Metabolic acidosis inhibits hypothalamic warm-sensitive receptors: a potential causative factor in heat stroke.
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Acidosis↗
Biomedical subjects
Jay B Dean
Publications and source records attributed to Jay B Dean.
Somatic vs. dendritic responses to hypercapnia in chemosensitive locus coeruleus neurons from neonatal rats.
Cardiorespiratory control is mediated in part by central chemosensitive neurons that respond to increased CO(2) (hypercapnia). Activation of these neurons is thought to involve hypercapnia-induced decreases in intracellular pH (pH(i)). All previous measurements of hypercapnia-induced pH(i) changes in chemosensitive neurons have been obtained from the soma, but chemosensitive signaling could be initiated in the dendrites of these neurons. In this study, membrane potential (V(m)) and pH(i) were measured simultaneously in chemosensitive locus coeruleus (LC) neurons from neonatal rat brain stem slices using whole cell pipettes and the pH-sensitive fluorescent dye pyranine. We measured pH(i) from the soma as well as from primary dendrites to a distance 160 mum from the edge of the soma. Hypercapnia [15% CO(2), external pH (pH(o)) 7.00; control, 5% CO(2), pH(o) 7.45] resulted in an acidification of similar magnitude in dendrites and soma ( approximately 0.26 pH unit), but acidification was faster in the more distal regions of the dendrites. Neither the dendrites nor the soma exhibited pH(i) recovery during hypercapnia-induced acidification; but both regions contained pH-regulating transporters, because they exhibited pH(i) recovery from an NH(4)Cl prepulse-induced acidification (at constant pH(o) 7.45). Exposure of a portion of the dendrites to hypercapnic solution did not increase the firing rate, but exposing the soma to hypercapnic solution resulted in a near-maximal increase in firing rate. These data show that while the pH(i) response to hypercapnia is similar in the dendrites and soma, somatic exposure to hypercapnia plays a major role in the activation of chemosensitive LC neurons from neonatal rats.
Animals↗
Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons.
Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O2 receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O2 and reactive O2 species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O2 and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O2 has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO2 chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O2 and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed.
Animals↗
Oxidative stress decreases pHi and Na(+)/H(+) exchange and increases excitability of solitary complex neurons from rat brain slices.
Putative chemoreceptors in the solitary complex (SC) are sensitive to hypercapnia and oxidative stress. We tested the hypothesis that oxidative stress stimulates SC neurons by a mechanism independent of intracellular pH (pH(i)). pH(i) was measured by using ratiometric fluorescence imaging microscopy, utilizing either the pH-sensitive fluorescent dye BCECF or, during whole cell recordings, pyranine in SC neurons in brain stem slices from rat pups. Oxidative stress decreased pH(i) in 270 of 436 (62%) SC neurons tested. Chloramine-T (CT), N-chlorosuccinimide (NCS), dihydroxyfumaric acid, and H(2)O(2) decreased pH(i) by 0.19 +/- 0.007, 0.20 +/- 0.015, 0.15 +/- 0.013, and 0.08 +/- 0.002 pH unit, respectively. Hypercapnia decreased pH(i) by 0.26 +/- 0.006 pH unit (n = 95). The combination of hypercapnia and CT or NCS had an additive effect on pH(i), causing a 0.42 +/- 0.03 (n = 21) pH unit acidification. CT slowed pH(i) recovery mediated by Na(+)/H(+) exchange (NHE) from NH(4)Cl-induced acidification by 53% (n = 20) in CO(2)/HCO(3)(-)-buffered medium and by 58% (n = 10) in HEPES-buffered medium. CT increased firing rate in 14 of 16 SC neurons, and there was no difference in the firing rate response to CT with or without a corresponding change in pH(i). These results indicate that oxidative stress 1). decreases pH(i) in some SC neurons, 2). together with hypercapnia has an additive effect on pH(i), 3). partially inhibits NHE, and 4) directly affects excitability of CO(2)/H(+)-chemosensitive SC neurons independently of pH(i) changes. These findings suggest that oxidative stress acidifies SC neurons in part by inhibiting NHE, and this acidification may contribute ultimately to respiratory control dysfunction.
Acids↗
Hyperbaric oxygen and chemical oxidants stimulate CO2/H+-sensitive neurons in rat brain stem slices.
Hyperoxia, a model of oxidative stress, can disrupt brain stem function, presumably by an increase in O2 free radicals. Breathing hyperbaric oxygen (HBO2) initially causes hyperoxic hyperventilation, whereas extended exposure to HBO2 disrupts cardiorespiratory control. Presently, it is unknown how hyperoxia affects brain stem neurons. We have tested the hypothesis that hyperoxia increases excitability of neurons of the solitary complex neurons, which is an important region for cardiorespiratory control and central CO2/H+ chemoreception. Intracellular recordings were made in rat medullary slices during exposure to 2-3 atm of HBO2, HBO2 plus antioxidant (Trolox C), and chemical oxidants (N-chlorosuccinimide, chloramine-T). HBO2 increased input resistance and stimulated firing rate in 38% of neurons; both effects of HBO2 were blocked by antioxidant and mimicked by chemical oxidants. Hypercapnia stimulated 32 of 60 (53%) neurons. Remarkably, these CO2/H+-chemosensitive neurons were preferentially sensitive to HBO2; 90% of neurons sensitive to HBO2 and/or chemical oxidants were also CO2/H+ chemosensitive. Conversely, only 19% of HBO2-insensitive neurons were CO2/H+ chemosensitive. We conclude that hyperoxia decreases membrane conductance and stimulates firing of putative central CO2/H+-chemoreceptor neurons by an O2 free radical mechanism. These findings may explain why hyperoxia, paradoxically, stimulates ventilation.
Acidosis↗
Pressure (< or=4 ATA) increases membrane conductance and firing rate in the rat solitary complex.
Neuronal sensitivity to pressure, barosensitivity, is illustrated by high-pressure nervous syndrome, which manifests as increased central nervous system excitability when heliox or trimix is breathed at >15 atmospheres absolute (ATA). We have tested the hypothesis that smaller levels of pressure (<or=4 ATA) also increase neuronal excitability. The effect of hyperbaric helium, which mimics increased hydrostatic pressure, was determined on putative CO2/H+-chemoreceptor neurons in the solitary complex in rat brain stem slices by intracellular recording. Pressure stimulated firing rate in 31% of neurons (barosensitivity) and decreased input resistance. Barosensitivity was retained during synaptic blockade and was unaffected by antioxidants. Barosensitivity was distributed among CO2/H+-chemosensitive and -insensitive neurons; in CO2/H+-chemosensitive neurons, pressure did not significantly reduce neuronal chemosensitivity. We conclude that moderate pressure stimulates certain solitary complex neurons by a mechanism that possibly involves an increased cation conductance, but that does not involve free radicals. Neuronal barosensitivity to <or=4 ATA may represent a physiological adaptive response to increased pressure or a pathophysiological response that is the early manifestation of high-pressure nervous syndrome.
Acidosis↗
Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures.
As ambient pressure increases, hydrostatic compression of the central nervous system, combined with increasing levels of inspired Po2, Pco2, and N2 partial pressure, has deleterious effects on neuronal function, resulting in O2 toxicity, CO2 toxicity, N2 narcosis, and high-pressure nervous syndrome. The cellular mechanisms responsible for each disorder have been difficult to study by using classic in vitro electrophysiological methods, due to the physical barrier imposed by the sealed pressure chamber and mechanical disturbances during tissue compression. Improved chamber designs and methods have made such experiments feasible in mammalian neurons, especially at ambient pressures <5 atmospheres absolute (ATA). Here we summarize these methods, the physiologically relevant test pressures, potential research applications, and results of previous research, focusing on the significance of electrophysiological studies at <5 ATA. Intracellular recordings and tissue Po2 measurements in slices of rat brain demonstrate how to differentiate the neuronal effects of increased gas pressures from pressure per se. Examples also highlight the use of hyperoxia (<or=3 ATA O2) as a model for studying the cellular mechanisms of oxidative stress in the mammalian central nervous system.
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Gap junctions in CO(2)-chemoreception and respiratory control.
Recent evidence indicates that gap junctions play a more prominent role in normal functioning of the mammalian central nervous system (CNS) than was once believed. Accumulating evidence from both neonatal and adult rodents indicates that gap junctions participate in multiple aspects of respiratory control, including central CO(2) chemoreception, respiratory rhythmogenesis, and respiratory motoneuron output. This review provides an overview of gap junction neurobiology in the mammalian CNS and presents the anatomical and electrophysiological evidence for gap junctions in CO(2) chemoreception and respiratory control.
Animals↗
Role of gap junctions in CO(2) chemoreception and respiratory control.
Gap junctions are composed of connexins, which are organized into intercellular channels that form transmembrane pathways between neurons (cell-cell coupling), and in some cases, neurons and glia, for exchange of ions and small molecules (metabolic coupling) and ionic current (electrical coupling). Cell-cell coupling via gap junctions has been identified in brain stem neurons that function in CO(2)/H(+) chemoreception and respiratory rhythmogenesis; however, the exact roles of gap junctions in respiratory control are undetermined. Here we review the methods commonly used to study gap junctions in the mammalian brain stem under in vitro and in vivo conditions and briefly summarize the anatomical, pharmacological, and electrophysiological evidence to date supporting roles for cell-cell coupling in respiratory rhythmogenesis and central chemoreception. Specific research questions related to the role of gap junctions in respiratory control are suggested for future research.
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