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Purpose: The larynx has a dual role in the regulation of gas flow into and out of the lungs while also establishing resistance required for vocal fold vibration. This study assessed reciprocal relations between phonatory functions--specifically, phonatory laryngeal airway resistance ([R.sub.law])--and respiratory homeostasis during states of ventilatory gas perturbations. Method: Twenty-four healthy women performed phonatory tasks while exposed to induced hypercapnia (high C[O.sub.2]), hypocapnia (low C[O.sub.2]), and normal breathing (eupnea). Effects of gas perturbations on [R.sub.law] were investigated as were the reciprocal effects of [R.sub.law] modulations on respiratory homeostasis. Results: [R.sub.law[remained stable despite manipulations of inspired gas concentrations. In contrast, end-tidal C[O.sub.2] levels increased significantly during all phonatory tasks. Thus, for the conditions tested, [R.sub.law] did not adjust to accommodate ventilatory needs as predicted. Rather, stable [R.sub.law] was spontaneously accomplished at the cost of those needs. Conclusions: Findings provide support for a theory of regulation wherein [R.sub.law] may be a control parameter in phonation. Results also provide insight into the influence of phonation on respiration. The work sets the foundation for future studies on laryngeal function during phonation in individuals with lower airway disease and other patient populations., The larynx, as part of the upper airway, has a challenging dual role in the simultaneous regulation of gas flow into and out of the lungs for respiration as well [...]

The Atlantic blue crab, Callinectes sapidus (Rathbun), is a highly mobile crustacean that must locomote to find food, evade predators, find mates, and avoid adverse conditions such as hypoxia. In this study we tested the effects of two levels of hypoxia (10.4 kPa, 50% air saturation = moderate hypoxia; 4 kPa, 20% air saturation = severe hypoxia) and hypercapnic hypoxia (50% air saturation [O.sub.2] with P[co.sub.2] = 2 kPa) on fatigue during sustained continuous exercise. Fatigue was induced by an exercise trial that entailed continuous sideways hexapedal walking on an underwater treadmill. Fatigue was quantified using two methods: (1) a pull force test that measures the holding strength of the legs, and (2) the number of fatigue-resisting behaviors (180° turns and stopping). Fatigue was defined as a pull force of 67% or less of the initial pre-exercise pull force and was reached after 6.12 h of walking for crabs in well-aerated normoxic seawater, 4 h in 50% air saturation, 2.07 h in 20% air saturation, and 4.58 h in 50% air saturation and hypercapnia. The number of fatigue-resisting behaviors increased with walking time in all treatments. Performance decreased in hypoxia, with fatigue being reached more quickly as the level of hypoxia intensified. Hypercapnia in moderate hypoxia did not have a deleterious influence on behavior and lengthened slightly the time it took crabs to fatigue. In addition, severe hypoxia exacerbated changes in gait kinematics as crabs became fatigued, by significantly increasing stride length and decreasing stride frequency., Introduction The Atlantic blue crab, Callinectes sapidus (Rathbun), is an important commercial and recreational species that is of economic interest in the southeastern United States and the Gulf of Mexico [...]

Hypercapnia is regularly observed in chronic lung disease, such as bronchopulmonary dysplasia in preterm infants. Hypercapnia results in increased nitric oxide synthase activity and in vitro formation of nitrates. Neural vasculature of the immature subject is particularly sensitive to nitrative stress. We investigated whether exposure to clinically relevant sustained high C[O.sub.2] causes microvascular degeneration in the newborn brain by inducing nitrative stress, and whether this microvascular degeneration has an impact on brain growth. Newborn rat pups were exposed to 10% C[O.sub.2] as inspired gas ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] = 60-70 mmHg) starting within 24 h of birth until postnatal day 7 (P7). Brains were notably collected at different time points to measure vascular density, determine brain cortical nitrite/nitrate, and trans-arachidonic acids (TAAs; products of nitration) levels as effectors of vessel damage. Chronic exposure of rat pups to high C[O.sub.2] [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] [approximately equal to] 65 mmHg) induced a 20% loss in cerebrovascular density at P3 and a 15% decrease in brain mass at P7; at P30, brain mass remained lower in C[O.sub.2]-exposed animals. Within 24 h of exposure to C[O.sub.2], brain eNOS expression and production of nitrite/nitrate doubled, lipid nitration products (TAAs) increased, and protein nitration (3-nitrotyrosine immunoreactivity) was also coincidently augmented on brain microvessels (lectin positive). Intracerebroventricular injection of TAAs (10 [micro]M) replicated cerebrovascular degeneration. Treatment of rat pups with NOS inhibitor (L-[N.sup.[omega]]-nitroarginine methyl ester) or a peroxynitrite decomposition catalyst (FeTPPS) prevented hypercapnia-induced microvascular degeneration and preserved brain mass. Cytotoxic effects of high C[O.sub.2] were reproduced in vitro/ex vivo on cultured endothelial cells and sprouting microvessels. In summary, hypercapnia at values frequently observed in preterm infants with chronic lung disease results in increased nitrative stress, which leads to cerebral cortical microvascular degeneration and curtails brain growth. brain microvasculature; cell death; reactive nitrogen species; transfatty acids. doi: 10.1152/ajpregu.00807.2009.

Breathing-disordered states, such as in obstructive sleep apnea, which are cyclical in nature, have been postulated to induce neurocognitive morbidity in both pediatric and adult populations. The oscillatory nature of intermittent hypoxia, especially when chronic, may mimic the paradigm of ischemia-reperfusion in that tissues and cells are exposed to episodes of low and high [O.sub.2] and this may lead to oxidant stress. Therefore, we decided to explore the potential contribution of oxidant stress in our intermittent hypoxia/hypercapnia animal model and the role that mitochondria might play in this stress. Neonatal mice were exposed to intermittent hypoxia/hypercapnia for 10 days and 2 wk. Combined intermittent hypoxia/hypercapnia led to a marked increase in apoptotic cell death in the cerebral cortex. Oxygen consumption studies in isolated mitochondria from intermittent hypoxia/hypercapnia-exposed brains demonstrated significant reductions in both state 4 and state 3 respiratory activities by ~60% and 75%, respectively. Electron paramagnetic resonance spectroscopy registered a significant increase in superoxide production during nonphosphorylating state 4 by 37%, although superoxide leakage during state 3 did not increase upon treatment. Neuronal superoxide-specific dihydroethidium oxidation was also greater in exposed animals. These studies indicate that intermittent hypoxia/hypercapnia leads to oxidative stress due to mitochondrial response within the mouse central nervous system. cyclical oxygen deprivation; mouse; central nervous system; apoptosis; superoxide doi: 10.1152/ajpcell.00298.2009.

Sturgeons are among the most C[O.sub.2] tolerant of fishes investigated to date. However, the basis of this exceptional C[O.sub.2] tolerance is unknown. Here, white sturgeon, Acipenser transmontanus, were exposed to elevated C[O.sub.2] to investigate the mechanisms associated with short-term hypercarbia tolerance. During exposure to 1.5 kPa [Pco.sub.2], transient blood pH [extracellular pH (phe)] depression was compensated within 24 h and associated with net plasma HC[O.sup.-.sub.3] accumulation and equimolar [Cl.sup.-] loss, and changes in gill morphology, such as a decrease in apical surface area of mitochondrial-rich cells. These findings indicate that pile recovery at this level of hypercarbia is accomplished in a manner similar to most freshwater teleost species studied to date, although branchial mechanisms involved may differ. White sturgeon exposed to more severe hypercarbia (3 and 6 kPa [Pco.sub.2]) for 48 h exhibited incomplete pH compensation in blood and red blood cells. Despite pile depression, intracellular pH (pHi) of white muscle, heart, brain, and liver did not decrease during a transient (6 h of 1.5 kPa [Pco.sub.2]) or prolonged (48 h at 3 and 6 kPa [Pco.sub.2]) blood acidosis. This pHi protection was not due to high intrinsic buffering in tissues. Such tight active cellular regulation of phi in the absence of pile compensation represents a unique pattern for non-air-breathing fishes, and we hypothesize that it is the basis for the exceptional C[O.sub.2] tolerance of white sturgeon and, likely, other C[O.sub.2] tolerant fishes. Further research to elucidate the specific mechanisms responsible for this tremendous pH regulatory capacity in tissues of white sturgeon is warranted. sturgeon; acid-base regulation; intracellular pH; C[O.sub.2] tolerance; hypercarbia/hypercapnia

Congenital central hypoventilation syndrome (CCHS) is a rare disease with variable severity, generally present from birth and chiefly characterized by impaired chemosensitivity to hypercapnia. The main cause of CCHS is a mutation in the PHOX2B gene, which encodes a transcription factor involved in the development of autonomic medullary reflex pathways. Temperature regulation is abnormal in many patients with CCHS. Here, we examined whether ambient temperature influenced C[O.sub.2] sensitivity in a mouse model of CCHS. A weak response to C[O.sub.2] at thermoneutrality (32[degrees]C) was noted previously in 2-day-old mice with an invalidated Phox2b allele (Phox2b+/-), compared with wild-type littermates. We exposed Phox2b+/- pups to 8% C[O.sub.2] at three ambient temperatures (TAs): 29[degrees]C, 32[degrees]C, and 35[degrees]C. We measured breathing variables and heart rate (HR) non-invasively using a novel whole body flow plethysmograph equipped with contact electrodes. Body temperature and baseline breathing increased similarly with TA in mutant and wild-type pups. The hypercapnic ventilatory response increased linearly with TA in both groups, while remaining smaller in mutant than in wild-type pups at all TAs. The differences between the absolute increases in ventilation in mutant and wild-type pups become more pronounced as temperature increased above 29[degrees]C. The ventilatory abnormalities in mutant pups were not associated with significant impairments of heart rate control. In both mutant and wild-type pups, baseline HR increased with TA. In conclusion, TA strongly influenced the hypercapnic ventilatory response in Phox2b+/- mutant mice. These findings suggest that abnormal temperature regulation may contribute to the severity of respiratory impairments in CCHS patients. chemosensitivity; Ondine syndrome; congenital central hypoventilation syndrome; thermoregulation

We reported previously that intermittent hypoxia with C[O.sub.2] to maintain eucapnia (IH-C) elevates plasma endothelin-1 (ET-1) and arterial pressure. In small mesenteric arteries (sMA; inner diameter = 150 [micro]m), IH-C augments ET-1 constrictor sensitivity but diminishes ET-l-induced increases in intracellular [Ca.sup.2+] concentration, suggesting IH-C exposure increases both ET-1 levels and ET-l-stimulated [Ca.sup.2+] sensitization. Because Rho-associated kinase (ROK) can mediate [Ca.sup.2+] sensitization, we hypothesized that augmented vasoconstrictor sensitivity to ET-1 in arteries from IH-C-exposed rats is dependent on ROK activation. In thoracic aortic rings, ET-1 contraction was not different between groups, but ROK inhibition (Y-27632, 3 and 10 [micro]M) attenuated ET-1 contraction more in IH-C than in sham arteries (50 [+ or -] 11 and 78 [+ or -] 7% vs. 41 [+ or -] 12 and 48 [+ or -] 9% inhibition, respectively). Therefore, ROK appears to contribute more to ET-1 contraction in IH-C than in sham aorta. In sMA, ROK inhibitors did not affect ET-1-mediated constriction in sham arteries and only modestly inhibited it in IH-C arteries. In ionomycin-permeabilized sMA with intracellular [Ca.sup.2+] concentration held at basal levels, Y-27632 did not affect ET-l-mediated constriction in either IH-C or sham sMA and ET-1 did not stimulate ROK translocation. In contrast, inhibition of myosin light-chain kinase (ML-9, 100 [micro]M) prevented ET-1-mediated constriction in sMA from both groups. Therefore, IH-C exposure increases ET-1 vasoconstrictor sensitivity in sMA but not in aorta. Furthermore, ET-1 constriction is myosin light-chain kinase dependent and mediated by [Ca.sup.2+] sensitization that is independent of ROK activation in sMA but not aorta. Thus ET-1-mediated signaling in aorta and sMA is altered by IH-C but is dependent on different second messenger systems in small vs. large arteries. sleep apnea; endothelin-1; vascular smooth muscle cells; Rho-associated kinase

5-HT2 receptor activity in the hypoglossal nucleus and hypercapnia is associated with airway dilation. 5-HT neurons in the medullary raphe and hypercapnia are responsible for tidal volume change. In this study, the effects of 5-HT2 receptors in the dorsomedial medulla oblongata (DMM), which receives projections from the medullary raphe, and hypercapnia on airway resistance and respiratory variables were studied in mice while monitoring 5-HT release in the DMM. A microdialysis probe was inserted into the DMM of anesthetized adult mice. Each mouse was placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to stepwise increases in C[O.sub.2] inhalation (5%, 7%, and 9% C[O.sub.2] in [O.sub.2]) at 8-min intervals with a selective serotonin reuptake inhibitor, fluoxetine, or fluoxetine plus a 5-HT2 receptor antagonist, LY-53857 in the DMM. In response to fluoxetine plus LY-53857 coperfusion, specific airway resistance was increased, and tidal volume and minute ventilation were decreased. C[O.sub.2] inhalation with fluoxetine plus LY-53857 coperfusion in the DMM largely decreased airway resistance and additively increased minute ventilation. Thus, 5-HT2 receptor activity in the DMM increases basal levels of airway dilation and ventilatory volume, dependent on central inspiratory activity and the volume threshold of the inspiratory off-switch mechanism. Hypercapnia with low 5-HT2 receptor activity in the DMM largely recovers airway dilation and additively increases ventilatory volume. Interaction between 5-HT2 receptor activity in the DMM and C[O.sub.2] drive may elicit a cycle of hyperventilation with airway dilation and hypoventilation with airway narrowing. serotonin; hypoglossal nucleus; airway resistance; solitary tract nucleus; respiration

Byline: Laurent Ducros (1), Katayoun Vahedi (2), Thomas Similowski (3), Marie-Germaine Bousser (2), Didier Payen (1) Keywords: Medulla oblongata Hypercapnia Cerebral infarction Abstract: Background.. Medullary infarcts can be associated with breathing disorders that usually consist in central hypoventilation. Patient.. We describe the case of a 54-year-old man, fully conscious, presenting with an uncontrollable high frequency and shallow tachypnea (95/min) at the onset of a unilateral medial medullary infarct. This disorder disappeared under inspiratory pressure support mechanical ventilation. Measurements and results.. Respiratory drive (respiratory rate, occlusion pressure, and mean inspiratory flow), efferent pathway (transcranial and cervical magnetic stimulation), and afferent pathway (response to CO.sub.2 and to lung inflation) were investigated. The respiratory drive was increased. The phrenic nerve conduction time was normal. The sensitivity of the central pattern generator to lung inflation and to CO.sub.2 was preserved. The territory of the infarct was supplied by the spinal anterior artery. Conclusions.. An extremely rapid and shallow tachypnea due to the increase in respiratory drive can be associated with unilateral medullary infarction. Author Affiliation: (1) Departement d'Anesthesie-Reanimation-SMUR, Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris, 2 rue Ambroise Pare, 75010, Paris, France (2) Service de Neurologie, Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris, Paris, France (3) Laboratoire de Physiopathologie Respiratoire, Service de Pneumologie, Groupe Hospitalier Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Paris, France Article History: Received Date: 09/08/2001 Accepted Date: 20/12/2002 Article note: Electronic Publication

Byline: Sebastian Prin (1), Karim Chergui (1), Rock Augarde (1), Bernard Page (1), Francois Jardin (1), Antoine Vieillard-Baron (1) Keywords: ARDS Protective ventilation Permissive hypercapnia Heat and moisture exchanger Heated humidifier Abstract: Abstract Objective. To assess the ability of a heated humidifier to improve CO.sub.2 clearance in ARDS patients submitted to protective ventilation. Design. Prospective clinical study. Setting. University hospital intensive care unit. Patients. During a 12-month period, we studied 11 ARDS patients under protective mechanical ventilation with severe hypercapnia. Intervention. When PaCO.sub.2 was above 55 mmHg, the heat and moisture exchanger (HME) was removed and patients were ventilated using a heated humidifier (HH) until their recovery or death. The heated humidifier was inserted on the inspiratory limb of the respirator and the inspirated air was saturated to achieve a temperature of 40 degC at the Y connector of ventilator tubing and of 37 degC at the outlet of the endotracheal tube. Measurements and results. Mechanical measurements and blood gas analysis were performed just before removal of the HME, and 30 min after mechanical ventilation using HH. Ventilator parameters were kept constant in the two conditions. Using HH instead of HME, PaCO.sub.2 was safely decreased by 11+-5 mmHg, without any need to change respiratory rate. No significant difference was noted in intrinsic PEEP or airway plateau pressure. Decrease in PaCO.sub.2 after HME removal was strongly correlated with the initial value of PaCO.sub.2. Conclusion. Supposing there is an interest in correcting or limiting hypercapnic acidosis in ARDS patients submitted to protective ventilation, HME removal and use of HH appears to be an efficient and safe way of increasing CO.sub.2 clearance. Author Affiliation: (1) Medical Intensive Care Unit, University Hospital Ambroise Pare, Assistance Publique Hopitaux de Paris, 9 avenue Charles de Gaulle, 92104, Boulogne, France Article History: Received Date: 23/05/2002 Accepted Date: 10/09/2002 Article note: Electronic Publication

Byline: Tomoyo Nishida (1), Masaji Nishimura (2), Kiyokazu Kagawa (3), Yukio Hayashi (4), Takashi Mashimo (4) Keywords: Dexmedetomidine Respiratory depression Respiratory response to carbon dioxide Abstract: Abstract Objective. Dexmedetomidine is a highly selective [alpha].sub.2-adrenergic agonist that can reduce anesthetic requirements. This study, to assess its effect on respiration, examined the effects of various doses of dexmedetomidine (1, 10, 30 and 50 Aug/kg) on the respiratory response to carbon dioxide (CO.sub.2) breathing in rabbits. Design. Randomized prospective study. Setting. Animal laboratory at a university school of medicine. Intervention. From 28 animals, four groups of seven were randomly assigned to receive different doses of dexmedetomidine (groups D1, D10, D30 and D50). Under inhalation of sevoflurane, each animal was tracheostomized and intubated with a 4 mm internal diameter (i.d.) endotracheal tube. Measurements and results. After end-tidal sevoflurane concentration had decreased below 0.03% and during quiet breathing (QB) respiratory rate (RR), tidal volume (V.sub.T) and inspiratory time (T.sub.I) were measured, from which minute ventilation (MV) and mean inspiratory flow (V.sub.T/T.sub.I) were calculated. After these measurements had been completed, each animal breathed the balloon gas (5% CO.sub.2 and 95% O.sub.2) until the end-tidal CO.sub.2 (ETCO.sub.2) reached 10%. The respiratory measurements were repeated during the latter period. After the collection of these data, dexmedetomidine was infused intravenously and the same measurements were repeated 15 and 45 min after dexmedetomidine infusion. The slope of the ventilatory response to hypercapnia in D50 was significantly higher compared with D30 animals. In the range 1--30 Aug/kg, during both QB and at 10% ETCO.sub.2, MV was decreased in a dose-dependent manner. Dexmedetomidine depressed both V.sub.T and RR during QB and at 10% ETCO.sub.2. Conclusion. Dexmedetomidine depressed resting ventilation and the respiratory response to CO.sub.2, but it did not induce profound hypoxemia or hypercapnia in rabbits. Author Affiliation: (1) Saiseikai Nakatsu Hospital, 2--10--39 Shibata, Kita-ku, Osaka, Japan 530--0012 (2) Intensive Care Unit, Osaka University Hospital, 2--15 Yamadaoka, Suita, Osaka, Japan 565--0871 (3) Department of Anesthesiology, National Cardiovascular Center, 5--7-1 Fujishirodai, Suita, Osaka 565--0873, Japan (4) Department of Anesthesiology, Osaka University Medical School, 1--1 Yamadaoka, Suita, Osaka 565--0871, Japan (5) Present address: Intensive Care Unit, Osaka University Hospital, 2--15 Yamadaoka, Suita, Osaka 565--0871, Japan Article History: Received Date: 04/06/2001 Accepted Date: 12/04/2002 Article note: Electronic Publication

A magnetic cell separation technique (MACS) was developed for isolating and characterizing peanut lectin agglutinin positive ([PNA.sup.+]) cells from rainbow trout gills. Percoll density separated mitochondria-rich (MR) cells were serially labeled with PNA-FITC and an anti-FITC antibody covalently coupled to a 50-nm iron particle and then applied to a magnetic column. [PNA.sup.+] MR cells were enriched to >95% purity. Transmission electron microscopy analysis of both the [PNA.sup.+] and PNA negative ([PNA.sup.-]) fraction showed that PNA binds to MR chloride cells while the [PNA.sup.-] cell fraction is comprised of MR cells with features characteristic of pavement cells. Western blotting demonstrated that both [PNA.sup.+] and [PNA.sup.-] fractions had high levels of [Na.sup.+]-[K.sup.+]-ATPase and Sco1 expression; however, relative expression of [H.sup.+]-ATPase in [PNA.sup.+] and [PNA.sup.-] cells demonstrated that untreated fish had twofold higher [H.sup.+]-ATPase levels in [PNA.sup.-] cells relative to the [PNA.sup.+] cells. Furthermore, hypercapnic acidosis significantly increased the relative [H.sup.+]-ATPase expression on [PNA.sup.-] cells only, whereas metabolic alkalosis had no significant effect. peanut lectin; pavement cell; fish; hypercapnia; hydrogen-adenosine-triphosphatase

Byline: Robert A. van Hulst (1), Djo Hasan (2), Burkhard Lachmann (1) Keywords: Permissive hypercapnia Hyperventilation Intracranial pressure Open lung concept Brain oxygen animal model Abstract: Objective: To evaluate in healthy, non-brain-traumatized animals the effects of hypo- and hyperventilation on intracranial pressure (ICP) and brain carbon dioxide, oxygen, and pH during the use of a ventilatory mode at constant mean airway pressure (MAwP). Design and setting: Prospective animal study in a university laboratory. Subjects: Eight crossbred Landrace/Yorkshire pigs. Interventions: The animals were ventilated in a pressure-controlled mode according to the open lung concept with an inspired oxygen fraction of 1.0. Starting at normoventilation, a stepwise hypo- and hyperventilation was performed to PaCO.sub.2 values of 90.4+-10.4 and 26.9+-4.1 mmHg, respectively. The ICP and brain parenchyma values [carbon dioxide (PbrCO.sub.2), oxygen (PbrO.sub.2), and pH (brpH)] measured by multiparameter sensors were recorded continuously during these maneuvres. Results: During hypoventilation there was a significant increase in PbrCO.sub.2 tension, PbrO.sub.2 tension, and ICP. During hyperventilation there was a significant decrease in PbrCO.sub.2 tension and ICP while the change in PbrO.sub.2 was not significant. MAwP was kept stable during the stepwise hypo- and hyperventilation, and this resulted in a constant mean arterial pressure. Conclusions: Controlled hypo- and hyperventilation at constant MAwP in non-brain-traumatized pigs appears to induce changes in ICP and cerebral perfusion pressure which, however, do not necessarily lead to cerebral ischemia. To achieve adequate cerebral perfusion at an increased ICP level due to hypoventilation one must maintain sufficient arterial blood pressure. Hypercapnia resulted in a significant increase in brain oxygenation however, this does not necessarily mean that permissive hypercapnia is neuroprotective. Author Affiliation: (1) Department of Anesthesiology, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands (2) Department of Neurology, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands (3) Diving Medical Center, Royal Netherlands Navy, Den Helder, The Netherlands Article History: Received Date: 15/11/2000 Accepted Date: 19/10/2001 Article note: Electronic Publication

Circadian pattern of ventilation during acute and chronic hypercapnia in conscious adult rats. Am J Physiol Regulatory Integrative Comp Physiol 282: R244-R251, 2002; 10.1152/ajpregu. 00290.2001.--Because metabolism is a determinant of the ventilatory chemosensitivity, we tested the hypothesis that the ventilatory response to acute and prolonged hypercapnia is adjusted to the circadian oscillations in oxygen consumption (V[O.sub.2]). Adult rats were instrumented for measurements of body temperature ([T.sub.b]) and activity by telemetry. Pulmonary ventilation (VE) was measured by the barometric method and V[O.sub.2] by the flow-through method. In the acute experiments, 16 conscious rats entrained to a 12:12-h light (L)-dark (D) cycle (lights on 7:00 AM) were exposed to air, 2%, and then 5% C[O.sub.2] in normoxia (30-45 min each) at 11:00 AM and 11:00 PM. In a separate group of seven rats, simultaneous recordings of all variables were made continuously for 3 consecutive days in air followed by 3 days in 2% C[O.sub.2] in normoxia, in a 12:12-h L-D cycle (lights on 7:00 AM). In air, all variables were significantly higher at night, whether rats were studied acutely or chronically. Acute C[O.sub.2] exposure had similar significant effects at 11:00 AM and 11:00 PM on VE (~25 and 100% increase with 2 and 5% C[O.sub.2], respectively) and V[O.sub.2] (~8% drop with 5% C[O.sub.2]), such that the hyperventilatory response (% increase in VE/V[O.sub.2] from air) was similar at both times. Chronic C[O.sub.2] breathing increased VE at all times of the day, but less so during the L phase (~15 vs. 22% increase in L and D, respectively), when activity was lower. However, V[O.sub.2] was reduced from the air level (~10% drop) in the L, such that the VE/V[O.sub.2] response was similar between L and D. The same result was obtained when the VE/V[O.sub.2] response was compared between the L and D phases for the same level of activity. These results suggest that, throughout the day, the hypercapnic hyperpnea, whether during acute or prolonged C[O.sub.2], is perfectly adjusted to the metabolic level. control of breathing; chemosensitivity; barometric method; oxygen consumption

Hypoxia- and hypercapnia-induced changes in the diameter of the intra-acinar arterioles, venules and capillaries of isolated rat lungs gathered from animals exposed for 48 hrs to 21% O2 or 90% O2 were investigated. Findings showed that microvessel reactions to hypoxia and hypercapnia are abnormal in hyperoxia-injured acini, in which NO directly attenuates hypoxia-induced arteriole constriction, while cyclooxygenase inhibited by excessive NO impedes hypercapnia-induced microvessel dilation.

The potential obligatory functions of cyclic guanylic acid (cGMP) and cyclic adenosine monophosphate (cAMP) in hypercapnia were examined using a closed cranial window in adult rats. The 7-nitroindazole and indomethacin-inhibitable increases in pial arteriolar diameter and cyclic nucleotide production during hypercapnia suggest a link between these two responses. It is possible that cyclic nucleotides have an obligatory function in the carbon dioxide response. Findings also imply interactions between the cGMP and cAMP vasodilating pathways.

Brain blood flow tracer techniques were employed in the investigation of the contributions of hypercapnia and trigeminal stimulation on the dilation of cerebral vessels during simulated diving in rats. Results indicate that by itself, trigeminal stimulation does not affect the caliber of cerebral vessels. On the other hand, hypercapnia was shown to significantly dilate cerebral vessels indicating that the reduction in cerebrovascular resistance during diving is brought about by asphyxia-associated progressive hypercapnia.

The role of PCO2 on the myogenic response of diaphragmatic arterioles to elevated transmural pressure was analyzed in isolated rodent arterioles. Exposure of rodent diaphragmatic arterioles to changes in transluminal pressure indicated the role of the vascular endothelium in mediating arteriolar myogenic response to a broad range of transmural pressures. Furthermore, hypercapnia enhanced arteriolar vasoconstrictor response to increasing levels of transmural pressure indicating the minor role of PCO2 in the regulation of skeletal muscle blood flow.

The effects of hypercapnic acidosis on the contractile adenosinetriphosphatase rate in intact mammalian fast and slow twitch muscles were analyzed by P-nuclear magnetic resonance (NMR). NMR analysis of perfused cat muscles indicated the role of acidosis in reducing muscle twitch force and peak tetanic force in isolated cat biceps muscles. However, acidosis to pH 6.5 did not alter the adenosine 5'-triphosphate cost of force generation in intact fast- and slow-twitch muscles. Furthermore, acidosis decreased the rate of phosphocreatine recovery after muscle contraction.

The modulatory effects of neurotransmitters on the metabolic rate of Sipunculus nudus were analyzed after the exposure of the nervous tissue of the marine invertebrate to anoxia or hypercapnia. Metabolic depression due to anoxia and hypercapnia reduced the levels of glutamate, glycine, taurine and monoamines in the nervous tissue of Sipunculus nudus. Furthermore, the marine invertebrate also exhibited extracellular acidosis in response to metabolic depression indicating the role of cellular mechanisms in mediating overall reductions in the metabolism of Sipunculus nudus.

Halothane-anesthetized rats were analyzed after the administration of exogenous NO to determine the effects of neuronal NO synthase (nNOS) on cerebral blood flow (CBF) regulation during hypercapnia. Administration of NO in anesthetized rats during hypercapnia enhanced cerebrocortical vasodilation. Inhibition of nNOS by 7-nitroindazole impaired CBF response to hypercapnia indicating the role of nNOS in modulating CBF response during hypercapnia.

The role of brain or aortic nitric oxide synthase (NOS) activity in the regulation of cerebral blood flow (CBF) was investigated in anesthetized rats. Intravenous infusion of L-NNA, an NOS inhibitor, inhibited brain and aortic NOS activity, whereas topical application of L-NNA inhibited only brain but not aortic NOS activity. Intravenous L-NNA also attenuated the hypercapnic rise of CBF more efficiently than topical L-NNA. Treatment of animals with 7-nitroindazole, another NOS inhibitor, produced similar results, whereas combination treatment slightly reduced the rise in CBF. These results suggest that NOS activity is required to modulate the hypercapnic rise of CBF.

The regulatory role of nitric oxide (NO) in the maintenance of brain cyclic guanosine monophosphate levels and blood vessel vasodilation were analyzed during hypercapnia and acetylcholine (ACh) or bradykinin (BK) stimulation. Resting levels of NO and cyclic guanosine monophosphate affected the vasodilation of cerebral blood vessels during hypercapnia. Furthermore, the vasodilatory activities of ACh of BK were mediated by the agonist-induced activation of NOS and NO concentrations.

The effects of hypoxia and hypercapnia were analyzed on the duration and frequency of apneas, breathing episodes and the amount of time spent in sleep were analyzed in Northern elephant seal pups. The Northern seal pups exhibited similar exhibited an arousal state distribution composed of 40% slow-wave sleep and 5% rapid eye movement sleep. Hypercapnia or hypoxia gases composed of 13% O2 and 6% CO2 did not alter the arousal state distribution patterns of the seal pups. The duration of sleep was also reduced by hypoxia but the length of the periods of apnea was not affected.

Anesthesized cats with cranial windows were analyzed to determine the inhibitory effects of arginine analogues to cerebral vasodilation during hypercapnic acidosis. Vasodilation of the cerebral arterioles of cats are blocked by arginine analogues by preventing the activation of adenosine triphosphate (ATP)-sensitive K+ channels during hypercapnic acidosis. However, vasodilation from sodium nitroprusside and 3-morpholinosydnonimine was not affected by arginine-induced blockade of the ATP-sensitive K+ channels.

The effects of hypercapnia on the formation of prostanoids and adenine 3',5'-cyclic monophosphate (cAMP) by cerebral microvascular cells were investigated in a cell model. Newborn pig cerebral microvascular smooth muscle cells and endothelial cells responded to hypercapnia by increasing prostanoid and cAMP production. This response is suggested to follow a prostanoid independent and an endothelium-dependent pathway.

The hypothesis that there is a relationship between the production pf thromboxane A2 (TxA2) and the stimulation of the adrenocorticotropic hormone (ACTH) was tested in the adult sheep. Cortisol concentrations and arterial pH were used as a function of TxA2 production. Sheep infused with HCl had increased ACTH and cortisol levels, had decreased pH and an increase in arterial partial pressure of oxygen and carbon dioxide, and showed no changes after treatment with flunixin. Sheep treated with flunixin alone had a marked reduction in fetal plasma TxA2. It was concluded that ACTH response to HCL is not mediated on the generation of TxA2.

The olfactory and pulmonary CO2-sensitive receptors of bullfrogs affect the breathing pattern, but do not solely control the episodic breathing pattern. The olfactory receptors suppress breathing during hypercarbia, a high CO2 concentration. Receptor denervation causes posthypercarbic hyperpnea. Total ventilation index of the lungs remains constant in vagotomized bullfrogs during hypercarbia. Thus, the pulmonary receptors affect the rate of air flow and the duration of lung ventilation and nonventilation. This suggests that episodic breathing is probably controlled by the central nervous system.

Naloxene particularly affect central neural mechanisms in the superior laryngeal nerve and therefore affects the control of respiration by exerting its action as an opioid antagonist. Administration of naloxene remarkably reduced the duration of poststimulatory apnea and attenuated the depression of phrenic minute output of the first recovery breath due to changes in peak phrenic activity. Naloxene also speeds up the time course of recovery. Hypercapnia did not affect apnea, but reduced recovery time and also lengthened the time of poststimulatory depression. Endogenous opioids may play a part of initiation or regulation of these effects.

Respiratory failure patients treated with mechanical ventilation may have fewer ventilator-induced lung injuries if air volumes and pressures are limited. Traditional mechanical ventilation requires high airway pressures to move large amounts of air in and out of the lungs, which may cause lung damage. Researchers reviewed published medical research on the effects of air pressure limitation, high levels of carbon dioxide in the blood (hypercapnia), and ventilator-induced lung injury. Animal research studies found that mechanical ventilation that overfills the air sacs in the lungs can cause injury. Patients with adult respiratory distress syndrome have both normal and damaged lung tissue, which reduces lung capacity. This makes the lungs more susceptible to injury from the high air volumes used in mechanical ventilation. Permissive hypercapnia minimizes overfilling of air sacs by limiting the airway pressure or volume. Some human studies of permissive hypercapnia revealed improved patient survival over model-based predictors of death rates., Objective.--To evaluate the potential efficacy of pressure limitation with permissive hypercapnia in the treatment of acute respiratory failure/adult respiratory distress syndrome on the basis of current theories of ventilator-induced lung injury, potential complications of systemic hypercarbia, and available human outcome studies. Data Sources.--Articles were identified through MEDLINE, reference citations of published data, and consultation with authorities in their respective fields. Study Selection.--Animal model experimentation and human clinical trials were selected on the basis of whether they addressed the questions of pressure limitation with or without hypercapnia, the pathophysiologic effects of hypercapnia, or the concept of ventilator-induced parenchymal lung injury. Frequently cited references were preferentially included. Data Extraction.--Datawere analyzed with particular emphasis on obtaining the following variables from the clinical studies: peak inspiratory pressures, tidal volumes, minute ventilation, and [PCO.sub.2]. Quantitative aspects of respiratory physiology were used to analyze the theoretical effects of permissive hypercapnia on ventilatory requirements in normal and injured lungs. Data Synthesis.--Extensive animal model data support the hypothesis that ventilator-driven alveolar overdistention can induce significant parenchymal lung injury. The heterogeneous nature of lung injury in adult respiratory distress syndrome, with its small physiologic lung volume, may render the lung susceptible to this type of injury through the use of conventional tidal volumes (10 to 15 mukg). Permissive hypercapnia is an approach whereby alveolar overdistention is minimized through either pressure or volume limitation, and the potential deleterious consequences of respiratory acidosis are accepted. Uncontrolled human trials of explicit or implicit permissive hypercapnia have demonstrated improved survival in comparison with models of predictive mortality. Conclusions.--Avoidance of alveolar overdistention through pressure or volume limitation has significant support based on animal models and computer simulation. Deleterious effects of the associated hypercarbia in severe lung injury do not appear to be a significant limiting factor in preliminary human clinical trials. Although current uncontrolled studies suggest benefit, controlled trials are urgently needed to confirm these findings before adoption of the treatment can be endorsed. (JAMA.1994;272:957-962)

Nitric oxide synthase (NOS) inhibition through N(G)-nitro-L-arginine (L-NNA) TTX modulates the increase of cerebral blood flow in cerebellar cortex and parietal cortex in response to hypercapnia. The NOS, L-NNA inhibitor stimulates action when transported in blood than when topically applied. TTX suppresses perivascular nerve function near the cortical and pial vessels.

Changes in the level of local cerebral blood flow (LCBF) in normal adult rats exposed to 8% CO2 were examined. An iodoantipyrine method was used to measure LCBF. Local microvascular distribution spaces of radiolabeled red blood cells (RBC) and plasma albumin were determined by a quantitative autoradiographic technique. Results indicate that by increasing RBC velocity and plasma flow in perfused microvessels, LCBF is also increased.

Capillary parameters influencing gas exchange was monitored inalbino frog, Xenopus laevis, skin under hypoxic- and hypercapnic-induced vasoconstriction. The only significant effect of hypoxia and hypercapnia on capillary dynamics in frog skin is the reduction in perfusion. All other parameters aken ino consideration, hypoxia or hypercapnia apparently does not affect gas exchange in frog skin.

The adrenocorticotrophic hormone (ACTH) and the arginine vasopressin (AVP) secretion in response to acidemia produced by maternal hypercapnia were monitored in normal and chemoreceptor-denervated fetal sheep. Maternal hypercapnia increased arterial carbon dioxide partial pressure and blood acidity in fetal sheep. Elevated ACTH secretion was observed only in the denervated group while AVP secretion was equal for both control and experimental groups. This indicate that AVP secretion is independent of peripheral chemoreceptor control.

In congenital central hypoventilation syndrome (CCHS), patients have a low rate of respiration, usually during sleep, although respiratory and neuromuscular systems appear normal. The disorder is rare, and children require ventilation support during sleep. The disease processes underlying the CCHS are unclear, but abnormal responses to hypercapnia (high levels of carbon dioxide) and hypoxia (low oxygen levels), situations which stimulate central or peripheral chemoreceptors, have been found. Whether the chemoreceptors or the nerve systems that integrate messages from the chemoreceptors are abnormal is unclear. To better understand this, the arousal responses to hypercapnea of eight children with CCHS were evaluated and compared with those in seven healthy children. Hypercapnea chiefly stimulates central chemoreceptors; if they were completely dysfunctional, then both respiratory and arousal responses to stimulation should be abnormal. However, if brain integration is abnormal, then respiration but not arousal responses would be affected. Seven of the eight CCHS children aroused to hypercapnea, one of whom needed a second challenge; all seven healthy children also aroused to hypercapnea. This indicates that central chemoreceptors in CCHS children are at least partially functional, but whether they are entirely normal is still unclear. It may be that the important defect in CCHS involves brain integration of chemoreceptor-derived information. (Consumer Summary produced by Reliance Medical Information, Inc.)

The effects of type III nitric oxide synthase (NOS) inhibition were analyzed in mutant mice that express type I NOS with a 96% reduction in type III NOS within their aortic homogenates. Decreased regional cerebral blood flow (rCBF) was detected in the mutant mice after the inhibition of type I NOS activity during moderate hypercapnia. Furthermore, rCBF was not inhibited by NG-nitro-L-arginine in type III NOS mutant mice but a decrease in baseline rCBF was detected in type I NOS mutant mice.