Increase In Breathing Frequency Research Articles

Optogenetic stimulation of C1 neurons activates breathing in mice

The C1 neurons regulate sympathetic tone and blood pressure, contribute to glucose homeostasis and regulate the CRF/ACTH/glucocorticoid cascade. Here, we tested whether the C1 cells also regulate respiration. We used a mouse line in which the Cre recombinase is expressed by dopamine‐beta hydroxylase synthesizing neurons. A Cre‐dependent AAV2 that expresses ChR2‐mCherry under promoter ef1‐alpha was injected unilaterally into the C1 region. The transgene was exclusively expressed by C1 neurons (>98% co‐localization with TH‐ir somata). We found that mouse C1 neurons express VGLUT2. Their projections were indistinguishable from those of the rat and included several regions involved in breathing regulation (pre‐Botzinger complex, retrotrapezoid nucleus, dorsal parabrachial and locus coeruleus). Photostimulation of the ChR2‐expressing C1 neurons with 473nm laser light (30 s; 5–20Hz; 1–10 ms pulses) increased diaphragm EMG frequency and/or amplitude in anesthetized mice (N=7) and increased breathing frequency in unanesthetized mice (N=7; plethysmography). These observations indicate that the C1 neurons have reciprocal connections with the respiratory network. They imply that breathing stimulation elicited by hypotension (barorespiratory reflex), carotid body stimulation, central hypoxia and nociception could also be partially relayed via C1 neurons. Support: HL 028785.

Gestation increases the energetic cost of breathing in the lizard, Tiliqua rugosa

High gestational loads result in fetuses that occupy a large proportion of the body cavity and may compress maternal organs. Compression of the lungs results in alterations in breathing patterns during gestation, which may affect the energetic cost of breathing. In this study, the energetic cost of breathing during gestation was determined in the viviparous skink Tiliqua rugosa. Radiographic imaging showed progressive lung compression during gestation and a 30% reduction in the lung inflation index (rib number at which the caudal margin of the lung was imaged divided by total rib number). Pneumotachography and open flow respirometry were used to measure breathing patterns and metabolic rates. Gestation induced a twofold increase in minute ventilation via increases in breathing frequency, but no change in inspired tidal volume. The rates of O(2) consumption and CO(2) production did not change significantly during gestation. Together, these results suggest that a relative hyperventilation occurs during gestation in T. rugosa, which in turn suggests that diffusion and/or perfusion limitations may exist at the lung during gestation. The energetic cost of breathing was estimated as a percentage of resting metabolic rate using hypercapnia to stimulate ventilation at different stages of pregnancy. The energetic cost of breathing in non-pregnant lizards was 19.96±3.85% of resting metabolic rate and increased threefold to 62.80±10.11% during late gestation. This significant increase in the energetic cost of breathing may have significant consequences for energy budgets during gestation.

Shortness of Breath with Minimal Exertion

HISTORY: A 44 y.o. male was referred for evaluation of shortness of breath (SOB) on exertion and cough. Symptoms began in Nov. 2009 when he inhaled particles from a litter box. Shortly after, patient developed fever and cough that progressed into SOB with minimal exertion. Spirometry showed restrictive pattern and flattening of inspiratory flow volume loop. Desaturation noted with moderate exertion. High-resolution CT angiogram showed small nodules but no infiltrates or interstitial lung disease. There was no evidence of myocardial ischemia by stress echo. PHYSICAL EXAMINATION: Well appearing Caucasian male. Ht: 72in; Wt: 206lb; Resting: HR: 81; BP: 110/80; SpO2: 97%; ECG: Normal; No dyspnea. DIFFERENTIAL DIAGNOSIS:Airway obstruction during exercise, Ventilatory limitation due to restriction, Exertional hypoxemia TEST AND RESULTS: PFTs: Spirometry: FVC: 61%pred; FEV1: 62%pred; FEV1/FVC: 83%; MVV: 96%pred; Inspiratory loop: Normal Lung Volumes: TLC: 66%pred; FRC PL: 66%pred; RV: 62%pred; Diffusion Capacity: DLCO: 51%pred; DLCO/VA: 87%pred EXERCISE TEST: Peak: WR: 120W; VO2: 17.5 ml/kg/min (49%pred); HR: 169; BP: 155/69; Qc: 13.1 L/min; VE: 77 L/min; VE/VCO2: 42; SpO2: 82% INTERPRETATION: Cardiovascular Response: Normal BP, HR, Qc & SV response; no ischemia; No ST segment changes; rare PVCs. Pulmonary Response: Ventilatory demand slightly increased; no expiratory flow limitations; limited inspiratory flow reserve at peak exercise; small tidal volume with increased breathing frequency driven by severe hypoxemia and restrictive lung disease. Metabolic Response: Normal O2 extraction and lactate production. FINAL/WORKING DIAGNOSIS: Impaired exercise capacity due to severe exercise induced hypoxemia (diffusion limitation) combined with restrictive lung disease. Possible development of right-to-left shunting during exercise, although unlikely. TREATMENT AND OUTCOMES: Negative right-to-left shunt by cardiac catheterization. Bronchocentric chronic interstitial pneumonitis with lymphocytes found by open lung biopsy. Patient advised to remove cats and litter box from home. He is placed on steroid therapy and antibiotic daily. He is able to increase activity, but continues to have exertional hypoxemia. Patient referred to an occupational pulmonologist for hypersensitivity pneumonitis.

Chronic hypoxia and chronic hypercapnia differentially regulate an NMDA-sensitive component of the acute hypercapnic ventilatory response in the cane toad (Rhinella marina)

This study addressed the hypotheses that exposure to chronic hypoxia (CH) and chronic hypercapnia (CHC) would modify the acute hypercapnic ventilatory response in the cane toad (Rhinella marina; formerly Bufo marinus or Chaunus marinus) and its regulation by NMDA-mediated processes. Cane toads were exposed to 10 days of CH (10% O(2)) or CHC (3.5% CO(2)) followed by acute in vivo hypercapnic breathing trials, conducted before and after an injection of the NMDA-receptor channel blocker, MK801 into the dorsal lymph sac. CH, CHC and MK801 did not alter ventilation under acute normoxic normocapnic conditions. CH blunted the increase in breathing frequency during acute hypercapnia while CHC had no effect. The effect of CH on breathing frequency was mediated by a decrease in the number of breaths per breathing episode. Neither CH nor CHC altered breath area (volume). MK801 augmented breathing frequency (via an increase in breaths per episode) and total ventilation during acute hypercapnia in control toads and toads exposed to CH; there was no effect of MK801 on the increase in breathing frequency or total ventilation, during acute hypercapnia in toads exposed to CHC. The results indicate that CH and CHC differentially alter breathing pattern. Furthermore, they indicate an absence of NMDA-mediated glutamatergic tone during normoxic normocapnia but that NMDA-mediated processes attenuate the increase in breathing frequency during acute hypercapnia under control conditions and following CH but not following CHC. Given that MK801 was administered systemically, the effects could be acting anywhere in the reflex pathway from CO(2)-sensing to respiratory motor output.

Neonatal stress increases respiratory instability in rat pups

Neonatal maternal separation (NMS) is a form of stress that has persistent, sex-specific effects on respiratory control development. In adult male (but not female) rats, NMS increases the hypoxic ventilatory response and augments respiratory instability during sleep; however, the effects of NMS on respiratory control prior to puberty are unknown. This study tested the hypothesis that NMS augments respiratory instability and the O(2) chemosensitivity in 12 days old rats. Pups subjected to NMS were placed in an incubator 3h/day from P3 to P12. Controls were undisturbed. Breathing and apnea index were measured in normoxia with plethysmography. The ventilatory chemoreflex was assessed by measuring the increase in breathing frequency upon brief exposure to a hypoxic challenge ( [Formula: see text]; 5 min). In normoxia, NMS augments the coefficient of variation (CV; an index of respiratory instability) of respiratory frequency and the number of apneas; this effect was more pronounced in male pups. We conclude that disruption of respiratory regulation by NMS is already apparent at P12. Based on results showing that plasma corticosterone levels of NMS pups were still elevated one day after the last NMS episode and the lack of effect of NMS on the O(2) chemoreflex index, we propose that disruption of hypothalamic regulation contributes to respiratory instability in NMS pups.

Ventilation-limited exercise capacity in a 59-year-old athlete

Aerobic exercise performance may be limited by the respiratory system in fit elderly adults whose lungs undergo the normal ageing process or who develop lung diseases but can maintain high pulmonary blood flows and ventilatory requirements. Here we describe a 59-year-old athlete demonstrating high aerobic exercise performance limited by his relatively low ventilatory capacity. The male hobby cyclist (59 years, 176 cm, 83 kg), undergoing cardiopulmonary exercise testing, reported no complaints except a history of dyspnoea and exercise intolerance at high altitude (> 2000 m). Lung function testing indicated mild airway obstruction (FEVC: 4.22 l, FEV1: 2.91 l, FEV1/FEVC: 69%) which was not reversed post-bronchodilator. However, FEV1/FEVC was slightly above the 5th percentile and thus not confirming the diagnosis of COPD. The athlete completed 300 W (3.6 W/kg) and his maximal oxygen uptake was 45 ml/min/kg (156% predicted!). Above 250 W he was unable further increasing minute ventilation, and oxygen pulse and oxygen uptake even decreased. The related changes of the respiratory pattern (increase of breathing frequency, decreases of inspiratory capacity and tidal volume) indicated dynamic lung hyperinflation resulting in cardiac output constraint, arterial oxygen desaturation, severe dyspnoea and exercise limitation. This case report delineates the pathophysiological situation of ventilation-limited exercise capacity in a well-trained middle-aged subject. However, beneficial adaptations to regular exercise may have helped maintain high aerobic performance without any adverse symptoms during submaximal exercise.

Breathing pattern and chest wall volumes during exercise in patients with cystic fibrosis, pulmonary fibrosis and COPD before and after lung transplantation

BackgroundPulmonary fibrosis (PF), cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often cause chronic respiratory failure (CRF).MethodsIn order to investigate if there are different patterns of adaptation of the...

Autoregulation of ventilation with neurally adjusted ventilatory assist on extracorporeal lung support

Extracorporeal membrane oxygenation (ECMO) can support oxygenation and carbon dioxide elimination in severe lung failure. Usually it is accompanied by controlled mechanical ventilation. Neurally adjusted ventilatory assist (NAVA) is a new mode of ventilation triggered by the diaphragmatic electrical activity and controlled by the patient's respiratory centre, which may allow a close interaction between ventilation and extracorporeal perfusion. This pilot study intended to measure the physiologic ventilatory response in patients with severe lung failure treated with ECMO and NAVA. We hypothesized that the combination of both methods could automatically provide a protective ventilation with optimized blood gases. We report a case series of six patients treated with ECMO for severe lung failure. In the recovery phase of the disease, patients were ventilated with NAVA and ventilatory response and gas exchange parameters were measured under different sweep gas flows and temporarily inactivated ECMO. Tidal volumes on ECMO ranged between 2 and 5 ml/kg predicted body weight and increased up to 8 ml/kg with inactivated ECMO. Peak inspiratory pressure reached 19-29 cmH(2)O with active, and 21-45 cmH(2)O with inactivated ECMO. Ventilatory response to decreased sweep gas flow was rapid, and patients immediately regulated PaCO(2) tightly towards a physiological pH value. Increase in minute ventilation was a result of increased breathing frequency and tidal volumes, and protective ventilation was only abandoned if pH control was not achieved. With NAVA ventilatory response to decreased ECMO sweep gas flow was rapid, and patients immediately regulated PaCO(2) tightly towards a physiological pH value. Therefore, combination of NAVA and ECMO may permit a closed-loop ventilation with automated protective ventilation.

In dystrophic hamsters losartan affects control of ventilation and dopamine D1 receptor density

The BIO 14.6 hamster (DV), an animal model of limb-girdle muscular dystrophy, has elevated angiotensin AT1 receptors that may affect ventilation. Moreover, AT1 receptors may modulate expression of dopamine D1 receptors. We investigated if chronic treatment of BIO 14.6 hamsters (DL) with losartan, an AT1 receptor blocker, affects D1 receptor density in the striatum and nucleus tractus solitarius (NTS) and normalizes ventilation during exposure to air, hypoxia, following hypoxia, and hypercapnia, Ventilation was evaluated using plethysmography. Compared to the golden Syrian hamsters (GS), DV hamsters exhibited lower hypercapnic and hypoxic responsiveness and ventilation during hypercapnic exposure. Relative to GS, DL hamsters increased breathing frequency in air and maintained ventilation during hypercapnia. Post-hypoxic minute ventilation decline occurred in DV but not in DL or GS hamsters. DL hamsters exhibited higher D1 receptor density in the striatum and NTS relative to DV hamsters. Thus, in dystrophic hamsters chronic losartan treatment stimulated frequency of breathing and increased the density of D1 receptors.

Pulmonary Oxidative Stress, Inflammation, and Dysregulated Iron Homeostasis in Rat Models of Cardiovascular Disease

Underlying cardiovascular disease (CVD) is a risk factor for the exacerbation of air pollution health effects. Pulmonary oxidative stress, inflammation, and altered iron (Fe) homeostasis secondary to CVD may influence mammalian susceptibility to air pollutants. Rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Baseline cardiac and pulmonary disease was characterized in healthy normotensive Wistar Kyoto (WKY) rats, cardiovascular compromised spontaneously hypertensive rats (SHR), and spontaneously hypertensive heart failure (SHHF) rats. Blood pressure, heart rate, and breathing frequencies were measured in rats 11 to 12 wk of age, followed by necropsy at 14 to 15 wk of age. Blood pressure and heart rate were increased in SHR and SHHF relative to WKY rats (SHR > SHHF > WKY). Increased breathing frequency in SHHF and SHR (SHR > SHHF > WKY) resulted in greater minute volume relative to WKY. Bronchoalveolar lavage fluid (BALF) protein and neutrophils were higher in SHHF and SHR relative to WKY (SHHF >> SHR > WKY). Lung ascorbate and glutathione levels were low in SHHF rats. BALF Fe-binding capacity was decreased in SHHF relative to WKY rats and was associated with increased transferrin (Trf) and ferritin. However, lung ferritin was lower and Trf was higher in SHHF relative to WKY or SHR rats. mRNA for markers of inflammation and oxidative stress (macrophage inflammatory protein [MIP]-2, interleukin [IL]-1α, and heme oxygenase [HO]-1) were greater in SHHF and SHR relative to WKY rats. Trf mRNA rose in SHR but not SHHF relative to WKY rats, whereas transferrin receptors 1 and 2 mRNA was lower in SHHF rats. Four of 12 WKY rats exhibited cardiac hypertrophy despite normal blood pressure, while demonstrating some of the pulmonary complications noted earlier. This study demonstrates that SHHF rats display greater underlying pulmonary complications such as oxidative stress, inflammation, and impaired Fe homeostasis than WKY or SHR rats, which may play a role in SHHF rats' increased susceptibility to air pollution.

μ-Opioid receptor agonist injections into the presumed pre-Bötzinger complex and the surrounding region of awake goats do not alter eupneic breathing

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a mu-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO(2) and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5-10 mul, 1 nM-10 muM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (Vi)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions (P > 0.10). However, DAMGO attenuated (P < 0.05) the evoked increase in breathing frequency when inspired CO(2) was increased, and DAMGO attenuated the Vi response to reduction of inspired O(2) to 10.8% (P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

Morte súbita em bovinos causada pela ingestão de Pseudocalymma elegans (Bignoniaceae) no município de Rio Bonito, RJ

Descreve-se a intoxicação natural por Pseudocalymma elegans em pelo menos um bovino em Rio Bonito, RJ e a reprodução experimental dessa intoxicação em três bovinos e em 3 coelhos com exemplares dessa planta colhida no local onde ocorreu a morte. Necropsia e histopatologia do bovino naturalmente intoxicado não revelaram alterações significativas. A administração, por via oral, de 1g/kg da brotação da planta causou a morte do bovino dentro de 5h e 30 minutos após o início da administração, já pela administração de 0,5 g/kg, a morte do animal ocorreu após 76 horas e 36 minutos. A dose de 0,25g/kg foi capaz de causar sintomas, mas não levou a morte. A sintomatologia caracterizou-se por arritmia cardíaca, taquicardia, aumento da freqüência respiratória, relutância em se mover, pulso venoso positivo, jugulares e grandes vasos ingurgitados, queda ao solo e movimentos de pedalagem, seguindo-se o óbito. À necropsia foram verificadas alterações compatíveis com às observadas na insuficiência cardíaca aguda, e o exame histopatológico revelou a lesão renal típica (degeneração hidrópica em túbulos contornados distais) de intoxicação por plantas que causam "morte súbita". Nos coelhos, a evolução variou entre menos de um minuto a dois minutos. O exame histopatológico do rim de dois coelhos também revelou a lesão microscópica característica. Essa planta ainda não havia sido mapeada nessa área do Estado do Rio de Janeiro. Conclui-se que a planta pode ser mais tóxica do que anteriormente descrito.

Influence of dorsal periaqueductal gray activation on respiratory occlusion reflexes in rats

The dorsal periaqueductal gray (dPAG) is an essential neural component for central integration of defense behavior and associated autonomic regulation. Electrical and chemical stimulation of this region results in a significant decrease of inspiratory (Ti) and expiratory (Te) breathing durations. In the present study it was hypothesized that breath timing changes elicited by dPAG activation would modulate respiratory load compensation volume–timing reflexes. The effect of dPAG activation of breathing pattern was investigated using chemical stimulation with microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) or disinhibition with GABAA (γ-aminobutyric acid) receptor antagonist bicuculline (BIC) in urethane-anesthetized, spontaneously breathing rats. Volume–timing reflexes were studied using inspiratory and expiratory occlusion before and after DLH or BIC dPAG activation. Both BIC and DLH activation of the dPAG significantly increased breathing frequency. Inspiratory occlusion significantly increased Ti before dPAG activation and DLH and BIC potentiated the relative increase in Ti during occlusion. BIC elicited a greater increase in inspiratory occlusion Ti than DLH. Inspiratory occlusion alone also significantly increased diaphragm EMG activity and this response was potentiated with dPAG activation. Expiratory occlusion significantly increased Te and DLH and BIC potentiated the relative increase in Te during expiratory occlusion. These results suggest that dPAG activation modulates the respiratory neural network, resulting in an increased respiratory drive and a decrease in volume–timing reflex sensitivity.

Design and evaluation of a methodology to perform personalized visual biofeedback for reducing respiratory amplitude in radiation treatment

A methodology to perform personalized visual biofeedback aimed to the reduction of respiratory amplitude is here proposed. A custom-made software allows to adapt the biofeedback parameters to a patient's respiratory pattern by calculating a limiting range for respiratory amplitude obtained from data acquired during free breathing. The proposed methodology has been tested on ten healthy volunteers and on five lung cancer patients undergoing radiotherapy treatment. The protocol for volunteers consisted of 3 min of data acquisition during the subject's free breathing, 2 min of visual biofeedback within the limits, and 3 min of free breathing. The patients' free breathing was acquired in 3 min and the visual biofeedback performed during all the sessions of the radiotherapy treatment, i.e., an average of eight sessions and an average total treatment time of 2000 s each patient. All the volunteers and three patients of the five found the protocol comfortable. The settlement time needed for considering the limiting range stabilized during free breathing has been calculated as 120 +/- 10 s (p < 0.05). During visual biofeedback the baseline shift was removed and the average respiratory amplitude was reduced by about 40% for all the subjects. The variability of the breathing amplitude remained unaltered during biofeedback. Eight volunteers and three patients remained within the limiting range for more than 90% of the biofeedback period; all subjects remained within the limiting range for more than 80% of the biofeedback period. During the biofeedback period both groups, volunteers and patients, showed a significant increase in breathing frequency which was mostly doubled. Patients with shallow breathing performed comfortably the biofeedback.

Gestational stress delays maturation of the hypoxic ventilatory response: an in vivo and in vitro study

Exposure to stress during gestation disrupts CNS development; however, its effects on the respiratory control system are unknown. We tested the hypothesis that exposing dams to a predator odor during gestation disrupts the maturation of the hypoxic ventilatory response (HVR) of newborn rats. From the 9th to the 19th day of pregnancy, females subjected to gestational stress (GS) were placed in a cage containing 35 μl of TMT, a component of fox odor for 20 min. For sham treatment, gestating females were exposed to a strong odor (butyric acid, 105 μl). Controls were undisturbed. Ventilatory activity was measured at post natal days 0, 2 and 4 using plethysmography (in vivo) and "en bloc" brainstem spinal cord preparations (in vitro). Measurements were performed under baseline conditions and hypoxia. In vivo: unlike controls, P4 male pups born to GS dams could not sustain a significant increase in breathing frequency through out the hypoxic period (12% O2, 20 min). This effect of GS was not observed in females. In vitro: at the end of hypoxia (7% O2, 20 min), preparations from GS pups showed a smaller phrenic burst frequency decrease than controls (‐58% vs ‐76%). No sexual dimorphism was observed in vitro. GS delays maturation of the hypoxic ventilatory response. Comparison of in vivo vs in vitro data suggests that GS affects peripheral chemoreceptor development and/or integration of afferent signal in the CNS. Supported by the CIHR.

Hypoxemia and Acute Mountain Sickness: Which Comes First?

Hypoxemia is usually associated with acute mountain sickness (AMS), but most studies have varied in time and magnitude of altitude exposure, exercise, diet, environmental conditions, and severity of pulmonary edema. We wished to determine whether hypoxemia occurred early in subjects who developed subsequent AMS while resting at a simulated altitude of 426 mmHg (approximately 16,000 ft or 4880 m). Exposures of 51 men and women were carried out for 8 to 12 h. AMS was determined by Lake Louise (LL) and AMS-C scores near the end of exposure, with spirometry and gas exchange measured the day before (C) and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude and arterial blood at C, A1, and A12. Responses of 16 subjects having the lowest AMS scores (nonAMS: mean LL=1.0, range=0-2.5) were compared with the 16 having the highest scores (+AMS: mean LL=7.4, range=5-11). Total and alveolar ventilation responses to altitude were not different between groups. +AMS had significantly lower PaO2 (4.6 mmHg) and SaO2 (4.8%) at A1 and 3.3 mmHg and 3.1% at A12. Spirometry changes were similar at A1, but at A6 and A12 reduced vital capacity (VC) and increased breathing frequency suggested interstitial pulmonary edema in +AMS. The early hypoxemia in +AMS appears to be the result of diffusion impairment or venous admixture, perhaps due to a unique autonomic response affecting pulmonary perfusion. Early hypoxemia may be useful to predict AMS susceptibility.

Enhancement of the breathing frequency response to hypoxia by neonatal caffeine treatment in adult male rats: The role of testosterone

Caffeine is a common treatment for apnea of prematurity. Although relatively safe, little is known about the potential long-term effects of this treatment on respiratory control development. We previously showed that adult male (but not female) rats previously subjected to neonatal caffeine treatment (NCT; 15 mg/kg/day, postnatal days 3-12) show a higher breathing frequency response during the early phase of hypoxic exposure. To address the role of sexual hormones in this sexual dimorphism, the present study tested the hypothesis that in adult male rats, circulating testosterone contributes to NCT-related augmentation of the acute breathing frequency response to hypoxia. Whole body plethysmography was used to compare the acute ventilatory response to moderate hypoxia (FIO2=0.12; 20 min) between rats previously subjected to NCT or neonatal water treatment (NWT; same treatment as NCT but using water). In each group, rats were either sham-operated or gonadectomized (GDX) 14 days prior to ventilatory measurements. In sham-operated rats, the increase in breathing frequency measured during the first 8 min of hypoxia was greater in NCT rats versus NWT. The hypoxic ventilatory response measured at the end of the hypoxia was not affected by treatment, thus indicating that NCT mainly affected the peripheral component of the chemoreflex. Gonadectomy had no effect on NCT but augmented the frequency response of NWT rats to the same level of NCT, thus eliminating the between-group difference. NCT may interfere with the inhibitory effect of circulating testosterone on carotid body function. Although appealing, additional experiments are necessary to substantiate this interpretation.

Autonomic dysregulation in young girls with Rett Syndrome during nighttime in‐home recordings

This study was designed to specifically characterize the autonomic phenotype of cardiorespiratory dysregulation during the nighttime in young girls with MECP2 mutation-confirmed Rett Syndrome (RS), studied in their home environment. Computerized breath-to-breath and beat-to-beat characterization of at-home continuously recorded respiratory inductance plethysmography of chest/abdomen and ECG (VivoMetrics, Inc.) was obtained during overnight recordings in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched screened controls (ages 2-7 years). We determined that although the breathing and heart rate appear more regular during the night compared to the day, young girls with RS demonstrate apparent nocturnal irregularities. Comparing daytime versus nighttime, breathing was more irregular, with an increased breathing frequency (and irregularity), mean amplitude of respiratory inductance plethysmography sum (AMP)/T(I), and heart rate and decreased AMP in girls with RS. Comparing girls with RS versus controls during nighttime recording, breathing was more irregular, with an increased breathing frequency (and irregularity), mean AMP/T(I), and heart rate. An increased uncoupling between measures of breathing and heart rate control indicates malregulation in the autonomic nervous system, and is apparent during the day as well as the night. This uncoupling may represent a mechanism that renders the girls with RS more vulnerable to sudden death.

Some effects of dopamine transporter and receptor ligands on discriminative stimulus, physiologic, and directly observable indices of opioid withdrawal in rhesus monkeys

Some monoamine uptake inhibitors (e.g., cocaine) attenuate the subjective and discriminative stimulus effects of opioid withdrawal. This study examined a role for dopamine transporters and receptors as targets for drugs to modify the discriminative stimulus effects of opioid withdrawal and further examined a subset of these drugs for their capacity to modify some directly observable and physiologic indices of withdrawal. Rhesus monkeys receiving 2 mg/kg/day of L: -alpha-acetylmethadol discriminated the opioid antagonist naltrexone (0.0178 mg/kg s.c.). The naltrexone discriminative stimulus was attenuated not only by the mu agonist morphine but also by the dopamine D(2)-like receptor agonists bromocryptine and quinpirole. In contrast, the naltrexone discriminative stimulus was not consistently modified by the non-selective, D(1)- and D(2)-like agonist apomorphine or by uptake inhibitors with high selectivity for dopamine transporters (GBR 12909, RTI 113, and RTI 177). In the same monkeys, naltrexone dose dependently decreased body temperature, increased breathing frequency, and induced directly observable signs (grimacing, salivation, and unusual posture). Hypothermia, hyperventilation, and signs of withdrawal were significantly attenuated by morphine and not by quinpirole. Attenuation of opioid withdrawal by D(2)-like receptor agonists that have lower efficacy than dopamine, and not by uptake inhibitors with selectivity for dopamine transporters, suggests that magnitude of receptor stimulation (e.g., efficacy) and selectivity at dopamine receptors are important factors in the modulation of opioid withdrawal. Attenuation of the naltrexone discriminative stimulus by drugs that inhibit both dopamine and serotonin uptake (e.g., cocaine) could result from an inhibitory effect of serotonin on dopamine. The role of dopamine in opioid withdrawal appears to be restricted to subjective (i.e., not somatic) indices [corrected]

Irradiation of Varying Volumes of Rat Lung to Same Mean Lung Dose: a Little to a Lot or a Lot to a Little?

To investigate whether irradiating small lung volumes with a large dose or irradiating large lung volumes with a small dose, given the same mean lung dose (MLD), has a different effect on pulmonary function in laboratory animals. WAG/Rij/MCW male rats were exposed to single fractions of 300 kVp X-rays. Four treatments, in decreasing order of irradiated lung volume, were administered: (1) whole lung irradiation, (2) right lung irradiation, (3) left lung irradiation, and (4) irradiation of a small lung volume with four narrow beams. The irradiation times were chosen to accumulate the same MLD of 10, 12.5, or 15 Gy with each irradiated lung volume. The development of radiation-induced lung injury for < or =20 weeks was evaluated as increased breathing frequency, mortality, and histopathologic changes in the irradiated and control rats. A significant elevation of respiratory rate, which correlated with the lung volume exposed to single small doses (> or =5 Gy), but not with the MLD, was observed. The survival of the rats in the whole-lung-irradiated group was MLD dependent, with all events occurring between 4.5 and 9 weeks after irradiation. No mortality was observed in the partial-volume irradiated rats. The lung volume irradiated to small doses might be the dominant factor influencing the loss of pulmonary function in the rat model of radiation-induced lung injury. Caution should be used when new radiotherapy techniques that result in irradiation of large volumes of normal tissue are used for the treatment of lung cancer and other tumors in the thorax.