CO2 Sensitivity Research Articles

Astrocytes in the Retrotrapezoid Nucleus Sense H+ by Inhibition of a Kir4.1–Kir5.1-Like Current and May Contribute to Chemoreception by a Purinergic Mechanism

Central chemoreception is the mechanism by which CO(2)/pH sensors regulate breathing in response to tissue pH changes. There is compelling evidence that pH-sensitive neurons in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO(2)/H(+)-evoked adenosine 5'-triphosphate (ATP) release in the RTN, from pH-sensitive astrocytes, contributes to chemoreception. However, mechanism(s) by which RTN astrocytes sense pH is unknown and their contribution to chemoreception remains controversial. Here, we use the brain slice preparation and a combination of patch-clamp electrophysiology and immunohistochemistry to confirm that RTN astrocytes are pH sensitive and to determine mechanisms by which they sense pH. We show that pH-sensitive RTN glia are immunoreactive for aldehyde dehydrogenase 1L1, a marker of astrocytes. In HEPES buffer the pH-sensitive current expressed by RTN astrocytes reversed near E(K(+)) (the equilibrium potential for K(+)) and was inhibited by Ba(2+) and desipramine (blocker of Kir4.1-containing channels), characteristics most consistent with heteromeric Kir4.1-Kir5.1 channels. In bicarbonate buffer, the sodium/bicarbonate cotransporter also contributed to the CO(2)/H(+)-sensitive current in RTN astrocytes. To test the hypothesis that RTN astrocytes contribute to chemoreception by a purinergic mechanism, we used fluorocitrate to selectively depolarize astrocytes while measuring neuronal activity. We found that fluorocitrate increased baseline activity and pH sensitivity of RTN neurons by a P2-receptor-dependent mechanism, suggesting that astrocytes may release ATP to activate RTN chemoreceptors. We also found in bicarbonate but not HEPES buffer that P2-receptor antagonists decreased CO(2) sensitivity of RTN neurons. We conclude that RTN astrocytes sense CO(2)/H(+) in part by inhibition of a Kir4.1-Kir5.1-like current and may provide an excitatory purinergic drive to pH-sensitive neurons.

Diode laser detection of greenhouse gases in the near-infrared region by wavelength modulation spectroscopy: pressure dependence of the detection sensitivity.

We have investigated the pressure dependence of the detection sensitivity of CO2, N2O and CH4 using wavelength modulation spectroscopy (WMS) with distributed feed-back diode lasers in the near infrared region. The spectral line shapes and the background noise of the second harmonics (2f) detection of the WMS were analyzed theoretically. We determined the optimum pressure conditions in the detection of CO2, N2O and CH4, by taking into consideration the background noise in the WMS. At the optimum total pressure for the detection of CO2, N2O and CH4, the limits of detection in the present system were determined.

Effects of increased CO2 levels on monsoons

Increased atmospheric carbon dioxide concentration provided warmer atmospheric temperature and higher atmospheric water vapor content, but not necessarily more precipitation. A set of experiments performed with a state-of-the-art coupled general circulation model forced with increased atmospheric CO2 concentration (2, 4 and 16 times the present-day mean value) were analyzed and compared with a control experiment to evaluate the effect of increased CO2 levels on monsoons. Generally, the monsoon precipitation responses to CO2 forcing are largest if extreme concentrations of carbon dioxide are used, but they are not necessarly proportional to the forcing applied. In fact, despite a common response in terms of an atmospheric water vapor increase to the atmospheric warming, two out of the six monsoons studied simulate less or equal summer mean precipitation in the 16×CO2 experiment compared to the intermediate sensitivity experiments. The precipitation differences between CO2 sensitivity experiments and CTRL have been investigated specifying the contribution of thermodynamic and purely dynamic processes. As a general rule, the differences depending on the atmospheric moisture content changes (thermodynamic component) are large and positive, and they tend to be damped by the dynamic component associated with the changes in the vertical velocity. However, differences are observed among monsoons in terms of the role played by other terms (like moisture advection and evaporation) in shaping the precipitation changes in warmer climates. The precipitation increase, even if weak, occurs despite a weakening of the mean circulation in the monsoon regions (“precipitation-wind paradox”). In particular, the tropical east-west Walker circulation is reduced, as found from velocity potential analysis. The meridional component of the monsoon circulation is changed as well, with larger (smaller) meridional (vertical) scales.

Hypoventilation in awake goats following unilateral lesions in the rostral ventrolateral medulla (RVLM) targeted by surface cooling‐induced apnea.

Thirty seconds of cooling the RVLM induces apnea and reduced breathing in anesthetized and awake goats, respectively (J Appl Physiol 78: 247–257, 1995). We recently studied the effects on breathing in two goats of unilateral ibotenic acid (IA: 1 μl) induced RVLM lesions 1 mm below the medullary surface at a critical site identified by cooling under anesthesia. Upon recovery from anesthesia, both goats hyperventilated at rest for 5 days, but thereafter hypoventilated (PaCO2 8–10 mmHg above control) for several days due to decreased tidal volume and breathing frequency. In one goat CO2 sensitivity was attenuated nearly 50% during the period of hypoventilation, but the ventilatory responses to hypoxia and exercise, and breathing during NREM sleep were unaffected. In this goat resting PaCO2 and CO2 sensitivity returned to control about 15 days post‐lesion. Both goats were in excellent health throughout the post surgery period. Post‐mortem histology indicated the lesioned sites were in an area of high density neurokinin‐1 receptor expressing neurons, near or including the retrotrapezoid nucleus. These data suggest that neurons near the RVLM surface are necessary to maintain normal levels of eupneic breathing, and contribute to respiratory CO2 chemoreception.

Regulation of cerebral blood flow during exercise in men and women

Cerebral autoregulation (CA) maintains cerebral blood flow (CBF) constant over a wide range of perfusion pressures (MAP). However, arterial PCO2 (PETCO2) may modify CBF if brain metabolism and total oxygen consumption (VO2) are modified. During exercise MAP, VO2 and VCO2 are increased and may affect CBF. Female (13) and male (9) subjects completed a CO2 sensitivity test at rest and a graded exercise treadmill test. Heart rate (HR), MAP, ventilation (VE) and CBF velocity (CBFV) were measured in both tests. During rest CBFV (45%) and VE (221%) increased linearly with PETCO2 (58%). During exercise CBFV increased (31%) from 61 ± 16 cm/s to 78 ± 16 cm/s at 80% of VO2max. Once above the ventilatory threshold, CBFV decreased to 65 ± 16 cm/s at 100% VO2max. The changes in CBFV paralleled the changes in PETCO2 (36 ± 5 to 46 ± 6 to 36 ± 6 mmHg), despite a linear increase in MAP with VO2. Multiple linear regression indicated that PETCO2 was contributing more to CBFV than MAP (CBFV = 5.001 + (0.759 * PETCO2) + (0.313 * MAP)). During exercise CA did not maintain CBFV and PETCO2 strongly influenced it, thus ventilatory regulation (PETCO2) in exercise is critical in determining CBF. Resting CO2 sensitivity did not predict exercise PETCO2. Regulation of PETCO2 during exercise may explain the differences in CBF among individuals or conditions. One example may be the dysregulation of CBF in post concussion syndrome patients.

The acetazolamide analogue N‐methyl acetazolamide does not alter the ventilatory response to hypoxia but reduces the hypercapnic response in the anesthetized cat

Acetazolamide (AZ) may have cardiorespiratory effects independently from inhibition of carbonic anhydrase (CA). In contrast to methazolamide, it impairs respiratory muscle function in rabbits and reduces the hypoxic ventilatory response in cats. In rat pulmonary arterial smooth muscle cells, AZ inhibits the hypoxia‐induced rise in [Ca2+]i, an effect that is shared by N‐methyl acetazolamide (NMA), an AZ analogue devoid of inhibiting effects on CA. We have studied the effect of NMA on the ventilatory response to hypoxia and hypercapnia in 7 anesthetized cats. NMA, (20 mg.kg−1, i.v.) did not influence the hypoxic response measured at a constant end‐tidal PCO2 of about 6 kPa, described with the exponential equation Vi (inspired ventilation) = G.{(exp) − DPO2} + R, with G = hypoxic sensitivity, D = shape factor and R = ventilation in hyperoxia. Mean values of G, D and R were not different in control and following NMA. Surprisingly however, the ventilatory CO2 response curve described with Vi = S(PCO2−B) with the CO2 sensitivity S and the extrapolated X‐intercept (apneic threshold) B underwent dramatic changes: S and B decreased by 60 and 72%, respectively. Whether these effects of NMA may be due to vascular effects remains to be examined.

The pontine respiratory group, particularly the Kölliker-Fuse nucleus, mediates phases of the hypoxic ventilatory response in unanesthetized goats.

The objective of the present study was to test the hypothesis that, in the in vivo awake goat model, perturbation/lesion in the pontine respiratory group (PRG) would decrease the sensitivity to hypercapnia and hypoxia. The study reported herein was part of two larger studies in which cholinergic modulation in the PRG was attenuated by microdialysis of atropine and subsequently ibotenic acid injections neurotoxically lesioned the PRG. In 14 goats, cannula were bilaterally implanted into either the lateral (n=4) or medial (n=4) parabrachial nuclei or the Kölliker-Fuse nucleus (KFN, n=6). Before and after cannula implantation, microdialysis of atropine, and injection of ibotenic acid, hypercapnic and hypoxic ventilatory sensitivities were assessed. Hypercapnic sensitivity was assessed by three 5-min periods at 3, 5, and 7% inspired CO2. In all groups of goats, CO2 sensitivity was unaffected (P>0.05) by any PRG perturbations/lesions. Hypoxic sensitivity was assessed with a 30-min period at 10.8% inspired O2. The response to hypoxia was typically triphasic, with a phase 1 increase in pulmonary ventilation, a phase 2 roll-off, and a phase 3 prolonged increase associated with shivering and increased metabolic rate and body temperature. In all groups of goats, the phase 1 of the hypoxic ventilatory responses was unaffected by any PRG perturbations/lesions, and there were no consistent effects on the phase 2 responses. However, in the KFN group of goats, the phase 3 ventilatory, shivering, metabolic rate, and temperature responses were markedly attenuated after the atropine dialysis studies, and the attenuation persisted after the ibotenic acid studies. These findings support an integrative or modulatory role for the KFN in the phase 3 responses to hypoxia.

Influence of high altitude on cerebrovascular and ventilatory responsiveness to CO2

An altered acid-base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO(2) sensitivity at high altitude. Likewise, if [H(+)] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO(2) (termed cerebrovascular CO(2) reactivity). However, the effect altered acid-base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO(2) remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O(2) and CO(2) were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO(2) reactivity (2.9 +/- 1.1 vs. 4.8 +/- 1.4% mmHg(1); P < 0.01) and CO(2) sensitivity (3.6 +/- 2.3 vs. 5.1 +/- 1.7 l min(1) mmHg(1); P < 0.01). Likewise, the hypocapnic MCAv CO(2) reactivity was increased at 5050 m (4.2 +/- 1.0 vs. 2.0 +/- 0.6% mmHg(1); P < 0.01). The hypercapnic MCAv CO(2) reactivity correlated with resting pH at high altitude (R(2) = 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R(2) = 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO(2) sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO(2) reactivity and central chemoreflex may be partly attributed to an acid-base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid-base balance in the regulation in CBF and ventilatory control.

Task2 potassium channels set central respiratory CO2 and O2 sensitivity.

Task2 K(+) channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including the retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost in mice bearing a Phox2b mutation that causes the human congenital central hypoventilation syndrome. In plethysmography, Task2(-/-) mice showed disturbed chemosensory function with hypersensitivity to low CO(2) concentrations, leading to hyperventilation. Task2 probably is needed to stabilize the membrane potential of chemoreceptive cells. In addition, Task2(-/-) mice lost the long-term hypoxia-induced respiratory decrease whereas the acute carotid-body-mediated increase was maintained. The lack of anoxia-induced respiratory depression in the isolated brainstem-spinal cord preparation suggested a central origin of the phenotype. Task2 activation by reactive oxygen species generated during hypoxia could silence RTN neurons, thus contributing to respiratory depression. These data identify Task2 as a determinant of central O(2) chemoreception and demonstrate that this phenomenon is due to the activity of a small number of neurons located at the ventral medullary surface.

Materials for capacitive carbon dioxide microsensors capable of operating at ambient temperatures

The responses of alkylamine functionalized organic bridged polysilsesquioxanes on chemicapacitive sensors to carbon dioxide (CO2) are described operating at temperatures ranging from 15 to 50°C. These hybrid organic–inorganic network materials were synthesized by the sol–gel polymerization of a mixture of a matrix monomer and functional monomer at various ratios followed by aging and ink-jet deposition of the sol on each capacitive sensor. During exposure of the sensor to known concentrations of analyte, the material’s capacitance was measured. From these changes in capacitance, detection limits ranging from 40 to 100 ppm were calculated. Furthermore, a correlation was observed with increasing length of the alkyl chain in the amine monomer correlating with an increase in CO2 sensitivity and a decrease in water sensitivity. These materials offer a new method for CO2 detection for building control systems or other low-power applications using low operating temperatures.

Revelle revisited: Buffer factors that quantify the response of ocean chemistry to changes in DIC and alkalinity

We derive explicit expressions of the Revelle factor and several other buffer factors of interest to climate change scientists and those studying ocean acidification. These buffer factors quantify the sensitivity of CO2 and H+ concentrations ([CO2] and [H+]) and CaCO3 saturation (Ω) to changes in dissolved inorganic carbon concentration (DIC) and alkalinity (Alk). The explicit expressions of these buffer factors provide a convenient means to compare the degree of buffering of [CO2], [H+], and Ω in different regions of the oceans and at different times in the future and to gain insight into the buffering mechanisms. All six buffer factors have roughly similar values, and all reach an absolute minimum when DIC = Alk (pH ∼ 7.5). Surface maps of the buffer factors generally show stronger buffering capacity in the subtropical gyres relative to the polar regions. As the dissolution of anthropogenic CO2 increases the DIC of surface seawater over the next century, all the buffer factors will decrease, resulting in a much greater sensitivity to local variations in DIC and Alk. For example, diurnal and seasonal variations in pH and Ω caused by photosynthesis and respiration will be greatly amplified. Buffer factors provide convenient means to quantify the effect that changes in DIC and Alk have on seawater chemistry. They should also help illuminate the role that various physical and biological processes have in determining the oceanic response to an increase in atmospheric CO2.

Examination of pre-industrial and future [CO2] reveals the temperature-dependent CO2 sensitivity of light energy partitioning at PSII in eucalypts

We grew faster-growing Eucalyptus saligna Sm. and slower-growing Eucalyptus sideroxylon A. Cunn ex Woolls tree seedlings in sunlit glasshouses at all combinations of 290 µL L–1 (pre-industrial), 400 µL L–1 (modern) or 650 µL L–1 (future) global atmospheric CO2 ([CO2]), and ambient or ambient + 4°C temperature. To assess photosynthetic performance, we simultaneously measured light-saturated CO2 assimilation (Asat) and chlorophyll fluorescence emission along with the capacity for photosynthetic O2 evolution and leaf pigment composition. Photosynthetic response to [CO2] was similar between species. Increasing [CO2] but not temperature increased Asat. The response of photosynthetic electron transport to [CO2] was temperature-dependent and manifested through adjustments in energy partitioning at PSII. Increasing [CO2] resulted in greater PSII operating efficiencies at the elevated temperature. We observed no associated acclimatory adjustments in the capacity for photosynthetic O2 evolution or changes in leaf chlorophyll content. Photoprotective energy dissipation responded to increasing [CO2] and temperature. Across species and treatments, increased energy partitioning to electron transport was always associated with decreased partitioning to energy dissipation. Our results suggest that in response to increasing [CO2] and temperature, E. saligna and E. sideroxylon meet increased demands for the products of electron transport via adjustments in energy partitioning, not through acclimation of the capacity for photosynthetic electron transport or light absorption.

Rare earth oxycarbonates as a material class for chemoresistive CO2 gas sensors

In this work we compare the CO2 gas sensing properties of two new materials synthesized from rare earth hydroxide (La(OH)3,Pr(OH)3) precursors, with the already reported ones for neodymium oxycarbonate, which was synthesized from the corresponding Nd(OH)3 precursor. In-situ XRD measurements show that by following similar thermal treatment, praseodymium hydroxide is transforming to the metal oxide while lanthanum hydroxide forms an oxycarbonate, like in the case of neodymium. The chemoresistive effects we found for the lanthanum oxycarbonate were even higher than the ones recorded for the neodymium oxycarbonate; for the praseodymium metal oxide we could not find any CO2 sensitivity. Accordingly, we think that the condition for CO2 sensing is the formation of the rare earth oxycarbonate.

Losing sleep over the caffeination of prematurity

Losing sleep over the caffeination of prematurity

Snow cover validation and sensitivity to CO2 in the UVic ESCM

The University of Victoria's (UVic) Earth System Climate model is used to conduct equilibrium atmospheric CO2 sensitivity experiments over the range 200–1600 ppm in order to explore changes in northern hemisphere snow cover and feedbacks on terrestrial surface air temperature (SAT). Simulations of warmer climates predict a retreat of snow cover over northern continents, in a northeasterly direction. The decline in northern hemisphere global snow mass is estimated to reach 33% at 600 ppm and 54% at 1200 ppm. In the most northerly regions, annual mean snow depth increases for simulations with CO2 levels higher than present day. The shift in the latitude of maximum snowfall is estimated to be inversely proportional to the CO2 concentration. The northern hemisphere net shortwave radiation changes are found to be greater over land than over the ocean, suggesting a stronger albedo feedback from changes in terrestrial snow cover than from changes in sea ice. Results also reveal high sensitivity of the snow mass balance under low CO2 conditions. The amplification feedback (defined as the zonal SAT anomaly caused by doubling CO2 divided by the equatorial anomaly) is greatest for scenarios with less than 300 ppm, reaching 1.9 at the pole for 250 ppm. The stronger feedback is attributed to the significant albedo changes over land areas. The simulation with 200 ppm triggers continuous accumulation of snow ('glaciation') in regions which, according to paleo‐reconstructions, were covered by ice during the last glacial cycle (the Canadian Arctic, Scandinavia, and the Taymir Peninsula).

MsbB deletion confers acute sensitivity to CO2 in Salmonella enterica serovar Typhimurium that can be suppressed by a loss-of-function mutation in zwf

BackgroundPathogens tolerate stress conditions that include low pH, oxidative stress, high salt and high temperature in order to survive inside and outside their hosts. Lipopolysaccharide (LPS), which forms the outer-leaflet of the outer membrane in Gram-negative bacteria, acts as a permeability barrier. The lipid A moiety of LPS anchors it to the outer membrane bilayer. The MsbB enzyme myristoylates the lipid A precursor and loss of this enzyme, in Salmonella, is correlated with reduced virulence and severe growth defects that can both be compensated with extragenic suppressor mutations.ResultsWe report here that msbB (or msbB somA) Salmonella are highly sensitive to physiological CO2 (5%), resulting in a 3-log reduction in plating efficiency. Under these conditions, msbB Salmonella form long filaments, bulge and lyse. These bacteria are also sensitive to acidic pH and high osmolarity. Although CO2 acidifies LB broth media, buffering LB to pH 7.5 did not restore growth of msbB mutants in CO2, indicating that the CO2-induced growth defects are not due to the effect of CO2 on the pH of the media. A transposon insertion in the glucose metabolism gene zwf compensates for the CO2 sensitivity of msbB Salmonella. The msbB zwf mutants grow on agar, or in broth, in the presence of 5% CO2. In addition, msbB zwf strains show improved growth in low pH or high osmolarity media compared to the single msbB mutant.ConclusionThese results demonstrate that msbB confers acute sensitivity to CO2, acidic pH, and high osmolarity. Disruption of zwf in msbB mutants restores growth in 5% CO2 and results in improved growth in acidic media or in media with high osmolarity. These results add to a growing list of phenotypes caused by msbB and mutations that suppress specific growth defects.

A Comparison of the Effects on Respiratory Carbon Dioxide Response, Arterial Blood Pressure, and Heart Rate of Dexmedetomidine, Propofol, and Midazolam in Sevoflurane-Anesthetized Rabbits

Dexmedetomidine, propofol, and midazolam are commonly used sedative-hypnotic drugs. Using a steady-state method, we examined the CO2 ventilatory response, mean arterial blood pressure (MAP) and heart rate (HR) effects of these three drugs in sevoflurane-anesthetized rabbits. New Zealand white rabbits weighing 2.9 +/- 0.2 kg (mean +/- SD) were used. After anesthetic induction and tracheostomy, the animals inhaled 2% sevoflurane to ensure a stable level of sedation throughout the experiment. After preparation, the rabbits were randomly assigned to four groups (n = 10 x 4) and received the following drugs: Group C, control; Group D, dexmedetomidine infused at 2 microg x kg(-1) x h(-1); Group P, propofol with the plasma concentration maintained at 15 microg/mL; Group M, midazolam initial IV 0.3 mg/kg bolus dose, followed by infusion at 1.86 mg x kg(-1) x h(-1). At 15 minutes after the start of infusion, for 20 min periods, in random sequences, gas including 0%, 1%, 2%, 3%, 4%, or 5% of CO2 was delivered to each animal. Fraction of inspired oxygen was maintained at 0.9. We did intergroup comparisons of minute ventilation (MV), respiratory rate, MAP, and HR during the final minute of each inspiratory carbon dioxide concentration (FiCO2) period. For Groups P and M, the rightward shift of plots for MV against FiCO2 indicated significant respiratory depression compared with Group C. There was also significantly more depression than in Group D. We found no significant differences between Groups P and M or between Groups C and D in the plots of MV against FiCO2. No significant differences among the four groups were apparent for respiratory rate. PaCO2-MV response plots were derived from linear regression analysis of data for mean MV and mean PaCO2 at each FiCO2 to compute apneic CO2 thresholds and CO2 sensitivities. The apneic CO2 thresholds of Groups P and M were larger than those of Groups C and D. The CO2 sensitivities of Group D were slightly lower than in Group C. No similar significant difference between the CO2 sensitivities of other group pairs was apparent. MAP in Group D was lower than in Groups C and M. In Group D, HR was lower than in Groups C, P, and M. The major finding is that, during sevoflurane anesthesia in rabbits, dexmedetomidine slightly altered the ventilatory response to CO2. It decreased MAP more than propofol and midazolam, which both significantly depressed the ventilatory response to CO2.

Respiratory manifestations of panic disorder: causes, consequences and therapeutic implications

Multiple respiratory abnormalities can be found in anxiety disorders, especially in panic disorder (PD). Individuals with PD experience unexpected panic attacks, characterized by anxiety and fear, resulting in a number of autonomic and respiratory symptoms. Respiratory stimulation is a common event during panic attacks. The respiratory abnormality most often reported in PD patients is increased CO2 sensitivity, which has given rise to the hypothesis of fundamental abnormalities in the physiological mechanisms that control breathing in PD. There is evidence that PD patients with dominant respiratory symptoms are more sensitive to respiratory tests than are those who do not manifest such symptoms, and that the former group constitutes a distinct subtype. Patients with PD tend to hyperventilate and to panic in response to respiratory stimulants such as CO2, triggering the activation of a hypersensitive fear network. Although respiratory physiology seems to remain normal in these subjects, recent evidence supports the idea that they present subclinical abnormalities in respiration and in other functions related to body homeostasis. The fear network, composed of the hippocampus, the medial prefrontal cortex, the amygdala and its brain stem projections, might be oversensitive in PD patients. This theory might explain why medication and cognitive-behavioral therapy are both clearly effective. Our aim was to review the relationship between respiration and PD, addressing the respiratory subtype of PD and the hyperventilation syndrome, with a focus on respiratory challenge tests, as well as on the current mechanistic concepts and the pharmacological implications of this relationship.

Chemosensory Responses to CO2 in Multiple Brain Stem Nuclei Determined Using a Voltage-Sensitive Dye in Brain Slices From Rats

We used epifluorescence microscopy and a voltage-sensitive dye, di-8-ANEPPS, to study changes in membrane potential during hypercapnia with or without synaptic blockade in chemosensory brain stem nuclei: the locus coeruleus (LC), the nucleus of the solitary tract, lateral paragigantocellularis nucleus, raphé pallidus, and raphé obscurus and, in putative nonchemosensitive nuclei, the gigantocellularis reticular nucleus and the spinotrigeminal nucleus. We studied the response to hypercapnia in LC cells to evaluate the performance characteristics of the voltage-sensitive dye. Hypercapnia depolarized many LC cells and the voltage responses to hypercapnia were diminished, but not eradicated, by synaptic blockade (there were intrinsically CO2-sensitive cells in the LC). The voltage response to hypercapnia was substantially diminished after inhibiting fast Na+ channels with tetrodotoxin. Thus action potential-related activity was responsible for most of the optical signal that we detected. We systematically examined CO2 sensitivity among cells in brain stem nuclei to test the hypothesis that CO2 sensitivity is a ubiquitous phenomenon, not restricted to nominally CO2 chemosensory nuclei. We found intrinsically CO2 sensitive neurons in all the nuclei that we examined; even the nonchemosensory nuclei had small numbers of intrinsically CO2 sensitive neurons. However, synaptic blockade significantly altered the distribution of CO2-sensitive cells in all of the nuclei so that the cellular response to CO2 in more intact preparations may be difficult to predict based on studies of intrinsic neuronal activity. Thus CO2-sensitive neurons are widely distributed in chemosensory and nonchemosensory nuclei and CO2 sensitivity is dependent on inhibitory and excitatory synaptic activity even within brain slices. Neuronal CO2 sensitivity important for the behavioral response to CO2 in intact animals will thus be determined as much by synaptic mechanisms and patterns of connectivity throughout the brain as by intrinsic CO2 sensitivity.

The Prevalence and Natural History of Complex Sleep Apnea

Central sleep apnea (CSA) may occasionally occur in patients with obstructive sleep apnea during titration with a continuous positive airway pressure (CPAP) device. To determine the prevalence and the natural history of CPAP-emergent CSA. This is a retrospective study of 1286 patients with a diagnosis of OSAwho underwent titration with a positive airway device during a 1-year period. Patients were seen in consultation and underwent full-night attended polysomnography followed by full-night attended CPAP titration. Four weeks after CPAP therapy, patients returned to the clinic for follow-up, and objective adherence to CPAP was recorded. In patients who had CSA on CPAP, a second full-night attended CPAP titration was recommended. Eighty-four of the 1286 patients developed a central apnea index (CAI) of 5 or greater per hour while on CPAP. The incidence of CSA varied from 3% to 10% monthly, with an overall incidence of 6.5%. Forty-two of the 84 patients returned for a second CPAP titration. In 33 patients, CSA was eliminated. In each of the remaining 9 patients, the CAI remained at 5 or greater per hour, with an average of 13 per hour. These patients characteristically had the most severe OSA, and 5 had a CAI of 5 or more per hour at baseline. Two of the 9 patients were on opioids In this large retrospective study of 1286 patients with a diagnosis of OSA, 6.5% had CPAP-emergent or persistent CSA. However, CPAP-emergent CSA was generally transitory and was eliminated within 8 weeks after CPAP therapy. The prevalence of CPAP-persistent CSA was about 1.5%. Severity of OSA, a CAI of 5 or greater per hour, and use of opioids were potential risk factors.