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)

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca(2+)-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K(+) channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K(+) channel activators; NS-1619 as a Ca(2+)-sensitive K(+) channel activator; and halothane as a TASK-like background K(+) channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.
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PMID:Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction. 1584 18

A considerable volume of evidence implicates the purine adenosine in the regulation of cerebral blood flow during states such as hypotension, neural activation, hypoxia/ischemia, and hypercapnia/acidosis. The aim of this review is to describe developments in our understanding of the roles that adenosine and the adenine nucleotides play in cerebral blood flow control, with some comparisons to coronary blood flow. The first part of the review focuses on the categorization of receptors for adenosine (A1, A2A, A2B, and A3) and the adenine nucleotides, ATP and ADP (P2X and P2Y). Frequently used agonists and antagonists for these different receptors are mentioned. A description follows of the distribution of these different receptors in cerebral arterioles. The second part of the review initially deals with the literature on the release of adenosine and adenine nucleotides into the extracellular space of the brain, describing the various techniques used to make these measurements and assessing the pitfalls associated with their use. This is followed by a discussion of the factors affecting purine release, which include cell swelling and acidosis. The third section evaluates the role of smooth muscle potassium channels in controlling arteriolar diameter. There is evidence for an important role of KATP and KCa channels, but less is known about the contributions of voltage-dependent (KV) and inwardly rectifying (KIR) channels. This section ends with a discussion on the reported inhibitory effect of nitric oxide synthase inhibitors on the KATP channel and the consequences of such an action for the interpretation of much of the published work on nitric oxide as a regulator of cerebral blood flow. The fourth section evaluates the data supporting a role of adenosine and ATP in the regulation of cerebral blood flow during autoregulation, hypotension, neural activity, hypoxia/ ischemia, and hypercapnia. Studies using antagonists and potentiators of adenosine's actions have led to the conclusion that adenosine is involved in vascular flow control, matching metabolic activity to blood flow in all of these conditions, possibly with the exceptions of autoregulation at mean arterial blood pressures above approximately 60 mmHg. Evidence is presented for a major role of A2A, and a more limited role of A2B receptors, in balancing blood flow with metabolism. The primary effect of receptor occupancy is activation of KATP and KCa channels with smooth muscle relaxation and elevated blood flow rates. There are presently fewer data on ATP's participation in flow control, but recent evidence regarding glial cell control of cerebral arteriolar diameter suggests that this may be an important mechanism. The semi-final section, which briefly describes the evidence for a comparable role of adenosine in regulating coronary blood flow, is followed by a concluding statement reaffirming the importance of adenosine as a cerebral blood flow regulator.
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PMID:Adenosine and adenine nucleotides as regulators of cerebral blood flow: roles of acidosis, cell swelling, and KATP channels. 1586 8

Modified Hb solutions have been developed as O(2) carrier transfusion fluids, but of concern is the possibility that increased scavenging of nitric oxide (NO) within the plasma will alter vascular reactivity even if the Hb does not readily extravasate. The effect of decreasing hematocrit from approximately 30% to 18% by an exchange transfusion of a 6% sebacyl cross-linked tetrameric Hb solution on the diameter of pial arterioles possessing tight endothelial junctions was examined through a cranial window in anesthetized cats with and without a NO synthase (NOS) inhibitor. Superfusion of a NOS inhibitor decreased diameter, and subsequent Hb transfusion produced additional constriction that was not different from Hb transfusion alone but was different from the dilation observed by exchange transfusion of an albumin solution after NOS inhibition. In contrast, abluminal application of the cross-linked Hb produced constriction that was attenuated by the NOS inhibitor. Neither abluminal nor intraluminal cross-linked Hb interfered with pial arteriolar dilation to cromakalim, an activator of ATP-sensitive potassium channels. Pial vascular reactivity to hypocapnia and hypercapnia was unaffected by Hb transfusion. Microsphere-determined regional blood flow indicated selective decreases in perfusion after Hb transfusion in the kidney, small intestine, and neurohypophysis, which does not have tight endothelial junctions. Administration of a NOS inhibitor to reduce the basal level of NO available for scavenging before Hb transfusion prevented further decreases in blood flow to these regions compared with NOS inhibition alone. In contrast, blood flow to skeletal and left ventricular muscle increased, and cerebral blood flow was unchanged after Hb transfusion. This cross-linked Hb tetramer is known to appear in renal lymph but not in urine. We conclude that cell-free tetrameric Hb does not scavenge sufficient NO in the plasma space to significantly affect baseline tone in vascular beds with tight endothelial junctions but does produce substantial constriction in beds with porous endothelium. The data support increasing the molecular size of Hb by polymerization or conjugation to limit extravasation in all vascular beds to preserve normal vascular reactivity.
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PMID:Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion. 1589 76

Peripheral and central respiratory chemoreceptors are ultimately responsible for maintenance of constant levels of arterial P(O2), P(CO2) and [H+], protecting the brain from hypoxia and ensuring that the breathing is always appropriate for metabolism. The aim of this discussion is to shed some light on the potential mechanisms of chemosensory transduction - the process which links chemosensory mechanisms to the central nervous mechanisms controlling breathing. Recent experimental data suggest that the purine nucleotide ATP acts as a common mediator of peripheral and central chemosensory transduction (within the carotid body and the medulla oblongata, respectively). In response to a decrease in P(O2) (hypoxia) oxygen-sensitive glomus cells of the carotid body release ATP to activate chemoafferent fibres of the carotid sinus nerve which transmit this information to the brainstem respiratory centres. In response to an increase in P(CO2)/[H+] (hypercapnia) chemosensitive structures located on the ventral surface of the medulla oblongata rapidly release ATP, which acts locally within the medullary respiratory network. The functional role of ATP released at both sites is similar--to evoke adaptive enhancement in breathing. Understanding the mechanisms of ATP release in response to chemosensory stimulation may prove to be essential for further detailed analysis of cellular and molecular mechanisms underlying respiratory chemosensitivity.
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PMID:On the peripheral and central chemoreception and control of breathing: an emerging role of ATP. 1614 Dec 66

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (approximately 40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.
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PMID:An acid-sensing ion channel that detects ischemic pain. 1625 23

The carotid body (CB) is a sensor of oxygen, carbon dioxide, hydrogen ion, and glucose in the arterial blood. Many studies of the CB's responses to low oxygen (hypoxia) have been reported. Recently attention has been increasingly focused on its responses to elevated CO2 (hypercapnia). An increase in ventilation or carotid body neural output (CBNO) can result from stimulating the CB with blood or perfusion fluids having an elevated CO2 or H+. The increase in ventilation seen with a hypoxic stimulus is accompanied with an increase in CBNO and an increased release of both acetylcholine (ACh) and ATP from the CB. The present in vitro study using both CBs harvested from six cats was undertaken to determine if hypercapnia also provoked an increased release of ACh from the incubated CBs. The anesthetizing, handling, and euthanizing of the animals were according to the guidelines of the Johns Hopkins Animal Care and Use Committee which are totally consonant with those of the NIH. CBs, once harvested and prepared for the experimental protocol, were subjected to the following steps each lasting 10 min: (1) control; (2) stress; (3) recovery. The stresses were respiratory acidosis (RAC; acidic hypercapnia), compensated respiratory acidosis (CRAC; isohydric hypercapnia), and metabolic acidosis (MtAC). The first and last forms of acidosis generated small but significant increases in the release of ACh from the CBs; the second generated a very small and insignificant increase in ACh release. Since it is generally accepted that ACh is a key excitatory neurotransmitter in the CB along with ATP, these data are consistent with other studies measuring the increase in ventilation in response to a small increase in CO2 and those studies recording CBNO in response to hypercapnia. In five of the six animals the responses to RAC and MtAC were compared to the responses to hypoxia. The latter were statistically indistinguishable from the former two.
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PMID:The impact of PCO2 and H+ on the release of acetylcholine from the cat carotid body. 1640 46

The mammalian carotid body (CB) is a polymodal chemosensor which can detect low blood glucose (hypoglycaemia), leading to increased afferent discharge and activation of counter-regulatory autonomic pathways. The underlying neurotransmitter mechanisms are unknown and controversy surrounds whether the action of low glucose is direct or indirect. To address this, we used a coculture model containing functional chemosensory units of rat CB receptor (type I) cell clusters and afferent petrosal neurones (PN). During perforated-patch, whole-cell recordings, low glucose (0-2 mM) stimulated sensory discharge in cocultured PN. When the background P(O2) was lowered to levels typical of arterial blood (approximately 90 mmHg), robust PN chemoexcitation could be induced by physiological hypoglycaemia (3.3-4 mM glucose). These sensory responses were reversibly inhibited by a combination of purinergic (suramin, 50 microM) and nicotinic (mecamylamine, 1 microM) receptor blockers, suggesting that transmission depended on corelease of ATP and ACh. Hypoglycaemic responses were additive with those evoked by hypoxia or hypercapnia; further, they could be potentiated by the GABAB receptor blocker (CGP 55845) and inhibited by 5-HT2A receptor blockers (ketanserin or ritanserin). During paired simultaneous recordings from a PN and a type I cell in an adjacent cluster, the afferent PN response coincided with type I cell depolarization, which was associated with a decrease in input resistance. In fresh tissue slices of rat CB, low glucose stimulated ATP secretion as determined by the luciferin-luciferase assay; this secretion was cadmium sensitive, potentiated by CGP 55845, and inhibited by ketanserin. Taken together these data indicate that CB receptors act as direct glucosensors, and that processing of hypoglycaemia utilizes similar neurotransmitter and neuromodulatory mechanisms as hypoxia.
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PMID:Neurotransmitter mechanisms mediating low-glucose signalling in cocultures and fresh tissue slices of rat carotid body. 1717 41

Increasing evidence indicates that there exists a reciprocal communication between the immune system and the brain. Interleukin 1beta (IL-1beta), a proinflammatory cytokine produced during immune challenge, is believed to be one of the mediators of immune-to-brain communication, but how it gets into the brain is unknown because of its large molecular weight and difficulty in crossing the blood-brain barrier. Our previous work has demonstrated that IL-1 receptor type I is strongly expressed in the glomus cells of rat carotid body (CB), a well characterized polymodal chemoreceptive organ which serves not only for the detection of hypoxia, hypercapnia and acidity, but also for low temperature and blood glucose. The present study was designed to test whether IL-1beta could stimulate the CB glomus cells and alter the discharge properties in the carotid sinus nerve, the afferent nerve innervating the organ. The results from whole-cell patch-clamp recordings and calcium imaging showed that extracellular application of IL-1beta significantly decreased the outward potassium current and triggered a transient rise in [Ca(2+)](i) in the cultured glomus cells of rat CB. Furthermore, by using extracellular recordings and pharmacological intervention, it was found that IL-1beta stimulation of the CB in the anaesthetized rat in vivo significantly increased the discharge rate in the carotid sinus nerve, most probably mediated by ATP release. This experiment provides evidence that the CB responds to cytokine stimulation and proposes the possibility that the CB might play a role in immune-to-brain communication.
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PMID:IL-1beta inhibits IK and increases [Ca2+]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat. 1761 May 83

The hypnotic agent propofol has pharmacokinetic characteristics that allow for rapid onset and offset of drug effect and fast elimination from the body. Elderly patients show a greater sensitivity to the hypnotic effect of propofol. The drug is extensively metabolized in the liver through the cytochrome P450 system and glucuronidation, with potential for drug interaction. Propofol does not cause significant inotropic depression at clinically relevant concentrations. But in vitro, propofol impairs isotonic relaxation of the heart and decreases free cytosolic Ca(2+) concentrations in myocardial cells. In animal models, the cardioprotective effects of propofol derive in part from its antioxidant and free radical scavenging properties. Propofol decreases cerebral blood flow and cerebral metabolic rate dose-dependently. The neuroprotective effect of propofol in animal models is attributed to its antioxidant property, the potentiation of gamma-aminobutyric acid type A (GABA(A))-mediated inhibition of synaptic transmission, and the inhibition of glutamate release. Subhypnotic doses of propofol induce sedative, amnestic, and anxiolytic effects in a dose-dependent fashion. Propofol impairs ventilation with a considerable effect on the control of ventilation and central chemoreceptor sensitivity. Propofol reduces the ventilatory response to hypercapnia and the ventilatory adaptation to hypoxia, even at subanesthetic doses. The drug potentiates hypoxic pulmonary vasoconstriction, an effect caused by inhibition of K(+) (ATP)-mediated pulmonary vasodilatation. Most of the pharmacological actions of propofol result from interaction with the GABA(A) receptor or with calcium channels. Propofol prolongs inhibitory postsynaptic currents mediated by GABA(A) receptors, indicating that its effects are associated with enhanced inhibitory synaptic transmission, but propofol also influences presynaptic mechanisms of GABAergic transmission. Propofol modulates various aspects of the host's inflammatory response. It decreases secretion of proinflammatory cytokines, alters the expression of nitric oxide, impairs monocyte and neutrophil functions, and has potent, dose-dependent radical scavenging activity similar to the endogenous antioxidant vitamin E.
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PMID:Propofol. 1817 94

Inhibitory GABAergic and glycinergic neurotransmission to cardioinhibitory cardiac vagal neurons (CVNs) increase during inspiratory activity and likely mediate respiratory sinus arrhythmia, while the frequency of excitatory postsynaptic currents (EPSCs) in CVNs are unaltered during the different phases of respiration. However, following hypoxia and hypercapnia (H/H), the parasympathetic activity to the heart increases and thus far, identification of the pathways and neurotransmitters that are responsible for exciting CVNs post H/H are unclear. This study identifies different excitatory pathways to CVNs recruited post H/H. Spontaneous and inspiratory-related EPSCs were recorded in CVNs before, during, and after 10 min of H/H in an in vitro slice preparation that retains rhythmic respiratory activity. Before and during H/H, EPSCs in CVNs were completely blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d(-)-2-amino-5-phosphonopentanoic acid (AP5), selective AMPA/kainate and N-methyl-d-apartate (NMDA) receptor blockers, respectively. However, after H/H, there was a significant increase in EPSCs during each inspiratory burst. While some of the inspiratory-related EPSCs were blocked by the broad purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS) and the specific P2X receptor antagonist 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate monolithium trisodium salt (TNP-ATP) a P2X receptor blocker, most of the recruited excitatory neurotransmission to CVNs is serotonergic because odansetron, a selective 5-HT3 antagonist, abolished the majority of the spontaneous and inspiratory-related EPSCs evoked during recovery from H/H. The results from this study suggest that following episodes of H/H, two nonglutamatergic excitatory pathways, purinergic and serotonergic, activating P2X and 5-HT3 receptors, respectively, are recruited to excite CVNs in the post H/H recovery period.
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PMID:Recruitment of excitatory serotonergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus post hypoxia and hypercapnia. 1818 87

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