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)

During the last decade intensive work on the relationships between the liver and the arachidonic acid cascade has greatly expanded our knowledge of this area of research. The liver has emerged as the major organ participating in the degradation and elimination of arachidonate products of systemic origin. The synthesis in the liver of arachidonate products derived from the cyclooxygenase, lipoxygenase and cytochrome P450 system pathways has been demonstrated. The participation of leukotriene B4 and cysteinyl-leukotrienes as mediators of liver damage and the possible therapeutic usefulness of prostaglandins (PGs) in acute liver injury has attracted the interest of clinicians. This article reviews the essential features regarding the role of arachidonate metabolites in liver disease and specially focuses on the cytoprotective effects on the liver displayed by PGE2, PGE1, PGI2 and synthetic PG analogs in experimental models of liver damage induced by ischemia-reperfusion injury, carbon tetrachloride, bacterial lipopolysaccharide and viral hepatitis and on the possible mechanisms underlying liver cytoprotection in these experimental models. The therapeutic usefulness of PGs in clinical practice is critically analyzed on the basis of available evidence in patients with fulminant hepatic failure and primary graft nonfunction following liver transplantation.
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PMID:Liver cytoprotection by prostaglandins. 841 74

In ischemic organs, arachidonic acid (AA) metabolites and mostly prostaglandins (PGs) have been found to be released in high amounts. The mechanism for this AA metabolism activation and its physiological implications are not clear. Because endothelial cells are an important source of PGs and because they seem to be very rapidly affected by ischemia, we developed an in vitro model where human endothelial cells were submitted to hypoxia. An important specific activation of phospholipase A2 was observed during hypoxia, which was concomitant with a rise in cytosolic calcium concentration. Endothelial cells synthetize in normal conditions as a mean 1.42, 1.00, 7.69, and 26.92 ng/mg proteins of, respectively, PGE2, PGD2, PGF2 alpha, PGI2. An important increase of about five- to ninefold in the synthesis of the four PGs was observed during hypoxia, which followed the same kinetics as the PLA2 activation. This increase in PG synthesis was sensitive to cyclooxygenase inhibitors. During reoxygenation, PG synthesis decreased back to the basal level of resting cells, suggesting that cells were able to recover their homeostasis after hypoxia. These observations indicate that endothelial cells exposed to oxygen deprivation are a major source of PGs and could contribute to the high amounts of PG released in vivo in ischemic organs.
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PMID:Stimulation of prostaglandin synthesis by human endothelial cells exposed to hypoxia. 847 19

This study examined the changes of prostaglandins (PGs) E2 and D2 in brain structures of conscious rats during one hour period following acute bleeding. The analyses were performed in brain structures which are important for cardiovascular homeostasis (medulla oblongata, hypothalamus) and these which are not directly involved in central homeostatic mechanisms but are selectively vulnerable to low-flow states (hippocampus, cortex). Haemorrhage was induced by gradual withdrawal of blood from the cannulated right femoral artery (18 ml/kg, LD30) during a 3-min interval. The brain prostanoid contents were measured by radioimmunoassays. The bleeding induced significant changes in brain prostanoid content which were expressed to the highest extent in medulla oblongata and hypothalamus. The time course of the alterations in PGD2 and PGE2 contents was different in m. oblongata and hypothalamus from that in cortex and hippocampus. It was observed that PGE2 and PGD2 levels rose significantly in brain structures which are important for cardiovascular homeostasis and that their alterations were less expressed with different time course in structures which are selectively vulnerable to ischemia. Therefore, the authors suppose that the prostanoid changes in m. oblongata and hypothalamus are induced by the activation of central homeostatic mechanisms rather than by cerebral ischemia produced by haemorrhagic hypotension.
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PMID:Brain PGD2 and PGE2 changes during posthaemorrhagic hypovolemia in rats. 856 Aug 54

We compared the effects of brief and prolonged myocardial ischemia on tissue prostaglandin synthesis. Regional ischemia was induced in dogs and maintained for 5 or 30 minutes. Isolated rat hearts were subjected to global ischemia in a working heart preparation for periods of 5 or 20 minutes. De novo synthesis of prostaglandins PGE2 and PGF2 alpha was measured in endocardial and epicardial explants from hearts subjected to transient ischemia. After 5 minutes of coronary ligation, PGE2 production by the ischemic canine endocardium increased by 68%, compared with non-ischemic tissue, and PGF2 alpha levels rose by 29%. In isolated rat hearts, 5-minute ischemia increased endocardial rate of PGE2 synthesis (13.2 +/- 1.7 pmol/g/h, as compared with 6.7 +/- 0.5 under normoxic conditions). Ischemic stimulation of eicosanoid production by the endocardium was no longer apparent after 30-minute regional or 20-minute global ischemia. In contrast, the epicardium showed significant changes only after 30-minute ischemia and only with respect to PGF2 alpha (12.0 +/- 6.2 in the ischemic vs 7.1 +/- 3.2 pmol/g/h in the non-ischemic tissue). Ischemia-induced differences in prostaglandin production were attenuated in the presence of arachidonic acid or aspirin.
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PMID:Effects of brief and prolonged ischemia on eicosanoid synthesis in dog and rat hearts. 856 77

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.
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PMID:A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis. 861 73

Variations of lipid peroxidation and arachidonic acid (AA) metabolism products were found when experimental subarachnoid hemorrhage or ischemia and reperfusion were performed in an animal brain model. In a previous study, we showed that hemoglobin (Hb) produces prostaglandins when incubated in AA. To elucidate how Hb affects lipid peroxidation and AA metabolism in the CNS, we measured lipid hydroperoxides (LOOH), PGE2 and thiobarbituric acid reactant substances (TBARS) in corticocerebral homogenates and slices of rats (normal rats) after incubation with different concentrations (10(-9) to 10(-5) M) of Hb. In addition, brain cortices of indomethacin-treated (40 mg/Kg) rats (IN-treated rat) were incubated in the presence of 10(-5) M indomethacin (IN) to exclude the interference of prostaglandin enzyme synthetase. Hb was able to affect LOOH, PGE2, and TBARS production in both normal and IN-treated rat brain cortex homogenates and slices. In all cases, we found an increase in prostaglandin when 10(-8) M Hb was used, whereas no effect was noticed with 10(-9) M. On the other hand, with higher Hb concentrations (10(-6)-10(-5) M), the LOOH and PGE2 values did not reach statistical significance, and TBARS significantly increased. In all cases, when 10(-4) M scavenger or metal-chelating compounds were added to an incubation mixture with 10(-8) M Hb, PGE2 formation was inhibited, whereas no variation occurred when 10(-4) M IN was further added to IN-treated rat corticocerebral homogenate or slices. We hypothesize that in in vivo experimental neuropathologies, Hb must attain the 10(-8) M concentration in the reaction cellular microenvironment to stimulate PGE2 production, and that an evaluable part of this PGE2 production may be directly ascribable to the iron-heme oxy-redoxy activity of Hb.
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PMID:Hemoglobin affects lipid peroxidation and prostaglandin E2 formation in rat corticocerebral tissues in vitro. 867 13

We studied the effects of the specific endothelin (ETA) receptor antagonist, BQ-123, on reperfusion injury in a rat model of kidney transplantation. First, Sprague-Dawley rats were divided into three groups: a sham nephrectomy (SNEPH), an autotransplantation (AUTO-Tx), and an allotransplantation (ALLO-Tx) group. In a fourth group, ALLO-Tx + BQ, allografts were flushed with 20 micrograms BQ-123 containing cold Ringer's lactate before transplantation. For the allograft groups, kidneys from white Wistar albino rats were transplanted into allogeneic Sprague Dawley recipients. Grafts were allowed 120 min of reperfusion after 40 min of cold ischemia. ET-1,2 plasma concentrations in the renal venous blood, and kidney tissue prostaglandin (PG) E2 and leukotriene (LT) B4 levels were studied. Diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels, as the products of lipid peroxidation, and protein carbonyls (PC) and protein sulphydryls (PS), as the parameters of protein oxidation, were also analyzed in the kidney tissue. Plasma ET concentrations increased significantly in the AUTO-Tx and ALLO-Tx groups (P < 0.05 and P < 0.01, respectively) but this increase was reversed in the ALLO-Tx + BQ group. None of the lipid peroxidation products except DCs (P < 0.05) increased in the AUTO-Tx group, whereas they all increased in the ALLO-Tx group (P < 0.01). Protein oxidation parameters also changed significantly (P < 0.01) in the ALLO-Tx group but did not in the AUTO-Tx group (P < 0.05). The differences in PGE2 and LTB4 levels were not significant. Histopathologic examination revealed prominent glomerular and tubular injury in the AUTO-Tx and ALLO-Tx groups but less in the ALLO-Tx + BQ group. In the last group, all parameters of lipid peroxidation (P < 0.001 for all) and PCs decreased, and PSs were preserved (P < 0.001 for both) when compared with the AUTO-Tx and ALLO-Tx groups. We conclude that BQ-123, in addition to inhibiting the binding of ET-1,2 to the ETA receptor, may also inhibit the release and/or synthesis of ET-1,2 and prevent reperfusion injury in kidney transplantation.
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PMID:BQ-123, a specific endothelin (ETA) receptor antagonist, prevents ischemia-reperfusion injury in kidney transplantation. 872 87

To permit long-term measurement of time-dependent changes in levels of dialyzable drugs and transmitters in the spinal intrathecal (i.t.) space of the unanesthetized rat, we developed a dialysis catheter for chronic placement. This was accomplished by constructing a loop probe 9 cm in length from 0.3-mm-diameter dialysis tubing that was made impermeable except for the distal loop. This loop catheter was readily inserted though an incision in the cisternal membrane and passed to the lumbar enlargement. The ends of the catheter were then externalized on the top of the head. To permit i.t. injections, an additional i.t. catheter could also be inserted simultaneously by the same route. For dialysis, an external end of the loop catheter was connected to a syringe pump and perfused with artificial CSF (10 microliters/min) and the out flow collected. A series of studies were performed to demonstrate the characteristics and utility of this technique. (1) Stability of resting release: glutamate and glucose concentrations in spinal dialysate showed no significant changes from 3 to 10 days after implantation. (2) Spinal cord ischemia: ischemia induced by aortic occlusion or cardiac arrest evoked a time dependent increase in retrieved glutamate. (3) Spinal cord compression caused a time-dependent glutamate, aspartate and PGE2 increase. (4) Noxious afferent stimulation induced by the injection of formalin into the hindpaw resulted in a rapid and transient increase in dialysate glutamate concentration. (5) Direct activation of spinal excitatory amino acids receptors by i.t. injection of kainic acid (1 microgram) evoked a significant increase in aspartate and taurine. (6) Continuous delivery of spinal opiate (alfentanil) via dialysis resulted in a maintained, concentration dependent elevation in the thermal escape latencies in the unanesthetized rat. The loop dialysis catheter provides a robust experimental tool for studying time dependent changes in the concentration of diffusible substances in spinal CSF over an extended post-implantation interval and allows comparison of these changes with concurrently assessed behavioral indices.
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PMID:The spinal loop dialysis catheter: characterization of use in the unanesthetized rat. 875 84

The effect of hypothermic intestinal ischemia and short-term reperfusion on mucosal arachidonic acid metabolism was studied in a dog model of intestinal preservation injury. Canine intestinal segments were flushed with cold Collins solution, cold stored (4 degrees C) for either 24 or 48 h, and subsequently reperfused in the donor for 1 h. Samples of intestinal mucosa obtained before ischemia, after the ischemia period, and after the reperfusion period were placed into tissue culture, and arachidonic acid metabolites were measured in the tissue incubation media. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) production significantly increased after 24 h of cold ischemia and after 1 h of reperfusion, respectively. Intestines cold stored for 48 h and after 1 h of reperfusion produced significantly elevated quantities of thromboxane B2, PGI2, PGE2, and leukotriene B4, relative to the production rates from nonischemic control tissue or tissue subjected to 48 h of hypothermic ischemia without reperfusion. Mucosal production of thiol ether leukotrienes (LTC4, LTD4, LTE4) was not altered by ischemia or reperfusion at any time of cold ischemia. The synthesis of the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE) was not altered by hypothermic ischemia or reperfusion, but this arachidonate metabolite was produced by small intestinal mucosa in the greatest quantities. Specifically, nanogram quantities of 12-HETE were produced by intestinal mucosa compared to picogram quantities of the other metabolites measured. Significant synthesis of the delta lactone derivative of 5-hydroxyeicosatetraenoic acid was detected by HPLC in many tissue samples undergoing 48 h of ischemia and reperfusion, relative to nonischemic tissue samples. In conclusion, significant increases in arachidonate cyclooxygenase and lipoxygenase metabolites have been identified in intestinal mucosa subjected to long-term hypothermic ischemia and short-term reperfusion. Synthesis of these products increases with the duration of cold ischemia and may play a role in intestinal preservation injury.
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PMID:Arachidonic acid metabolism in intestinal hypothermic preservation injury. 876 48

This study examines the hypothesis that acute thermal injury decreases renal and splanchnic blood flow which correlates with altered endogenous vasodilator eicosanoid release. Anesthetized male Wistar rats were subjected to sham or a non-resuscitated 30% total body surface area burn. At 1, 2, 4, 8, and 24 h post-burn mean arterial pressure as well as superior mesenteric and renal artery in vivo blood flow were measured. The superior mesenteric and renal arteries were cannulated and perfused in vitro with their end organs with Krebs buffer (pH 7.4, 37 degrees C). Renal and splanchnic 6-keto-PGF1 alpha (PGI2), PGE2, and thromboxane B2 (TXB2) release were measured by EIA at 15 min of perfusion. Renal and superior mesenteric artery blood flow decreased by 40% or more at 1 and 2 h post-burn despite mean arterial pressure remaining unchanged. The major eicosanoids released were PGI2 from the splanchnic bed and PGI2 and PGE2 from the kidney. Splanchnic PGI2 and TXB2 release and renal TXB2 increased 2-3 fold at 1 h post-burn but returned to the sham level at 2 h post-burn. By 24 h post-burn the vasodilator eicosanoids were increased in both the splanchnic and renal vascular beds. These data show that decreased renal and splanchnic blood flow was associated with increased endogenous release of the potent vasoconstrictor TXB2. By 2 h post-burn, renal and splanchnic blood flow began returning toward the sham level as endogenous release of TXB2 from both organs fell to sham levels. These data suggest that increased endogenous release of TXB2 may contribute to the short-term decrease in renal and splanchnic blood flow in the immediate post-burn period and thus may contribute to ischemia of both vascular beds.
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PMID:Differential effects of acute thermal injury on rat splanchnic and renal blood flow and prostanoid release. 882 Nov 26


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