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)

Metabolic disturbances in the canine liver during warm ischemia by Pringle's method for 60 minutes and the role of Coenzyme Q10 (CoQ10), Prostaglandin E1 (PGE1) and ONO-3708, TXA2 receptor antagonist, were studied. Mongrel dogs were divided into five groups; control group, group of liver ischemia without drugs, groups of liver ischemia with CoQ10, PGE1 and ONO-3708 pretreatment. Metabolic rates of PGI2, TXA2, insulin, glucagon and glucose and production of lipid peroxides in the five groups were measured at the points before Pringle's procedure, 5 minutes, 60 minutes and 120 minutes after declamping. In the group of ischemia without drug administration, the hepatic metabolism of PGI2, TXA2, insulin and glucose were decreased after declamping. The metabolism of glucagon, however, was not disturbed by warm ischemia. The production of lipid peroxides increased at 5 minutes after declamping. In the groups of CoQ10, PGE1 and ONO-3708 pretreatment, changes of PGI2, TXA2 and insulin metabolism in the liver were improved, and an increased production of lipid peroxides by warm ischemia was normalized. This study suggests that CoQ10, PGE1 and ONO-3708 protect liver damage by warm ischemia as results of improvement of metabolic disturbances of PGI2, TXA2, insulin and suppression of lipid peroxides production.
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PMID:[Assessment for protective effects of CoQ10, PGE1 and TXA2 receptor antagonist (ONO-3708) on warm ischemic liver]. 138 60

Prostacyclin (PGI2) improves regional contractility of postischemically dysfunctional ("stunned") myocardium. We determined whether defibrotide, a fraction of mammalian DNA known to stimulate endogenous formation of PGI2, also improves contractile recovery of stunned myocardium. Anesthetized, open-chest minipigs were subjected to coronary occlusion of 5 min (left anterior descending branch, LAD) followed by 120 min of reperfusion. The animals were treated with defibrotide (32 mg x kg-1 x h-1, intravenously, i.v.) or vehicle throughout the experimental period. Defibrotide improved regional contractility in the ischemic reperfused area from 30 (vehicle) to 78% of the preischemic control without altering the contractility of nonischemic myocardium. Transcardiac PGI2 formation, determined from the difference between coronary venous and arterial plasma concentrations, was elevated from 437 (preischemic control) to 869 pmol x l-1 in defibrotide-treated animals, but was unchanged in the vehicle-treated and a sham-operated group. Thromboxane A2 (TXA2) release was not modified. Defibrotide reduced ischemia-induced formation of platelet aggregates but did not affect the activity of polymorphonuclear neutrophil granulocytes. The data demonstrate an improvement of contractile recovery from stunning by defibrotide that may be related to an inhibition of ischemia-induced platelet activation and (or) membrane protection owing to enhanced transcardiac formation of PGI2.
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PMID:Stimulation of prostacyclin synthesis by defibrotide: improved contractile recovery from myocardial "stunning". 170 43

The origin of pre-eclampsia lies in uteroplacental ischemia due to an anomaly of the "vascular insertion" of the placenta. Although the cause of this anomaly remains unknown, it would appear to include both a genetic and an immunological origin possibly favourised by special underlying conditions and certain obstetric circumstances. Prostaglandin imbalance (in particular prostacyclins and Thromboxane A2) appears to be one of the chief factors governing these anomalies. One of the consequences of these mechanisms is the onset of hypertension but other disturbances are essential features. In particular, disseminated intravascular coagulation may occur leading to the release of numerous microthrombi which cause placental (leading to chronic fetal distress), renal, hepatic and cerebral lesions.
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PMID:[Physiopathological elements of pre-eclampsia and the role of the main complementary tests]. 176 67

An examination of the cellular and molecular mechanisms of neuronal cell damage may lead to the design of pharmacologic interventions during presumed or actual fetal asphyxia. Hypoxia-ischemia in its severest form results in insufficient adenosine 5'-triphosphate production. The most important effect of this is failure of adenosine 5'-triphosphate-dependent membrane functions, which maintain ionic homeostasis, that is, ionic pumping. There is K+ efflux and Na+ influx across the cell membrane, depolarization of the cell membrane, opening of the voltage-dependent calcium channels, and entrance of Ca++ into the cell. Cytosolic Ca++ is also increased by Ca++ efflux from the mitochondria and the sarcoplasmic reticulum. Ca++ is a toxin in high cytosolic concentrations; it activates phospholipases A and C, which cause membrane breakdown and release of free fatty acids, including arachidonic acid. The membrane is damaged, lysis occurs, and the neuron dies. High cytosolic Ca++ also causes release of excitatory amino acids (especially glutamate), which overwhelm the suppressant neurotransmitters, causing seizures, increased metabolism, and aggravation of the insufficient adenosine 5'-triphosphate availability. Thromboxane A2 is generated from arachidonic acid, increasing smooth muscle tone and thereby worsening the ischemia. Cyclooxygenase activity also results in formation of oxygen-free radicals that contribute to cell membrane damage, lysis, and death. Possibilities for pharmacologic interventions include (1) calcium channel blockers and antagonists, (2) excitatory neurotransmitter blockers, (3) oxygen-free radical scavengers (e.g., superoxide dismutase), (4) cyclooxygenase or prostaglandin synthesis inhibitors, and (5) seizure suppressants (e.g., phenobarbital). Some of these treatments have been shown experimentally to limit neuronal death in the adult and fetus, and after more investigative work they may be applicable to clinical practice.
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PMID:Mechanisms of asphyxial brain damage, and possible pharmacologic interventions, in the fetus. 190 82

Arachidonic acid is liberated from damaged cell membranes during ischemia and is the source of vasoactive prostanoids. In this study, specific drugs that influence AA metabolism were investigated for their effects on brain edema and energy metabolites during ischemia. The agents tested were: methylprednisolone (phospholipase A2 inhibition), indomethacin (cyclooxygenase inhibitor), trapidil (TXA2 synthetase inhibitor), and OP-41483 (prostacyclin derivative). Cerebral ischemia was produced using bilateral common carotid artery occlusion in spontaneously hypertensive rats. Brain water content and concentrations of ATP, pyruvate, and lactate were determined 3 hr after occlusion. Compared with its vehicle, methylprednisolone significantly reduced water content and lactate concentration and maintained high levels of ATP. Indomethacin had no effect on brain water content nor metabolite levels. Trapidil decreased water content and lactate levels and increased levels of ATP and pyruvate. OP-41483 had no effect on water content and lactate, but maintained ATP and pyruvate at high levels. These results indicate that some of the AA metabolites may play an important role in the development of brain edema and in the impairment of energy metabolism.
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PMID:Role of arachidonic acid metabolism on ischemic brain edema and metabolism. 211 11

Dazoxiben, a selective TXA2 synthetase inhibitor, was studied in the incubating sections of porcine basilar arteries with arachidonic acid (AA) 50 mumols/L and calcimycin (calcium inophore A-23187) 50 mumol/L. TXB2 and 6-keto-PGF1 alpha were determined by radioimmunoassay. Leukotrienes (LT) were extracted and purified with SEP-PAK column, identified by HPLC and determined by bioassay with ileum of guinea pig. The results showed that the production of TXB2 was unaltered whether or not the incubation of arteries were induced by AA or calcimycin. Dazoxiben and indomethacin 0.05-50 mumols/L had no effects on the production of TXB2. However, dazoxiben 0.5, 5 and 50 mumols/L increased the production of 6-keto-PGF1 alpha by 16.3%, 19.0% and 30.7%, respectively. Indomethacin 0.5, 5 and 50 mumols/L decreased the production of 6-keto-PGF1 alpha by 22.3%, 24.9% and 24.0%, respectively. Meanwhile dazoxiben 1, 10 and 100 mumols/L decreased the production of LT by 33.4%, 45.6% and 66.4%, respectively. These results suggest that the protective effect of dazoxiben on the damages which resulted from brain ischemia may be related to the change of TAX2/PGI2 balance in the brain tissue as well as the inhibition of production of LT.
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PMID:[Effect of dazoxiben on the metabolism of arachidonic acid in isolated porcine basilar arteries]. 212 32

Sudden fissuring of an atherosclerotic plaque has been suggested as the primary trigger of transient spontaneous ischemia in both the coronary and cerebral circulation. Measurements of urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2, as well as results of Aspirin trials, have suggested that episodic platelet activation at the site of this acute vascular lesion is mediated, at least partly, by enhanced thromboxane (TX) A2 biosynthesis. Thus, episodic increases in metabolite excretion have been detected in unstable angina. Aspirin (75-325 mg/day) prevents about one third of all fatal and nonfatal thrombotic events in this setting. That a similar "dynamic" thrombotic process occurs during the early phase of acute myocardial infarction is suggested by thromboxane metabolite measurements and by the results of the ISIS-2 trial showing a similar impact of short-term Aspirin therapy to that seen in unstable angina. Percutaneous transluminal coronary angioplasty is associated with transiently enhanced TXA2 biosynthesis and Aspirin-suppressable periprocedural thrombotic complications. On the other hand, both non-insulin-dependent diabetes mellitus and type IIa hypercholesterolemia are associated with a relatively reproducible and persisting abnormality of TXA2-dependent platelet function. This association is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Low-dose (50 mg/day) Aspirin can largely suppress thromboxane metabolite excretion in both diseases. Thus, low-dose Aspirin and/or selective prostaglandin H2/TXA2-receptor antagonists may be important tools to test the hypothesis that TXA2-dependent platelet activation represents an important transducer of the enhanced thrombotic risk associated with these metabolic abnormalities.
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PMID:Thromboxane biosynthesis in cardiovascular diseases. 226 Jan 37

The effect of 48 hours of hypothermic renal ischemia utilizing Euro-Collins flush and short term reperfusion on renal prostaglandin synthesis was studied in dogs. Hypothermic ischemia followed by 60 minutes of reperfusion in-vivo resulted in significant elevations in renal Thromboxane B2 (TXB2) production in the outer cortex, inner cortex, and medulla, relative to non-ischemic kidneys. Prostaglandin E2 (PGE2) and 6-keto Prostaglandin F1 alpha (6-K PGF1 alpha) production were not significantly affected by ischemia and reperfusion. Enhanced TXB2 production was not seen with ischemia alone (without reperfusion) or with reperfusion with O2 saturated buffer, indicating a blood born source or stimuli. Early postreperfusion renal blood flow after hypothermic ischemia followed a biphasic pattern; blood flow increased for the first 10 minutes of reperfusion to achieve normal values, and then steadily declined over the next 20 minutes. This pattern was not altered by the cyclooxygenase inhibitors Idomethacin (5 mg/kg, P.O.) or Mefenamic acid (10 mg/kg, I.V.). Administration of the TXA2 synthesis inhibitor CGS-12970 (3 mg/kg, I.V.) or the TXA2/endoperoxide receptor antagonist SQ-29548 (80 micrograms/min, I.A.) significantly increased renal blood flow during reperfusion but neither agent altered the basic time dependent pattern observed in the control group. These data indicate that 48 hours of hypothermic renal ischemia results in dramatic changes in intrarenal TXA2 synthesis at the time of reperfusion. Enhanced TXA2 production is not dependent on reoxygenation per se, but rather requires reperfusion with blood suggesting a circulatory source.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostanoids and hypothermic renal preservation injury. 228 Nov 20

Thromboxane A2 (TxA2) has been implicated as a potential mediator of myocardial damage during acute ischemia. A potent and specific TxA2 receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg/h) was tested in a cat acute coronary ligation model of myocardial ischemia over a 5-h observation period. Those cats given the TxA2 receptor antagonist had a significant reduction in elevated S-T segment from 0.32 to 0.17 mV (p less than 0.01) in contrast to cats given only vehicle which showed a progressive increase in S-T segment elevation over the 5-h course of the experiment. Furthermore, the rise in plasma creatine kinase (CK) activity during myocardial ischemia was significantly attenuated after SQ-29,548 administration (p less than 0.05). This was confirmed by direct myocardial biopsies which demonstrated a reduction in the loss of myocardial CK and nitrogenous compounds from the ischemic region. Because heart rate (HR), mean arterial blood pressure (MABP), and the pressure rate index (PRI) were unaffected by SQ-29,548 administration, its mechanism of protection probably does not occur through reduction of myocardial oxygen demand. Furthermore, specificity of SQ-29,548 for thromboxane/endoperoxide receptors was demonstrated in the isolated cat coronary arteries. These data suggest that SQ-29,548 reduces the damage associated with myocardial ischemia through direct TxA2 receptor antagonism. The data are also consistent with an important role of TxA2 in the pathophysiology of myocardial ischemia.
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PMID:Cardioprotective actions of specific thromboxane receptor antagonist in acute myocardial ischemia. 243 97

Activated polymorphonuclear leukocytes (PMNs) contribute to myocardial injury during ischemia and reperfusion. There is evidence that activation of the complement pathway may be one of the mechanisms of PMN activation during ischemia. Intracoronary infusion of complement C5a during normal perfusion pressure is associated with decreased coronary flow, contractile dysfunction, and PMN accumulation. The mechanisms responsible for these changes have not been identified. Thromboxane A2 (TXA2) is a potential mediator of this myocardial ischemic response. Activated PMNs produce TXA2, a known coronary vasoconstrictor, and TXA2 was shown to be a mediator of the pulmonary hypertensive response to activated complement. The goal of the present study was to determine if an enhanced TXA2 production is associated with the myocardial response to C5a and whether cyclooxygenase blockade would reduce the myocardial ischemia. In open-chest pigs, intracoronary C5a (500 ng) caused reversible reductions in blood flow (50.0% of control), regional contractile function (25.8% of control), leukocyte trapping (1.0 x 10(6) cells/g myocardium or a peak artery-coronary venous difference of 5.3 x 10(3) cells/microliters blood), and increased coronary venous TXB2 (the TXA2 breakdown product) from 1.6 pmol/ml to a peak of 6.9 pmol/ml. Cyclooxygenase blockade with aspirin or indomethacin, which prevented TXB2 production, did not alter the response in flow, function, or PMN trapping. Ibuprofen, a known direct inhibitor of PMNs in addition to its cyclooxygenase blockade effect, reduced the response slightly. The pig coronary vascular bed was responsive to the TXA2 agonist U46619, which reduced flow and function without PMN trapping. Mechanical reductions in coronary flow to levels equivalent to those during the C5a infusions did not increase coronary venous TXB2 nor cause PMN trapping but did cause equivalent contractile dysfunction. Incubation of whole blood with C5a at concentrations equivalent to those achieved in vivo did not cause TXB2 production. We conclude that 1) TXA2 is produced in response to intracoronary C5a and 2) cyclooxygenase blockade does not prevent the C5a-induced myocardial ischemia, contractile dysfunction, and PMN trapping. The TXA2 production likely involves a vascular site or a blood cell-vascular interaction. This model system indicates the potential for persistently activated PMNs to cause continued ischemia during myocardial reperfusion.
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PMID:Thromboxane is produced in response to intracoronary infusions of complement C5a in pigs. Cyclooxygenase blockade does not reduce the myocardial ischemia and leukocyte accumulation. 250 96


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