidler & Kay, 1975). Although little is known about the cellular mechanisms which mediate these remarkable morphological changes (Pequignot et al 1987; Bisgard, 2000), similar (O2-sensitive changes occur in the lung and heart where CH elicits constriction and thickening of vessel walls in the pulmonary circuit and hypertrophy of the right ventricle, resulting in pulmonary hypertension (Rabinovitch et al., 1979).

Carotid body chemoreceptor function is impaired by vecuronium during hypoxia.

Neuromuscular blocking agents reduce the human ventilatory response to hypoxia at partial neuromuscular block. It was hypothesized that vecuronium impairs carotid body chemoreceptor function during hypoxia. The effect of systemic administration of vecuronium on single chemoreceptor activity during hypoxia, as recorded from a single nerve fiber preparation of the carotid sinus nerve, was studied in seven mechanically ventilated New Zealand White rabbits during continuous thiopental anesthesia. During normoventilation, the isocapnic hypoxic chemosensitivity of the single carotid body chemoreceptor was measured at four levels of oxygenation; these measurements were repeated at six separate occasions: control recording before injection, after intravenous administrations of 0.1 mg and 0.5 mg of vecuronium, and then at three occasions during a 90-min recovery period. Chemoreceptor chemosensitivity during isocapnic hypoxia was expressed as a hyperbolic function: Chemoreceptor output (Hz) = a + b x PaO2(-1) (mmHg). Chemosensitivity was reduced after both 0.1 mg and 0.5 mg vecuronium intravenous administration compared with control measurements; the hypoxic response curve was significantly depressed after both doses (P < 0.05). Notably, there was variation in the effect of vecuronium; some chemoreceptor preparations showed only minimal impairment, whereas some showed an almost abolished response to hypoxia. The chemosensitivity remained significantly depressed at 30 and 60 min but had recovered spontaneously at 90 min after 0.5 mg vecuronium. It is concluded that vecuronium depresses carotid body chemoreceptor function to a varying extent during hypoxia and that the depression recovers spontaneously.

Ventilatory response to moderate hypoxia in awake chemodenervated cats

In humans and cats the ventilatory response to 30 min of moderate hypoxia (arterial PO2 40-55 Torr) is biphasic: ventilation increases sharply for the first 5 min and then declines. In humans there is evidence that the decline is dependent on the initial increase. We therefore examined ventilatory responses to moderate isocapnic hypoxia in awake cats with and without carotid body denervation. Cats underwent denervation or a sham operation. Then they were studied in a Drorbaugh-Fenn plethysmograph while ventilation, arterial PO2, and end-tidal PO2 and PCO2 were measured. Three sham-operated and four denervated cats were studied with room air as the control. Sham animals demonstrated a biphasic response: ventilation rose to 211% of control at 5 min and fell to 114% of control at 25 min. Denervated animals showed neither the initial increase nor the subsequent decrease in ventilation. Three sham-operated and three denervated cats were studied with 2% CO2 added to the inspirate. Results were similar: intact cats showed a biphasic response to hypoxia, whereas denervated cats showed neither an increase nor a decrease in ventilation. Preliminary experiments showed that hypoxia was not associated with changes in CO2 output or systemic blood pressure in either denervated or intact animals. We conclude that depression of ventilation does not occur in awake denervated cats in response to moderate hypoxia and that the decline in ventilation that occurs in intact cats is in some way dependent on peripheral chemoreceptor output.

Abnormal control of ventilation in adolescents with myelodysplasia

Infants with myelomeningocele have abnormalities in ventilatory control. To determine whether these persist into later life, we studied 14 patients with myelomeningocele and Arnold-Chiari malformation (age 18.0 +/- 0.8 (SE) years), and compared them with 14 control subjects (age 24.0 +/- 0.9 years). Pulmonary function and ventilatory muscle strength did not differ between patients with myelomeningocele and control subjects. Hypercapnic ventilatory responses were significantly lower in the group with myelomeningocele (1.98 L/min/mm Hg) compared with control values (3.33 L/min/mm Hg; p less than 0.01). Hypoxic ventilatory responses (-1.4 L/min/%oxygen saturation of hemoglobin in arterial blood) were not significantly different from control values (-2.14 L/min/%oxygen saturation). In control subjects the hypercapnic and hypoxic ventilatory responses were highly correlated with each other within subjects (r = 0.84; p less than 0.002) but not in those with myelomeningocele (r = 0.34; not significant). We concluded that adolescents and young adults with myelomeningocele have abnormalities in control of ventilation during sleep and wakefulness. We speculate that the Arnold-Chiari malformation interferes with central chemosensitivity (hypercapnic ventilatory response) and central integration of chemoreceptor output.

Regular fetal breathing induced by pilocarpine infusion in the near-term fetal lamb.

We report that pilocarpine, a cholinergic drug, stimulated regular sustained breathing movements in 10 near-term fetal lambs with chronically implanted catheters in the carotid artery, jugular vein, and trachea. With increasing doses of pilocarpine (0.1-5.9 mg), there was an enhanced respiratory response as measured by the duration of continuous breathing movements (14 +/- 12 min, increasing to 82 +/- 50 min; mean +/- SD), and the mean tracheal pressure per breath at end inspiration during the first 2 min after drug infusion (18 +/- 5, increasing to 38 +/- 12 mmHg). The mean pressure per breath during the control periods was 8 +/- 3 mmHg. There was no significant change in the breath frequency with increasing drug dose. A similar breathing response was not seen with epinephrine, suggesting that pilocarpine does not act by stimulating release of endogenous catecholamines. There was no fetal breathing response to pilocarpine infusion in atropine-pretreated fetal lambs, suggesting tha pilocarpine acts through a muscarinic mechanism. In eight acute experiments on exteriorized fetal lambs, we measured responses to pilocarpine before and after carotid sinus nerve ligation. The response to pilocarpine was abolished by sinus nerve section, suggesting possible mechanisms whereby pilocarpine may stimulate fetal breathing: the drug may increase peripheral chemoreceptor output, may sensitized the central respiratory centers to peripheral chemoreceptor input, of both.