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Cystic fibrosis (CF) airway epithelium is constantly subjected to injury events due to chronic infection and inflammation. Moreover, abnormalities in CF airway epithelium repair have been described and contribute to the lung function decline seen in CF patients. In the last past years, it has been proposed that anoctamin 1 (ANO1), a Ca2+-activated Cl− channel, might offset the CFTR deficiency but this protein has not been characterized in CF airways. Interestingly, recent evidence indicates a role for ANO1 in cell proliferation and tumor growth. Our aims were to study non-CF and CF bronchial epithelial repair and to determine whether ANO1 is involved in airway epithelial repair. Here, we showed, with human bronchial epithelial cell lines and primary cells, that both cell proliferation and migration during epithelial repair are delayed in CF compared to non-CF cells. We then demonstrated that ANO1 Cl− channel activity was significantly decreased in CF versus non-CF cells. To explain this decreased Cl− channel activity in CF context, we compared ANO1 expression in non-CF vs. CF bronchial epithelial cell lines and primary cells, in lung explants from wild-type vs. F508del mice and non-CF vs. CF patients. In all these models, ANO1 expression was markedly lower in CF compared to non-CF. Finally, we established that ANO1 inhibition or overexpression was associated respectively with decreases and increases in cell proliferation and migration. In summary, our study demonstrates involvement of ANO1 decreased activity and expression in abnormal CF airway epithelial repair and suggests that ANO1 correction may improve this process.

Summary Background Forced vital capacity (FVC) and maximal inspiratory pressure correlate with nocturnal hypoventilation in adults with neuromuscular disease, but children may not be able to perform these volitional tests. Objective To identify volitional and non-volitional parameters reflecting lung and respiratory muscle function which differ in children treated or not with nocturnal noninvasive positive pressure ventilation (NPPV). Methods Parameters reflecting lung function and respiratory muscle performance were measured in 27 children not treated with NPPV ( Unventilated group ) and 8 children treated with NPPV ( Ventilated group ). Results Concerning noninvasive tests, the Ventilated group had a rapid shallow breathing and a lower ventilatory response to carbon dioxide compared to the Unventilated group . FVC (performed by 69% of the patients) and sniff nasal inspiratory pressure were lower in the Ventilated group . Concerning invasive tests, the non-volitional measurement of diaphragmatic strength by magnetic stimulation of the phrenic nerves showed lower results in the Ventilated group as compared to the Unventilated group . Volitional tests evaluating inspiratory and expiratory muscle strength and endurance by means of the sniff and cough manoeuvres and the tension time indexes, revealed lower values in the Ventilated group as compared to the Unventilated group . Conclusions Several lung function and respiratory muscle function tests are lower in children treated with NPPV as compared to children not treated with NPPV. A prospective hierarchical evaluation of these tests, according to their feasibility and invasiveness, may be helpful to identify children with neuromuscular disease at risk for nocturnal hypoventilation.

In cystic fibrosis (CF) patients, the major alteration in pulmonary function is due to peripheral airway obstruction. In the present study, we investigated the possibility that alterations in the extrathoracic airways, particularly in the trachea that expresses high levels of CFTR (CF transmembrane conductance regulator), may contribute to respiratory dysfunction. We performed morphological analyses of the trachea and airway functional studies in adult Cftr knockout (Cftr(-/-)) and F508del-CFTR mice and their controls. Macroscopic and histological examination of the trachea showed the presence of one to seven disrupted or incomplete cartilage rings in Cftr(-/-) mice (23/25) while only a few Cftr(+/+) mice (6/25) had one abnormal ring. Tracheal defects were mainly localized in the proximal trachea. In 14 Cftr(-/-) mice, frontal disruption of the first three to six rings below the cricoid cartilage were associated with upper tracheal constriction. Similar tracheal abnormalities were detected in adult F508del-CFTR and in newborn Cftr(-/-) and F508del-CFTR mice. Tracheal and ventilatory function analyses showed in Cftr(-/-) mice a decreased contractile response of the proximal trachea and a reduced breathing rate due to an increase in the inspiratory and expiratory times. In F508del-CFTR mice, the expiratory time was longer than in controls. Therefore, these structural and functional abnormalities detected in adult and newborn CF mouse models may represent congenital malformations related to CFTR dysfunction. These results raise important questions concerning the mechanisms governing tracheal development within the context of CFTR protein dysfunction and the implication of such abnormalities in the pathogenesis of airway disease in CF.

To elucidate the impact of nutrition in cystic fibrosis (CF), we compared the phenotypic traits of Cftr -/- mice fed either a lipid-enriched liquid diet (Peptamen) or a standard chow combined with polyethylenglycol osmotic laxative (PEG), two strategies commonly used to prevent intestinal obstruction in CF mice. Survival, growth, liver, and ventilatory status were determined in Cftr -/- and Cftr +/+ mice, followed-up until 120 d. Ventilation was recorded in conscious animals using whole-body plethysmography. We found that the survival rate was similar in Peptamen and PEG Cftr -/- mice. Cftr -/- mice had lower minute ventilation than Cftr +/+ mice, whatever the diet. Both Cftr -/- and Cftr +/+ mice fed Peptamen displayed preadult growth delay compared with PEG-treated animals. Despite subsequent growth catch-up, Cftr -/- mice remained smaller than Cftr +/+ mice, whatever the diet. All Peptamen fed Cftr -/- mice showed hepatomegaly and liver steatosis, which also occurred but to a lesser extent in Peptamen fed Cftr +/+ animals. Therefore, while both treatment strategies are similarly efficient to avoid high mortality at weaning, Peptamen induces preadult growth delay and liver steatosis. These effects of diet are important to consider in future animal studies and also prompt to evaluate high-energy diets in CF patients.

The aim of the study was to determine whether a decrease in the ventilatory response to carbon dioxide (CO2) in children with cystic fibrosis (CF) is related to a mechanical limitation of the respiratory muscle capacity. The ventilatory response during CO2 rebreathing was performed in 15 patients (mean forced expiratory volume in 1 s (FEV1): 37 +/- 21% predicted, mean arterial CO2: 41+/- 5 mmHg). The slope of the minute ventilation normalised for weight per mmHg CO2 increment correlated negatively with respiratory muscle output, assessed by the oesophageal (p = 0.002), the diaphragmatic pressure time product (p = 0.01), and the tension time index (p = 0.005). In addition, this slope was correlated with dynamic lung compliance (p < 0.0001) and FEV1 (p = 0.03) but not with airway resistance and maximal transdiaphragmatic pressure. Therefore, an excessive load imposed on the respiratory muscles explains the blunting of the ventilatory response to CO2 in young patients with CF.

This study was designed to examine the ventilatory performance and the lung histopathology of cystic fibrosis knockout mice (Cftr-/-) compared with heterozygous (Cftr+/-) or wild-type (Cftr+/+) littermates. Ventilation was recorded in conscious animals using whole-body plethysmography. Tidal volume (VT), respiratory frequency (f), and minute ventilation (VE) were measured during air breathing and in response to various levels of hypercapnia (2, 4, 6, or 8% CO2) or hypoxia (14, 12, 10, or 8% O2). The results for Cftr+/- and Cftr+/+ were pooled into one control group because they did not differ. In air and in response to hypercapnia, VE, VT, and f were similar in Cftr-/- mice and in controls. During graded hypoxia, VE was decreased in Cftr-/- mice at 10 and 8% O2 because of a lower f. Histology showed neither inflammation nor obstruction of airways in Cftr-/- mice. Morphometric analysis showed alveolar dilation as a result of either distension or impaired development. In conclusion, cystic fibrosis knockout mice have normal baseline breathing and ventilatory response to hypercapnia but a decreased ventilatory response to severe hypoxia. This latter result associated with the morphometric analysis suggests that Cftr-/- mice may exhibit immaturity of the respiratory system.

Gautier, Henry, Cristina Murariu, and Monique Bonora.Ventilatory and metabolic responses to ambient hypoxia or hypercapnia in rats exposed to CO hypoxia. J. Appl. Physiol.83(1): 253–261, 1997.—We have investigated at ambient temperatures (Tam) of 25 and 5°C the effects of ambient hypoxia (Hxam; fractional inspired O2 = 0.14) and hypercapnia (fractional inspired CO2 = 0.04) on ventilation (V˙), O2 uptake (V˙o 2), and colonic temperature (Tc) in 12 conscious rats before and after carotid body denervation (CBD). The rats were concomitantly exposed to CO hypoxia (HxCO; fractional inspired CO = 0.03–0.05%), which decreases arterial O2 saturation by ∼25–40%. The results demonstrate the following. 1) At Tam of 5°C, in both intact and CBD rats,V˙/V˙o 2 is larger when Hxam or CO2 is associated with HxCO than with normoxia. At Tam of 25°C, this is also the case except for CO2 in CBD rats. 2) At Tam of 5°C, the changes inV˙o 2 and Tc seem to result from additive effects of the separate changes induced by Hxam, CO2, and HxCO. It is concluded that, in conscious rats, central hypoxia does not depress respiratory activity. On the contrary, particularly whenV˙o 2 is augmented during a cold stress, bothV˙/V˙o 2during HxCO and the ventilatory responses to Hxam and CO2 are increased. The mechanisms involved in this relative hyperventilation are likely to involve diencephalic integrative structures.

Background Insulin-like growth factors (IGF-I and -II) are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R). Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue. Methods and findings We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1r(neo)) and a null (Igf1r(-)) allele. These IGF-1R(neo/-) mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1R(neo/-) mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R(-/-)) and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R(-/-) embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R(-/-) lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R(-/-) lung tissue as compared with IGF-1R(+/+) controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R(-/-) mutant mice. Conclusions/significance We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays essential roles in cell proliferation and timing of cell differentiation during fetal lung development.

Experiments were carried out in awake rats to compare the effects of ambient and CO-induced hypoxia on thermoregulation and ventilatory control. Measurements of metabolic rate (VO2), ventilation (V), shivering (EMG) and colonic temperature (Tc) were made at fixed ambient temperature (Ta) of 25, 15 and 5 degrees C. Animals were exposed to ambient hypoxia (FIO2 of 21, 17, 14, 12 and 10%) or to CO hypoxia (FICO of 0.03% in air). The results show that: (1) Both ambient and CO-induced hypoxia provoked decreases in VO2 and Tc which were more marked at low Ta values; non-shivering thermogenesis was depressed with both types of hypoxia, whereas shivering was depressed only with ambient hypoxia; (2) Ventilatory response to ambient hypoxia was blunted at low Ta values and CO-induced hypoxia did not affect ventilation. It is concluded that: (1) hypoxia affects markedly the control of Tc by altering thermogenesis: inhibition of non-shivering thermogenesis seems to result from a decrease in CaO2 whereas inhibition of shivering seems to result from a decrease in PaO2; (2) during hypoxia, ventilation is controlled by the opposite stimulation from chemoreceptors and inhibition from hypometabolism. However, as revealed by CO-induced hypoxia, another stimulatory factor may also interact with the control of breathing.

12-O-tetradecanoyl phorbol-13-acetate-induced sequence 7/interferon related development regulator 1 (Tis7/IFRD1) has been recently identified as a modifier gene in lung inflammatory disease severity in patients with cystic fibrosis (CF), based upon its capacity to regulate inflammatory activities in neutrophils. In CF patients, the F508del mutation in the Cftr gene encoding a chloride channel, the CF transmembrane conductance regulator (CFTR) in airway epithelial cells results in an exaggerated inflammatory response of these cells. At present, it is unknown whether the Tis7/IFRD1 gene product is expressed in airway epithelial cells. We therefore investigated the possibility there is an intrinsic alteration in Tis7/IFRD1 protein level in cells lacking CFTR function in tracheal homogenates of F508del-CFTR mice and in a F508del-CFTR human bronchial epithelial cell line (CFBE41o− cells). When Tis7/IFRD1 protein was detectable, trachea from F508del-CFTR mice showed a reduction in the level of Tis7/IFRD1 protein compared to wild-type control littermates. A significant reduction of IFRD1 protein level was found in CFBE41o− cells compared to normal bronchial epithelial cells 16HBE14o−. Surprisingly, messenger RNA level of IFRD1 in CFBE41o− cells was found elevated. Treating CFBE41o− cells with the antioxidant glutathione rescued the IFRD1 protein level closer to control level and also reduced the pro-inflammatory cytokine IL-8 release. This work provides evidence for the first time of reduced level of IFRD1 protein in murine and human F508del-CFTR airway epithelial cell models, possibly mediated in response to oxidative stress which might contribute to the exaggerated inflammatory airway response observed in CF patients homozygous for the F508del mutation.

Cystic fibrosis (CF) is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene which is a Cl− channel and a regulator of the epithelial Na+ channel (ENaC). We have recently shown that newborn CFTR-deficient mice exhibit abnormalities of the tracheal cartilage leading to altered ventilation ( Bonvin et al., 2008 ). However, the mechanism by which a lack of CFTR causes tracheal cartilage defects remains unknown. The main goal of the present study was to determine whether the development of airway cartilage defects is related to ENac channel dysfunction. We thus performed macroscopic analysis of the trachea and explored ventilatory function in adult βENaC-overexpressing (βENaC-Tg) mice with airway Na+ hyperabsorption and “CF-lung” lung disease, at 2 and 5 month of age. Only minor cartilaginous abnormalities were observed in 8 out of 16 βENaC-Tg mice and in 2 out of 20 littermate controls. Breathing pattern was progressively altered in βENaC-Tg mice as evidenced by a significant decrease in respiratory frequency. Our results suggest that Na+ hyperabsorption alone is not a major contributor to the development of tracheal malformation observed in CF mice and that breathing pattern changes in βENaC-Tg mice likely reflect airflow limitation due to airway mucus obstruction.

Cystic fibrosis is a lethal inherited disorder caused by mutations in a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in progressive oxidative lung damage. In this study, we evaluated the role of CFTR in the control of ubiquitin-proteasome activity and nuclear factor (NF)-kappaB/IkappaB-alpha signaling after lung oxidative stress. After a 64-hour exposure to hyperoxia-mediated oxidative stress, CFTR-deficient (cftr(-/-)) mice exhibited significantly elevated lung proteasomal activity compared with wild-type (cftr(+/+)) animals. This was accompanied by reduced lung caspase-3 activity and defective degradation of NF-kappaB inhibitor IkappaB-alpha. In vitro, human CFTR-deficient lung cells exposed to oxidative stress exhibited increased proteasomal activity and decreased NF-kappaB-dependent transcriptional activity compared with CFTR-sufficient lung cells. Inhibition of the CFTR Cl(-) channel by CFTR(inh-172) in the normal bronchial immortalized cell line 16HBE14o- increased proteasomal degradation after exposure to oxidative stress. Caspase-3 inhibition by Z-DQMD in CFTR-sufficient lung cells mimicked the response profile of increased proteasomal degradation and reduced NF-kappaB activity observed in CFTR-deficient lung cells exposed to oxidative stress. Taken together, these results suggest that functional CFTR Cl(-) channel activity is crucial for regulation of lung proteasomal degradation and NF-kappaB activity in conditions of oxidative stress.

Background Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R). Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. Methods Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1r neo ) and a knockout (Igf-1r -) receptor allele. These IGF-1Rneo/- mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. Results Strikingly, after 72 h of exposure to 90% O2, IGF-1Rneo/- mice had a significantly better survival rate during recovery than IGF-1R+/+ mice (77% versus 53%, P < 0.05). The pulmonary injury was consistently, and significantly, milder in IGF-1Rneo/- mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1Rneo/- mice. Conclusion Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.

We determined the effects of chronic hypoxia on end-expiratory lung volume (EELV), end-expiratory diaphragmatic activity (DE) and ventilation (VE) in 27 intact (awake and anesthetized) and six carotid body-denervated (CBD; anesthetized) rats. Twenty-nine control animals were also studied. Recordings were made during hypoxia and normoxia before and after 2 or 3 weeks of hypoxia (+3 days of recovery from chronic hypoxia). In awake rats, 2 weeks of chronic hypoxia increased only normoxic VE, while 3 weeks of chronic hypoxia did not change VE or DE. In anesthetized intact rats, after both exposures, hypoxic and normoxic VE tended to decrease, DE did not change and hypoxic and normoxic EELV were enlarged. In CBD animals, 2 weeks of chronic hypoxia did not affect hypoxic VE but decreased normoxic ventilation and enlarged EELV similar to the intact animals. After 3 days of recovery in normoxia, all parameters except EELV were restored to prehypoxic values. Also, transition from hypoxia to normoxia induced parallel changes in EELV and DE while chronic hypoxia increased only EELV. Therefore, chronic normobaric hypoxia induced, (1) an increase in normoxic ventilation reflecting a process of acclimatization; (2) an enlargement of EELV that did not depend on changes in DE and carotid chemoreceptors.

We tested whether the enhancement of end-expiratory activity of the diaphragm (DE) induced by acute hypoxia persists during long-lasting hypoxia and participates in the enlargement of end-expiratory lung volume (EELV). We thus measured these two parameters together with ventilation (VE) in 30 rats, either awake or anesthetized, exposed to (1) poikilocapnic hypoxia sustained for 2 or 3 h; or (2) chronic normobaric hypoxia for 7 days interrupted by short episodes of normoxia. Twelve control animals were also studied. (1) Sustained hypoxia induced a stable increase in DE, VE and EELV. (2) In awake rats, chronic hypoxia induced a transient increase in VE after 1 day of hypoxia, and an increase persisting during acute normoxia throughout the exposure. DE followed the same, although less pronounced, course as VE. In anesthetized animals, only EELV was increased in both chronic hypoxia and acute normoxia, but its enlargement in normoxia was not associated with a concomitant increase in DE. The transition from hypoxia to normoxia always induced a decrease in DE and EELV. Therefore, (1) during hypoxia sustained for 2 or 3 h, the ventilatory and diaphragmatic responses were stable; (2) during chronic hypoxia lasting 1 week, a ventilatory acclimatization was expressed by a transient increase in hypoxic VE and a hyperventilation continuing during acute normoxia; (3) EELV enlargement in chronic hypoxia was partly related to changes in DE and partly due to another mechanism possibly involving morphological adaptations.

Recently, we have described the effects of hypoxia and of hypercapnia on the metabolic (V O 2 ) and ventilatory responses to cold in unanesthetized intact and carotid body-denervated (CBD) rats (Gautier et al., J. Appl. Physiol. 73: 847–854, 1992 and 75: 2570–2579, 1993). In the present paper, we have reanalyzed the above results for a more detailed study of the interactions of hypoxia (F i O 2 = 0.12), hypercapnia (F i CO 2 = 0.04) and changes in V O 2 with the ventilatory control. The results show that: (1) Compared to normoxia, in hypoxia increments in V and V t are proportional to V O 2 whereas in hypercapnia increments in ventilation (V) and tidal volume (V t ) are independent of V O 2 . In both hypoxia and hypercapnia, increases in respiratory frequency (f r ) are independent of V O 2 ; and (2) Interactions of hypoxia, hypercapnia and V O 2 with control of V persist in CBD rats but, for a given V O 2 , V, V t and f r are lower than in intact rats. These interactions are essentially similar to those observed during muscular exercise performed in normoxia, hypoxia or hypercapnia. It is suggested that during cold exposure or muscular exercise, resulting both in increased V O 2 , there are common integrative structures probably located in the hypothalamus which are involved in the control of breathing.

Effects of steady-state hypoxia (inspired O2 fraction = 0.11) on ventilation and breathing pattern were studied during postnatal development in unanesthetized kittens. Studies were done from 2 days to 8 mo of age, every week during the first month and every month thereafter. During the first 2 months, states of consciousness were determined. In the first month, minute ventilation (VE) was depressed in hypoxia compared with control values in air, whereas in the older kittens VE was increased in hypoxia, as in adult cats. The inhibitory effect of hypoxia was observed in all three states of consciousness in 7- and 14-day-old kittens. In the 21- and 28-day-old kittens, VE could not be reliably related to the state of consciousness. In the 2-mo-old kittens, VE increased in all states. Tidal volume (VT) was markedly decreased in kittens up to 14 days of age, and respiratory frequency increased. In the 21- and 28-day-old kittens, changes in breathing pattern were variable. In the oldest, the increase of VE was mainly due to an increase of VT. We conclude that in unanesthetized kittens, the ventilatory response to hypoxia is mature at 2 mo of age. The hypoxic tachypnea observed at 7 and 14 days resembles that previously seen in adult carotid-denervated cats, and may be due to a low level of carotid chemoreceptor drive and to a central excitatory effect of hypoxia on respiratory frequency. The complex response observed during the first month of life must reflect the development of peripheral and central mechanisms and their interactions.

Publisher Summary This chapter highlights the role of brain catecholamines in hypoxic-tachypnea presented by carotid-denervated (CD) cats. After surgical denervation of carotid-chemoreceptors, conscious cats breathing ambient air exhibit a decrease in ventilation and concomitantly, an increase in end-tidal PCO2. This indicates that, in normoxia, the carotid-body has a tonic influence on the respiratory control centers. On the other hand, when breathing a hyperoxic mixture, the same animals exhibit, as compared to ambient air, an increase in ventilation and a decrease in end-tidal PCO2. This suggests that even in normoxia, there exists a central depression of the respiratory control mechanisms, which can be unmasked in carotid-denervated animals and overcome by oxygen breathing. The studies discussed in the chapter indicate that the ventilatory response to hypoxia is a complex response involving the interactions of peripheral and central structures. Brain catecholamine depletion by hypoxia may initiate a characteristic tachypnea through structures rostral to the brain stem. On the other hand, vascular changes may, in the CD animal submitted to hypoxia, come into play as demonstrated by the spectacular effects of hypercapnia in restoring a normal breathing pattern and a reversal of hypotension.

The influence of head position on the respiratory activity of the diaphgram (DIA), posterior cricoarytenoid (PCA) and genioglossus (GG) muscles was studied in conscious cats with chronically implanted electromyographic electrodes. Tracheal pressure was also recorded through a small implanted catheter. Spontaneous or passive downward movements of the head resulted in sustained increases in the respiratory excursions of tracheal pressure in PCA and GG activities. Conversely, these variables all decreased when the head was raised. Activity of the DIA was little affected. In animals with chronic tracheostomies, which greatly diminished tracheal pressure excursions and their changes with head movements, the postural responses of PCA and GG activities persisted, but were attenuated. The responses also persisted after bilateral superior laryngeal nerve section. These findings demonstrate responses that act to maintain the patency of the upper respiratory tract, probably by reflex mechanisms. Receptors in the upper airway contribute to the responses, but other afferents - possibly from vestibular or joint receptors - are also involved.

Ventilation and the breathing pattern of 12 intact, unanesthetized, unrestrained kittens, were recorded at intervals from the second postnatal day to the end of the eight month. Five of the animals were also studied at 12 months of age. Ventilation (V e ) became stable by the 5th month, whereas body weight was still increasing. The relationship between tidal volume ( Vt ) and breathing rate (BR) changed with age. During the 1st month, BR fell and Vt increased, V e increasing slowly. From 1 to 5 months, BR remained nearly constant while Vt increased. Finally, from 5 to 12 months. BR decreased slightly, Vt increased slightly, and V e did not change. The results are compared with relevant data from the literature, especially those derived from interspecific analyses.

The effects of heating and cooling on the electrically evoked mechanical and contractile properties of the triceps surae in relation to the maximal dynamic performance of the leg muscles during cycling and vertical jumping have been examined in five healthy male subjects. A mean rise of 3.1 degrees C in muscle temperature (Tm) was associated with a decrease in time to peak tension (TPT) and half-relaxation time (1/2RT) but was without effect on twitch (Pto) and tetanic tension at 20 Hz (Po20) and 40 Hz (Po40) and maximal voluntary contraction (MVC). Reducing Tm by 8.4 degrees C had the opposite effect on TPT and 1/2RT and produced a fall in Pto, Po40, and MVC. The peak power output during cycling (W1) and jumping (W) was linearly related to Tm as well as negatively associated with TPT. The best single guide to W and W1 was given by a ratio of MVC to TPT: W (W) = 626.5 + 79.04 (MVC/TPT)(N/ms; r = +0.82) and W1 (W) = 1,342 + 84.9 (MVC/TPT)(N/ms; r = +0.87). The results underline the importance of the contractile and force generating capacity of human muscle in determining maximal power output and performance during exercise of a few seconds duration.

Developmental changes in body temperature (Tb) and minute ventilation (V) were studied in unanesthetized kittens of 1, 2, 4, 6 and 8 weeks of postnatal age while breathing either air, 11 % O2, or 11% O2 + 2.5% CO2. Experiments were mainly carried out at the ambient temperature (Ta) of 26–28 °C at which Tb was similar to that measured in the nesting box with the mother and littermates. In air, Tb progressively rose with increasing age to approach adult values by the age of 8 weeks. In hypoxia, Tb significantly decreased relative to room air values at all ages. However, the greatest decline occurred during the first month after birth, whereas by 6 and 8 weeks Tb was only slightly affected by hypoxia. The hypoxic-induced fall in Tb was partially prevented by the addition of 2.5% CO2 to the hypoxic mixture at 1,2 and 4 weeks and slightly enhanced in the oldest kittens. On the other hand, V was consistently depressed by hypoxia relative to room air in the 1- and 2-week-old kittens. After 4 weeks of age, hypoxia induced a marked and sustained increase in V as in adult cats. Therefore, the depressant effect of hypoxia on body temperature which becomes progressively less effective during the first two months after birth appears to follow a similar postnatal evolution as the ventilatory response to hypoxia. It is suggested that maturity may be a contributing factor to the hypoxic-induced fall in Tb and that the maturational changes in V and Tb in response to hypoxia may be under the influence of the same central mechanisms.

The dose effect of pentobarbital sodium on integrated (“moving time average”) phrenic activity (EPHR), transdiaphragmatic pressure (Pdi), gastric pressure (Pga), changes in lung volume (V), and mechanical properties of the respiratory system was studied in six cats breathing room air. Increased pentobarbital dose from an initial value of 35 mg/kg ip, had no substantial effect on the relationship between EPHR and Pdi during both unoccluded and occluded inspirations, indicating that the diaphragmatic excitation-contraction coupling was not affected. Similarly, increased anesthetic dose had no effect on the relationship between EPHR and delta Pga during both occluded and unoccluded breaths, suggesting that the contribution of the diaphragm to the breathing movements did not change with increasing depth of anesthesia. Although the time course of phrenic activity showed substantial interanimal differences, the shape of the phrenic neurogram did not change substantially with increased pentobarbital dose in any of the cats studied. Increased anesthetic dose depressed, in the same proportion, the rate of rise of EPHR, Pdi, and V, but the mechanical properties of the respiratory system remained unchanged. The depression of ventilation with increased anesthetic dose was not proportional to the drop in central inspiratory activity, as quantified in terms of rate of rise of EPHR.