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)

Novel compounds that induce or inhibit platelet aggregation and constrict or dilate blood vessels were recently discovered. These compounds are all derivatives of arachidonic acid and include prostaglandin endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. Thromboxane A2 (TxA2) could be one of the precipitating factors in coronary or cerebrovascular ischemia because it is a potent vasoconstrictor that is produced by platelets during their aggregation. On the other hand, prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation produced by vessel walls whose enhanced production should be beneficial. Aspirin inhibits prostaglandin endoperoxide synthetase and therefore prevents the subsequent production of TxA2, PGI2 and other prostaglandins. It has been suggested but not yet established that low doses of aspirin preferentially inhibit TxA2 biosynthesis. The roles of classic prostaglandins PGD2, PGE2 and PGF2 alpha in ischemia have not been determined.
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PMID:Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation. 700 50

Prostaglandins may induce or inhibit platelet aggregation and constrict ro dilate blood vessels. Recent interest has focused on prostaglandins which are derivatives of arachidonic acid including prostaglandin, endoperoxides, thromboxane A2, prostaglandin E2, prostaglandin D2 and prostacyclin. Prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation whose enhanced production by vessel walls should be beneficial. It now appears that the circulating levels of PGI2 in man are extremely low and little is known about the manner in which to increase them. Furthermore, aspirin, in doses of as little as 4 mg/kg inhibits prostacyclin as well as thromboxane formation. Thromboxane A2 may be involved in coronary ischemia because it is a potent vasoconstrictor that is biosynthesized during platelet aggregation. Although thromboxane A2 is very unstable indirect evidence obtained by using thromboxane A generating systems or a stable analogue called carbocyclic thromboxane A2 (CTA2) suggests that it exacerbates ischaemic damage because of a selective increase in vascular resistance due to coronary vasospasm and platelet aggregation which acts to decrease myocardial blood flow. The stable prostaglandins PGD2 and PGE2 are also of interest as both are formed during platelet aggregation. Like PGI2, PGD2 inhibits platelet aggregation.
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PMID:Prostaglandins and platelet aggregation. 703 81

KC-764, developed as a cyclo-oxygenase inhibitor, was administered to gerbils in a dose of 10 mg/kg, i.p., before subjecting them to 5-minute bilateral forebrain ischemia in order to determine whether it would have any protective effects. No post-ischemic hyperthermia (over 39 degrees C for 120 min) was observed in the KC-764 group. Behavior recovery time after ischemia was 11.4 +/- 2.8 minutes in the KC-764 group versus 87.3 +/- 13.4 minutes in the control group (p < 0.05). Delayed neuronal death (DND) in the CA1 region of the hippocampus was inhibited in the KC-764 group, but when the KC-764-treated animals were exposed to hyperthermia, the degree of DND was the same as in the control group. EEG voltage recovery time in the CA1 region of the hippocampus was almost the same in the control group, the KC-764 group, and the KC-764-plus-hyperthermia (HT) group. Although tissue blood flow measurements in the CA1 region of the hippocampus showed post-ischemic hypoperfusion (81 +/- 18% of the pre-ischemic level at 60 minutes), it was prevented in the KC-764 group (102 +/- 21%) (p < 0.05) and the KC-764-plus-HT group (96 +/- 28%). There was a tremendous increase in PGD2 (1461.4 +/- 863.4 p mol/g) and PGF2 alpha (219.6 +/- 104.2 p mol/g) in the forebrain after 5 minutes of reflow, but this increase in prostaglandin levels was inhibited (p < 0.05) in the KC-764 group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Protective effects of KC-764 on short-term forebrain ischemia in gerbils]. 787 77

Abnormal smooth muscle cell (SMC) proliferation is observed in several pathological situations such as atherosclerosis, pulmonary hypertension, and venous pathologies, resulting in a thickening of the vessel wall. If endothelial cells have been assumed to play a role in the triggering of this proliferation, no direct evidence is available. As ischemia is often linked to these situations, we exposed human umbilical vein endothelial cells (HUVEC) to hypoxia. The HUVEC-conditioned medium was then added to SMC and the proliferation of these cells was measured. We observed a pro-proliferative activity for SMC of the hypoxic HUVEC-conditioned medium but not of the normoxic HUVEC one. This pro-proliferative activity could not be inhibited if HUVEC were treated with cycloheximide but was blocked if the synthesis of prostaglandins by HUVEC was inhibited during hypoxia. PGD2, and especially PGF2 alpha at the concentration found in the hypoxic HUVEC-conditioned medium, were demonstrated to have a mitogenic effect on SMC. PGE2 also showed a pro-proliferative activity but at higher concentrations. In addition, the kinetics of increase in SMC proliferation induced by a mixture of the four prostaglandins at the corresponding concentrations was the same as the one observed with hypoxic HUVEC-conditioned medium. However, when tested on fibroblasts which do not respond to PGF2 alpha, hypoxic HUVEC-conditioned medium also had a pro-proliferative activity. In addition, anti-bFGF antibodies but not anti-PDGF blocked the mitogenic activity of this conditioned medium for SMC. Finally, the mitogenic effects of PGF2 alpha and of bFGF on SMC are additive. These results indicate that bFGF is probably also involved. These results indicate that these prostaglandins act in synergy with bFGF and are the molecules responsible for the pro-proliferative activity observed in hypoxic HUVEC-conditioned medium. We propose that these findings can explain the excessive growth of SMC in blood vessels following chronic ischemic situations.
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PMID:Hypoxia stimulates human endothelial cells to release smooth muscle cell mitogens: role of prostaglandins and bFGF. 802 Jun 5

We measured hippocampal CA1 concentrations of PGD2, TxB2 and 6-keto-PGF1 alpha in 18 anesthetized rats with stereotaxically implanted microdialysis probes before, during and after 20 min of global cerebral ischemia. The insertion of the microdialysis probe did not appear to cause a continuous major disturbance of arachidonic acid (AA) metabolism because stable eicosanoid concentrations were obtained prior to ischemia. During reperfusion all three eicosanoids increased significantly reaching a peak after 30-60 min and then gradually declined to baseline levels over the next 2-3 h. The ratio of average peak concentrations for PGD2, TxB2 and 6-keto-PGF1 alpha were approximately 80:2:1, respectively. The results extend previous work by demonstrating the time course of eicosanoid release in a distinct brain region and confirm the role of PGD2 as the major PG metabolite in brain. We conclude that future studies employing microdialysis may be able to provide a more detailed understanding of the role of AA metabolites in ischemic brain.
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PMID:Microdialysis measurements of PGD2, TXB2 and 6-KETO-PGF1 alpha in rat CA1 hippocampus during transient cerebral ischemia. 843 Feb 28

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

Medium osmolarity sensitively regulates Kupffer cell functions like phagocytosis and prostaglandin (PG) and cytokine production. Betaine and taurine, recently identified as osmolytes in liver cells, interfere with these effects. Because Kupffer cell activation is an important pathogenic mechanism in ischemia-reoxygenation injury, the influence of osmolarity and osmolytes was investigated in a rat liver perfusion model of warm ischemia. Livers were perfused with different medium osmolarities for 60 to 90 minutes in the absence of oxygen, followed by another 90 minutes of reoxygenation. Lactate dehydrogenase (LDH) leakage into the effluent perfusate during the hypoxic and the reoxygenation period was eight- to 10-fold higher with a medium osmolarity of 385 mosmol/L than in normo-osmolarity, and further decreased with hypo-osmolar perfusion buffer. Betaine and taurine addition to the perfusate in near physiological concentrations decreased hypoxia-reoxygenation-induced LDH leakage, aspartate transaminase (AST) leakage, and perfusion pressure increase in hyperosmolar and normo-osmolar perfusions. Stimulation of PGD2, PGE2, thromboxane B2 (TXB2), and tumor necrosis factor alpha (TNF-alpha) release, as well as induction of carbon uptake by the liver during reoxygenation, were suppressed by betaine and taurine, pointing to an interference of these osmolytes with Kupffer cell function. In contrast, endothelial cell function as assessed by hyaluronic acid (HA) uptake was not influenced. It is concluded that warm ischemia-reoxygenation injury in rat liver is aggravated by hyperosmolarity and attenuated by hypo-osmolarity. The osmolytes betaine and taurine have a protective effect, presumably by inhibition of Kupffer cell activation.
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PMID:Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation injury in the perfused rat liver. 939 98

The effects of ZK-118.182, a stable analogue of PGD2, were evaluated in an endothelin-1-induced cerebral ischemia rabbit model. Ischemia was induced by endothelin-1 injection (0.25 ng bolus) into subcavian artery and ischemic changes were assessed histologically by the number of ischemic neurons in the brain stem. ZK-118.182 (2 micrograms/kg, bolus into subclavian artery) reduced the number of ischemic neurons when injected 20 min after endothelin-1 injection, Iloprost, a stable analogue of PGI2, was also effective in reducing the number of ischemic neurons in a dose of 0.5 microgram/kg (bolus into subclavian artery). The results suggested that ZK-118.182 has a potent antiischemic effect which is comparable to that of iloprost in rabbits.
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PMID:Antiischemic effect of ZK-118.182 in rabbits: a comparative study with iloprost. 965 84

Changes in prostanoids concentration and effects of the non-specific COX inhibitor indomethacin on prostanoids levels and extension of tissue damage were studied following focal ischemia induction in the fronto-parietal region of rat brain. Ischemia was induced in animals bearing a transcerebral microdialysis probe by injection of Rose Bengal, a photosensitive dye, followed by light activation. Prostanoid levels were determined in the dialysate using immunoenzymatic techniques. PGD2 levels rose significantly up to 237+/-22 pg/ml compared to a basal level measured before ischemia induction which was below the detection limit. TXB2 changes were smaller and had a different time course. Treatment with indomethacin abolished the ischemia-induced PGD2 release and reduced the extent of injury to the area by 43+/-3.7%. These results suggest that prostanoid release may play an important role in neurodegenerative processes and that cyclooxygenase inhibitors may contribute to protect against cerebral tissue damage.
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PMID:Inhibition of prostanoid synthesis protects against neuronal damage induced by focal ischemia in rat brain. 987 Mar 35


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