Interaction between vagal and chemoreceptors afferents in ventilatory response to transient hypercapnia (awake rabbits).

The ventilatory response to a transient hypercapnia was studied in four awake rabbits maintained in a volume displacement plethysmograph : the increase in inspiratory volume (VI) was associated or not with an increase in inspiratory and expiratory durations (TI and TE). These ventilatory variations were consistent with the activation of the peripheral chemoreceptors by carbon dioxide (short latency of the initial response). After vagal blockade by local anaesthesia, relative ventilatory variations were not significantly different from those previously measured. Central activity seems an important factor reducing inhibitory vagal input and favouring peripheral chemoreceptor afferents.     

Role of vagal C-fiber afferents in respiratory response to hypercapnia

The respiratory response to hypercapnia has been investigated in 10 anesthetized rabbits by use of a rebreathing technique. The responses were obtained in three situations: with one intact vagus nerve (control), during differential block of conduction, and after vagotomy. Differential block was achieved using anodal hyperpolarization by application of a direct current to the cervical vagus nerve. Great care was taken during the differential block to establish that all impulse conduction in myelinated fibers of the cervical vagus nerve was abolished but that the nonmyelinated fibers conducted normally. Additionally, in five more rabbits the nature of the differential block was confirmed from single-fiber recordings of activity in both myelinated and nonmyelinated fibers. The same increase in tidal volume in response to hypercapnia was present in all three experimental situations, indicating that it was not vagally mediated. The increase in frequency in response to hypercapnia in the control state was abolished by vagotomy but preserved when only the nonmyelinated fibers were functioning during the differential block. This increased frequency response, attributable to decreases in both inspiratory and expiratory durations, was usually enhanced during the differential block, despite the slower deeper pattern of breathing attributed to loss of activity in myelinated fibers. The implications of this reflex increase in frequency in response to hypercapnia, mediated by nonmyelinated vagal endings in the lung, are discussed.     

Relationships between eupnoeic pattern of breathing and ventilatory control in man II. Early response to transient hypercapnia.

The individual importance of peripheral chemosensitive afferents was studied using a transient hypercapnia (inhalation of a 5% or a 10% CO2 in air gas mixture respectively during 4 or 2 breaths) in human conscious subjects chosen for their different eupnoeic ventilatory patterns. Calculation of the speed of change in end-tidal CO2 pressure in tracheal gas (sPETCO2) and of the rate of change in tidal volume (sVI) gave assessment for quantifying the sensitivity of arterial chemoreceptors to hypercapnia (sCO2=SVI/SPETCO2). Our results showed that, independently of any outside influence of the eupnoeic ventilatory pattern on the components of the chemical stimulus, sVI and sCO2 were found to be much smaller in subjects whose pattern of breathing was slow (i.e. having a large tidal volume). The possible causes of the weak importance of peripheral chemosensitive afferents in such subjects were discussed.     

Plasma vasopressin response to haemorrhage in the anaesthetized rabbit

In chloralose-urethane anaesthetized rabbits the acute circulatory and plasma vasopressin (pAVP) responses to moderate haemorrhage of 6 mL/kg body weight (10% blood volume) were followed after serial section of the aortic, vagus, and carotid sinus nerves. With all nerves intact, haemorrhage resulted in significant increases in pAVP, accompanied by decreases in systemic arterial pressure and right atrial pressure. With subsequent section of each afferent nerve, pAVP still increased in response to haemorrhage regardless of the order of nerve section. These results suggest that, in the anaesthetized rabbit, there is a further component of the pAVP response to haemorrhage, in addition to those carried in the aortic, vagus, and carotid sinus nerves.     

CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents

Capsaicin treatment destroys vagal afferent C fibers and markedly attenuates reduction of food intake and induction of hindbrain Fos expression by CCK. However, both anatomical and electrophysiological data indicate that some gastric vagal afferents are not destroyed by capsaicin. Because CCK enhances behavioral and electrophysiological responses to gastric distension in rats and people, we hypothesized that CCK might enhance the vagal afferent response to gastric distension via an action on capsaicin-insensitive vagal afferents. To test this hypothesis, we quantified expression of Fos-like immunoreactivity (Fos) in the dorsal vagal complex (DVC) of capsaicin-treated (Cap) and control rats (Veh), following gastric balloon distension alone and in combination with CCK injection. In Veh rats, intraperitoneal CCK significantly increased DVC Fos, especially in nucleus of the solitary tract (NTS), whereas in Cap rats, CCK did not significantly increase DVC Fos. In contrast to CCK, gastric distension did significantly increase Fos expression in the NTS of both Veh and Cap rats, although distension-induced Fos was attenuated in Cap rats. When CCK was administered during gastric distension, it significantly enhanced NTS Fos expression in response to distension in Cap rats. Furthermore, CCK's enhancement of distension-induced Fos in Cap rats was reversed by the selective CCK-A receptor antagonist lorglumide. We conclude that CCK directly activates capsaicin-sensitive C-type vagal afferents. However, in capsaicin-resistant A-type afferents, CCK's principal action may be facilitation of responses to gastric distension.     

The role of vagal afferents and carbon dioxide in the respiratory response to thyrotropin-releasing hormone

Rats treated neonatally with pargyline and 5,7-dihydroxytryptamine to decrease central serotonin-containing neurons have an accentuated respiratory response to i.c.v. thyrotropin-releasing hormone (TRH). Since these treated rats also evidence an elevated PaCO2, we sought to evaluate the importance of CO2 in determining the magnitude of the respiratory response to TRH. Neonatal treatment with capsaicin or acute vagotomy also produced adult animals whose basal PaCO2 was elevated and whose respiratory response to TRH was greater than that seen in control rats with lower PaCO2 values. In normal rats, however, administration of CO2 immediately before and after TRH administration does not alter the subsequent response to TRH. Thus, it appears that TRH facilitates the processing of CO2-dependent afferent impulses, and that CO2 does not alter disposition or pharmacokinetics of TRH.     

Differences in ventilatory responses to hypoxia and hypercapnia between normal and judo athletes with moderate obesity

Hypercapnic and hypoxic ventilatory sensitivities were compared in twenty-one judoists and 24 control subjects with similar degrees of moderate obesity. Data from ten non-obese control subjects were also included as a reference. Mean body weight (BW) and % of ideal body weight in the judoists and the obese and non-obese controls were 100 +/- 14.8, 94.4 +/- 5.3 and 63.4 +/- 6.1 (mean +/- SD) kg, and 142.3 +/- 16.7, 142.2 +/- 12.9 and 98.4 +/- 10.7%, respectively. Mean body fat in the judoists was 16.2 +/- 13.9%, being 25.3 +/- 7.7% in the obese control group, the difference being significant (p less than 0.01). Hypercapnic sensitivities in terms of the CO2 ventilatory response slope (S) and its normalized value for 70 kg BW (SN) of the obese controls were higher than the judoists. These findings were also verified by the CO2-occlusion pressure responses. S and SN in the obese controls were significantly correlated with BW and % body fat. However, no positive correlation was found between BW and S or SN in the judoists as well as between lean body mass and S or SN in the obese control. Hypoxic sensitivity in terms of the PETO2-ventilation hyperbola slope (A) and its normalized value (AN) in the obese control was significantly higher than the non-obese control, but the difference from the judoists was not significant. A and AN were found to increase with increasing % body fat in both judoists and obese controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pattern of the ventilatory response to transient hypoxia in man: differences from transient hypercapnic test.

The pattern of change in ventilatory variables after inhalation of pure N2 for two breaths was studied in normal children and adults. In six subjects the trends of change were compared to the ventilatory response to transient hypercapnia. We observed differences in the patterns of increasing ventilation with an initial abrupt increase of tidal volume for transient hypoxia and a progressive change for hypercapnia. In both cases respiratory frequency was progressively but unsystematically enhanced. A highly significant positive correlation was demonstrated between individual sensitivities to CO2 and O2, with a greater response to hypercapnia (5.6 time) than to hypoxia. Finally, a very short-latency decrease in expiratory duration occurred in the first breath after inhalation of hypercapnic mixture, supporting the recent data of Cunningham et al. (1977).     

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.     

Time-dependency of the response to a single vagal stimulus in the rabbit heart

The time-dependency of vagal effects on P-P cycle was studied in rabbits, chosen because of high heart rate, in order to verify the occurrence of this phenomenon already described for animals with lower heart rate. In five rabbits with different resting cardiac cycles, vagal stimuli were delivered randomly. The results indicate that for heart rates higher than 120 beats/min no occurrence of Brown and Eccles' time-dependency was observed. It is evident, however, the different responsiveness of the pacemaker to vagal stimuli delivered at different times of the cardiac cycle. In particular a stimulus given beyond 40-50% of the cardiac cycle does not affect the same but the next cycle.     

Stomach-brain communication by vagal afferents in response to luminal acid backdiffusion, gastrin, and gastric acid secretion

Vagal afferents play a role in gut-brain signaling of physiological and pathological stimuli. Here, we investigated how backdiffusion of luminal HCl or NH(4)OH and pentagastrin-stimulated acid secretion interact in the communication between rat stomach and brain stem. Rats were pretreated intraperitoneally with vehicle or appropriate doses of cimetidine, omeprazole, pentagastrin, dexloxiglumide (CCK(1) receptor antagonist), and itriglumide (CCK(2) receptor antagonist) before intragastric administration of saline or backdiffusing concentrations of HCl or NH(4)OH. Two hours later, neuronal activation in the nucleus of the solitary tract (NTS) and area postrema was visualized by c-Fos immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15-0.5 M) or NH(4)OH (0.1-0.3 M) led to a concentration-dependent expression of c-Fos in the NTS, which was not related to gender, gastric mucosal injury, or gastropyloric motor alterations. The c-Fos response to HCl was diminished by cimetidine and omeprazole, enhanced by pentagastrin, and left unchanged by dexloxiglumide and itriglumide. Pentagastrin alone caused an omeprazole-resistant expression of c-fos, which in the NTS was attenuated by itriglumide and prevented by dexloxiglumide but in the area postrema was reduced by dexloxiglumide and abolished by itriglumide. We conclude that vagal afferents transmit physiological stimuli (gastrin) and pathological events (backdiffusion of luminal HCl or NH(4)OH) from the stomach to the brain stem. These communication modalities interact because, firstly, acid secretion enhances afferent signaling of gastric acid backdiffusion and, secondly, gastrin activates NTS neurons through stimulation of CCK(1) receptors on vagal afferents and of CCK(2) receptors on area postrema neurons projecting to the NTS.     

Plasma vasopressin and atrial natriuretic factor in response to blood volume changes in the anaesthetized rabbit

The influence of aortic baroreceptors and vagal afferent nerves on the release of immunoreactive vasopressin (iVP) and immunoreactive atrial natriuretic factor (iANF) was examined in anaesthetized rabbits. Changes in plasma concentrations of iVP and iANF, heart rate, mean arterial pressure, and right atrial pressure were measured in response to blood volume changes (+20, +10, -10, -20%). Carotid sinus pressure was maintained at 100 mmHg (1 mmHg = 133.3 Pa), and blood volume changes were performed before and after bilateral vagotomy (VNX) in all experiments. Two experimental groups were studied: rabbits with aortic depressor nerves intact (ADNI) and those with aortic depressor nerves sectioned (ADNX). Mean arterial and right atrial pressures decreased during haemorrhage and increased in response to volume expansion. Plasma iVP concentrations increased with haemorrhage and decreased with volume expansion in the ADNI group. Plasma iANF, however, decreased with haemorrhage and increased during volume expansion in both ADNI and ADNX groups. Vagotomy caused an increase in baseline plasma iANF in the ADNX group. The responses of iANF to blood volume changes were augmented after VNX and ADNX. The results show that neither the aortic baroreceptor nor the vagal afferent input are needed for the iANF response to changes in blood volume, over the range of +/- 20%. In contrast, intact aortic baroreceptors are essential for changes in circulating iVP in this preparation.     

The ventilatory responses of the caecilian Typhlonectes natans to hypoxia and hypercapnia

Typhlonectes natans empty their lungs in a single extended exhalation and subsequently fill their lungs by using a series of 10-20 inspiratory buccal oscillations. These animals always use this breathing pattern, which effectively separates inspiratory and expiratory airflows, unlike most urodele and anuran amphibians that may use one to many buccal oscillations for lung inflation and typically mix expired and inspired gases. Aquatic hypoxia had no significant effect on the breathing pattern or mechanics in these animals. Aerial hypoxia stimulated ventilatory frequency and increased the number of inspiratory oscillations but had little effect on inspiratory and expiratory tidal volume. Aquatic hypercapnia elicited a large significant increase in air-breathing frequency and minute ventilation compared to the small stimulation of minute ventilation seen during aerial hypercapnia. Some animals responded to aquatic hypercapnia with a series of three or four closely spaced breaths separated by long nonventilatory periods. Overall, T. natans showed little capacity to modulate expiratory or inspiratory tidal volumes and depended heavily on changing air-breathing frequency to meet hypoxic and hypercapnic challenges. These responses are different from those of anurans or urodeles studied to date, which modulate both the number of ventilatory oscillations in lung-inflation cycles and the degree of lung inflation when challenged with peripheral or central chemoreceptor stimulation.     

Response of muscular and cutaneous vessels to physiologic stimulation of chemoreceptors (38505).

Experiments were performed to determine whether physiologic stimulation of carotid chemoreceptors produces different responses in blood vessels of skin and muscle. Carotid chemoreceptors of anesthetized dogs were stimulated with hypoxic and hypercapnic blood and responses were observed in the isolated, perfused gracilis muscle and hindpaw. Chemoreceptor stimulation produced vasoconstriction in the muscle and vadodilatation in the paw (a predominantly cutaneous vascular bed). Responses to hypoxia without hypercapnic acidosis tended to be less pronounced. The study indicates that physiologic stimulation of carotid chemoreceptors produces contrasting responses in different vascular beds.     

Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors.

We assessed the speed of the ventilatory response to square-wave changes in alveolar P(CO2) and the relative gains of the steady-state ventilatory response to CO2 of the central chemoreceptors vs. the carotid body chemoreceptors in intact, unanesthetized dogs. We used extracorporeal perfusion of the reversibly isolated carotid sinus to maintain normal tonic activity of the carotid body chemoreceptor while preventing it from sensing systemic changes in CO2, thereby allowing us to determine the response of the central chemoreceptors alone. We found the following. 1) The ventilatory response of the central chemoreceptors alone is 11.2 (SD = 3.6) s slower than when carotid bodies are allowed to sense CO2 changes. 2) On average, the central chemoreceptors contribute approximately 63% of the gain to steady-state increases in CO2. There was wide dog-to-dog variability in the relative contributions of central vs. carotid body chemoreceptors; the central exceeded the carotid body gain in four of six dogs, but in two dogs carotid body gain exceeded central CO2 gain. If humans respond similarly to dogs, we propose that the slower response of the central chemoreceptors vs. the carotid chemoreceptors prevents the central chemoreceptors from contributing significantly to ventilatory responses to rapid, transient changes in arterial P(CO2) such as those after periods of hypoventilation or hyperventilation ("ventilatory undershoots or overshoots") observed during sleep-disordered breathing. However, the greater average responsiveness of the central chemoreceptors to brain hypercapnia in the steady-state suggests that these receptors may contribute significantly to ventilatory overshoots once unstable/periodic breathing is fully established.