Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated whether enkephalin-containing peptides and catecholamines are increased in fetal plasma during periods of reduced uterine blood flow which produce moderate fetal asphyxia (i.e. hypoxemia, hypercapnia and acidemia). Experiments (n = 16) were performed in 11 ewes between 121-139 days gestation. In 8 experiments a clamp placed around the common iliac artery of the ewe was adjusted to produce a 50% reduction in the partial pressure of arterial oxygen (PO2) in fetal plasma for 30 min between 121-125 days gestation (n = 4) and between 131-139 days gestation (n = 4). Control (n = 8) experiments were performed when the arterial clamp was not adjusted. There was no significant effect of asphyxia on fetal plasma noradrenaline concentrations before 126 days gestation. After 130 days gestation during asphyxia, fetal plasma noradrenaline concentrations increased significantly from 2.20 +/- 0.72 pmol/ml (-15 min) to 14.06 +/- 0.75 pmol/ml (+5 min). The fetal adrenaline response to asphyxia did not change with increasing gestational age and after 130 days gestation fetal plasma adrenaline increased significantly from 1.48 +/- 0.46 pmol/ml (-15 min) to 4.05 +/- 1.22 pmol/ml (+10 min). Met-enkephalin-arg6-phe7 immunoreactivity was measurable (25-117 pg/ml) in all pre-experimental fetal sheep plasma samples collected between 121-139 days gestation. There was no specific effect of asphyxia on fetal plasma [Met]-enkephalin-arg6-phe7-IR before 130 days gestation. However after 130 days gestation, there was a significant increase in fetal plasma (Met-enkephalin Arg-6-phe7-IR above baseline values, when compared to control experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Fetal asphyxia stimulates an increase in fetal plasma catecholamines and [Met]-enkephalin-arg6-phe7 in the late-gestation sheep fetus. 212 44

The effects of methionine enkephalin (ME) and substance P (SP) were tested on the chemosensory discharge of the cat carotid body-nerve preparation in vitro. ME superfused in concentrations of 10(-8) to 10(-5) M depressed the sensory discharge, an effect followed by receptor excitation (rebound). Bolus applications of ME (30 ng to 3.0 microgram) induced variable effects (excitation or depression) on the discharge, excitation being more pronounced with the smaller doses. Superfusions with SP (10(-8) to 10(-5) M) either excited or depressed the discharge, excitation being more pronounced with higher SP concentrations (i.e. 10(-6) M). Bolus applications of SP (43 ng to 0.5 micrograms) also excited or depressed the sensory discharge. These variations may be dose-dependent. Superfused ME (10(-6) M) significantly depressed the chemoreceptor response to hypoxia (100% N2) and hypercapnia (6% CO2, pH 7.43). The responses to NaCN and acidity (pH 6.0) were marginally depressed. Superfused SP (10(-6) M) clearly depressed the responses to hypoxia, those to hypercapnia and NaCN were marginally affected but the effects of acidity were not altered. When the peptides were tested against the receptor responses to exogenously applied putative neurotransmitters (ACh, dopamine--DA), it was found that ME tended to depress both the ACh and DA actions whereas SP (10(-6) M) tended to increase their effects. Superfusions with naloxone (10(-6) M) increased the basal chemosensory discharge and this enkephalin blocker partially relieved the depressant effect of ME on the ACh-induced response. It is concluded that carotid body chemoreceptors have excitatory and inhibitory reactive sites to both ME and SP although their precise location is still unknown.
 ...
PMID:Effects of methionine-enkephalin and substance P on the chemosensory discharge of the cat carotid body. 241 43

The effects of selective opioid receptor agonists and antagonists on neural discharge recorded from carotid body arterial chemoreceptors in vivo were studied in anaesthetized cats. Mean ID50 values were determined for each agonist and used to assess chemodepressant potency on intracarotid (i.c.) injection in animals artificially ventilated with air. [Met]enkephalin, [Leu]enkephalin, [D-Ala2, D-Leu5]enkephalin and [D-Pen2, D-Pen5]enkephalin were more potent chemodepressants than [D-Ala2, Me-Phe4, Gly-ol5]enkephalin, dynorphin (1-8) or ethylketocyclazocine; morphiceptin (mu-agonist) was inactive. The rank order of potency was compatible with the involvement of delta-opioid receptors in opioid-induced depression of chemosensory discharge. ICI 154129, a delta-opioid receptor antagonist, was used in fairly high doses and caused reversible dose-related antagonism of chemodepression induced by [Met]enkephalin. It also antagonized depression caused by single doses of [Leu]enkephalin, [D-Ala2, D-Leu5]enkephalin, [D-Ala2, Me-Phe4, Gly-ol5]enkephalin or dynorphin (1-8). ICI 174864, a more potent and selective delta-opioid receptor antagonist, also antagonized chemodepression induced by [Met]enkephalin or by the selective delta-receptor agonist [D-Pen2, D-Pen5]enkephalin. Comparison of background or 'spontaneous' chemosensory discharge during the 30 min periods immediately before and after injecting ICI 174864 (0.1-0.2 mg kg-1 i.c.) showed a significant increase in discharge in one experiment, but in four others discharge was either unaffected or decreased after the antagonist, which argues against a toxic depression of chemosensors by endogenous opioids under resting conditions in our preparation. Sensitivity of the carotid chemoreceptors to hypoxia (ventilating with 10% O2) was increased significantly after ICI 174864, which could be taken as evidence that endogenous opioids depress chemosensitivity during hypoxia. In contrast, responsiveness to hypercapnia was reduced after the antagonist, implying that endogenous opioids may potentiate chemoreceptor sensitivity during hypercapnia. The results obtained using 'selective' agonists and antagonists provide evidence that depression of chemosensory discharge caused by injected opioids involves a delta type of opioid receptor within the cat carotid body. Endogenous opioids may modulate arterial chemoreceptor sensitivity to physiological stimuli such as hypoxia and hypercapnia.
 ...
PMID:Characterization of opioid receptors in the cat carotid body involved in chemosensory depression in vivo. 287 62

Endogenous opioid peptides are present in cerebral perivascular nerves and in the CSF, and their concentrations are changing in response to stimuli that activate regulatory mechanisms of the cerebral circulation (e.g., alterations of the perfusion pressure or changes of the arterial O2 tension). Opiate receptors are expressed in the cells of the CNS and the cerebrovascular bed, and their activation modulates the function of other vasoregulatory mechanisms (i.e., the autonomic nervous system, nitric oxide, prostanoids, vasopressin) that are involved in the control of the cerebrovascular tone. The direct vasomotor effects of opioid peptides and opiates on the cerebral arteries under in vitro or in situ conditions appear to be weak or absent in several species. However, Met- and Leu-enkephalin induce pial arterial vasodilation in the newborn pig. In this species, beta-endorphin acts as a constrictor, whereas dynorphin may induce either dilation or constriction depending on the experimental conditions. The influence of exogenously applied natural and synthetic opioids on the cerebral blood flow (CBF) is determined mainly by their metabolic, neuronal, and respiratory effects. Hypothalamic and pituitary circulations are especially sensitive to opioids. Under resting conditions, endogenous opioid peptides do not participate in the regulation of the cerebrovascular tone and CBF. On the other hand, mu and delta opiate receptor stimulation by endogenous opioid peptides, interacting with other vasoactive factors, obviously contributes to the hypoxia- and hypercapnia-induced cerebral vasodilation. Furthermore, endogenous opioid mechanisms are involved in the autoregulation of the hypothalamic blood flow. Thus, the endogenous opioid system may well represent a latent regulatory mechanism, which is of limited importance under basal conditions, but becomes more important under conditions of stress. Synthetic exogenous opioids do not appear to influence the hypoxic or hypercapnic CBF responses or the cerebral autoregulatory process.
 ...
PMID:Opiate receptor-mediated mechanisms in the regulation of cerebral blood flow. 896 68

Hypercarbia is a common complication of respiratory failure, and the technique of "permissive hypercapnia" is used to ventilate individuals with increased peak airway pressures on mechanical ventilators, resulting in elevated arterial PCO2. We studied the effects of hypercarbia on cultured bovine aortic and main pulmonary artery endothelial cell surface proteins, assessing cell surface iodination using lactoperoxidase bound to latex microspheres. We found that 4 h of exposure to 10% CO2 increased the display of substances of apparent molecular masses of 27, 47, and 52 kDa. This effect was not mimicked by acidotic media. Western blots of detergent extracts of main pulmonary artery endothelial cell monolayers did not show increased expression of carbonic anhydrase IV (molecular mass = 52 kDa) after incubation under hypercarbic conditions. Hypercarbia did not change the pattern of [35S]methionine incorporation into endothelial cell proteins. We conclude that hypercarbia of 4-h duration changes iodinated endothelial cell surface proteins. We speculate that this effect may be related to changes in secretion or display of apical cell membrane-associated proteins.
 ...
PMID:Effect of hypercarbia on surface proteins of cultured bovine endothelial cells. 943 68

Ammonia intoxication, which results in astrocytic edema and glutamine accumulation, blocks cerebral vasodilation during hypercapnia but not during hypoxia. Ammonia's effect on blood flow during hypocapnia is unclear, with some brain regions showing a paradoxical increase in flow. Here, we studied the responses to hypocapnia of pial arterioles not surrounded by astrocytic end feet to avoid mechanical compression by local edema. Blood flow was measured by microspheres in pentobarbital sodium-anesthetized rats equipped with closed cranial windows that permitted intravital microscopy. The normal pial arterial constriction in hypocapnia (12 +/- 1%; mean +/- SE) was blocked (2 +/- 1%) during a 6-h intravenous infusion of ammonium acetate, with some regions (cerebrum, midbrain) showing increased flow during hypocapnia. After pretreatment with methionine sulfoximine (MSO), which inhibits glutamine synthesis, the normal hypocapnic constrictor response was retained in pial arterioles (11 +/- 2%) during hyperammonemia. The increase in the calculated cerebrovascular resistance also was retained. An analog of MSO that does not block glutamine synthesis (buthionine sulfoximine) was ineffective in maintaining hypocapnic reactivity. In a sodium acetate-treated control group, MSO did not alter the pial arteriolar response. Normal vasoconstrictive ability was shown during ammonium infusion in response to U-46619, a thromboxane analog. We conclude that the inhibition of hypocapnic responsivity induced by ammonium is not due to paralysis of the pial arteriolar smooth muscle or to vascular compression by swollen astrocytes but is in some way due to glutamine metabolically produced from the ammonium.
 ...
PMID:Preserved hypocapnic pial arteriolar constriction during hyperammonemia by glutamine synthetase inhibition. 995 Aug 45

CO2 chemoreception may be mediated by the modulation of certain ion channels in neurons. Kir4.1 and Kir5.1, two members of the inward rectifier K+ channel family, are expressed in several brain regions including the brainstem. To test the hypothesis that Kir4.1 and Kir5. 1 are modulated by CO2 and pH, we carried out experiments by expressing Kir4.1 and coexpressing Kir4.1 with Kir5.1 (Kir4.1-Kir5. 1) in Xenopus oocytes. K+ currents were then studied using two-electrode voltage clamp and excised patches. Exposure of the oocytes to CO2 (5, 10 and 15 %) produced a concentration-dependent inhibition of the whole-cell K+ currents. This inhibition was fast and reversible. Exposure to 15 % CO2 suppressed Kir4.1 currents by approximately 20 % and Kir4.1-Kir5.1 currents by approximately 60 %. The effect of CO2 was likely to be mediated by intracellular acidification, because selective intracellular, but not extracellular, acidification to the measured hypercapnic pH levels lowered the currents as effectively as hypercapnia. In excised inside-out patches, exposure of the cytosolic side of membranes to solutions with various pH levels brought about a dose-dependent inhibition of the macroscopic K+ currents. The pK value (-log of dissociation constant) for the inhibition was 6.03 in the Kir4.1 channels, while it was 7.45 in Kir4.1-Kir5.1 channels, an increase in pH sensitivity of 1.4 pH units. Hypercapnia without changing pH did not inhibit the Kir4.1 and Kir4.1-Kir5.1 currents, suggesting that these channels are inhibited by protons rather than molecular CO2. A lysine residue in the N terminus of Kir4.1 is critical. Mutation of this lysine at position 67 to methionine (K67M) completely eliminated the CO2 sensitivity of both the homomeric Kir4. 1 and heteromeric Kir4.1-Kir5.1. These results therefore indicate that the Kir4.1 channel is inhibited during hypercapnia by a decrease in intracellular pH, and the coexpression of Kir4.1 with Kir5.1 greatly enhances channel sensitivity to CO2/pH and may enable cells to detect both increases and decreases in PCO2 and intracellular pH at physiological levels.
 ...
PMID:Modulation of kir4.1 and kir5.1 by hypercapnia and intracellular acidosis. 1079 Jan 54

Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.
 ...
PMID:Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. 1112 82

Recent in vitro data suggest that astrocytes may modulate respiration. To examine this question in vivo, we treated 5-day-old rat pups with methionine sulfoximine (MS), a compound that alters carbohydrate and glutamate metabolism in astrocytes, but not neurons. MS-treated pups displayed a reduced breathing frequency (f) in baseline conditions relative to saline-treated pups. Hypercapnia (5% CO(2)) increased f in both groups, but f still remained significantly lower in the MS-treated group. No differences between treatment groups in the responses to hypoxia (8% O(2)) were observed. Also, MS-treated rats showed an enhanced accumulation of glycogen in neurons of the facial nucleus, the nucleus ambiguus, and the hypoglossal nucleus, structures that regulate respiratory activity and airway patency. An altered transfer of nutrient molecules from astrocytes to neurons may underlie these effects of MS, although direct effects of MS upon neurons or upon peripheral structures that regulate respiration cannot be completely ruled out as an explanation.
 ...
PMID:An astrocyte toxin influences the pattern of breathing and the ventilatory response to hypercapnia in neonatal rats. 1584 20