Chemoreceptor Sensitivity Research Articles

Sleep Deprivation Per Se Does Not Decrease the Hypercapnic Ventilatory Response in Humans

Several studies have found that sleep deprivation reduces the hypercapnic ventilatory response (HCVR). Such results may have been affected by uncontrolled activities or environmental influences during the sleep deprivation period. The current study determined the "pure" effect of sleep deprivation on respiratory control under strictly controlled behavioral and environmental conditions. After 2 d of acclimation in the laboratory, 10 subjects maintained wakefulness (confirmed by EEG), a constant semirecumbent posture, ate regular small meals, had constant interaction with experimenters, and stayed in an environment with constant low light (10 lux) and constant room temperature for 41 consecutive hours. Measurements of HCVR, resting ventilation, V O(2) and V CO(2) were performed every 2 h. Comparisons were made of six pairs of measurements, with each pair separated by 24 h of sleep deprivation. None of the respiratory variables changed significantly with 24 h of sleep deprivation. Mean HCVR increased by 17% with sleep deprivation (3.12 versus 3.54 L x min(-1) x mm Hg(-1); not significant). These results show that sleep deprivation per se does not reduce the sensitivity of central chemoreceptors nor change resting ventilation or metabolism. The reduced HCVR after sleep loss found in previous studies may have been affected by uncontrolled activities or environmental influences during sleep deprivation periods.

Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3.

In the present study, the role of nitric oxide (NO) generated by endothelial nitric oxide synthase (NOS-3) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-3. Experiments were performed on awake and anesthetized mutant and wild-type (WT) control mice. Respiratory responses to 100, 21, and 12% O(2) and 3 and 5% CO(2)-balance O(2) were analyzed. In awake animals, respiration was monitored by body plethysmography along with O(2) consumption (VO(2)) and CO(2) production (VCO(2)). In anesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Under both experimental conditions, WT mice responded with greater increases in respiration during 12% O(2) than mutant mice. Respiratory responses to hyperoxic hypercapnia were comparable between both groups of mice. Arterial blood gases, changes in blood pressure, VO(2), and VCO(2) during hypoxia were comparable between both groups of mice. Respiratory responses to cyanide and brief hyperoxia were attenuated in mutant compared with WT mice, indicating reduced peripheral chemoreceptor sensitivity. cGMP levels in the brain stem during 12% O(2), taken as an index of NO production, were greater in mutant compared with WT mice. These observations demonstrate that NOS-3 mutant mice exhibit selective blunting of the respiratory responses to hypoxia but not to hypercapnia, which in part is due to reduced peripheral chemosensitivity. These results support the idea that NO generated by NOS-3 is an important physiological modulator of respiration during hypoxia.

Lung deflation stimulates fictive ventilation in decerebrated and unidirectionally ventilated toads

We describe how the degree of lung inflation and hypercapnia influenced fictive ventilation in five toads ( Bufo marinus) that were decerebrated and paralysed with roccuronium. Both lungs were unidirectionally ventilated and the degree of lung inflation was determined by controlling the outflow resistance of these catheters, while ventilatory motor output was assessed on the basis of nervous activity in the mandibular branch of the Vth cranial nerve. The pattern of the recorded activity (‘fictive ventilation’) resembled the ventilatory patterns previously described for conscious toads. Increasing the fraction of CO 2 in the gas mixture used for unidirectional ventilation from 0.00 to 0.05 stimulated fictive breathing. fictive ventilation was also greatly stimulated, at all CO 2 levels, by reduced lung volume, while complete inflation of the lungs abated fictive ventilation at all levels of CO 2. Stimulation of CO 2 sensitive chemoreceptors and pulmonary stretch receptors appear to have interactive effects on the central generation of ventilatory output in toads.

Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats.

Chronic exposure to hypoxia results in a time-dependent increase in ventilation called ventilatory acclimatization to hypoxia. Increased O(2) sensitivity of arterial chemoreceptors contributes to ventilatory acclimatization to hypoxia, but other mechanisms have also been hypothesized. We designed this experiment to determine whether central nervous system processing of peripheral chemoreceptor input is affected by chronic hypoxic exposure. The carotid sinus nerve was stimulated supramaximally at different frequencies (0.5-20 Hz, 0.2-ms duration) during recording of phrenic nerve activity in two groups of anesthetized, ventilated, vagotomized rats. In the chronically hypoxic group (7 days at 80 Torr inspired PO(2)), phrenic burst frequency (f(R), bursts/min) was significantly higher than in the normoxic control group with carotid sinus nerve stimulation frequencies >5 Hz. In the chronically hypoxic group, peak amplitude of integrated phrenic nerve activity ( integral Phr, percent baseline) or change in integral Phr was significantly greater at stimulation frequencies between 5 and 17 Hz, and minute phrenic activity ( integral Phr x f(R)) was significantly greater at stimulation frequencies >5 Hz. These experiments show that chronic hypoxia facilitates the translation of arterial chemoreceptor afferent input to ventilatory efferent output through a mechanism in the central nervous system.

Cardiovascular and respiratory reflexes: the tropical fish, traira ( Hoplias malabaricus) O 2 chemoresponses

To determine the location and distribution of chemoreceptors involved in the cardiovascular and respiratory responses to hypoxia of traira ( Hoplias malabaricus), we measured heart rate, arterial blood pressure, ventilation frequency and amplitude of opercular movements during exposure to hypoxia and application of NaCN to either water bathing the gills (external) or the ventral aortic blood (internal). This was done before and after selective denervation of branchial branches of the IXth and Xth cranial nerves to various gill arches. The data suggest that hypoxia elicits a bradycardia that arises from internal receptors located in the first gill arch. They also indicate the presence of branchial and extra branchial O 2-chemoreceptors that reflexively elevate systemic vascular resistance during hypoxia. Hypoxia induced increases in ventilation frequency arose primarily from external receptors located exclusively within the gills while increases in breathing amplitude also involved extra branchial receptors. In addition, the data suggest there are O 2 sensitive chemoreceptors located in the first gill arch that attenuate the respiratory responses.

Resetting and postnatal maturation of oxygen chemosensitivity in rat carotid chemoreceptor cells.

1. Carotid chemoreceptor sensitivity is minimal immediately after birth and increases with postnatal age. In the present study we have investigated the peri- and postnatal developmental time course of [Ca2+]i responses to hypoxia in clusters of type I cells isolated from near-term fetal rats and rats that were 1, 3, 7, 11, 14 and 21 days old, using the Ca2+-sensitive fluoroprobe fura-2. 2. In type I cells from all age groups a graded increase in [Ca2+]i occurred in response to lowering the PO2 from 150 mmHg to 70, 35, 14, 7, 2 and 0 mmHg. The graded [Ca2+]i response to hypoxia was hyperbolic at all ages. 3. Type I cells from rats near-term fetal to 1 day old exhibited small [Ca2+]i responses, mainly to the most severe levels of hypoxia. After day 1, an increase in the [Ca2+]i responses to submaximal hypoxia stimulation resulted in a rightward shift in the O2 response curve. Using the Delta[Ca2+]i between 35 and 2 mmHg PO2 as an index of O2 sensitivity, type I cell O2 sensitivity increased approximately 4- to 5-fold between near-term fetal to 1 day old and 11 to 14 days of age. 4. Exposure to elevated extracellular potassium (10, 20 and 40 mM K+) caused a dose-dependent [Ca2+]i rise in type I cells from all age groups. There were no age-related changes in [Ca2+]i responses to any level of K+ between near-term fetal and 21 days. 5. We conclude that the maximal type I cell [Ca2+]i response to anoxia, as well as the sensitivity to submaximal hypoxic stimulation, of rats aged from near-term fetal to 21 days depends on the level of postnatal maturity. The lack of an age-related increase in the [Ca2+]i response to elevated K+ during the timeframe of maximal development of O2 sensitivity suggests that resetting involves maturation of O2 sensing, rather than non-specific developmental changes in the [Ca2+]i rise resulting from depolarization.

The pulmonary neuroendocrine system: the past decade.

The pulmonary neuroendocrine system consists of specialized airway endocrine epithelial cells, associated with nerve fibres. The epithelial cells, the pulmonary neuroendocrine cells (PNEC), can be solitary or clustered to form neuroepithelial bodies (NEB). During the last thirty years, the pulmonary neuroendocrine system has been intensively investigated and much knowledge of its function has been obtained. This text reviews work which dates from the last ten years. In this period, the picture of the pulmonary neuroendocrine system we previously had, has not fundamentally changed. The pulmonary neuroendocrine system is still regarded as an oxygen sensitive chemoreceptor with local and reflex-mediated regulatory functions, and as a regulator of airway growth and development. Continuing research has much more refined this picture. This text reviews several aspects of the pulmonary neuroendocrine system: phylogeny, the amine and peptide content of its epithelial cells, ontogeny and influence on lung development, the influence of hypoxia and nonhypoxic stimuli, immunomodulatory function, innervation and pathology. Among the discoveries of the past decade, three stand out prominently because of their great significance: additional proof that the neural component of the pulmonary neuroendocrine system is sensory, sound experimental evidence that PNEC stimulate airway epithelial cell differentiation and the discovery of a specific membrane oxygen receptor in the PNEC.

Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase.

1. The role of endogenous nitric oxide (NO) generated by neuronal nitric oxide synthase (NOS-1) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-1. 2. Experiments were performed on awake and anaesthetized mutant and wild-type control mice. Respiratory responses to varying levels of inspired oxygen (100, 21 and 12% O2) and carbon dioxide (3 and 5% CO2 balanced oxygen) were analysed. In awake animals, respiration was monitored by body plethysmograph along with oxygen consumption (VO2), CO2 production (VCO2) and body temperature. In anaesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Cyclic 3',5'-guanosine monophosphate (cGMP) levels in the brainstem were analysed by radioimmunoassay as an index of nitric oxide generation. 3. Unanaesthetized mutant mice exhibited greater respiratory responses during 21 and 12% O2 than the wild-type controls. Respiratory responses were associated with significant decreases in oxygen consumption in both groups of mice, and the magnitude of change was greater in mutant than wild-type mice. Changes in CO2 production and body temperature, however, were comparable between both groups of mice. 4. Similar augmentation of respiratory responses during hypoxia was also observed in anaesthetized mutant mice. In addition, five of the fourteen mutant mice displayed periodic oscillations in respiration (brief episodes of increases in respiratory rate and tidal phrenic nerve activity) while breathing 21 and 12% O2, but not during 100% O2. The time interval between the episodes decreased by reducing inspired oxygen from 21 to 12% O2. 5. Changes in arterial blood pressure and arterial blood gases were comparable at any given level of inspired oxygen between both groups of mice, indicating that changes in these variables do not account for the differences in the response to hypoxia. 6. Respiratory responses to brief hyperoxia (Dejours test) and to cyanide, a potent chemoreceptor stimulant, were more pronounced in mutant mice, suggesting augmented peripheral chemoreceptor sensitivity. 7. cGMP levels were elevated in the brainstem during 21 and 12% O2 in wild-type but not in mutant mice, indicating decreased formation of nitric oxide in mutant mice. 8. The magnitude of respiratory responses to hypercapnia (3 and 5% CO2 balanced oxygen) was comparable in both groups of mice in the awake and anaesthetized conditions. 9. These observations suggest that the hypoxic responses were selectively augmented in mutant mice deficient in NOS-1. Peripheral as well as central mechanisms contributed to the altered responses to hypoxia. These results support the idea that nitric oxide generated by NOS-1 is an important physiological modulator of respiration during hypoxia.

Role of Chemoreceptors in Effects of Chronic Hypoxia

Effects of chronic hypoxia on chemoreceptors and chemoreflexes in the fetus and neonate are reviewed. The effects are discussed in relation to those in the adult, in which there is an apparent paradox between the increase in chemoreflex gain during acclimatisation to the hypoxia of altitude vs the `blunting' reported during chronic hypoxia. The possible location and importance of “chemoreceptors” in the brainstem is discussed. In the neonate, chronic hypoxia blunts the ventilatory response to acute hypoxia, an effect largely due to blunting of chemoreceptor sensitivity. Whether this is mediated via a reduction or delay in the normal process of postnatal resetting of hypoxia sensitivity is not known. In addition, there is evidence that the effects on neonatal chemoreceptors are reversible on return to normoxia. Such differences from the adult suggest that special processes, affected by chronic hypoxia, operate in the neonate. In the fetus there is no direct information on the effect of chronic hypoxia on chemoreceptor responses, but it appears that chemoreflexes are augmented, as may occur in the adult during acclimatisation to hypoxia. Recent evidence suggests that arterial chemoreceptors play an important role in fetal cardiovascular and endocrine responses to prolonged hypoxaemia. This will be a productive avenue for future research.

Focal central chemoreceptor sensitivity in the RTN studied with a CO2 diffusion pipette in vivo.

We describe and use a CO2 diffusion pipette to produce a quickly reversible focal acidosis in the retrotrapezoid nucleus region of the rat brain stem. No tissue injection is made. Instead, artificial cerebrospinal fluid (aCSF) equilibrated with CO2 circulates within the micropipette, providing a source for continued CO2 diffusion into the tissue from the pipette tip. Tissue pH electrodes show the acidosis is limited to 500 micron from the tip. In controls (aCSF equilibrated with air), 1-min pipette perfusions increased tissue pH slightly and decreased phrenic nerve amplitude. In moderate- and high-CO2 groups (aCSF equilibrated with 50 or 100% CO2), 1-min perfusions significantly decreased tissue pH and increased phrenic nerve amplitude in a dose-dependent manner. The responses developed and reversed within minutes. Compared with our prior use of medullary acetazolamide injections to produce a focal acidosis, in this approach the acidosis 1) arises and reverses quickly and 2) its intensity can be varied. This allows study of sensitivity and mechanism. We conclude from this initial experiment that retrotrapezoid nucleus region chemoreceptors operate within the normal physiological range of CO2-induced tissue pH changes.

Mechanisms and implications of autonomic nervous system dysfunction in heart failure.

Neurohumoral activation characterizes heart failure. Patients with the greatest amount of neurohumoral activation, as estimated by plasma norepinephrine levels, have the worst prognosis. The fundamental mechanisms underlying this neurohumoral activation remain unknown, however. Recent data support the hypothesis that early sympathetic dysregulation in heart failure is attributable to early attenuation of cardiac and arterial baroreceptor control of sympathetic nerve activity. Neurohumoral excitation is organ specific, affecting the heart first. Neurohumoral activation follows a stepwise pattern, with resistance to atrial natriuretic peptide and marked sympathetic activation characterizing a transition period from left ventricular dysfunction to overt heart failure. Renin-angiotensin-aldosterone system activation then occurs. Additional abnormalities of afferent systems, such as augmented muscle metaboreceptor sensitivity and increased peripheral chemoreceptor sensitivity, may modulate the sympathetic activation in established heart failure. Brain ouabainlike activity has been shown to cause sympathetic excitation in two animal models of heart failure and may play a key (although presently undefined) role in neurohumoral excitation in humans with heart failure. Therapies that interrupt, or even reverse, the neurohumoral activation in heart failure hold the greatest promise for the growing patient population afflicted with this syndrome.

Cardiorespiratory Stimuli: Receptor Cell Versus Whole Animal

SYNOPSIS. Research on the sensory inputs regulating ventilation and perfusion in vertebrates has slowly moved from studies of receptor cells to studies of the receptor proteins on receptor cells involved in signal transduction. With this new emphasis and the insights gained from this work, questions arise about the significance of specific transduction mechanisms and their link to whole animal responses to various stimuli. This is illustrated in the present chapter using two examples. The first describes pulmonary mechanoreceptors in identical locations but with different orientations. As a result of the differences in their orientation, although the receptors have identical signal transduction mechanisms and identical roles in terms of the reflex effects they elicit, they respond to different stimuli at the whole animal level. The second example suggests that different populations of O2 sensitive chemoreceptors may exist that have identical signal transduction mechanisms but, because of differences in their balance of oxygen supply to demand, may respond to different stimuli at the whole animal level. The lesson to be learned from these examples is that accompanying the growing knowledge of receptor cell function at the molecular level is a growing need to integrate this knowledge with empirical observations of whole animal responses.

Chemoreceptor dependence of very low frequency rhythms in advanced chronic heart failure.

Factors responsible for very low frequency oscillations (VLF; cycle > 30 s) in the cardiovascular system remain obscure. We tested the hypothesis that increased peripheral chemosensitivity is important in the pathogenesis of VLF oscillations in patients with chronic heart failure (CHF). Fourteen male patients with stable, moderate to severe CHF (age 60 +/- 1.1 yr, ejection fraction 23 +/- 11%) and reproducible VLF oscillations in heart rate underwent a protocol consisting of three consecutive 20-min phases during which they breathed air, hyperoxia (O2 via mask, 60% O2 concn), and air again. Autoregressive spectral analysis of R-R intervals, blood pressure, and respiration was used to quantify total oscillatory power (TP), VLF, low (0.04-0.15 Hz)- and high (0.15-0.40Hz)-frequency power, and the coherence between these signals. Peripheral chemosensitivity was studied by assessing the ventilatory response to hypoxia using transient inhalations of pure N2. Discrete VLF rhythms were seen in R-R intervals in all 14 patients, in blood pressure in 7 of 14, and in respiration in 8 of 14 patients. A significant coherence (> 0.5) between heart rate and systolic blood pressure within the VLF band with mean phase value of -140 degrees, suggesting an antibaroreflex relationship, was seen in six subjects. Transient hyperoxia abolished the VLF oscillations in most subjects (12 of 14 in R-R intervals) and decreased R-R variability power within the VLF band. This response significantly correlated with peripheral chemoreceptor sensitivity (r = 0.77, P = 0.014). This study suggests that in CHF, enhanced peripheral chemoreceptor activity may facilitate slow oscillations in the cardiorespiratory signals.

Increased esophageal chemoreceptor sensitivity to acid in patients after successful reversal of Barrett's esophagus.

When compared to patients with erosive esophagitis, patients with Barrett's esophagus have demonstrated reduced chemo- and mechanoreceptor sensitivity to acid infusion and balloon distension, respectively. However, anecdotal clinical experience suggested an increase in symptom perception in patients after successful elimination of Barrett's epithelium, using multipolar electrocoagulation (MPEC) and high-dose proton pump inhibitor (PPI). To determine perception thresholds to acid infusion, we evaluated eight consecutive patients after a series of MPEC treatments resulted in complete elimination of Barrett's mucosa and compared them to 10 age-matched patients with nonreversed Barrett's esophagus and 10 patients with symptomatic, endoscopy-documented erosive esophagitis (Hetzel-Dent grade 2 or greater). Chemosensitivity was determined by a modified acid perfusion test, where acid perception thresholds were quantified by the lag time to initial typical symptom perception, sensory intensity rating, and an acid perfusion sensory score (APSS). While patients after successful elimination of Barrett's esophagus had similar sensory intensity ratings and APSS as patients with erosive esophagitis, the lag times differed significantly between the groups, and both groups had significantly higher sensory intensity ratings and APSS than patients with nonreversed Barrett's esophagus. In conclusion, patients after complete reversal of Barrett's mucosa are unexpectedly as sensitive to acid as symptomatic patients with erosive esophagitis.

Contribution of peripheral chemoreceptors to ventilation and the effects of their suppression on exercise tolerance in chronic heart failure.

To assess the contribution of peripheral chemoreceptors to ventilation and the effects of continuous inspired oxygen on exercise tolerance in chronic heart failure patients. The role of peripheral chemoreceptors in mediating hyperpnoea in chronic heart failure is unknown. Hyperoxia is known to suppress the peripheral chemoreceptor drive. The magnitude of decrease in ventilation with transient inhalations of oxygen thus provides a measure of the contribution of the peripheral chemoreceptors to ventilation. Tertiary specialist hospital. Three breaths of 100% oxygen were given at rest and also during cycle ergometry at 25 W to 8 healthy controls (age 52.0 (4.7) (SEM) years) and 13 patients with chronic heart failure (age 60.5 (2.1) years (P = NS); radionuclide left ventricular ejection fraction 25.5 (4.3)%). The peripheral chemoreceptor sensitivity was also measured by assessing the ventilatory response to hypoxia using transient inhalations of pure nitrogen. Another group of 12 patients with chronic heart failure (age 65.5 (1.5) years; left ventricular ejection fraction 21.3 (3.0)%) underwent treadmill exercise testing on 2 occasions, breathing air or 100% oxygen in a randomised single-blind manner, to examine the effects of continuous inspired oxygen on exercise tolerance. The reduction in ventilation with transient hyperoxia was 18.1 (2.9)% v 17.9 (2.6)% (P = NS) at rest and 20.4 (2.8)% v 21.0 (1.6)% (P = NS) during cycle ergometry, for controls and patients respectively. The hypoxic chemosensitivity was higher in patients (0.232 (0.022) v 0.572 (0.082) 1/min/%SaO2; P = 0.002). Continuous inspired oxygen increased exercise time (517 (31) v 455 (27) seconds; P = 0.003), and a trend towards a reduction in the ventilatory response to exercise, characterised by the regression slope relating ventilation to carbon dioxide output, was evident (31.27 (2.60) v 34.19 (2.35); P = 0.08). Despite an increased peripheral chemoreceptor sensitivity, the proportionate contribution of peripheral chemoreceptors to ventilation remained similar in heart failure patients (about 20%). This suggests that the peripheral chemoreceptors are not the main mediator of increased ventilation and there are other non-peripheral chemoreceptor-mediated mechanisms involved. Hyperoxia reduced ventilation at rest and during cycle ergometry. The increase in exercise duration with continuous inspired oxygen that was associated with a reduction in exercise ventilatory response suggests that suppression of the peripheral chemoreceptors may improve exercise tolerance; the effects of possible reduced skeletal muscle anaerobiosis cannot be excluded, however.

Extracellular potassium and chemosensitivity in the rat carotid body, in vitro.

1. The effects of raising extracellular potassium concentration ([K+]o) from 3.0 to 5.3, 9.5 or 16.8 mM on chemoreceptor responses to hypoxia, hypercapnia and asphyxia were examined in a superfused in vitro rat carotid body preparation. 2. Single-exponential functions with offset were fitted to the chemoreceptor discharge responses to ramp decreases in Po2. Increasing [K+]o was without effect upon the rate constants of the fitted exponential functions (P > 0.20). Increasing [K+]o, significantly increased the horizontal asymptote (chemoreceptor discharge in hyperoxia) in a non-linear fashion when all levels of [K+]o were included in the analysis (P < 0.001) but not when a comparison was made only between 3.0 and 5.3 mM Ko+ (P > 0.40). The rightward position of the response curves, as quantified by the Po2 at 50% maximum discharge, was linearly related to [K+]o but only when all levels of [K+]o were included in the analysis (P < 0.03). Chemoreceptor sensitivity to [K+]o increased non-linearly as [K+]o was increased but this effect was not dependent upon the Po2 (P > 0.90). 4. Increasing PCO2 in hyperoxia increased chemoreceptor discharge linearly at all levels of [K+]o. Whilst discharge at any level of PCO2 was elevated by increased levels of [K+]o, raising [K+]o did not increase CO2 sensitivity (P > 0.20). Similarly, increasing PCO2 did not increase chemosensitivity to [K+]o. The lack of effect of [K+]o upon CO2 chemosensitivity was also observed as Po2 was decreased to hypoxic levels (P > 0.10). 5. Our data demonstrate that an elevation of [K+]o can increase chemoreceptor discharge in the in vitro carotid body in a PO2- and PCO2-independent manner, suggesting that the PO2-dependent effects of [K+]o, previously reported in vivo may be due to other indirect effects of [K+]o or hypoxia.

Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure

Objectives. This study sought to establish the chemosensitivity of patients with chronic heart failure.Background. The ventilatory response to exercise is often increased in patients with chronic heart failure, as characterized by the steeper regression slope relating minute ventilation to carbon dioxide output. We hypothesized that the sensitivity of chemoreceptors may be reset and may in part mediate the exercise hyperpnea seen in this condition.Methods. Hypoxic and peripheral hypercapnic chemosensitivity were studied in 38 patients with chronic heart failure (35 men, 3 women; mean [±SE] age 60.2 ± 1.3 years; radionuclide left ventricular ejection fraction 25.7 ± 2.3%) and 15 healthy control subjects (11 mean, 4 women; mean age 54.9 ± 3.0 years) using transient inhalations of pure nitrogen and single breaths of 13% carbon dioxide, respectively. The change in chemosensitivity during mild exercise (25 W) was assessed in the first 15 patients and all control subjects. Central hypercapnic chemosensitivity was also characterized in 25 patients and 10 control subjects by the rebreathing of 7% carbon dioxide in 93% oxygen. Cardiopulmonary exercise testing was performed in all subjects.Results. Maximal oxygen consumption was 16.6 ± 0.9 versus 29.7 ± 2.2 ml/kg per min (p < 0.0001), and the ventilation-carbon dioxide output regression slope was 37.2 ± 1.5 versus 26.5 ± 1.4 (p < 0.0001) in patients and control subjects, respectively. Hypoxic and central hypercapnic chemosensitivity were enhanced in patients (0.707 ± 0.076 vs. 0.293 ± 0.056 liters/min per % arterial oxygen saturation [Sao2], p = 0.0001 and 3.15 ± 0.41 vs. 2.02 ± 0.25 liters/min per mm Hg, p = 0.025, respectively) and correlated significantly with the ventilatory response to exercise. Hypoxic chemosensitivity was augmented during exercise in patients and in control subjects but remained higher in the former (1.530 ± 0.27 vs. 0.685 ± 0.12 liters/min per %Sao2, p = 0.01). The peripheral hypercapnic chemosensitivity of patients at rest and during exercise was similar to that in control subjects, consistent with its lesser contribution to overall carbon dioxide chemosensitivity.Conclusions. Enhanced hypoxic and central hypercapnic chemosensitivity may play a role in mediating the increased ventilatory response to exercise in chronic heart failure.

Maxillary appendages used by western corn rootworms, Diabrotica virgifera virgifera, to discriminate between a phagostimulant and ‐deterrent

AbstractAblation of maxillary appendages on western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), were used to determine which mouthparts were involved in discrimination between the phagostimulant, cucurbitacin B, and the phagodeterrent, strychnine. Strychnine deterred feeding in unablated beetles when its concentration on disks was equal to or higher than cucurbitacin B. Unilateral or bilateral lacinea ablation did not affect discrimination between cucurbitacin B and strychnine. Galeal ablations abolished strychnine deterrence at equimolar concentrations of both compounds but not at higher strychnine concentrations, whereas maxillary palp ablation had no effect. However, bilateral ablation of both galea and maxillary palps resulted in a loss of deterrence at all strychnine concentrations. These results indicated strychnine sensitive chemoreceptors were primarily located on the galeae and maxillary palps. However, beetles without galeae and palps still feed on disks suggesting that cucurbitacin B sensitive chemoreceptors were located on other mouthparts and contributed to cucurbitacin B phagostimulation.

Role of exercise ventilation in the limitation of functional capacity in patients with congestive heart failure

Patients with heart failure have, compared with normal subjects, an increased minute ventilation (VE) at matched workloads. This heightened ventilatory drive may contribute to their limitation of functional capacity through an increase in the work of breathing and further worsening in the lung ventilation-perfusion mismatch. To measure the ventilatory response to exercise, VE should not be assessed in absolute units but be related to one of its main determinants, e.g., carbon dioxide production (VCO2). Particularly, as VE is closely related to VCO2 during exercise, the ventilatory response to exercise has been assessed using the slope of the relation of VE versus VCO2. This slope is significantly increased in heart failure patients compared with normal subjects and is inversely related to other parameters of maximal exercise capacity, namely peak VO2. The mechanisms of exercise hyperpnea in heart failure patients are still unsettled. A first possibility is that it is a compensatory response to the abnormal exercise hemodynamics with secondary increase of the pulmonary dead space to tidal volume ratio. This mechanism should be aimed to maintain constancy of the arterial gas composition and acid-base balance. However, exercise-induced hypoxemia and/or hypercapnia do not generally develop in heart failure patients. This might imply that other mechanisms, such as an increased sensitivity of the arterial chemoreceptors and/or the activation of reflexes by the abnormal skeletal muscles, stimulate the ventilatory response in heart failure patients. Regardless of its mechanisms, exercise hyperpnea may be clinically relevant in the assessment of patients with chronic heart failure. In fact, it is inversely related with peak exercise capacity, and interventions known to improve peak functional capacity such as therapy with ACE inhibitors, physical training and heart transplantation, also tend to normalize exercise hyperpnea.

Dynamic sensitivity of carotid chemoreceptors to CO2 in the newborn lamb.

In previous studies we examined the development of the response of carotid and aortic chemoreceptors to hypoxia in the lamb and kitten (Blanco et al, 1984; Hanson et al, 1989; Kumar & Hanson, 1989). Recently we have been examining the question of whether the response of the arterial chemoreceptors to CO2 also develops post-natally. The issue is important because, whilst elevation in arterial PCO2 (PaCO2) stimulates fetal chemoreceptors and fetal breathing movements, the effect of rapid changes in PaCO2 on chemoreceptors in the neonate is largely unknown. Because CO2 production is linked to metabolism, it provides an important component of the drive to breathe in the neonate, especially at an age when the response to hypoxia is poor. This might be an important consideration in apnoea and respiratory failure in the neonate. Environmental temperature will, of course, affect metabolism and overheating has been proposed to play a role in the aetiology of certain types of respiratory failure, including sudden infant death syndrome. In previous studies (Watanabe et al, 1993) we found that environmental temperatures affected the gain of respiratory chemoreflex responses to changes in PaO2 and PaCO2. However, without direct information on chemoreceptor responses to CO2, the mechanisms underlying such effects cannot be determined. For this reason we embarked on a study of the maturation of carotid chemoreceptor responses to CO2 in the lamb. Preliminary data on the maturation of steady state and dynamic responses to CO2 has already been published (Calder et al, 1995). In this report we concentrate on the adaptive nature of the chemoreceptor response to CO2.