Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous studies indicate that function of ATP-dependent K+ channels (K(ATP)) in cerebral arterioles is suppressed after ischemia. In the current study, we examined pial arteriolar responses to forskolin, dibutyryl-cAMP, NS-1619, and methionine (met)-enkephalin, activators of calcium-dependent K+ channels (K(Ca)) before and 1 hour after 10 minutes of total, global ischemia in anesthetized piglets. Arteriolar diameters were measured using a closed cranial window and intravital microscopy. All pharmacologic agents were given topically. Baseline diameters were approximately 100 microm, and diameters had returned to normal by 1 hour after ischemia. Forskolin dilated arterioles by 9 +/- 3%, 18 +/- 4%, and 31 +/- 12% at 5 x 10(-8), 5 x 10(-7), and 10(-6) mol/L, respectively (P < 0.05, n = 10). In addition, dibutyryl-cAMP dilated arterioles by 8 +/- 2% at 10(-4) mol/L and 14 +/- 2% at 3 x 10(-4) mol/L (P < 0.05, n = 6). Also, NS-1619 increased diameter of arterioles by 9 +/- 2% at 10(-7) mol/L and 17 +/- 9% at 10(-5) mol/L (P < 0.05, n = 5). Finally, met-enkephalin dilated arterioles by 9 +/- 2% at 10(-8) mol/L and 16 +/- 3% at 10(-6) mol/L (P < 0.05, n = 5). At 1 hour after ischemia, arteriolar dilator effects to forskolin, dibutyryl-cAMP and NS-1619, and met-enkephalin were intact. Thus, in contrast to K(ATP), K(Ca) in cerebral arterioles are resistant to ischemic stress.
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PMID:Calcium-activated K+ channels in cerebral arterioles in piglets are resistant to ischemia. 939 Jun 46

In this study the effect of post-treatment with rolipram, an inhibitor of cAMP phosphodiesterase, on neuronal damage following global ischemia was evaluated. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 minutes. Rolipram was administered 6 hours after onset of ischemia and thereafter the following 7 days daily once at a dose of 0.3 or 3.0 mg/kg intraperitoneally. Four weeks after ischemia the amount of intact neurons in the hippocampus and in the striatum was assessed following perfusion fixation. The ischemia-induced neuronal damage in the CA1 sector of the hippocampus and in the striatum was reduced by rolipram at either dose. The present results show that treatment with rolipram reduces ischemic neuronal damage at a therapeutic window of 6 hours.
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PMID:Delayed treatment with rolipram protects against neuronal damage following global ischemia in rats. 942 78

Elevation of intracellular glucose within retinal vascular cells is believed to be an important causal factor in the development of diabetic retinopathy. The intracellular glucose concentration is regulated by both the rate of glucose metabolism and glucose transport. Because retinal hypoxia often precedes proliferative diabetic retinopathy, we have studied the regulation of the glucose transport system by hypoxia in cultured bovine retinal endothelial cells (BRECs). Because retinal ischemia is known to increase intracellular adenosine levels, which subsequently regulate hypoxia-inducible genes, such as vascular endothelial growth factor and erythropoietin, the role of adenosine and its receptor-mediated pathways has also been evaluated. Hypoxia (0.5% O2, 5% CO2, and 94.5% N2) stimulated GLUT1 mRNA expression in BRECs in a time-dependent manner with an 8.9 +/- 1.5-fold (P < 0.01) increase observed after 12 h. GLUT1 mRNA expression returned to baseline (1.4 +/- 0.3-fold of control) within 12 h after reinstitution of normoxia. N6-Cyclopentyl adenosine (adenosine A1 receptor agonist, Kd = 1 nmol/l) did not affect GLUT1 mRNA expression at concentrations up to 1 micromol/l, while 2-p-(2-carboxyethyl)-phenethyl-amino-5'-N-ethylcarboxamidoadenosine and 5'-(N-ethylcalboxamido)-adenosine (adenosine A2 receptor [A2R] agonists, Kd = 15 and 16 nmol/l, respectively) increased mRNA levels at concentrations as low as 10 nmol/l. Maximal stimulation was 2.3 +/- 0.2- and 2.1 +/- 0.2-fold, respectively (P < 0.01). The adenosine A2a receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) (Kd = 100 nmol/l for A2R) inhibited hypoxia-stimulated GLUT1 mRNA expression by 40 +/- 8% at 100 nmo/l. Hypoxia upregulated GLUT1 protein expression by 3.0 +/- 0.3-fold after 12 h (P < 0.01), but this response was attenuated by CSC (P < 0.05). Hypoxia increased glucose transport activity by 2.1 +/- 0.3-fold (P < 0.001) after 12 h, a response inhibited 65% by CSC (P < 0.01). A protein kinase A (PKA) inhibitor (H89, 20 micromol/l) suppressed hypoxia-induced GLUT1 mRNA expression by 42 +/- 9% (P < 0.01). These data suggest that hypoxia in BRECs upregulates glucose transport activity through an increase of GLUT1 expression that is partially mediated by adenosine, A2R, and the cAMP-PKA pathway.
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PMID:Hypoxia upregulates glucose transport activity through an adenosine-mediated increase of GLUT1 expression in retinal capillary endothelial cells. 972 38

Several signal transduction pathways have been implicated in the mechanism of protection induced by ischemic preconditioning (PC). For example, stimulation of a variety of G-protein coupled receptors results in stimulation of protein kinase C (PKC) which has been suggested to act as common denominator in eliciting protection. PC also significantly attenuated cAMP accumulation during sustained ischemia, suggesting involvement of an anti-adrenergic mechanism. The aim of this study was to evaluate the beta-adrenergic signal transduction pathway (as evidenced by changes in tissue cAMP and cAMP- and cGMP-phosphodiesterase) during the PC protocol as well as during sustained ischemia. Isolated perfused rat hearts were preconditioned by 3 x 5 min global ischemia (PC1,2,3) interspersed by 5 min reperfusion, followed by 25 min global ischemia. Tissue cAMP- and cGMP-PDE activity as well as cAMP and cGMP levels were determined at different time intervals during the PC protocol and sustained ischemia. Tissue cAMP increased with each PC ischemic event and normalized upon reperfusion, while PDE activity showed the opposite, viz a reduction during ischemia and an increase during reperfusion. Except for PC1, tissue cGMP showed similar fluctuations. Throughout 25 min sustained ischemia, cAMP- and cGMP-PDE activities were higher in PC than in nonpreconditioned hearts, associated with a significantly lesser accumulation in cAMP and higher cGMP levels in the former. Fluctuations in cyclic nucleotides during preconditioning were associated with concomitant changes in PDE activity, while the attenuated beta-adrenergic response of preconditioned hearts during sustained ischemia may partially be due to increased PDE activity.
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PMID:Role of cyclic nucleotide phosphodiesterases in ischemic preconditioning. 977 98

To elucidate the mechanism of ischemia-induced signal transduction in vivo, we investigated the effect of the targeted disruption of the alpha and delta isoforms of the cAMP-responsive element-binding protein (CREB) on c-fos and heatshock protein (hsp) 72 gene induction. Permanent focal ischemia was induced by occlusion of the middle cerebral artery of the CREB mutant mice (CREB(-/-), n = 5) and the wild-type mice (n = 6). Three hours after onset of ischemia, the neurologic score was assessed and pictorial measurements of ATP and cerebral protein synthesis (CPS) were carried out to differentiate between the ischemic core (where ATP is depleted), the ischemic penumbra (where ATP is preserved but CPS is inhibited), and the intact tissue (where both ATP and CPS are preserved). There were no significant differences in neurologic score or in ATP, pH, and CPS between the two groups, suggesting that the sensitivity of both strains to ischemia is the same. Targeted disruption of the CREB gene significantly attenuated c-fos gene induction in the periischemic ipsilateral hemisphere but had no effect on either c-fos or hsp72 mRNA expression in the penumbra. The observations demonstrate that CREB expression, despite its differential effect on c-fos, does not modulate acute focal ischemic injury.
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PMID:Attenuated c-fos mRNA induction after middle cerebral artery occlusion in CREB knockout mice does not modulate focal ischemic injury. 985 Jan 45

We have previously shown that PGI2 and PGE2 have a synergistic role in restoring electrical transepithelial resistance (R) in ischemia-injured porcine ileum via the second messengers Ca2+ and cAMP. Because Ca2+ and cAMP stimulate Cl- secretion, we assessed the role of PG-induced Cl- secretion in recovery of R. Mucosa from porcine ileum subjected to ischemia for 45 min was mounted in Ussing chambers and bathed in indomethacin and Ringer solution. Addition of PGs stimulated a twofold increase in R, which was preceded by elevations in short-circuit current (increase of 25 microA/cm2). The PG-induced effect on R was partially inhibited with bumetanide, an inhibitor of Cl- secretion. The remaining elevations in R were similar in magnitude to those induced in ischemic tissues by amiloride, an inhibitor of Na+ absorption. Treatment with 10(-4) M 8-bromo-cGMP or 300 mosM mucosal urea resulted in elevations in R similar to those attained with PG treatment. PGs signal recovery of R via induction of Cl- secretion and inhibition of Na+ absorption, possibly by establishing a transmucosal osmotic gradient.
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PMID:Prostaglandin-induced recovery of barrier function in porcine ileum is triggered by chloride secretion. 988 75

Ventilation during ischemia attenuates ischemia-reperfusion lung injury, but the mechanism is unknown. Increasing tissue cyclic nucleotide levels has been shown to attenuate lung ischemia-reperfusion injury. We hypothesized that ventilation prevented increased pulmonary vascular permeability during ischemia by increasing lung cyclic nucleotide concentrations. To test this hypothesis, we measured vascular permeability and cGMP and cAMP concentrations in ischemic (75 min) sheep lungs that were ventilated (12 ml/kg tidal volume) or statically inflated with the same positive end-expiratory pressure (5 Torr). The reflection coefficient for albumin (sigmaalb) was 0.54 +/- 0.07 and 0.74 +/- 0. 02 (SE) in nonventilated and ventilated lungs, respectively (n = 5, P < 0.05). Filtration coefficients and capillary blood gas tensions were not different. The effect of ventilation was not mediated by cyclic compression of alveolar capillaries, because negative-pressure ventilation (n = 4) also was protective (sigmaalb = 0.78 +/- 0.09). The final cGMP concentration was less in nonventilated than in ventilated lungs (0.02 +/- 0.02 and 0.49 +/- 0. 18 nmol/g blood-free dry wt, respectively, n = 5, P < 0.05). cAMP concentrations were not different between groups or over time. Sodium nitroprusside increased cGMP (1.97 +/- 0.35 nmol/g blood-free dry wt) and sigmaalb (0.81 +/- 0.09) in nonventilated lungs (n = 5, P < 0.05). Isoproterenol increased cAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on sigmaalb. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester had no effect on lung cGMP (n = 9) or sigmaalb (n = 16) in ventilated lungs but did increase pulmonary vascular resistance threefold (P < 0.05) in perfused sheep lungs (n = 3). These results suggest that ventilation during ischemia prevented an increase in pulmonary vascular protein permeability, possibly through maintenance of lung cGMP by a nitric oxide-independent mechanism.
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PMID:Effect of ventilation on vascular permeability and cyclic nucleotide concentrations in ischemic sheep lungs. 988 22

The authors hypothesized that augmenting skeletal muscle adenosine 3',5'-cyclic monophosphate (cAMP) levels could reduce tissue inflammation and improve muscle survival in response to ischemia/ reperfusion (I/R) injury. Gracilis muscle flaps in male Wistar rats were subject to 4 hr of ischemia followed by 3 hr of reperfusion, to assess neutrophil accumulation and microvessel tone, or by 24 hr to evaluate percentage of muscle survival. Animals were grouped as follows: positive (saline) or negative (sham) control, or with infused cAMP elevating agents (8 Bromo-cAMP (8 Br-cAMP) or forskolin). Radioimmunoassay demonstrated significant increases in tissue cAMP levels throughout 3 hr of reperfusion with forskolin, while the 8 Br-cAMP-treated group showed only a temporary increase. Compared with vehicle-infused controls, forskolin administered 5 min prior to reperfusion and repeated as an infusion during the first 45 min of reperfusion, resulted in reduced neutrophil adherence and transmigration, and muscle edema with sustained vasodilatation. The percentage of muscle survival using nitro-blue tetrazolium staining demonstrated enhanced muscle-flap preservation with forskolin. There was no beneficial change in the presence of 8 Br-cAMP These observations suggested that sustained elevation of the cAMP pathway may reduce ischemia-reperfusion injury by decreasing neutrophil-mediated injury and improving vessel tone. Elucidation of the cAMP pathway may provide novel opportunities to modulate ischemia/ reperfusion injury.
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PMID:Augmentation of cAMP improves muscle-flap survival and tissue inflammation in response to ischemia/reperfusion injury. 1002 29

Although extracellular adenosine concentrations in brain are increased markedly by a variety of stimuli such as hypoxia and ischemia, it has been difficult to demonstrate large increases in adenosine with stimuli that do not result in pathological tissue damage. The present studies demonstrate that increasing the temperature at which rat hippocampal brain slices are maintained (typically from 32.5 to 38.5 degrees C) markedly inhibits excitatory synaptic transmission. This effect was reversible on cooling, readily repeatable, and was blocked by A1 receptor antagonists and by adenosine deaminase, suggesting that it was mediated by increased activation of presynaptic adenosine A1 receptors by endogenous adenosine. This increase in adenosinergic inhibition was not a response to hyperthermia per se, because it could be elicited by temperatures that remained entirely within the hypothermic range (e. g., from 32.5 to 35.5 degrees C). The increased activity at A1 receptors appeared to be attributable to the direct release of adenosine via nucleoside transporters; the release of adenine nucleotides, linked to either the activation of NMDA receptors or the increased efflux of cAMP, appeared not to be involved. These results suggest that changes in brain temperature can alter the regulation of extracellular adenosine in rat brain slices and that increased adenosine release may be an important regulatory mechanism for countering increased excitability consequent to increased brain temperature.
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PMID:Temperature-dependent modulation of excitatory transmission in hippocampal slices is mediated by extracellular adenosine. 1006 46

Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A2B and A3 adenosine receptor subtypes. The presence of A2B receptors was confirmed by flow cytometry using specific Abs. The A2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A2B receptors, but not agonists for A1, A2A, or A3, lead to an increase in cAMP levels. IFN-gamma up-regulates the surface protein and gene expression of the A2B adenosine receptor by induction of de novo synthesis. The up-regulation of A2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A2B receptors by adenosine or its analogues inhibits the IFN-gamma-induced expression of MHC class II genes and also the IFN-gamma-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A2B adenosine receptor expression induced by IFN-gamma could be a feedback mechanism for macrophage deactivation.
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PMID:IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. 1009 21


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