Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.13.11.12 (lipoxygenase)
 8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dissolution of infarcted myocardium occurs after the infiltration of leukocytes. In the search for a mechanism of the leukocyte infiltration, we measured the production of lipoxygenase metabolites of arachidonic acid in the canine myocardium after ligation of the circumflex branch of the left coronary artery. At least 2 lipoxygenase products, namely 5- and 12-hydroxyeicosatetraenoic acids (HETEs), were augmented in myocardium subjected to ischemia lasting more than 6 hours, with levels of the latter being raised much more than the former. Augmentation of the HETEs in ischemic myocardium appeared to occur prior to any significant infiltration of leukocytes. More than 12 hours after coronary ligation, the infiltration of leukocytes became prominent and an increase in 12-HETE was observed. Calcium content in the infarcted myocardium appeared to be increased several hours before the increase in 12-HETE. These data suggest that the initial increment in 12-HETE may result from it being a product of infarcted myocardium, where Ca2+ is accumulated in the cell, and that the increased HETEs work as a leukocyte chemoattractant in infarcted myocardium. This hypothesis is supported by the independent experiment which showed that cultured cardiomyocytes produced lipoxygenase metabolites of arachidonic acid, including 12-HETEs etc, which exhibited neutrophil-chemoattractant activity when they were challenged by calcium ionophore and/or arachidonic acid. Azelastine-HCl, a lipoxygenase inhibitor, attenuated not only the above production of HETEs from the cardiomyocytes, but also production of HETEs and infiltration of neutrophils in ischemic myocardium, resulting in attenuation of the fibrous scar of infarcted myocardium.
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PMID:Augmentation of eicosanoids in ischemic heart muscle in dogs: its role in the deterioration of the ischemic lesion. 314 56

To determine the relative importance of arachidonic acid pathway products on vulnerability to ventricular fibrillation (VF), we examined the effects of synthesis inhibitors and a receptor blocker acting in the cyclooxygenase (C) and lipoxygenase (L) pathways on VF thresholds in a feline model of coronary occlusion. Thresholds for the induction of VF wer measured before and after a 5-minute coronary occlusion in drug-treated animals and control subjects. Animals were treated with BW755c, a dual L and C inhibitor, CGS-8515, and L inhibitor, FPL-55712, a leukotriene receptor blocker, or sulfinpyrazone, a C inhibitor. BW755c, CGS-8515, and FPL-55712 all prevented an otherwise significant fall in VF threshold during coronary occlusion (p less than 0.01) independent of an effect on effective refractory period, heart rate, or blood pressure. In contrast, sulfinpyrazone, the only compound devoid of an effect on the L pathway, did not protect against an occlusion-related fall in VF threshold. BW755c and CGS-8515 inhibited the synthesis of L and C metabolites coincident with their protection against VF (p less than 0.01). We conclude that agents that antagonize the effects of L products protect against enhanced ventricular vulnerability during acute ischemia, whereas C inhibition alone may not afford this protection.
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PMID:Modulation of arachidonic acid metabolites and vulnerability to ventricular fibrillation during myocardial ischemia in the cat. 314 41

BW755C is an inhibitor of both cyclo-oxygenase and lipoxygenase, which has been found to have protective effects after myocardial ischemia in dogs. Impact injury to the spinal cord is associated with tissue ischemia as well as with the accumulation of eicosanoids. In the present studies we evaluated the effects of BW755C after traumatic spinal cord injury in rats. Drug treatment reduced thromboxane B2 levels and improved neurological recovery as compared to treatment with equal-volume physiological saline. The findings suggest that this drug or related compounds may be useful for the treatment of clinical spinal cord injury.
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PMID:Effects of BW755C, a mixed cyclo-oxygenase-lipoxygenase inhibitor, following traumatic spinal cord injury in rats. 314 69

Superior mesenteric artery occlusion leads to mesenteric ischemia, activation of arachidonic acid metabolism and release of endotoxins into the systemic circulation. The effect of leukotriene and prostaglandin antagonists on hemodynamic response and survival of rats after superior mesenteric artery (SMA) occlusion was investigated. The animals were divided into five groups: in group 1 (n = 105) the SMA was clamped for 2 h and mortality assessed after 24 h. Group 2 animals (n = 20) were pretreated with 5 mg/kg indomethacin and the SMA clamped similarly to group 1, group 3 animals (n = 15) were pretreated with 5 mg/kg Voltaren, group 4 animals (n = 20) received 20 mg/kg BW 755C before mesenteric artery occlusion, and group 5 animals (n = 50) were pretreated with 100 mg diethylcarbamazine. The blood pressure and pulse response as well as histologic appearance of the bowel 1 h after declamping was similar in all five groups. The mortality rate after 24 h was 34% in the control group, 36% with indomethacin treatment, 36% with voltaren, 47% with BW 755C and 40% with diethylcarbamazine. The mortality rate in all the treated groups was not significantly different from the control group. Plasma thromboxane B2 levels were inhibited significantly by indomethacin and Voltaren and to a lesser extent by BW 755C. There was a paradoxical rise in thromboxane B2 following diethylcarbamazine treatment. It is concluded that inhibition of the cyclooxygenase and/or the lipoxygenase pathways of arachidonic acid did not alter the hemodynamic response and mortality following 2 h of acute superior mesenteric artery occlusion.
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PMID:Effect of prostaglandin and leukotriene antagonists in acute mesenteric artery occlusion. 314 80

This study tests the role of white blood cells (WBC) and leukotrienes in mediating the increased microvascular permeability following ischemia and reperfusion. Anesthetized dogs (n = 23) underwent 2 hours of hind limb ischemia induced by tourniquet inflation to 300 mmHg. In untreated animals (n = 7), tourniquet release led after 5 minutes to a rise in plasma thromboxane (Tx) B2 levels from 360 to 1702 pg/ml (p less than 0.05); after 2 hours, lymph TxB2 concentration had risen from 412 to 1598 pg/ml (p less than 0.05). There were decreases in circulating WBC from 11,766 to 6550/mm3 and platelets from 230 to 155 x 10(3)/mm3. During reperfusion, popliteal lymph flow (QL) increased from 0.07 to 0.24 ml/hour (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged from 0.39, changes consistent with increased microvascular permeability. WBC depletion (n = 7) to 302/mm3 by hydroxyurea or nitrogen mustard attentuated (p less than 0.05) the reperfusion induced rise in plasma TxB2 from 91 to 248 pg/ml and prevented the increase in lymph TxB2 concentration. Within 5 minutes of tourniquet release WBC counts further decreased to 191/mm3 (p less than 0.05) and platelets declined from 175 to 93 x 10(3)/mm3 (p less than 0.05). QL increased from 0.07 to 0.12 ml/hour (p less than 0.05), lower than untreated animals (p less than 0.05), and the L/P protein ratio declined from 0.49 to 0.37 (p less than 0.05), dilutional changes consistent with increased filtration pressure but not permeability to protein. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC) (n = 8) prevented the reperfusion-induced increase in plasma and lymph TxB2 levels (p less than 0.05) and the fall in WBC counts (p less than 0.05), while platelet counts declined from 381 to 210 x 10(3)/mm3 (p less than 0.05). QL rose from 0.09 to 0.23 ml/hour (p less than 0.05) during reperfusion, and the L/P protein ratio of 0.3 remained unchanged, a value lower than in untreated dogs (p less than 0.05). In two animals of each group, vascular recruitment was induced by tourniquet inflation to 50 mmHg. This led to a high QL of 0.25 ml/hour and a low L/P ratio of 0.18. In untreated animals during reperfusion, QL further increased to 1.3 ml/hour, and L/P ratio rose to 0.44, documenting increased vascular permeability. In contrast, reperfusion in leukopenic or diethylcarbamazine (DEC)-treated dogs with vascular recruitment, was not associated with increases in QL or the L/P protein ratio.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Limb ischemia-induced increase in permeability is mediated by leukocytes and leukotrienes. 319 98

Six anesthetized dogs treated with indomethacin, prostacyclin (PGI2), and heparin were compared with 7 anesthetized controls (ischemia without treatment) to determine whether cyclooxygenase inhibition would lead to enhanced granulocyte accumulation because of preferential formation of lipoxygenase products. Cortical somatosensory evoked response, [14C]iodoantipyrine autoradiographic blood flow, and 111In-labelled granulocyte accumulation were compared 4 hours after a 60-minute exposure to multifocal brain ischemia. Treatment with indomethacin, PGI2, and heparin eliminated neuron-disabling brain blood flows without altering early postischemic granulocyte accumulation. Granulocyte accumulation after 4 hours of reperfusion was not significantly different in control and treated dogs. The final amplitude of the cortical somatosensory evoked response in the treated group averaged 38.0 +/- 13.6% (mean +/- SEM) of the corresponding baseline value compared with 21.0 +/- 4.6% in the control group, but this difference was not significant.
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PMID:Indomethacin, prostacyclin, and heparin improve postischemic cerebral blood flow without affecting early postischemic granulocyte accumulation. 329 33

The present studies show that ischemia and reperfusion cause severe injury without evidence of generation of large amounts of reactive oxygen. Calculations show that it is necessary that amounts of reactive oxygen several orders of magnitude greater than that measured during ischemia-reflow injury be generated intracellularly by redox-cycling compounds such as diquat or by direct oxidants such as t-butyl hydroperoxide before endogenous cellular antioxidant systems in ischemia-reperfused rat liver or canine heart are overwhelmed. Thus, our data are incompatible with the hypothesis that oxygen radicals cause ischemia-reflow injury by lipid peroxidation or tissue thiol oxidation as postulated in Figure 1. How might one reconcile these results with the important experiments documenting protection against ischemia-reflow injury by treatment with antioxidants, antioxidant enzymes, allopurinol, cyclooxygenase/lipoxygenase inhibitors, cobra venom factor, and antisera against leukocytes (Table 1)? It seems most likely that the small amounts of reactive oxygen that can be generated in a reduced, acidic environment, such as occurs in tissue ischemia, could only be playing a catalytic function and not producing a massive oxidative attack on tissue membranes. Thus, future studies might best be directed at the catalytic function of superoxide/hydrogen peroxide in modulating the availability of substances such as lipoxygenase and cyclooxygenase products and of endothelium-derived relaxing factor during ischemia-reflow injury.
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PMID:No evidence for reactive oxygen damage in ischemia-reflow injury. 345 76

The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
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PMID:Molsidomine: alternative approaches to treat myocardial ischemia. 355 58

To clarify possible roles in the pathogenesis of ischemic brain edema, identification and quantitative analysis of hydroxy-eicosatetraenoic acids (HETEs) in rat brains exposed to middle cerebral artery occlusion were carried out using high-performance liquid chromatography. Rat brain sampling was done by in situ freezing 24 and 72 hours after occlusion. Only a small amount of 15-HETE was found in control rat brains. Twenty-four hours after ischemia, 11-HETE appeared, and the amount of 15-HETE tended to increase. Seventy-two hours after ischemia, when brain edema reached its maximum, 5-, 8-, 9-, 11-, 12-, and 15-HETEs were identified, and the amounts of all HETEs except 8- and 12-HETE were significantly increased. The detection of 5-HETE in ischemic rat brain indicates the simultaneous production of leukotrienes in the same brain area. The above results support the view that lipoxygenase products may play significant roles in the formation of ischemic brain edema.
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PMID:Identification and quantitative analysis of hydroxy-eicosatetraenoic acids in rat brains exposed to regional ischemia. 356 8

Lower torso ischemia leads to acute respiratory failure, an event associated with the accumulation of inflammatory cells in the lungs. This study tests whether ischemia-induced eicosanoid synthesis leads to polymorphonuclear leukocyte (PMN) accumulation in the lungs. Anesthetized rats (N = 51) were randomized into five groups: nonischemic sham rats (N = 10); the remaining four groups were rats made ischemic for 4 hours with bilateral thigh tourniquets treated just before tourniquet release with saline vehicle (N = 17): the thromboxane (Tx) synthase inhibitor OKY-046 (Ono Pharmaceutica, Osaka, Japan) 2 mg/kg intravenously every 2 hours (N = 8); the lipoxygenase inhibitor diethylcarbamazine (DEC) (Sigma, St. Louis, MO) 0.2 mg/kg/min intravenously (N = 8); the platelet-activating factor receptor antagonist SRI (Sandoz Inc., East Hanover, NJ) 63-072 3 mg/kg intravenously every 30 minutes (N = 8). Four hours after ischemia, plasma TxB2 levels in the ischemic placebo-treated group was 3570 +/- 695 pg/mL, compared with 495 +/- 73 pg/mL in sham rats (p less than 0.001). Lung microscopy showed foci of proteinaceous exudate in alveoli and 121 +/- 10 PMN/20 high power fields (HPF) compared with 59 +/- 9 PMN/20 HPF in the sham group (p less than 0.001). One day after ischemia PMN accumulations remained elevated at 119 PMN/20 HPF. Pretreatment with OKY-046 led to reduced TxB2 levels of 149 +/- 17 pg/mL, normal lung histology, and 83 +/- 13 PMN/20 HPF, a value similar to that of the sham group and lower than that of the placebo-treated group (p less than 0.05). Treatment with DEC yielded TxB2 levels of 1419 +/- 492 pg/mL, which was lower than that of the placebo group (p less than 0.05) but higher than that of the sham group (p less than 0.05). Microscopy showed normal lungs with 79 +/- 7 PMN/20 HPF lower than the placebo group (p less than 0.05). SRI 63-072 did not inhibit Tx synthesis or leukosequestration in the lungs. Platelet counts decreased in all groups relative to sham animals (p less than 0.05). The results indicate that Tx synthesis induced by ischemia moderates PMN accumulations in the lungs. Inhibition of lipoxygenase is believed to prevent PMN accumulations both by limiting leukotriene-induced Tx synthesis as well as by limiting production of chemoattractants.
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PMID:Pulmonary leukosequestration induced by hind limb ischemia. 360 41


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