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

We determined whether several dilator stimuli could counteract phorbol ester-induced constriction of pial arterioles. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy in newborn pigs. Diameter of one pial arteriole was determined during baseline conditions and topical application of 10(-5) M phorbol 12, 13-dibutyrate (PDB) and during subsequent application of one of the following: arterial hypercapnia (inhalation of 10% CO2), topical application of cerebrospinal fluid with 12 mM K+, or topical application of 10(-5) M isoproterenol in cerebrospinal fluid. PDB constricted the arterioles from 101 +/- 5 to 70 +/- 5 microns (27 +/- 4%; n = 28). During this period of constriction which lasted longer than subsequent interventions (> 90 min), arterial hypercapnia dilated the arterioles by 85 +/- 19% (n = 12), and topical 12 mM K+ dilated the arterioles by 59 +/- 12% and caused vasomotion (n = 7). Despite blockade of direct dilator effects of arterial hypercapnia by indomethacin, arterial hypercapnia still reversed phorbol ester-induced constriction, suggesting that acidosis by itself is sufficient to cause this effect. In contrast, topical isoproterenol did not dilate PDB-constricted arterioles (n = 9); however, topical forskolin (2.4 x 10(-7) M) did reverse constriction, implying that protein kinase C activation may interfere with proper functioning of the beta-adrenoceptor. Therefore, increased extracellular fluid levels of K+ and H+, but not isoproterenol, are able to interfere with cerebrovascular consequences of protein kinase C activation.
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PMID:Reversal by increased CSF [H+] and [K+] of phorbol ester-induced arteriolar constriction in piglets. 144 98

The involvement of protein kinase C (PKC) and protein tyrosine kinase (PTK) in hypercapnia-induced cerebral vasodilation in newborn pigs was investigated with closed cranial windows using the PKC stimulator phorbol 12-myristate 13-acetate (PMA), and the PTK inhibitors, genistein and herbimycin A. The influence of prostaglandin I2 was eliminated using the prostaglandin cyclooxygenase inhibitor, indomethacin. Changes in pial arteriolar diameters in response to hypercapnia [partial pressure of arterial CO2 approximately 9.3 kPa (70 torr)] were analyzed. Genistein (40 micrograms/mL), herbimycin A (10 microM), or PMA (1 microM) did not affect cerebral vasodilation to hypercapnia when applied topically. Indomethacin (5 mg/kg i.v.) treatment blocked the dilation to hypercapnia and attenuated hypercapnia-induced increase in cortical cAMP. Genistein and herbimycin A restored the response to hypercapnia to indomethacin-treated piglets. PMA also restored the pial arteriolar dilation and the cAMP response to hypercapnia to indomethacin-treated piglets. One-hour exposure to 10 microM PMA, to down-regulate PKC, blocked vasodilation to hypercapnia but did not inhibit vasodilation to sodium nitroprusside. After prolonged (2 h) topical exposure of indomethacin-treated piglets to 10 microM PMA, neither genistein nor iloprost could restore dilation to hypercapnia. These results indicate that PKC stimulation and/or PTK inhibition may permit hypercapnia-induced vasodilation. These data further suggest that PKC is downstream from PTK in the regulatory pathway. Because previous data showed prostaglandin I2 at subdilator concentrations can also return dilation to hypercapnia to piglets treated with indomethacin, prostaglandin I2 could provide its permissive input by activating PKC and/or inhibiting PTK.
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PMID:Protein kinase Cs and tyrosine kinases in permissive action of prostacyclin on cerebrovascular regulation in newborn pigs. 897 94

Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains undefined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg i.p.) were assessed by whole body plethysmography during normoxia, hypoxia (10% O2), and hyperoxia (100% O2) in unrestrained Sprague-Dawley rats. A sustained expiratory time increase occurred within 8-10 min of injection in room air[mean 44.8 +/- 5.2 (SE) % ], was similar to expiratory time prolongations after Ro-32-0432 administration during 100% O2 (45.5 +/- 8.1%; not significant), and was associated with mild minute ventilation (VE) decreases. Hypercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32-0432. During 10% O2, VE increased from 122.6 +/- 15.6 to 195.7 +/- 10.1 ml/min in vehicle-treated rats (P < 0.001). In contrast, marked attenuation of VE hypoxic responses occurred after Ro-32-0432 [86.2 +/- 6.2 ml/min in room air to 104.1 +/- 7.1 ml/min in 10% O2; pre- vs. post-Ro32-0432, P < 0.001 (analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilatory reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.
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PMID:Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats. 947 76

Recently we have found that hypercapnia induces nuclear protein (FOS) expression in the brainstem chemosensitive neurons, including catecholamine-containing cells. In the present studies we examined the role of protein kinase C (PKC) pathway in CO2-induced c-fos expression. Because of the complexity of the CNS system, experiments were performed in pheochromocytoma cells (PC12 cells). These cells originate from neuronal crest and express catecholaminergic traits. We depleted PKC from PC12 cells by prolonged (48 h) exposure to high concentration of phorbol 12-myristate, 13-acetate (PMA, 100 nM), and then determined the expression of: (1) c-fos mRNA by Northern blot (2) PKC isoforms, tyrosine phosphorylated and unphosphorylated MAP (mitogen activated protein) kinases by Western blot. Depletion of PKC abolished the effect of CO2 on c-fos mRNA expression, inhibited MAP kinases tyrosine phosphorylation and suppressed the expression of PKC(alpha) and PKC(zeta). These results suggest that MAP kinases, PKC(alpha) and/or PKC(beta) might be involved in CO2-induced c-fos mRNA expression.
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PMID:A possible role for protein kinase C in CO2/H+-induced c-fos mRNA expression in PC12 cells. 957 65

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.
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PMID:PTX-sensitive G proteins and permissive action of prostacyclin in newborn pig cerebral circulation. 968 22

Platelet activating factor (PAF) has recently emerged as an important modulator of neuronal excitability by enhancing synaptic glutamate release. Since PAF receptors (PAFR) are ubiquitously distributed in the brain, we hypothesized that PAF may play a role in respiratory control. To examine this issue, hypoxic (10% O2 for 15 min, n = 14) and hypercapnic (5% CO2 for 30 min, n = 6) challenges were performed in chronically-instrumented, unrestrained adult rats following administration of the pre-synaptic PAFR antagonist BN52021 (i.p. 20 mg/kg in 0.5 ml) or vehicle (Veh). In normoxia, BN52021 elicited VT decreases and corresponding f increases such that minute ventilation (VE) was unaffected. During hypercapnia, peak VE increased similarly after both treatments (103+/-18% in BN52021 vs. 94+/-19% in Veh, p-NS). In contrast, significant reductions in the peak hypoxic VE response occurred after BN52021 (42+/-10% vs. 104+/-18% in Veh, P<0.002). BN52021 increased normoxic arterial blood pressure and decreased heart rate. However, hypoxia-induced chronotropic responses were attenuated and depressor responses were enhanced by BN52021. We further examined protein kinase C (PKC) translocation patterns during acute hypoxia after systemic BN52021 administration. Activation of PKC beta and delta was blocked by BN52021, PKC gamma was attenuated, with no effects on PKC alpha, epsilon, theta, iota, mu, and zeta. We conclude that systemic administration of a PAFR antagonist attenuates cardioventilatory recruitment to hypoxia and selectively attenuates activation of PKC in the rat brainstem. We speculate that enhanced regional PAF production and release during hypoxic conditions may contribute important excitatory inputs and signal transduction pathways within neuronal structures underlying cardiovascular and respiratory control.
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PMID:Modulation of hypoxic ventilatory response by systemic platelet-activating factor receptor antagonist in the rat. 992 86

Systemic hyperglycemia and hypercapnia severely aggravate ischemic brain damage when instituted prior to cerebral ischemia. An aberrant cell signaling following ischemia has been proposed to be involved in ischemic cell death, affecting protein kinase C (PKC) and the calcium calmodulin kinase II (CaMKII). Using a cardiac arrest model of global brain ischemia of 10 min duration, we investigated the effect of hyperglycemia (20 mM) and hypercapnia (pCO(2) 300 mmHg) on the subcellular redistribution of PKC (alpha, beta, gamma) and CaMKII to synaptic membranes and to the microsomes, as well as the effect on PKC activity. We confirmed the marked translocation of PKC and CaMKII to cell membranes induced by ischemia, concomitantly with a decrease in the PKC activity in both the membrane fraction and cytosol. Hyperglycemia and hypercapnia markedly enhanced the translocation of PKC-gamma to cell membranes while other PKC isoforms were less affected. There was no effect of acidosis on PKC activity, or on translocation of CaMKII to cell membranes. Our data strongly suggest that the enhanced translocation of PKC to cell membranes induced by hyperglycemia and hypercapnia may contribute to the detrimental effect of tissue acidosis on the outcome following ischemia.
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PMID:Acidosis enhances translocation of protein kinase C but not Ca(2+)/calmodulin-dependent protein kinase II to cell membranes during complete cerebral ischemia. 1059 93

Mild to moderate hypoxemia without major changes in pH and pCO(2) does not reduce fetal renal blood flow and fetal urine production rate. Other factors such as acidemia, hypercapnia or changes in lung liquid production or fetal swallowing are candidates for the reduced amniotic fluid in the growth retarded fetus. Mild hypoxemia influences the fetal brain development in that the migration of PKC immunoreactive cells is delayed after a period of 48 h of hypoxemia. This could be due to the fact that under these circumstances the expected compensatory increase in fetal cerebral blood flow was only significant 1 h after the onset of hypoxemia. Further research on the final position of the hippocampal neurons in term lambs, subjected to fetal mild hypoxemia, can give more information on the effects of hypoxemia on the fetal brain.
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PMID:Renal and cerebral responses to hypoxemia in the ovine fetus. 1116 23

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.
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PMID:Mechanism of permissive prostacyclin action in cerebrovascular smooth muscle. 1157 79

Current evidence suggests that maternal smoking is associated with decreased respiratory drive and blunted hypoxic ventilatory response (HVR) in the newborn. The effect of prenatal nicotine exposure on overall changes in HVR has been studied; however, there is limited data on the effect of nicotine exposure on each component of biphasic HVR. To examine this issue, 5-day timed-pregnant Sprague-Dawley rats underwent surgical implantation of an osmotic minipump containing either normal saline (Con) or a solution of nicotine tartrate (Nic) to continuously deliver free nicotine at 6 mg.kg of maternal weight(-1).day(-1). Rat pups at postnatal days 5, 10, 15, and 20 underwent hypoxic challenges with 10% O(2) for 20 min using whole body plethysmography. At postnatal day 5, Nic was associated with attenuation of peak HVR; peak minute ventilaton increased 44.0 +/- 6.8% (SE) from baseline in Nic pups, whereas that of Con pups increased 62.9 +/- 5.1% (P < 0.05). Nic pups also had a reduction in the magnitude of ventilatory roll-off; minute ventilation at 15 min decreased 7.3 +/- 7.1% in Nic pups compared with 27.3 +/- 4.0% in Con pups (P < 0.05). No significant difference in HVR was noted at postnatal days 10, 15, and 20. Hypercapnic response was similar at all ages. We further investigated the effect of prenatal nicotine exposure on PKC expression in the caudal brain stem (CB) of developing rats. At postnatal day 5, Nic was associated with increased expression of PKC-beta and PKC-delta in CB, whereas other PKC isoforms were not affected. It is concluded that prenatal nicotine exposure is associated with modulation of biphasic HVR and a selective increase in the expression of PKC-beta and PKC-delta within the CB of developing rats.
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PMID:Effect of prenatal nicotine exposure on biphasic hypoxic ventilatory response and protein kinase C expression in caudal brain stem of developing rats. 1475 22


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