Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

The present study of newborn pig cerebral circulation investigated the role of pertussis toxin (PTX)-sensitive GTP binding proteins in the permissive action of prostacyclin in specific dilator responses. Pial arterioles of anesthetized piglets were observed through closed cranial windows. The piglets were treated topically with PTX and intravenously with indomethacin. The effects of hypercapnia (10% CO2 ventilation) and topical 5,6-epoxyeicosatrienoic acid (5,6-EET) on pial arteriolar diameter were noted before and after the intervention. Samples of the artificial cerebrospinal fluid (aCSF) were collected from beneath the cranial windows for determination of the cAMP concentration. After administration of PTX, indomethacin still abolished pial arteriolar dilation to both hypercapnia and 5, 6-EET and also inhibited the cAMP elevation caused by hypercapnia. The addition of phorbol 12-myristate 13-acetate (PMA), but not iloprost, restored the increase in cAMP and vascular responses to hypercapnia and 5,6-EET. Therefore, in the newborn pig cerebral microvasculature, PTX appears to inhibit a G protein involved in the permissive action of prostacyclin. However, the protein kinase C (PKC) activator PMA appears to act downstream from the block, and, therefore, the permissive action of PMA is not affected by PTX. We suggest that the prostacyclin IP receptor may be coupled to phospholipase C via a PTX-sensitive G protein that normally permits vasodilation to specific stimuli via activation of a PKC, resulting in phosphorylation of a component of the adenylyl cyclase pathway.
...
PMID:PTX-sensitive G proteins and permissive action of prostacyclin in newborn pig cerebral circulation. 968 22

Prostacyclin permissively allows increased cAMP and cerebral vasodilation to hypercapnia in piglets. The prostacyclin receptor (IP) is coupled to phospholipase C (PLC) in piglet cerebral microvascular smooth muscle cells (SMC). We hypothesize that inhibition of PLC blocks the permissive action of IP receptor agonist, iloprost, and direct activation of PKC substitutes for the IP receptor agonist in SMC. SMC cAMP production was measured at normal pHi/pHo and with reduced pHi/pHo in the absence and presence of iloprost (100 pM). Half of the cells were pretreated with U73122, the PLC inhibitor, which decreased the basal IP3 and blocked the increase in IP3 caused by iloprost. Without iloprost, decreasing pHi/pHo increased cAMP production (40%). With iloprost, the cAMP response to acidosis increased to over 80%. U73122 prevented accentuation of the cAMP response by iloprost. Phorbol myristate acetate augmented the response to acidosis similarly to iloprost. These data suggest IP agonists augment the cAMP response to acidosis via coupling through PLC to activate PKC.
...
PMID:Mechanism of permissive prostacyclin action in cerebrovascular smooth muscle. 1157 79

Ischemic damage is greatly enhanced by preischemic hyperglycemia or hypercapnia, which affects many intracellular responses including protein kinase C (PKC) translocation. We explored whether hyperglycemic or hypercapnic ischemia affects lipid metabolism, especially ischemia-induced release of free fatty acids (FFAs) and diacylglycerols (DAGs). A change in intraischemic level of acidosis was induced either by injecting glucose (hyperglycemic, HG) or by adding CO(2) (hypercapnic, HC). Complete cerebral ischemia was induced, and the brain was frozen in situ after 3, 5, and 10 min at 37 degrees C. Frontoparietal neocortex was dissected for FFA and DAG lipid analysis by thin-layer chromatography and gas-liquid chromatography. Significant differences were shown between normoglycemic and either hypercapnic or hyperglycemic values for individual and total FFAs. A significant delay in the release of FFA in ischemia with hyperglycemia or hypercapnia was observed. Significant differences were also shown in individual DAG-acyl groups and total DAGs. Hyperglycemic or hypercapnic ischemia resulted in a significant decrease of DAG at 10 min of ischemia. This was unexpected because a previous study showed that PKC translocation was significantly enhanced under similar condition at this time point. Upon cellular depolarization, massive influx of calcium and FFA accumulation may decrease the PKC dependence of DAG for translocation. In addition, PKC activation may lead to a negative feedback inhibition of phospholipase C.
...
PMID:Effects of hyperglycemia and hypercapnia on lipid metabolism during complete brain ischemia. 1556 45

Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca²⁺ responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y₁ receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca²⁺ responses in astrocytes are mediated by interaction between TRPV4 and Cx43 channels, leading to Cx43-mediated release of ATP which propagates/amplifies Ca²⁺ signals via P2Y₁ receptors and Ca²⁺ recruitment from the intracellular stores. In astrocyte-specific Cx43 knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by Cx43 deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits.SIGNIFICANCE STATEMENT There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of connexin 43 (Cx43) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca²⁺ responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia, hypercapnia, and reduced perfusion.
...
PMID:Mechanosensory Signaling in Astrocytes. 3312 90

---