Branchial chemoreceptors mediate ventilatory responses to hypercapnic acidosis in channel catfish

The effects of hyperoxic hypercapnia on cardiovascular and ventilatory variables and blood gas and acid/base parameters were examined in conscious and anesthetized spontaneously breathing (ASB) channel catfish, Ictalurus punctatus. These separate experiments were designed to determine: (1) if channel catfish show a ventilatory response to hypercapnic acidosis when blood O(2) content is maintained in conscious animals; and (2) whether branchial receptors innervated by cranial nerves IX and X mediate this response. The combination of high O(2) and CO(2) tensions allowed the cardioventilatory effects of hypercapnic acidosis to be assessed independently of Root or Bohr mediated changes in blood O(2) content. In the absence of significant changes in dorsal or ventral aorta O(2) content, hyperoxic hypercapnia significantly stimulated ventilation, relative to hyperoxic exposure. Hypercapnic acidosis, however, had no significant effects on blood pressure or heart rate. Branchial denervation in ASB fish abolished the ventilatory response to hypercapnic acidosis. The results indicate that hypercapnic acidosis independently stimulates ventilation in channel catfish. This response is mediated by CO(2)/pH-sensitive branchial receptors innervated by cranial nerves IX and X.     

Maturation of baseline breathing and of hypercapnic and hypoxic ventilatory responses in newborn mice

Breathing during the first postnatal hours has not been examined in mice, the preferred mammalian species for genetic studies. We used whole body plethysmography to measure ventilation (VE), breath duration (T(TOT)), and tidal volume (VT) in mice delivered vaginally (VD) or by cesarean section (CS). In experiment 1, 101 VD and 100 CS pups aged 1, 6, 12, 24, or 48 h were exposed to 8% CO2 or 10% O2 for 90 s. In experiment 2, 31 VD pups aged 1, 12, or 24 h were exposed to 10% O2 for 5 min. Baseline breathing maturation was delayed in CS pups, but VE responses to hypercapnia and hypoxia were not significantly different between VD and CS pups [at postnatal age of 1 h (H1): 48 +/- 44 and 18 +/- 32%, respectively, in VD and CS pups combined]. The VE increase induced by hypoxia was greater at H12 (46 +/- 27%) because of T(TOT) response maturation. At all ages, hypoxic decline was ascribable mainly to a VT decrease, and posthypoxic decline was ascribable to a T(TOT) increase with apneas, suggesting different underlying neuronal mechanisms.     

Depression of ventilatory responses after daily, cyclic hypercapnic hypoxia in piglets.

Ventilatory responses (VRs) were measured via a sealed face mask and pneumotachograph in 30 unsedated, mixed-breed miniature piglets at 12.6 +/- 2.3 days of age (day 1) and then repeated after seven daily 24-min exposures to 10% O(2)-6% CO(2) [hypercapnic hypoxia (HH)]. Arterial blood was sampled at baseline, after 10 min of exposure, and after 10 min of recovery. VRs included hypoxia (10% O(2) in N(2)), hypercapnia (6% CO(2) in air), and HH (10% O(2)-6% CO(2)-balance N(2)). Treatment groups (n = 10 each) were exposed to 24 min of HH from day 2 to 8 as sustained HH (24 min of HH and then 24 min of air) or cyclic HH (4 min of HH alternating with 4 min of air). Day 1 and 9 data were compared in treatment and control groups. After cyclic HH, respiratory responses to CO(2) were reduced during hypercapnia and during HH (P < 0.001 vs. control for minute ventilation in both). In both treatment groups, time to peak minute ventilation was delayed in hypoxia (P = 0.02, ANOVA), and response amplitude was increased (P < 0.001 and P = 0.003, sustained and cyclic HH, respectively, vs. control). Respiratory pattern was also altered during the VRs and among treatment groups. Stimulus presentation characteristics exert effects on VRs that are independent of those elicited by daily HH.     

Adaptive changes in hypercapnic ventilatory response during training and detraining

To confirm the effects of physical training and detraining on CO2 chemosensitivity, we followed hypercapnic ventilatory response at rest in the same five subjects during pre-, post- and detraining for 6 years. They joined our university badminton teams as freshmen and participated regularly in their team's training for about 3 h a day, three times a week, for 4 years. After that they retired from their teams and stopped training in order to study in the graduate school for 2 years. Maximum pulmonary ventilation (VEmax) and maximal oxygen uptake (VO2max) for each subject were determined during maximal treadmill exercise. The slope (S) of ventilatory response to carbon dioxide at rest was measured by Read's rebreathing method. Mean values of VEmax increased statistically during training and decreased statistically during detraining. A similar tendency was observed in VO2max. The average value of S before training was 1.91 l.min-1.mmHg-1, (+/- ) SD 0.52 and it decreased gradually with increasing training periods; the difference between the S values before (1980) and after training (1982, 1983 and 1984) were all significant. Furthermore, the mean values of S increased significantly during detraining as compared with those obtained at the end of training (April 1984). We concluded that in normal subjects, long-term physical training increases aerobic work capacity and decreases CO2 ventilatory responsiveness, and that the ventilatory adaptations with training observed here are reversible through detraining.     

Beta-endorphin activity and hypercapnic ventilatory responsiveness after marathon running

To investigate the hypothesis that endurance exercise may lead to a decrease in ventilatory chemosensitivity as possibly mediated by an increase in endogenous beta-endorphins, we measured hypercapnic ventilatory responsiveness (HCVR) and circulating beta-endorphin immunoreactivity in six runners before and after a marathon (42.2 km) race and after administration of 10 mg iv naloxone. Similar testing was performed at identical time periods on the day before the marathon as control data. On each occasion, HCVR was measured twice 15 min apart, and the mean value was used for analysis. Six active (training distance 50-104 km/wk) and experienced (no. of marathons completed, 1-25) runners participated in the study. There were no significant changes in beta-endorphin activity or HCVR on the control day. All runners experienced a rise in beta-endorphin activity from premarathon (21.3 +/- 16.0 pg/ml) to immediate postmarathon (89.6 +/- 84.9 pg/ml) values (P less than 0.05). However, HCVR showed no significant change at any of the three testing periods on the marathon day. To investigate whether a time delay may have affected the lack of response to naloxone, additional testing was performed in five subjects, except that 10 mg iv naloxone was given within 10 min after completion of the marathon, and then HCVR was measured. Although there was a greater than fourfold increase in beta-endorphin immunoreactivity after the marathon, there was no significant change in HCVR after naloxone administration. We conclude that natural increases in endogenous beta-endorphin activity associated with marathon running do not modulate central chemosensitivity.     

Interrelation of respiratory variability and ventilatory sensitivity to a hypercapnic stimulus

Breathing variability and ventilatory response to carbon dioxide (SCO2) were studied after premedication with moradol, in healthy subjects and those with acute pain syndrome. Inverse relationship between SCO2 and breathing variability was established. SCO2 was the highest in the group of patients with acute pain syndrome and the lowest in patients after premedication with moradol.     

Hypoxic ventilatory response and arterial desaturation during heavy work

Arterial desaturation in athletes during intense exercise has been reported by several authors, yet the etiology of this phenomenon remains obscure. Inadequate pulmonary ventilation, due to a blunted respiratory drive, has been implicated as a factor. To investigate the relationship between the ventilatory response to hypoxia, exercise ventilation, and arterial desaturation, 12 healthy male subjects [age, 23.8 +/- 3.6 yr; height, 181.6 +/- 5.6 cm; weight, 73.7 +/- 6.2 kg; and maximal O2 uptake (VO2max), 63.0 +/- 2.2 ml.kg-1 min-1] performed a 5-min treadmill test at 100% of VO2max, during which arterial blood samples and ventilatory data were collected every 15 s. Alveolar PO2 (PAO2) was determined using the ideal gas equation. On a separate occasion the ventilatory response to isocapnic hypoxia was measured. Arterial PO2 decreased by an average of 29 Torr during the test, associated with arterial desaturation [arterial O2 saturation (SaO2) 92.0%]. PAO2 was maintained; however, alveolar-arterial gas pressure difference increased progressively to greater than 40 Torr. Minimal hypocapnia was observed, despite marked metabolic acidosis. There was no significant correlation observed between hypoxic drives and ventilation-to-O2 uptake ratio or SaO2 (r = 0.1 and 0.06, respectively, P = NS). These data support the conclusions that hypoxic drives are not related to maximal exercise ventilation or to the development of arterial desaturation during maximal exercise.     

Stress-induced attenuation of the hypercapnic ventilatory response in awake rats.

To test the hypothesis that stress alters the performance of the respiratory control system, we compared the acute (20 min) responses to moderate hypoxia and hypercapnia of rats previously subjected to immobilization stress (90 min/day) with responses of control animals. Ventilatory measurements were performed on awake rats using whole body plethysmography. Under baseline conditions, there were no differences in minute ventilation between stressed and unstressed groups. Rats previously exposed to immobilization stress had a 45% lower ventilatory response to hypercapnia (inspiratory CO(2) fraction = 0.05) than controls. In contrast, stress exposure had no statistically significant effect on the ventilatory response to hypoxia (inspiratory O(2) fraction = 0.12). Stress-induced attenuation of the hypercapnic response was associated with reduced tidal volume and inspiratory flow increases; the frequency and timing components of the response were not different between groups. We conclude that previous exposure to a stressful condition that does not constitute a direct challenge to respiratory homeostasis can elicit persistent (> or =24 h) functional plasticity in the ventilatory control system.     

Hypoxic and hypercapnic challenges unveil respiratory vulnerability of Surf1 knockout mice, an animal model of Leigh syndrome

Surf1 gene mutations were detected as a main cause for Leigh syndrome (LS), also known as infantile subacute necrotizing encephalomyelopathy. This syndrome which is commonly associated with systemic cytochrome c oxidase (COX) deficiency manifests in early childhood and has an invariable poor prognosis. Progressive disturbances of the respiratory function, for which both the metabolic condition and necrotizing brainstem lesions contribute, belong to the major symptoms of LS. A constitutive knockout (KO) mouse for Surf1 enables invasive investigations of distinct aspects of LS. In the present study the respiratory function was analyzed applying an arterially perfused brainstem preparation. Compared to wild type (WT) preparations Surf1 KO preparations had a higher baseline respiratory frequency and abnormal responses to hypoxia and hypercapnia that involved both respiratory frequency and motor nerve discharge pattern. These data suggest that COX deficiency impairs peripheral and/or central chemoreceptor function.