Avian ventilatory responses to dynamic CO2 signals.

This study uses an awake unidirectionally ventilated avian preparation to examine the effects of dynamic CO2 signals on the respiratory drive. Results show that minute ventilation is affected by both 1) mean CO2 level and 2) amplitude of CO2 oscillations at the frequency of breathing. An increase in mean CO2 level increased minute ventilation. Comparisons of the effects of CO2 oscillations at the same mean CO2 level, however, showed minute ventilation to be less with the larger amplitudes of oscillations than with smaller ones. Graphs of minute ventilation (V) versus mean CO2 for families of oscillation sizes (0.5%, 1% and 2%) showed that the ventilatory sensitivity (slop) was least for the 2% oscillations and greatest for the 0.5% oscillations. Therefore, a static model for the respiratory regulator is not adequate. However, the apneic level of CO2 (V = O intercept) was independent of the size of the CO2 oscillations.     

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. End-tidal Pco2 decreased significantly during poikilocapnic (Delta = -1.5 +/- 0.5 Torr, P < 0.001), but not isocapnic, passive exercise. Despite this difference, the ventilatory responses to passive exercise were not different between the two conditions. Using the fast changes in ventilation at the start (5.46 +/- 0.40 l/min, P < 0.001) and end (3.72 +/- 0.33 l/min, P < 0.001) of passive exercise as measures of the drive to breathe from afferent feedback, we found a decline of 68%. We conclude that the decline in ventilation during passive exercise is due to an adaptation in the afferent feedback from the moving limbs, not a decline in CO2 levels.     

Effects of O2 on the ventilatory response to CO2 in preterm infants.

To measure the effects of O2 on the ventilatory response to CO2 in preterm infants, we studied eight babies (birth wt 1-2 kg; gestational age 32-36 wk) 10 times during the first 11 days of life. After breathing 21% O2 for 3 min, they were given 15%, 21%, 40%, or 100% O2 for 4 min and then 2% CO2 plus the various concentrations of O2 for 4 min each. The mean slopes of the CO2 response curves were 0.013, 0.027, 0.034, and 0.056 1/(min-kg-mmHg PACO2) with 15%, 21%, 40%, and 100% inspired O2, respectively. Thus, the more hypoxic the infant, the flatter was the response to CO2. These findings suggest that in preterm infants 1) the response to inhaled CO2 is the reverse of that seen in adult man where the higher the inspired O2 concentration, the flatter the response, and 2) the respiratory center is depressed during hypoxia.     

Awake baboon's ventilatory response to venous and inhaled CO2 loading.

Steady-state ventilatory responses to CO2 in trained awake baboons were studied to determine the response to a venous CO2 load. CO2 was loaded either directly into the venous blood through an arteriovenous shunt or by addition to the inhaled air. The two modes of loading were adjusted to produce the same increase in minute volume. Minute volume, tidal volume respiratory frequency, end-tidal PCO2, PaCO2, and pHa were measured. PaCO2 and PETCO2 increased the same amount during the two modes of CO2 loading; thus, the response to changes in arterial PCO2, deltaVE/deltaPaCO2, was the same. I conclude that the ventilatory response to venous CO2 loading occurs only through the change in mean arterial PCO2 and thus it is unlikely that there are any important venous CO2 receptors.     

Control of breathing in uremia: ventilatory response to CO2 after hemodialysis.

The mechanisms responsible for the transient respiratory alkalosis which follows clinical hemodialysis were evaluated by studying the ventilatory response to carbon dioxide in chronic uremic patients, and in unanesthetized normal and chronic uremic goats. A significant increase in sensitivity to CO2 was found in acidotic uremic patients immediately (within 30 min) following hemodialysis (P less than 0.01). Sensitivity to CO2 returned to the predialysis value within 24 h. Lung volume and maximal breathing capacity were unchanged. A similar increase in sensitivity to CO2 was seen in nonacidotic uremic goats following hemodialysis. In the goats, these changes in sensitivity could not be explained by changes in cerebrospinal fluid acid-base status. Adding sufficient urea to the dialysate to prevent a fall in plasma urea concentration, eliminated this increase in sensitivity to CO2 in both uremic patients and goats. These results suggests that the transient respiratory alkalosis following hemodialysis is due to an increase in the sensitivity of the ventilatory response to carbon dioxide and is a consequence of dialysis-induced osmotic disequilibrium.     

Intracisternal DIDS enhances ventilatory response to rebreathing CO2 in rats

In 11 anesthetized rats, we tested the hypothesis that carrier-mediated anion transport in part determines the medullary chemoreceptor response to acute hypercapnia by infusing the transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in mock cerebrospinal fluid (CSF) into the cisterna magna. In five additional rats with sham CSF infusion, we found no effect of mock CSF on the response to rebreathing CO2. Dye infused into the cistern stained the putative chemoreceptor areas on the ventral surface of the medulla. DIDS, at 10 to 1,000 nM, increased the respiratory response to CO2 in a dose-related manner but had no effect on arterial pressure or heart rate. At 1,000 nM, the hypercapnic minute ventilation response was almost doubled because of both volume and rate of breathing. We conclude that the net effect of anion transport is to mitigate the stimulus to the medullary chemoreceptors during acute hypercapnia.     

Raphe magnus nucleus is involved in ventilatory but not hypothermic response to CO2.

There is evidence that serotonin [5-hydroxytryptamine (5-HT)] is involved in the physiological responses to hypercapnia. Serotonergic neurons represent the major cell type (comprising 15-20% of the neurons) in raphe magnus nucleus (RMg), which is a medullary raphe nucleus. In the present study, we tested the hypothesis 1) that RMg plays a role in the ventilatory and thermal responses to hypercapnia, and 2) that RMg serotonergic neurons are involved in these responses. To this end, we microinjected 1) ibotenic acid to promote nonspecific lesioning of neurons in the RMg, or 2) anti-SERT-SAP (an immunotoxin that utilizes a monoclonal antibody to the third extracellular domain of the serotonin reuptake transporter) to specifically kill the serotonergic neurons in the RMg. Hypercapnia caused hyperventilation and hypothermia in all groups. RMg nonspecific lesions elicited a significant reduction of the ventilatory response to hypercapnia due to lower tidal volume (Vt) and respiratory frequency. Rats submitted to specific killing of RMg serotonergic neurons showed no consistent difference in ventilation during air breathing but had a decreased ventilatory response to CO(2) due to lower Vt. The hypercapnia-induced hypothermia was not affected by specific or nonspecific lesions of RMg serotonergic neurons. These data suggest that RMg serotonergic neurons do not participate in the tonic maintenance of ventilation during air breathing but contribute to the ventilatory response to CO(2). Ultimately, this nucleus may not be involved in the thermal responses to CO(2).     

Very low pressures drive ventilatory flow in chimaeroid fishes

Chimaera (Holocephali) are cartilaginous fishes with flexible operculi rather than external gill slits, suggesting ventilation occurs in a manner different from other fishes. We examined holocephalan ventilation morphology, behavior, and performance by anatomical investigations, high‐speed video, and in vivo pressure measurements from the buccal and parabranchial cranial cavities in Hydrolagus colliei and Callorhinchus callorynchus. Ventilatory modes ranged from quiet resting breathing to rapid “active” breathing, yet external cranial movements—excepting the passive movement of the opercular flap—were always extremely subtle, and pressures generated were one to two orders of magnitude lower than those of other fishes. To explain ventilation with such minimal pressure generation and cranial motion, we propose an “accordion” model, whereby rostrocaudal movement of the visceral arches drives pressure differentials, albeit with little lateral or ventral movement. Chimaeroids have comparatively large oropharyngeal cavities, which can move fluid with a smaller linear dimension change than the comparatively smaller cavities of other fishes. Orobranchial pressures are often less than parabranchial pressures, suggesting flow in the “wrong” direction; however, the long gill curtains of chimaeroids may passively restrict backflow. We suggest that constraints on holocephalan jaw and hyoid movements were compensated for evolutionarily by novel visceral arch mechanics and kinematics. J. Morphol., 2012. © 2011 Wiley Periodicals, Inc.     

Carotid chemoreceptors in ventilatory responses to changes in venous CO2 load

We examined the role of the carotid chemoreceptors in the ventilatory response to changes in venous CO2 load in 12 awake sheep using a venovenous extracorporeal perfusion circuit and two carbon dioxide membrane lungs (CDML). Three of the sheep had undergone surgical denervation of the carotid bodies (CBD). In the nine intact sheep, as CO2 was removed from or added to the peripheral venous blood through the CDML under normoxic conditions, there was a linear relationship between the rate of pulmonary CO2 excretion (VCO2) and the resulting rate of ventilation over a VCO2 range of 0--800% of control, so that arterial PCO2 remained close to isocapnic. In contrast, in the three CBD sheep, the ventilatory response to changes in VCO2 was significantly decreased under normoxic conditions, resulting in marked hypercapnia. The results indicate that the carotid chemoreceptors exert a major influence on the ventilatory response to changes in venous CO2 load.