UMLS:C0020440 - FACTA Search

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Query: UMLS:C0020440 (hypercapnia)
7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peripheral arterial chemoreceptors of the carotid body participate in the ventilatory responses to hypoxia and hypercapnia, the arousal responses to asphyxial apnea, and the acclimatization to high altitude. In response to an excitatory stimuli, glomus cells in the carotid body depolarize, their intracellular calcium levels rise, and neurotransmitters are released from them. Neurotransmitters then bind to autoreceptors on glomus cells and postsynaptic receptors on chemoafferents of the carotid sinus nerve. Binding to inhibitory or excitatory receptors on chemoafferents control the electrical activity of the carotid sinus nerve, which provides the input to respiratory-related brainstem nuclei. We and others have used gene expression in the carotid body as a tool to determine what neurotransmitters mediate the response of peripheral arterial chemoreceptors to excitatory stimuli, specifically hypoxia. Data from physiological studies support the involvement of numerous putative neurotransmitters in hypoxic chemosensitivity. This article reviews how in situ hybridization histochemistry and other cellular localization techniques confirm, refute, or expand what is known about the role of dopamine, norepinephrine, substance P, acetylcholine, adenosine, and ATP in chemotransmission. In spite of some species differences, review of the available data support that 1). dopamine and norepinephrine are synthesized and released from glomus cells in all species and play an inhibitory role in hypoxic chemosensitivity; 2). substance P and acetylcholine are not synthesized in glomus cells of most species but may be made and released from nerve fibers innervating the carotid body in essentially all species; 3). adenosine and ATP are ubiquitous molecules that most likely play an excitatory role in hypoxic chemosensitivity.
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PMID:Gene expression in peripheral arterial chemoreceptors. 1238 60

ATP-sensitive K+ channels (KATP) couple intermediary metabolism to cellular activity, and may play a role in the autoregulation of vascular tones. Such a regulation requires cellular mechanisms for sensing O2, CO2, and pH. Our recent studies have shown that the pancreatic KATP isoform (Kir6.2/SUR1) is regulated by CO2/pH. To identify the vascular KATP isoform(s) and elucidate its response to hypercapnic acidosis, we performed these studies on vascular smooth myocytes (VSMs). Whole-cell and single-channel currents were studied on VSMs acutely dissociated from mesenteric arteries and HEK293 cells expressing Kir6.1/SUR2B. Hypercapnic acidosis activated an inward rectifier current that was K+-selective and sensitive to levcromakalim and glibenclamide with unitary conductance of approximately 35pS. The maximal activation occurred at pH 6.5 to 6.8, and the current was inhibited at pH 6.2 to 5.9. The cloned Kir6.1/SUR2B channel responded to hypercapnia and intracellular acidification in an almost identical pattern to the VSM current. In situ hybridization histochemistry revealed expression of Kir6.1/SUR2B mRNAs in mesenteric arteries. Hypercapnia produced vasodilation of the isolated and perfused mesenteric arteries. Pharmacological interference of the KATP channels greatly eliminated the hypercapnic vasodilation. These results thus indicate that the Kir6.1/SUR2B channel is a critical player in the regulation of vascular tones during hypercapnic acidosis.
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PMID:Hypercapnic acidosis activates KATP channels in vascular smooth muscles. 1273 54

ATP is involved in central respiratory control and may mediate changes in the activity of medullary respiratory neurones during hypercapnia, thus playing an important role in central chemoreception. The main objective of this study was to explore further the role of ATP-mediated signalling in respiratory control and central chemoreception by characterising the profile of the P2X receptors expressed by physiologically identified respiratory neurones. In particular we determined whether respiratory neurones in the rostral ventrolateral medulla (VLM) express P2X2 receptor subunits of the ATP-gated ion channel, since ATP currents evoked at recombinant P2X2 receptors are potentiated by lowering extracellular pH. Experiments were performed on anaesthetised (pentobarbitone sodium 60 mg kg-1 I.P., then 10 mg kg-1 I.V. as required), gallamine-triethiodide-treated (10 mg kg-1 I.V., then 2-4 mg kg-1 h-1 I.V.) and artificially ventilated rats. The VLM respiratory neurones were classified according to the timing of their discharge pattern in relation to that of the phrenic nerve and by the exclusion of pump cells from the study population; these were labelled with Neurobiotin using the juxtacellular method, and visualised with fluorescence microscopy. It was found that a substantial proportion of the VLM respiratory neurones express the P2X2 receptor subunit. P2X2 receptor subunit immunoreactivity was detected in approximately 50 % (six out of 12) of expiratory neurones and in approximately 20 % (two out of 11) of neurones with inspiratory-related discharge (pre-inspiratory and inspiratory). In contrast, no Neurobiotin-labelled VLM respiratory neurones (n = 19) were detectably immunoreactive for the P2X1 receptor subunit. Microionophoretic application of ATP (0.2 M, 20-80 nA for 40 s) increased the activity of approximately 80 % (13 out of 16) of expiratory neurones and of approximately 30 % (five out of 18) of VLM neurones with inspiratory-related discharge. These effects were abolished by the P2 receptor blocker suramin (0.02 M, 80 nA), which also reduced the baseline firing in some expiratory neurones. These data indicate that modulation of P2X2 receptor function, such as that evoked by acidification of the extracellular environment during hypercapnia, may contribute to the changes in activity of the VLM respiratory neurones that express these receptors.
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PMID:Purinergic signalling in the medullary mechanisms of respiratory control in the rat: respiratory neurones express the P2X2 receptor subunit. 1287 56

Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.
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PMID:Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2+-activated potassium channels. 1452 33

In mammals, the ventilatory response to decreased oxygen tension in the arterial blood is initiated by excitation of specialized O2-sensitive chemoreceptor cells in the carotid body that release neurotransmitters to activate endings of the sinus nerve afferent fibers. We investigated the role of ATP acting via ionotropic P2X receptors in the carotid body function and ventilatory response to hypoxia in mice. Mice deficient in P2X2 receptor subunit showed a markedly attenuated ventilatory response to hypoxia, whereas the response to hypoxia in P2X3-deficient mice was comparable with that seen in wild-type controls. P2X2 and P2X3 receptor subunit deficiency did not affect the ventilatory responses to hypercapnia. P2X2 subunit deficiency resulted in a dramatic reduction in the responses of the carotid sinus nerve to hypoxia in the in vitro carotid body-sinus nerve preparation. ATP and its stable analog alpha,beta-methyleneATP both evoked rapid excitation of sinus nerve afferents, and the P2 receptor antagonist PPADS (pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulphonic acid) (100 microm) blocked hypoxia-induced increase in sinus nerve discharge. Immunoreactivities for P2X2 and P2X3 subunits were both detected on afferent terminals surrounding clusters of glomus cells in the wild-type animals but were absent in mice deficient in P2X2 and P2X3 receptor subunits. These observations provide the first definitive evidence that, in the carotid body, ATP is a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibers. We conclude that P2X receptors containing the P2X2 subunit play a pivotal role in carotid body function and in mediating ventilatory responses to hypoxia.
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PMID:Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel mediating ventilatory responses to hypoxia. 1467 95

The neurotransmitter mechanisms that process acid hypercapnia in the mammalian carotid body (CB) are poorly understood. Using a co-culture model containing rat CB chemoreceptor (type 1 cell) clusters and petrosal neurons (PN), we tested the hypothesis that co-released ACh and ATP was an important mechanism. Sensory transmission from type I clusters to PN in co-culture occurred at chemical synapses via co-release of ATP and ACh because isohydric hypercapnia depolarized and/or increased firing in co-cultured PN, but not in PN cultured alone; PN chemoexcitatory responses were inhibited by decreasing the extracellular Ca(2+):Mg2+ ratio; partial inhibition of these responses occurred during separate perfusion of cholinergic (hexamethonium or mecamylamine) and P2X (suramin) receptor blockers, although inhibition was often complete with both blockers present; and rapid chemoexcitatory responses to hypercapnia were inhibited by acetazolamide (10 microM), an inhibitor of carbonic anhydrase, localized in type I cells. Acidosis (pH = 7.0, 7.2) enhanced the ATP-induced whole cell current in functional PN relative to that at physiologic pH (7.4), suggesting that increased sensitivity of postsynaptic P2X receptors may contribute to acid chemotransmission. Type I cells in CB tissue sections expressed vesicular acetylcholine transporter (VAChT), a cholinergic marker, as revealed by confocal immunofluorescence. Thus co-release of ACh and ATP is an important neurotransmitter mechanism for processing isohydric and acidic hypercapnia in the rat carotid body.
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PMID:CO2/pH chemosensory signaling in co-cultures of rat carotid body receptors and petrosal neurons: role of ATP and ACh. 1505 81

Recent evidence suggests that ATP is a mediator of central (within the ventral surface of the medulla) and peripheral (within the carotid body) chemosensory transduction. This short review discusses the data obtained in experiments in vivo and in vitro supporting this hypothesis. P2 receptors for ATP are expressed within the ventrolateral medulla as well as by the peripheral chemosensory afferent neurones. Blockade of P2 receptors in the ventrolateral medulla attenuates the CO2-induced increase in respiration while blockade of purinergic signalling impairs carotid body function and diminishes the ventilatory response to hypoxia. Furthermore, ATP is released from the ventral surface of the medulla during hypercapnia and from the carotid body during hypoxia. Finally, exogenous ATP applied on the ventral surface of the medulla evokes rapid increase in phrenic nerve activity, while ATP applied to the carotid body evokes marked excitation of the carotid sinus nerve afferents. We suggest that in the ventrolateral medulla ATP is produced following CO2/H(+)-induced activation of central chemosensory elements (neuronal and/or glial) and acts within the respiratory network to produce physiologically relevant changes in ventilation. In the carotid body, ATP contributes in a significant manner to the transmission of the sensitivity of the carotid body to changes in arterial PO2 and may be considered as a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibres.
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PMID:ATP is a key mediator of central and peripheral chemosensory transduction. 1510 9

There is significant controversy over the effects of hypercapnia on the human newborn brain. Previous studies have shown that 1 h of an arterial CO2 pressure (Paco2) of 80 mm Hg alters brain cell membrane Na+K+-ATPase enzyme activity in the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypercapnia (either a Paco2 of 65 or 80 mm Hg) results in decreased energy metabolism and alters neuronal nuclear enzyme activity and protein expression, specifically Ca++/calmodulin-dependent kinase (CaMK) IV activity, phosphorylation of cAMP response element binding protein (CREB), and expression of apoptotic proteins in cortical neuronal nuclei of newborn piglets. Studies were performed in 20 anesthetized normoxic piglets ventilated at either a Paco2 of 65 mm Hg, 80 mm Hg, or 40 mm Hg for 6 h. Energy metabolism was documented by ATP and phosphocreatine (PCr) levels. Results show ATP and PCr levels were significantly lower in the hypercapnic groups than the normocapnic. CaMK IV activity, phosphorylated CREB density, and Bax protein expression were all significantly higher in the hypercapnic groups than the normocapnic group. Bcl-2 protein was similar in all three groups, making the ratio of Bax/Bcl-2 significantly higher in the hypercapnic groups than in the normocapnic group. We conclude that hypercapnia alters neuronal energy metabolism, increases phosphorylation of transcription factors, and increases the expression of apoptotic proteins in the cerebral cortex of newborn piglets and therefore may be deleterious to the newborn brain.
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PMID:Hypercapnia-induced modifications of neuronal function in the cerebral cortex of newborn piglets. 1558 83

It is not clear whether activation of ATP-sensitive potassium channels (K(ATP)) with pinacidil in advance of ischemia and reperfusion promotes or suppresses arrhythmias. This study determines the effects of pinacidil pretreatment on arrhythmias and the changes in cellular electrophysiological parameters in segments of guinea pig right ventricular free walls exposed to simulated ischemia and reperfusion. Microelectrode recordings were made from endo- and epicardium during endocardial pacing. Preparations were superfused with Tyrode's solution and then exposed for 5 min to either 100 muM pinacidil or its solvent. After a 5-min washout, preparations were exposed to 15 min of ischemic conditions (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, and glucose-free) followed by reperfusion with Tyrode's solution. Pinacidil pretreatment increased ischemia-induced abbreviation of endo- and epicardial action potential durations and effective refractory periods. Pinacidil had no effect on endocardial conduction times but greatly prolonged transmural conduction during ischemia and early reperfusion, and it increased the incidence of transmural conduction block. Pinacidil pretreatment caused a significant increase in the incidence of arrhythmias in ischemia and reperfusion. Reperfusion arrhythmias in control preparations had electrophysiological characteristics of activity initiated by afterpotentials; however, arrhythmias with these characteristics were absent in pinacidil-pretreated preparations, and all reperfusion arrhythmias exhibited characteristics of reentry. The increased incidence of re-entrant arrhythmias is likely explained by pinacidil-induced reduction in effective refractory periods in combination with prolonged transmural conduction times. Thus, pinacidil pretreatment enhanced the effects of ischemia and reperfusion on action potential duration, effective refractory period, and transmural conduction, and it promoted re-entrant arrhythmias.
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PMID:Pretreatment with pinacidil promotes arrhythmias in an isolated tissue model of cardiac ischemia and reperfusion. 1567 Dec 2

Diazoxide (Diaz), an activator of mitochondrial ATP-sensitive K+ (mitoKATP) channels, is neuroprotective, but the mechanism of action is unclear. We tested whether Diaz preserves endothelium-dependent (hypercapnia) or -independent [iloprost (Ilo)] cerebrovascular dilator responses after ischemia-reperfusion (I/R) in newborn pigs and whether the effect of Diaz is sensitive to 5-hydroxydecanoate (5-HD), an inhibitor of mitoKATP channels. Anesthetized, ventilated piglets (n = 48) were equipped with closed cranial windows. Changes in diameter of pial arterioles were determined with intravital microscopy in response to graded hypercapnia (5-10% CO2 - 21% O2-balance N2, n = 25) or Ilo (0.1-1 microg/ml, n = 18) before and 1 h after 10 min of global I/R. Experimental groups were pretreated with vehicle, NS-398 (a selective cyclooxygenase-2 inhibitor, 1 mg/kg), Diaz (3 mg/kg), or 5-HD (20 mg/kg) + Diaz. Potential direct effects of Diaz and 5-HD on hypercapnic vasodilation were also tested in the absence of I/R (n = 5). To confirm the direct effect of Diaz on mitochondria, mitochondrial membrane potential in cultured piglet cerebrovascular endothelial cells was monitored using Mito Tracker Red. Hypercapnia resulted in dose-dependent pial arteriolar vasodilation, which was attenuated by approximately 70% after I/R in vehicle- and NS-398-treated animals. Diaz and 5-HD did not affect the CO2 response. Diaz significantly preserved the postischemic vasodilation response to hypercapnia, but not to Ilo. Diaz depolarized mitochondria in cultured piglet cerebrovascular endothelial cells, and 5-HD completely abolished the protective effect of Diaz, both findings indicate a role for mitoKATP channels. In summary, preservation of arteriolar dilator responsiveness by Diaz may contribute to neuroprotection.
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PMID:Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. 1573 86

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