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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Isolated rat hearts were made totally ischemic after a 5-min infusion of p1,p5-diadenosine pentaphosphate, alpha, beta-methylene adenosine diphosphate, nitrobenzyl-6-thioinosine, or erythro-9-(2-hydroxy-3-nonyl) adenine, which are inhibitors of adenylate kinase, 5'-nucleotidase, adenosine translocase, and adenosine deaminase, respectively. Following 30 min of ischemia, only hearts infused with alpha, beta-methylene adenosine diphosphate recovered significantly better ventricular function than did the control (P less than 0.05), but all hearts had increased adenosine triphosphate and creatine phosphate regeneration (P less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites were not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion which may have potential benefits in elective ischemic arrest.
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PMID:Influence of inhibitors of ATP catabolism on myocardial recovery after ischemia. 304 Nov 5

The enhancement of ATP regeneration following global myocardial ischemia in dogs by both ATP catabolic enzyme blockade and precursor infusion was investigated. The breakdown of AMP to adenosine is catalyzed by 5'-nucleotidase and this enzyme was inhibited during the ischemic period with either concanavalin A (Con A, 3 mg/kg) or alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 250 microM). To provide additional ATP precursors, adenine (30 mg/kg) and ribose (25 mg/kg) (A/R) were also infused into the coronary vasculature during ischemia and recovery on cardiopulmonary bypass. Left ventricular myocardial ATP levels in control animals decreased to 52% of preischemic values during aortic cross clamping, but ATP levels in dogs treated with AMP-CP + A/R fell to only 67% of preischemic values (P less than 0.05). During reperfusion, ATP levels in Con A + A/R (3.43 +/- 0.26 mumol/g wet wt) and AMP-CP + A/R (3.77 +/- 0.42) treated animals were higher than values found in control dogs (2.73 +/- 0.16, P less than 0.05). Infusions of A/R alone without enzyme inhibition did not increase ATP regeneration. The adenine nucleotide energy charge ratio was also increased by enzyme blockade with either inhibitor when combined with precursor infusion. On bypass, left ventricular myocardial blood flow (measured by the microsphere technique) was increased by 140% (P less than 0.01) over control values in all groups receiving A/R; therefore, enhanced ATP levels were not merely the result of increased flow. Renal blood flow was not adversely affected by this combination of drugs as has been previously found with adenosine infusion and inhibition of adenosine catabolism.
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PMID:Prevention of ATP catabolism during myocardial ischemia: a preliminary report. 683 14

Extracellular ATP released from nerves onto vascular smooth muscle or released from damaged tissues during traumatic injury, shock, or ischemia profoundly alters cardiovascular physiology. We have used patch-clamp methods to investigate the effects of extracellular ATP on guinea pig ventricular myocytes because guinea pigs are a commonly used model for the study of cardiac electrophysiology. We have found that ATP activates a rapid, desensitizing, inward current. This inward current is activated by a P2 receptor that does not conform to published receptor subclasses. A concentration of 100 microM ATP activates more current than 100 microM alpha, beta-methyleneadenosine 5'-triphosphate, which in turn activates more current than 100 microM ADP. 2-Methylthioadenosine 5'-triphosphate (2-MeS-ATP) and adenosine 5'-O-(3-thiotriphosphate) are also effective agonists. Adenosine, AMP, guanosine 5'-triphosphate, and uridine 5'-triphosphate are ineffective at 100 microM. The inward conductance has a reversal potential near 0 mV and in ion-substitution experiments was found to be carried through nonselective cation channels rather than chloride channels. The conductance has inwardly rectifying current-voltage (I-V) relations. When ATP is used as the agonist, fluctuation analysis yields an apparent unitary conductance of 0.08 pA at a holding potential of -120 mV with sodium as the main charge-carrying ion. The combination of inwardly rectifying I-V relations, the efficacy of 2-MeS-ATP, and the very low conductance distinguish this conductance from other ATP-activated nonselective channels, including those recently cloned from rat vas deferens and PC-12 cells.
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PMID:An ATP-activated nonselective cation channel in guinea pig ventricular myocytes. 757 19

The kinetics of protein kinase C (PKC) translocation and down-regulation in the 20-day-old fetal brain following short and long episodes of maternal-fetal blood flow occlusion were examined. Restriction for up to 15 min increased the specific enzymatic activity in the membrane by 73%, indicative of translocation. After a 30-min restriction and a 2.5-h reperfusion the total PKC activity in the cytosol was reduced to approximately 50%, consistent with down-regulation/inactivation. The total membrane PKC activity remained unchanged. Several PKC isoenzymes, including alpha, beta 1, beta 2, epsilon, and zeta, but not gamma, were identified in the fetal brain on western blots using specific antibodies. Compared with postnatal day 15, a greater proportion of the fetal PKC isoforms, particularly alpha and epsilon, were membrane bound, alpha, beta 2, epsilon, and zeta, but not beta 1, were translocated into the membrane compartment after episodes of ischemia alone or ischemia and reperfusion. There were no major identifiable proteolytic fragments in the 50-kDa region. Major losses in the total enzymatic activity were encountered in both cytosol and membrane fractions after storage of the enzyme for 10 days at 4 degrees C. These losses were less profound in membrane fractions from ischemic than control animals, suggesting a relative sparing of activity in the membrane as a result of the insult. Preincubation of DEAE-purified PKC for 30 min at 50 degrees C resulted in enzyme inactivation. This was accompanied by a size reduction (approximately 2-5 kDa) in the gel migration of several isozymes in both cytosol and membrane fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ischemia-triggered translocation and inactivation of protein kinase C isoforms in the fetal brain. 759 56

This study describes immunocytochemical distribution of the protein kinase C (PKC) subspecies: alpha, beta and gamma in the CAI sector of gerbil hippocampus. Immunolabelling was performed with 10 nm gold-antibody complexes against each of the PKC subspecies. The subspecies of PKC were expressed specifically in different populations of hippocampal cells. An enhanced PKC immunoreactivity was noted in the animals after ischemia. We propose that this phenomenon reflects an activation of PKC in the early phase of brain ischemia.
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PMID:Protein kinase C-like immunoreactivity in gerbil hippocampus after a transient cerebral ischemia. 795 73

We have reported that ischemic preconditioning may limit infarct size by increasing 5'-nucleotidase activity. The present study tested whether alpha 1-adrenoceptor stimulation in ischemic preconditioning mediates the infarct size-limiting effect through augmentation of 5'-nucleotidase activity. The coronary artery was occluded four times for 5 min separated by 5 min of reperfusion (ischemic preconditioning) in 82 dogs. Then the coronary artery was occluded for 90 min followed by 6 h of reperfusion. Infarct size normalized by risk area was smaller after ischemic preconditioning than in the control group (40.6 +/- 2.3 vs 6.7 +/- 2.0%, P < 0.001), even though no difference existed in endomyocardial collateral flow during ischemia (8.7 +/- 1.0 vs 8.9 +/- 1.0 ml/100 g per min). Ectosolic and cytosolic 5'-nucleotidase activity was increased after ischemic preconditioning. However, prazosin blunted the infarct size-limiting effect of ischemic preconditioning (infarct size: 42.8 +/- 3.7%). Intermittent alpha 1-adrenoceptor stimulation by methoxamine mimicked the increase in 5'-nucleotidase activity and the infarct size-limiting effect, which were abolished by alpha, beta,-methyleneadenosine 5'-diphosphate. Identical results were obtained in the conscious model (n = 20). Therefore, we conclude that increases in ectosolic 5'-nucleotidase activity due to alpha 1-adrenoceptor activation may contribute to the infarct size-limiting effect of ischemic preconditioning.
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PMID:Alpha 1-adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5'-nucleotidase activity. 818 51

Mechanisms of myocardial stunning include myocardial adenosine triphosphate (ATP) depletion, catecholamine release, and oxygen free radical formation. Although the latter is the most widely supported mechanism, levels of 5'-nucleotidase (directs AMP dephosphorylation) are inversely related to functional recovery following ischemia and may also have a role in ischemic injury. Previous studies reveal that 5'-nucleotidase levels increase with age and also vary with species. An inhibitor of this enzyme (alpha, beta methylene adenosine 5'-diphosphate) was effective in maintaining AMP levels in vitro but was ineffective in dogs due to limited permeability. Observed species-specific differences in recovery from myocardial stunning may be related to differences in AMP accumulation and subsequent metabolism. Species showing improved recovery from stunning may accumulate AMP as a result of feedback inhibition of 5'-nucleotidase. Using a model of extreme experimentally-induced ischemia, we found that adenosine treatment allowed full recovery of ventricular function within 30 minutes, probably by entrapping ATP catabolites. Similarly, enhancement of adenosine production by N-diarylalkylpeprazine derivatives has also been shown to be cardioprotective in the setting of global normothermic ischemia. Novel strategies for pharmacological intervention in the ATP catabolic pathway should use animal models involving species that are tolerant to myocardial stunning.
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PMID:Myocardial stunning and preconditioning: age, species, and model related differences: role of AMP-5'-nucleotidase in myocardial injury and protection. 846 14

Adenosine, synthesized by ecto-5'-nucleotidase, is cardioprotective against ischemia and reperfusion injury. We have previously reported that activation of protein kinase C increases ecto-5'-nucleotidase activity of the rat cardiomyocytes, raising the possibility that activation of protein kinase C protects cardiomyocytes from the irreversible cellular injury via activation of ecto-5'-nucleotidase. To test this hypothesis, cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode buffer solution. The cardiomyocytes were incubated with and without exposure to methoxamine (1 x 10(-6) mol/l) or phorbol 12-myristate 13-acetate (PMA. 1 x 10(-8) mol/l). Ecto-5'-nucleotidase activity increased 15 min after the onset of an exposure to either methoxamine or PMA. Adenosine release during hypoxia and reperfusion was augmented in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated cardiomyocytes, which was inhibited by alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase. Irreversible cellular injury assessed by the extent of release of lactate dehydrogenase and the trypan blue exclusion test following 60 min of hypoxia and 60 min of reoxygenation was attenuated in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated group, which was also blunted by AOPCP and 8-sulfophenyltheophylline, an adenosine receptor antagonist. An adenosine A1 receptor agonist, N6-cyclohexyladenosine, restored the cardioprotection under the treatment with PMA and AOPCP. We conclude that activation of ecto-5'-nucleotidase via protein kinase C contributes to the attenuation of the irreversible injury of the rat cardiomyocytes due to hypoxia and reoxygenation.
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PMID:Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes. 889 53

The cytoprotective role of heat shock proteins (HSP) described in variety of human diseases, including ischemia, inflammation, and infection, suggests new therapeutic strategies relying upon the development of drugs that selectively turn on heat shock genes. Cyclopentenone prostaglandins, which contain an alpha, beta-unsaturated carbonyl group in the cyclopentane ring and possess antiviral activity against several RNA and DNA viruses, were shown to function as signal for HSP synthesis in a nonstressful situation in a variety of mammalian cells. We now report that 2-cyclopenten-1-one selectively induces the expression of the 70-kDa HSP (HSP70) in human cells, through cycloheximide-sensitive activation of heat shock transcription factor 1 (HSF1). The alpha, beta-unsaturated carbonyl group is the key structure triggering HSF1 activation. Induction is associated with antiviral activity during infection with vesicular stomatitis virus. These results identify the molecular structure of natural prostaglandins responsible for HSF1 activation and open new perspectives in the search for novel antiviral and cytoprotective drugs.
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PMID:2-Cyclopenten-1-one, a new inducer of heat shock protein 70 with antiviral activity. 894 75

The presence of the non-selective protein kinase C (PKC) inhibitors, staurosporine (100 nM) and polymyxin B (100 microM) in cultured human RPE cells for more than 24 h triggers apoptotic death. Apoptosis is characterized by a diminishing number of cells, a labelling of nuclei by the TUNEL method and by observable morphological changes. An inhibitor of PKC and cyclic nucleotide-dependent protein kinases, 1-(5-isoquinolinesulphonyl)-2-methyl piperazine (H-7; 100 microM), was without effect, as was the specific PKC inhibitor, calphostin C (100 nM). The PKC-activating phorbol esters, phorbol-12-myristate-13-acetate (PMA; 1 microM) and phorbol-12,13-dibutyrate (PDB; 1 microM) and the non-tumour-promoting phorbol ester, 4 alpha-PMA (1 microM) were without effect, as was the diacyl glycerol analogue, 1,2-dioctanoyl-snglycerol (DOG; 10 microM). The PKC activators did not attenuate the apoptosis induced by staurosporine or polymyxin B. Furthermore, deprivation of glucose and oxygen (simulated ischemia) for 72 h induced apoptosis: this could be prevented by inclusion of 10% (v/v) foetal bovine serum (FBS) but not by a variety of PKC activators. Six PKC isoenzymes were shown to be present in RPE cells (alpha, beta 1, beta 2, delta, epsilon, E) and only the calcium-dependent cPKC levels changed after treatment with staurosporine or simulated ischaemia. Since only the less selective inhibitors of PKC induced apoptosis, it is suggested that PKC is not involved directly in the induction process of apoptosis in RPE cells. It is possible that the staurosporine and polymyxin B-induced effects of apoptosis in RPE cells are triggered by an unknown kinase-dependent pathway, but whether the 'ischaemia'-induced death is related to this same process remains to be elucidated.
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PMID:Induction of apoptosis in cultured human retinal pigmented epithelial cells: the effect of protein kinase C activation and inhibition. 922 Apr 59


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