A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

Kiwull-Schöne, Heidrun; Wiemann, Martin; Frede, Stilla; Bingmann, D.; Wirth, Klaus; Heinelt, Uwe; Lang, Hans‐Jochen; Kiwull, P.

doi:10.1164/ajrccm.164.7.2010147

Cited by 29 publications

(30 citation statements)

References 38 publications

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“…Tight regulation of the carrier allows the adjustment of epithelial transport to the respective functional requirements (29,39,43,50,51,60). Beyond that, NHE3 serves in the regulation of cytosolic pH in several nonpolarized cells (19,34,37,71). Signaling molecules regulating NHE3 activity include serum-and glucocorticoid-inducible kinase (SGK)1, which has originally been cloned as a glucocorticoid-inducible gene (23,68,69).…”

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confidence: 99%

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Sandu

Artunc²,

Palmada³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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In vitro experiments have demonstrated the stimulating effect of serum- and glucocorticoid-inducible kinase (SGK)1 on the activity of the Na+/H+ exchanger (NHE3). SGK1 requires activation by phosphoinositide-dependent kinase (PDK)1, which may thus similarly play a role in the regulation of NHE3-dependent epithelial electrolyte transport. The present study was performed to explore the role of PDK1 in the regulation of NHE3 activity. Because mice completely lacking functional PDK1 are not viable, hypomorphic mice expressing ∼20% of PDK1 ( pdk1 hm) were compared with their wild-type littermates ( pdk1 wt). NHE3 activity in the intestine and PDK1-overexpressing HEK-293 cells was estimated by utilizing 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein fluorescence for the determination of intracellular pH. NHE activity was reflected by the Na+-dependent pH recovery from an ammonium prepulse (ΔpHNHE). The pH changes after an ammonium pulse allowed the calculation of cellular buffer capacity, which was not significantly different between pdk1 hm and pdk1 wt mice. ΔpHNHE was in pdk1 hm mice, only 30 ± 6% of the value obtained in pdk1 wt mice. Conversely, ΔpHNHE was 32 ± 7% larger in PDK1-overexpressing HEK-293 cells than in HEK-293 cells expressing the empty vector. The difference between pdk1 hm and pdk1 wt mice and between PDK1-overexpressing and empty vector-transfected HEK cells, respectively, was completely abolished in the presence of the NHE3 inhibitor S3226 (10 μM). In conclusion, defective PDK1 expression leads to significant impairment of NHE3 activity in the intestine, pointing to a role of PDK1-dependent signaling in the regulation of NHE-mediated electrolyte transport.

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mentioning

confidence: 99%

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Sandu

Artunc²,

Palmada³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…NHE3 is present in ventrolateral neurons from medullary organotypic cultures, and blockade of this exchanger using high-affinity inhibitors caused a drop in pHi and potentiated the response of these cells to CO 2 (13). The NHE3 inhibitor S8218 was found to activate CO 2 /H ϩ -sensitive neurons in vitro (12) and to potentiate the CO 2 ventilatory response and decrease the apneic threshold in rabbits (28). NHE3 seems to be the predominant NHE subtype in chemosensitive neurons.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Na+/H+ Exchanger Type 3 Reduces Duration of Apnea Induced by Laryngeal Stimulation in Piglets

Abu-Shaweesh

2002

Pediatric Research

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Reflexes from the larynx induce cessation of breathing in newborn animals. The magnitude of respiratory inhibition is inversely related to the level of central chemical input. Recent studies indicate that selective inhibition of Na ϩ /H ϩ exchanger type 3 (NHE3) activates CO 2 /H ϩ -sensitive neurons, resembling the responses evoked by hypercapnic stimuli. Hence, the use of NHE3 inhibitors may reduce reflexly mediated respiratory depression and duration of apnea in the neonatal period. This possibility was examined in decerebrate, vagotomized, ventilated, and paralyzed piglets by testing the effects of i.v. administration of NHE3 blocker S8218 on the response of phrenic nerve amplitude, frequency, and duration of apnea induced by graded electrical stimulation of the superior laryngeal nerve. Superior laryngeal nerve stimulation caused a significant decrease in phrenic nerve amplitude, frequency, minute phrenic activity, and inspiratory time (all p Ͻ 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea both during and after cessation of stimulation. NHE3 blocker S8218 reduced the superior laryngeal nerve stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency (all p Ͻ 0.05) and reduced superior laryngeal nerve stimulation-induced apnea and duration of poststimulation apnea (p Ͻ 0.05). In six other pigs the brain concentrations of S8218 were measured at different intervals after i.v. administration of the drug and were found to be higher in the brain tissue than plasma at all intervals. These findings suggest that the use of NHE3 blockers may decrease the duration of apnea and possibly reduce the pathophysiologic consequences of potentially lifethreatening apnea in infants. Disorders of rhythmic breathing, including apnea, are common in premature infants. If prolonged or frequent, apnea may impair gas exchange and have adverse reflex cardiovascular consequences. It has been shown that infants who exhibited periodic apnea of more than 20 s duration have a higher incidence of intraventricular hemorrhage, hydrocephalus, need for mechanical ventilation, and abnormal neurologic development during the first year of life (1). Apnea has also been associated with impaired cognitive function and poor academic achievement in early school-age children (2). Furthermore, apnea of infancy requiring treatment with theophylline was associated with later development of cerebral palsy, possibly reflecting the effects of repeated hypoxia induced by such apneic episodes (3). However, a cause and effect relationship between poor neurologic outcome and apnea is not established.Depression and cessation of breathing can be elicited by multiple pathways, including laryngeal reflexes, which are enhanced in premature infants and in newborn animals (4 -7). Newborn animals respond to instillation of water or some other liquids to the laryngeal mucosa with a sustained apnea, which may lead to death unless the off...

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“…Furthermore, these traditional chemoreceptors show attenuated pH i recovery during a normal hypercapnic stimulus because their NHEs are inhibited by extracellular acidosis (7,14,40,42). Recently, inhibition of the NHE-3 isoform with the selective blocker S8218 has been shown to increase the mammalian central CO 2 ventilatory response and lower the apneic threshold, suggesting an important function of NHE-3 in mammalian CO 2 sensing (30). Avian IPC also appear to rely on NHEs for their inverse response to CO 2 stimuli as demonstrated in the current investigation.…”

Section: Comparison To Other Co 2 Chemoreceptorsmentioning

confidence: 99%

CO₂transduction in avian intrapulmonary chemoreceptors is critically dependent on transmembrane Na⁺/H⁺exchange

Hempleman

Adamson

Begay

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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R1551-R1559, 2003. First published February 20, 2003 10.1152/ajpregu.00519.2002Avian intrapulmonary chemoreceptors (IPC) are vagal respiratory afferents that are inhibited by high lung PCO 2 and excited by low lung PCO 2. Previous work suggests that increased CO 2 inhibits IPC by acidifying intracellular pH (pHi) and that pH i is determined by a kinetic balance between the rate of intracellular carbonic anhydrase-catalyzed CO 2 hydration/dehydration and transmembrane extrusion of acids and/or bases by various exchangers. Here, the role of amiloride-sensitive Na ϩ /H ϩ exchange (NHE) in the IPC CO2 response was tested by recording single-unit action potentials from IPC in anesthetized ducks, Anas platyrhynchos. For each of the IPC tested, blockade of the NHE using dimethyl amiloride (DMA) elicited a marked (Ͼ50%) dose-dependent decrease in mean IPC discharge (P Ͻ 0.05), suggesting that NHE is important for pH i regulation and CO2 transduction in IPC. In addition, activation of the NHE using 12-O-tetradecanoylphorbol 13-acetate stimulated six of the seven IPC tested, although the overall effect was not statistically significantly (P ϭ 0.07). Taken together, these findings suggest that CO 2 transduction in IPC is dependent on transmembrane NHE although it is likely to be much slower than carbonic anhydrase-catalyzed hydration-dehydration of CO2. carbon dioxide chemosensitivity; intracellular pH regulation; respiratory control; neuron; acid; base BIRDS HAVE INTRAPULMONARY chemoreceptors (IPC) that monitor lung PCO 2 and exert reflex effects on the pattern of breathing (9,15,16,36,37,43,45). These IPC have afferent axons in the vagus nerves, cell bodies in the nodose ganglia, and sensory endings in the parabronchial tissue of the lungs (9, 25, 34). The action potential discharge of IPCs responds to both rapidly changing (i.e., phasic) and sustained (or tonic) levels of intrapulmonary PCO 2 , thereby encoding information about the temporal relationships between ventilation, perfusion, and metabolism (4,9,15,16,19,24,34). IPC sensory feedback helps terminate inspiration by sensing CO 2 washout from the lung, helps maintain arterial homeostasis in response to moderate inspired hypercapnia (35,37,45), and helps adjust breathing to metabolic demands (4,9,19,24,50).IPC are unusual respiratory chemoreceptors because their action potential discharge rate is inversely proportional to intrapulmonary PCO 2 . Low PCO 2 stimulates IPC firing, and high PCO 2 inhibits firing (9, 15, 16); thus the IPC response is backward compared with that of traditional respiratory chemoreceptors like the carotid bodies (18, 29), many presumptive central chemoreceptors (40), and snail pneumostome ganglia chemoreceptors (13,14). Many presumptive chemoreceptor neurons located in the mammalian medullary raphe, however, have also been shown to be inhibited by high PCO 2 (41, 54), as are reptilian IPC, mammalian pulmonary stretch receptors, and mammalian laryngeal CO 2 chemoreceptors (10,32,39,44). Thus the inverse CO 2 response (discharge rate inhi...

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A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

Cited by 29 publications

References 38 publications

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Inhibition of Na+/H+ Exchanger Type 3 Reduces Duration of Apnea Induced by Laryngeal Stimulation in Piglets

CO₂transduction in avian intrapulmonary chemoreceptors is critically dependent on transmembrane Na⁺/H⁺exchange

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A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

Cited by 29 publications

References 38 publications

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Impaired intestinal NHE3 activity in the PDK1 hypomorphic mouse

Inhibition of Na+/H+ Exchanger Type 3 Reduces Duration of Apnea Induced by Laryngeal Stimulation in Piglets

CO2transduction in avian intrapulmonary chemoreceptors is critically dependent on transmembrane Na+/H+exchange

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A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

CO₂transduction in avian intrapulmonary chemoreceptors is critically dependent on transmembrane Na⁺/H⁺exchange