Decrease In Respiratory Frequency Research Articles

Unraveling the Role of Enkephalin Signaling in Respiratory Control

Opioid-induced respiratory depression (OIRD) is the primary cause of death during opioid overdose characterized by a dramatic decrease in respiratory frequency and regularity. Opioid drugs cause neural depression in the ventral respiratory column (VRC) of the medulla via activation of mu-opioid receptors (MORs) that partially contribute to breathing cessation. Nonetheless, little is known about the role of endogenous opioid signaling in respiratory modulation. This study investigates the role of endogenous MORs ligands, enkephalins encoded by the Penk gene, in breathing control. To test whether enkephalin-expressing neurons of the preBӧtzinger Complex (preBӧtC) — the inspiratory rhythm-generating region of the VRC — are necessary for breathing rhythmogenesis, we permanently silenced the region’s Penk+ population via AAV1 injections encoding tetanus toxin light chain. Using whole-body plethysmography, we recorded the animals' respiratory performance within 14 days post-injection. During the second week of testing, we observed unexpected mortality in some experimental but not control animals; post-hoc analysis of breathing traces revealed the development of severe tachypnea in succumbed mice. These data suggest that Penk+ preBӧtC cells are integral for normal respiration. Still, these observations did not assess the specific contribution of enkephalin, as opposed to other types of signaling, to breathing stability. To directly dissect the effects of enkephalin on respiratory rhythm, we utilized optogenetics and pharmacological approaches in brainstem slice preparation from neonatal mice. Brief optogenetic activation of Penk+ neurons in the preBӧtC evoked population bursts while prolonged stimulation increased the rhythm frequency. However, the application of MOR antagonist Naloxone did not affect the network’s responses to light stimulations indicating the lack of MOR/enkephalin involvement in mediating these excitatory effects. High fidelity and temporal coordination of evoked bursts implicated glutamatergic transmission as the primary mechanism of excitation. Likewise, we were able to optogenetically drive respiratory rhythm in urethane-anesthetized spontaneously breathing adult mice by stimulating the preBӧtC. Further, there was a small but significant difference in breathing responses in the presence of Naloxone compared to control conditions. We hypothesized that longitudinal projections to the VRC that might be disrupted during slice preparation contributed enkephalin to the respiratory circuits in the whole-body preparation. We utilized recombinase-dependent reporter mice crosses and retrograde AAV tracers to identify brain-wide Penk inputs to the preBӧtC. Using conventional and light sheet fluorescence microscopy, we located regions in the pons, midbrain, and forebrain that send direct enkephalinergic projections to the VRC. Functional characterizations of these projections will potentially uncover state-dependent mechanisms of respiratory modulation via endogenous opioids. Untimely, this study will help elucidate the role of enkephalin signaling in breathing control and may establish therapeutic targets for preventing OIRD. R01HL166317, R00HL145004. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Nebulization with Semi Fowler Position on Breath Frequency in Bronchial Asthma Patients in Grandmed Lubuk Pakam Hospital

Bronchial asthma is a condition of chronic inflammation of the respiratory tract which triggers bronchial hyperactivity resulting in a feeling of heaviness in the chest and shortness of breath. Asthma patients panic easily by breathing as hard as possible when shallow and short inspirations occur. If asthma occurs for a long duration, apnea will occur and in the worst case it can result in death for the sufferer. Procedures via nebulization using the semi-Fowler position in patients with bronchial asthma can affect respiratory frequency. Nebulizer administration is a type of medication directly on targets such as the lungs so that this action can be carried out more quickly and effectively. The method in this research uses a quasi-experimental pre-test and post-test type by selecting bronchial asthma patients as respondents/sample of 15 participants who were determined using the total sampling method. Research data was collected using an observation sheet instrument containing data regarding respiratory frequency. After the intervention was given, the respondents showed that there was a decrease in respiratory frequency until it was at the normal threshold. Data analysis using a paired T-Test shows that the p-value is 0.000, which means that nebulization in the semi-Fowler position can affect the respiratory frequency of bronchial asthma patients at Grandmed Lubuk Pakam Hospital. It seems that administering nebulization in a semi-Fowler's position could be an appropriate choice in treating bronchial asthma patients in order to achieve better respiratory health.

Buprenorphine differentially alters breathing among four congenic mouse lines as a function of dose, sex, and leptin status

The opioid buprenorphine alters breathing and the cytokine leptin stimulates breathing. Obesity increases the risk for respiratory disorders and can lead to leptin resistance. This study tested the hypothesis that buprenorphine causes dose-dependent changes in breathing that vary as a function of obesity, leptin status, and sex. Breathing measures were acquired from four congenic mouse lines: female and male wild type C57BL/6J (B6) mice, obese db/db and ob/ob mice with leptin dysfunction, and male B6 mice with diet-induced obesity. Mice were injected intraperitoneally with saline (control) and five doses of buprenorphine (0.1, 0.3, 1.0, 3.0, 10 mg/kg). Buprenorphine caused dose-dependent decreases in respiratory frequency while increasing tidal volume, minute ventilation, and respiratory duty cycle. The effects of buprenorphine varied significantly with leptin status and sex. Buprenorphine decreased minute ventilation variability in all mice. The present findings highlight leptin status as an important modulator of respiration and encourage future studies aiming to elucidate the mechanisms through which leptin status alters breathing.

Mandibular advancement device as treatment trial for catathrenia (nocturnal groaning).

Catathrenia is a rare disease, classified as isolated symptoms and normal variants under sleep-related breathing disorders in the International Classification of Sleep Disorders, third edition. Because of its rarity, the research on its pathogenesis and treatment is insufficient. This study aimed to evaluate whether the mandibular advancement device (MAD) could be considered an alternative treatment trial and if so, to explore factors predicting its effectiveness. Thirty patients (12 men and 18 women, aged 16-67 years) with catathrenia participated in the study. They underwent standard clinical evaluation, questionnaires, physical examinations, craniofacial evaluations, video polysomnography, and imaging of the upper airway before and after the insertion of the MAD. The groaning index (groaning episodes per hour of sleep) and apnea-hypopnea index were evaluated, and anatomic factors predicting effectiveness were explored. The sleep efficiency of most patients was higher than 80%, and groaning was present throughout all stages of sleep. With the insertion of the MAD, the groaning index decreased significantly from 5.8 (2.7-14.3) to 2.8 (1.3-12.2) events/h (P = .014). Age had a negative effect on efficacy. Mandibular repositioning of the MAD, especially the amount of vertical opening and changes of the cross-sectional area of the hypopharynx, was positively related with efficacy. The MAD could be considered a possible treatment trial for those seeking treatment for groaning. Registry: Chinese Clinical Trial Register; Name: The etiology of catathrenia based on oral and maxillofacial system; URL: http://www.chictr.org.cn/showproj.aspx?proj=22286; Identifier: ChiCTR-COC-17013239. Yu M, Hao Z, Xu L, Wen Y, Han F, Gao X. Mandibular advancement device as treatment trial for catathrenia (nocturnal groaning). J Clin Sleep Med. 2021;17(9):1767-1776.

High Flow Nasal Cannula Oxygen Therapy in Long Hauler Covid-19 Patients

Long Hauler Covid-19 is a condition that describes a person who has recovered from Covid-19 and is declared with a negative PCR smear 2 times but still feels signs and symptoms for a longer period of time, even severe and critical symptoms. Most cases complicate Acute Respiratory Disorder Syndrome (ARDS), which can lead to death. Fulfilment of non-invasive high concentration oxygenation requirements as an intervention modality in this case. The purpose of this case study was to determine the effect of giving oxygen therapy through the High Flow Nasal Cannula (HFNC) on the respiratory function of Covid-19 long haulier patients. The method of nursing care was a case study on 2 respondents with a descriptive approach method. There were 2 cases of Long haulier Covid-19 patients with comorbid smokers, Diabetes Mellitus, experiencing moderate ARDS complications, desaturation, and tachypnea. Patients received oxygen therapy intervention through HFNC while being treated in the critical care room, and after being given HFNC oxygen therapy for 5 days there was a decrease in respiratory frequency, a change in breathing pattern from shortness of breath to shortness of breath, an increase in oxygen saturation, an increase in the ROX Index, an increase in PO2 and blood pH in normal limit. Nursing care that focuses on respiratory management in covid-19 long haulier patients improves patient outcomes in particular, namely decreased respiratory rate, changes in the respiratory pattern of shortness of breath, increased oxygen saturation, increased ROX index, increased PO2 and blood pH within normal limits.

Risk assessment for irritating chemicals - Derivation of extrapolation factors.

Irritation of the eyes and the upper respiratory tract are important endpoints for setting guide values for chemicals. To optimize the use of the often-limited data, we analysed controlled human exposure studies (CHS) with 1-4h inhalation of the test substance, repeated dose inhalation studies in rodents, and Alarie-Tests and derived extrapolation factors (EF) for exposure duration, inter- and intraspecies differences. For the endpoint irritating effects in the respiratory tract in rodents, geometric mean (GM) values of 1.9 were obtained for the EF for subacute→subchronic (n=16), 2.1 for subchronic→chronic (n=40), and 2.9 for subacute→chronic (n=10) extrapolation. Based on these data we suggest an EF of 2 for subchronic→chronic and of 4 for subacute→chronic extrapolation. In CHS, exposure concentration determines the effects rather than exposure duration. Slight reversible effects during 4h exposure indicate that an EF of 1 can be considered for assessing chronic exposures. To assess species extrapolation, 10 chemicals were identified with both, reliable rat inhalation studies and CHS. The GM of the ratio between the No Observed Adverse Effect Concentration (NOAEC) in rats and humans was 2.3 and increased to 3.6 when expanding the dataset to all available EF (n=25). Based on these analyses, an EF of 3 is suggested to extrapolate from a NOAEC in a chronic rat study to a NOAEC in a CHS. The analysis of EFs for the extrapolation from a 50% decrease in respiratory frequency in the Alarie test in mice (RD50) to a NOAEC in a CHS resulted in a GM of 40, for both, the reliable (n=11) and the overall dataset (n=19). We propose to use the RD50 from the Alarie test for setting guide values and to use 40 as EF. Efs for intraspecies differences in the human population must account for susceptible persons, most importantly for persons with chemical intolerance (CI), who show subjective signs of irritation at low concentrations. The limited data available do not justify to deviate from an EF of 10 - 20 as currently used in different regulatory settings.

Impact of cervical spinal cord contusion on the breathing pattern across the sleep-wake cycle in the rat.

The present study was designed to investigate breathing patterns across the sleep-wake state following a high cervical spinal injury in rats. The breathing patterns (e.g., respiratory frequency, tidal volume, and minute ventilation), neck electromyogram, and electroencephalography of unanesthetized adult male rats were measured at the acute (i.e., 1 day), subchronic (i.e., 2 wk), and/or chronic (i.e., 6 wk) injured stages after unilateral contusion of the second cervical spinal cord. Cervical spinal cord injury caused a long-term reduction in the tidal volume but did not influence the sleep-wake cycle duration. The minute ventilation during sleep was usually lower than that during the wake period in uninjured animals due to a decrease in respiratory frequency. However, this sleep-induced reduction in respiratory frequency was not observed in contused animals at the acute injured stage. By contrast, the tidal volume was significantly lower during sleep in contused animals but not uninjured animals from the acute to the chronic injured stage. Moreover, the frequency of sigh and postsigh apnea was elevated in acutely contused animals. These results indicated that high cervical spinal contusion is associated with exacerbated sleep-induced attenuation of the tidal volume and higher occurrence of sleep apnea, which may be detrimental to respiratory functional recovery after cervical spinal cord injury. NEW & NOTEWORTHY Cervical spinal injury is usually associated with sleep-disordered breathing. The present study investigated breathing patterns across sleep-wake state following cervical spinal injury in the rat. Unilateral cervical spinal contusion significantly impacted sleep-induced alteration of breathing patterns, showing a blunted frequency response and exacerbated attenuated tidal volume and occurrence of sleep apnea. The result enables us to investigate effects of cervical spinal injury on the pathogenesis of sleep-disordered breathing and evaluate potential therapies to improve respiration.

High Dose of Pralidoxime Reverses Paraoxon-Induced Respiratory Toxicity in Mice.

The efficiency of pralidoxime in the treatment of human organophosphates poisoning is still unclear. In a rat model, we showed that pralidoxime induced a complete but concentration-dependent reversal of paraoxon-induced respiratory toxicity. The aim of this study was to assess the efficiency of pralidoxime in a species other than rats. A dose of diethylparaoxon corresponding to 50% of the median lethal dose was administered subcutaneously to male F1B6D2 mice. Ascending single pralidoxime doses of 10, 50-100 and 150 mg kg-1 were administered intramuscularly 30 min after diethylparaoxon administration. Ventilation at rest was assessed using whole-body plethysmography and mice temperature was assessed using infrared telemetry. Results are expressed as mean±SE. Statistical analysis used non-parametric tests. From 30 to 150 min post-injection, diethylparaoxon induced clinical symptoms and a decrease in respiratory frequency, which resulted from an increase in expiratory and inspiratory times associated with an increase in the tidal volume. In the 10-, 50- and 100-mg kg-1 pralidoxime groups, there was a trend towards a non-significant improvement of paraoxon-induced respiratory toxicity. The 150 mg kg-1 dose of pralidoxime induced a significant reversal of all respiratory parameters. In the present study, a toxic but non-lethal model of diethylparaoxon in awake, unrestrained mice was observed. By administering an equipotent dose of diethylparaoxon to rats, a 150 mg kg-1 dose of pralidoxime administered alone completely reversed diethylparaoxon-induced respiratory toxicity in mice. The dose dependency of reversal suggests that further studies are needed for assessing plasma concentrations of pralidoxime resulting in reversal of toxicity.

Abstract W P95: Disordered Breathing in a Mouse Model of Ischemic Stoke

Background: Stroke induced respiratory dysfunction is a common complication after stroke prolonging recovery and increasing mortality. Animal models are lacking. Central chemoreceptors play a vital role in regulating breathing patterns in response to changes in CO2/H+. The retrotrapezoid nucleus (RTN) in the caudal brainstem contains a population of chemoreceptors that regulate frequency and tidal volume. Activity of these neurons may be regulated by KCNQ channels. We hypothesize that targeting KCNQ channels is a viable option for the treatment of stroke induced breathing disorders. Methods: Whole body plethysmography was performed on WT C57/B6 male mice to establish baseline frequency (BPM), tidal volume (TV), minute volume (MV), periods/durations of apnea and approximate entropy of the system (ApEn). Mice were then subjected to 90 minute MCAO or sham surgery. 72 hours after surgery whole body plethysmography was performed again to identify the stroke disordered breathing phenotype. Mice were randomly assigned to one of two treatment groups: Retigabine (a KCNQ channel activator) or saline at a dose of 50ul/10g SQ, respiratory activity was monitored during a 5 day drug treatment regime. Results: All MCAO-treated mice exhibited disordered breathing characterized by pronounced decrease in respiratory frequency (254.3 ± 15.8 vs.478.2 ± 24.5 BPM) and MCAO-treated mice showed lower ApEn values compared to Sham (0.64 ± .04 vs. 1.02 ± 0.09). There was also a trend for increased number of apneic events in post-stroke animals. No significant differences were observed in TV, suggesting the respiratory phenotype observed in MCAO mice is not due to phenomena. Systemic injection of retigabine suppressed basal respiratory activity of Sham and MCAO-treated animals. Conclusions: Our results suggest that ischemic stroke results in hypoventilation and decreased respiratory stability as evidenced by a decrease in ApEn. Further, considering that retigabine worsened stroke-disordered breathing also suggests that stroke-induced respiratory problems do not result from over activation of the chemoreflex as previously proposed.

P.1.h.012 SLC6A15, a neuronal aminoacid transporter, regulates emotional behaviour through glutamatergic system

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.

Effects of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing newborn rats.

Dexmedetomidine, a selective α2-adrenoceptor agonist, is a new sedative agent. To examine the dexmedetomidine-associated changes in cardiorespiratory indices in spontaneously breathing newborn rats. An abdominal catheter to administer drugs and subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 4-day-old rats under isoflurane anesthesia; the rats were then placed in individual chambers. After recovery from the anesthesia, the rats received intraperitoneal administrations of normal saline (NS, vehicle), dexmedetomidine (50 μg·kg(-1)), or dexmedetomidine (50 μg·kg(-1)) followed 5 min later with NS or the selective α2-adrenoceptor antagonist atipamezole (1 mg·kg(-1)) (n = 10 in each group). Cardiorespiratory indices were recorded for each animal throughout the experiment. Dexmedetomidine administration significantly decreased heart rate (HR) and minute ventilation (V'E) (P < 0.05) compared with control, whereas NS administration did not. The decrease in HR and V'E after dexmedetomidine administration was significantly less in rats that received atipamezole (P < 0.05) than in those that received NS after dexmedetomidine administration. The dexmedetomidine-associated V'E depression was attributed to a significant decrease in respiratory frequency (fR) but not tidal volume (VT ). The change in fR was reversed by atipamezole administration, which itself induced no significant changes in HR and fR. In spontaneously breathing immature rats, dexmedetomidine administration significantly reduced HR and V'E. Because atipamezole fully reversed decreases in fR and therefore V'E, dexmedetomidine-related respiratory suppression occurs predominantly through α2-adrenoceptor-related suppression of fR.

Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats

The locus coeruleus (LC) plays an important role in central chemoreception. In young rats (P9 or younger), 85% of LC neurons increase firing rate in response to hypercapnia vs. only about 45% of neurons from rats P10 or older. Carbenoxolone (CARB – gap junction blocker) does not affect the % of LC neurons responding in young rats but it decreases the % responding by half in older animals. We evaluated the participation of gap junctions in the CO2 ventilatory response in unanesthetized adult rats by bilaterally microinjecting CARB (300μM, 1mM or 3mM/100nL), glycyrrhizic acid (GZA, CARB analog, 3mM) or vehicle (aCSF – artificial cerebrospinal fluid) into the LC of Wistar rats. Bilateral gap junction blockade in LC neurons did not affect resting ventilation; however, the increase in ventilation produced by hypercapnia (7% CO2) was reduced by ∼25% after CARB 1mM or 3mM injection (1939.7±104.8mLkg−1min−1 for the aCSF group and 1468.3±122.2mLkg−1min−1 for 1mM CARB, P<0.05; 1939.7±104.8mLkg−1min−1 for the aCSF group and 1540.9±68.4mLkg−1min−1 for the 3mM CARB group, P<0.05) due largely to a decrease in respiratory frequency. GZA injection or CARB injection outside the LC (peri-LC) had no effect on ventilation under any conditions. The results suggest that gap junctions in the LC modulate the hypercapnic ventilatory response of adult rats.

Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg). Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

Gap junction blockade in the locus coeruleus (LC) decreases the hypercapnic ventilatory response

The LC has an important role in central chemoreception and its contribution decreases with development. In neurons from young rats (P9 or younger), the % of LC neurons that increase firing rate in response to hypercapnia is 85% while it is only about 45% in neurons from rats P10 or older. Carbenoxolone (CARB ‐ gap junction blocker) has very little effect on this response in neurons from the youngest rats, with the % responding dropping only to 70% in the presence of CARB. However, CARB decreases the % responding by half in older animals, dropping it to 21%. We evaluated the participation of gap junctions in the CO2 ventilatory response in conscious adult rats by bilaterally microinjecting CARB (1mM or 3mM / 0.1 μL) or vehicle (artificial cerebrospinal fluid) into the LC of Wistar rats. Bilateral gap junction blockade in LC neurons did not affect resting ventilation. However, the increase in ventilation produced by hypercapnia (7% CO2) was reduced by 20% after CARB injection (1904.5 ± 95.2 in vehicle group vs 1518.0 ± 76.1 mL/kg/min in CARB 3mM group and 1468.3 ± 122.2 mL/kg/min in CARB 1mM) due largely to a decrease in respiratory frequency. The results suggest that gap junctions modulate the hypercapnic ventilatory response, but that they are not involved in respiratory control during normocapnia, in the LC of rats older than P10.Financial support: INCT‐Fisiologia Comparada, FAPESP, CNPq, and NIH Grant HL56683.

Effects of tiotropium on sympathetic activation during exercise in stable chronic obstructive pulmonary disease patients

BackgroundTiotropium partially relieves exertional dyspnea and reduces the risk of congestive heart failure in chronic obstructive pulmonary disease (COPD) patients. However, its effect on the sympathetic activation response to exercise is unknown.AimsThis study aimed to determine whether tiotropium use results in a sustained reduction in sympathetic activation during exercise.MethodsWe conducted a 12-week, open-label (treatments: tiotropium 18 μg or oxitropium 0.2 mg × 3 mg), crossover study in 17 COPD patients. Treatment order was randomized across subjects. The subjects underwent a pulmonary function test and two modes of cardiopulmonary exercise (constant work rate and incremental exercise) testing using a cycle ergometer, with measurement of arterial catecholamines after each treatment period.ResultsForced expiratory volume in 1 second and forced vital capacity were significantly larger in the tiotropium treatment group. In constant exercise testing, exercise endurance time was longer, with improvement in dyspnea during exercise and reduction in dynamic hyperinflation in the tiotropium treatment group. Similarly, in incremental exercise testing, exercise time, carbon dioxide production, and minute ventilation at peak exercise were significantly higher in the tiotropium treatment group. Plasma norepinephrine concentrations and dyspnea intensity were also lower during submaximal isotime exercise and throughout the incremental workload exercise in the tiotropium treatment group.ConclusionTiotropium suppressed the increase of sympathetic activation during exercise at the end of the 6-week treatment, as compared with the effect of oxipropium. This effect might be attributed to improvement in lung function and exercise capacity and reduction in exertional dyspnea, which were associated with decreases in respiratory frequency and heart rate and reduced progression of arterial acidosis.

The kreisler mutation leads to the loss of intrinsically hypoxia-activated spots in the region of the retrotrapezoid nucleus/parafacial respiratory group

Acute hypoxia elicits a biphasic respiratory response characterized in the newborn by a transient hyperventilation followed by a severe decrease in respiratory drive known as hypoxic respiratory depression. Medullary O(2) chemosensitivity is known to contribute to respiratory depression induced by hypoxia, although precise involvement of cell populations remains to be determined. Having a thorough knowledge of these populations is of relevance because perturbations in the respiratory response to hypoxia may participate in respiratory diseases in newborns. We aimed to analyze the hypoxic response of ponto-medullary cell populations of kreisler mutant mice. These mice have defects in a gene expressed in two rhombomeres encompassing a part of the medulla oblongata implicated in hypoxic respiratory depression. Central responses to hypoxia were analyzed in newborn mice by measuring respiratory rhythm in ex vivo caudal pons-medullary-spinal cord preparations and c-fos expression in wild-type and kreisler mutants. The homozygous kreisler mutation, which eliminates most of rhombomere 5 and mis-specifies rhombomere 6, abolished (1) an early decrease in respiratory frequency within 10 min of hypoxia and (2) an intrinsic hypoxic activation, which is characterized by an increase in c-fos expression in the region of the ventral medullary surface encompassing the retrotrapezoid nucleus/parafacial respiratory group expressing Phox2b. This increase in c-fos expression persisted in wild-type Phox2b-negative and Phox2b-positive cells after blockade of synaptic transmission and rhythmogenesis by a low [Ca(2+)](0). Another central response was retained in homozygous kreisler mutant mice; it was distinguished by (1) a delayed (10-30 min) depression of respiratory frequency and (2) a downregulation of c-fos expression in the ventrolateral reticular nucleus of the medulla, the nucleus of the solitary tract, and the area of the A5 region. Thus, two types of ponto-medullary cell groups, with distinct anatomical locations, participate in central hypoxic respiratory depression in newborns.

Morphological analysis of the trachea and pattern of breathing in βENaC-Tg mice

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.

Comparison of non-invasive mechanical ventilation with helmet or face mask in patients with acute exacerbation of chronic obstructive pulmonary disease

Exacerbation of chronic obstructive pulmonary disease (COPD) is one of the frequent causes of acute respiratory failure. In our study, we aimed to compare helmet with face mask in noninvasive mechanical ventilation (NIMV) on patients who had acute respiratory failure because of exacerbation of COPD in intensive care unit (ICU). Thirty patients, taken into ICU for exacerbation of COPD, were included in the study. Patients were divided into two groups as face mask group (Group Y) and helmet group (Group H). Appropriate mechanical ventilation settings were recorded after the starting period and NIMV was applied to patients continuously for two hours with these settings. Respiratory frequency (f), blood gas (PaO(2), PaCO(2), PH) and PaO(2)/FiO(2) values and hemodynamic data of all patients were recorded periodically. Compliance of patients were evaluated with patient tolerance scale (PTS). Duration of stay of the patients in ICU and complications were also noted. Demographic characteristics of patients, mechanical ventilator settings and hemodynamic data of the patients in the two groups were found to be similar (p>0.05). Frequency values measured during NIMV are also similar at all measurement times (p>0.05). It was determined that there was a remarkable decrease in respiratory frequency, in both groups after the application of NIMV (p< 0.001). There was no difference with respect to PaO(2), PH and PaO(2)/FiO(2) values at all measurement times, between groups (p> 0.05). PaCO(2) values in the beginning were similar in both groups but PaCO(2) measured at other measurement times for group H were statistically higher compared to the other group (p< 0.05). PTC score measured at during NIMV in group H were remarkably higher (p< 0.05). Helmet developed as an alternative to face mask has a better patient tolerance and accordingly in increases success rate in NIMV. But it must be keeping mind that the decrease in PaCO(2) value is slow with helmet.

Respiratory responses to somatostatin microinjections into the Bötzinger complex and the pre-Bötzinger complex of the rabbit

The respiratory responses to bilateral microinjections (30–50nl) of 5mM somatostatin (SOM) or 10mM cyclosomatostatin (c-SOM, a SOM antagonist) into the Bötzinger complex (BötC), the pre-Bötzinger complex (preBötC) and the rostral inspiratory portion of the ventral respiratory group (iVRG) were investigated in urethane–chloralose anesthetized, vagotomized, paralysed and artificially ventilated rabbits. SOM microinjections into the BötC decreased respiratory frequency and the rate of rise of phrenic nerve activity without obvious changes in its peak amplitude. SOM microinjected into the preBötC caused increases in respiratory frequency and decreases in peak phrenic activity associated with increases in its rate of rise. No changes in respiration were induced by SOM microinjections into the iVRG. Microinjections of c-SOM into the preBötC caused decreases in respiratory frequency as well as in peak amplitude and rate of rise of phrenic nerve activity. The results show that endogenously released SOM within the preBötC contributes to shape the pattern of baseline respiratory activity and that SOM receptors within the BötC and the preBötC have a role in the modulation of respiration in the rabbit.

Effect of chronic pain on morphine-induced respiratory depression in mice

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.