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)

These data indicate that chronic administration of CGS-12970 to renal allograft recipients maintains renal allograft function. These effects are probably due to selective inhibition of local tissue TXA2 production. These data also suggest that elevations in renal allograft tissue prostacyclin production may be secondary to ischemia since improving renal blood flow and GFR with selective thromboxane synthesis inhibitors leads to normalization of renal prostacyclin synthesis. The possible utility of using CGS-12970 as an adjunct therapy in human renal allotransplantation should be strongly considered.
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PMID:Thromboxane synthesis inhibition and renal allograft function. 265 85

Our previous studies indicate that the blockade of the sympathetic nervous system by spinal anesthesia or epidural anesthesia inhibits the release of TXA2 induced by limb ischemia with thigh tourniquet in patients with lower limb surgery. The present study was undertaken to confirm this phenomenon in anesthetized dogs. Twenty one anesthetized dogs underwent 60 min occlusion of the abdominal aorta and the inferior vena cava, followed by reperfusion. They were randomized into three groups: no treatment group and pretreatment groups with either 2 ml of 0.5% bupivacaine intrathecally or 4 mg.kg-1 of labetalol intravenously. In no treatment group plasma TXB2 levels were increased significantly after reperfusion. However, prior treatments with bupivacaine intrathecally or labetalol intravenously inhibited the increases in plasma TXB2 levels after reperfusion. These results suggest that limb ischemia stimulates the TXA2 production, which may be influenced not only by endothelial cell damage and the generation of oxygen free radicals but also by the activation of the sympathetic nervous system.
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PMID:[The participation of the sympathetic nervous system in thromboxane A2 release induced by limb ischemia]. 273 38

If myocardial ischemia always results from an imbalance between the needs and supplies in oxygen of the myocardium cells, the physiopathology of this process seems today infinitely more complex than the mere diminution or interruption of the output in a coronary artery. The extension of atheromatous lesions, the platelets aggregation, thrombosis, the coronary spasm, the release of products from the arachidonic cascade, the reactivity of the vascular endothelium, the profibrinolytic activity of the tissues are many of the intricate factors inducing myocardial ischemia. Cellular alterations, of which some are triggered by the release of oxygenated free radicals, lead then to an irreversible necrosis. The medications used until now in the treatment of angina are oxygen scavengers and research goes on in this direction with vaso-dilators beta-blockers, prolonged action nitro-compounds (nicorandil) or nitro-compounds with an action reinforced by N-acetyl-cysteine, bradycardiac derivates of alinidine and the new calcium antagonists dihydropyridine. However, the new physiopathological concepts of ischemia have opened new directions for the research: products which modify the arachidonic cascade by increase of synthesis or release of PGI2 (nafazatrom, defibrotide), by inhibition of TXA2 synthesis or blocking of TXA2 receptors, and similar products of PGI2 (iloprost); thrombolytic agents more specific of thrombin (PTA) or fibrinolysis activators (defibrotide), and anticoagulants with extended action; chelating agents of oxygenated free radicals (peroxide dismutase, catalase, peroxidase) or xanthine oxidase inhibitors; platelets anti-aggregates like ticlopidine which blocks the platelets receptors to fibrinogen, or inhibitors of the synthesis of pro-aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current therapeutic concepts in the treatment of myocardial ischemia. Current and future drugs]. 287 4

The involvement of a thromboxane (TX) A2-like substance in the decrease of mucosal blood flow (MBF) and occurrence of gastric erosions in rats under water-immersion stress was examined. MBF was estimated by aminopyrine clearance. Stress increased acid output without a parallel increase in MBF and caused erosions. OKY-046, an inhibitor of TXA2 synthesis, and ONO-11120, an antagonist of TXA2 receptors, increased MBF during stress in parallel with an increase in acid output, and erosions did not form. In another experiment, the effects of a TXA2-like substance on MBF during vagal stimulation were examined. Although vagal stimulation alone increased acid output, there were no erosions in the stomach, probably because MBF was increased in parallel with acid output. Intra-arterial administration of a TXA2-like substance formed by the metabolism of arachidonic acid in the blood reduced MBF during vagal stimulation. Intra-arterial administration of ONO-11113, an agonist of TXA2 receptors, also reduced MBF during vagal stimulation. Neither agent affected the elevated level of acid output during vagal stimulation, and erosions formed in the glandular part of the stomach. These results suggested that the gastric mucosal erosions induced by water-immersion stress in rats were due to mucosal ischemia produced by the presumed formation of a TXA2-like substance and to the increased secretion of acid.
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PMID:Gastric mucosal erosion due to a mucosal ischemia produced by thromboxane A2-like substance in rats under water-immersion stress. 293 10

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g., sudden death, myocardial ischemia, circulatory shock). It does so because it propagates its own formation by activating platelets and constricting blood vessels, thus activating more TxA2 and trapping it locally within an ischemic or hypoxic region. TxA2 concentrations in the extracellular fluid of lymph of ischemic regions may be much higher than that occurring in nonischemic, normally perfused regions. Specific and potent Tx receptor antagonists (TxRA) have recently become available for study. The TxRA are useful tools in the study of the pathophysiology of Tx-dependent disease processes and have been found to be effective in a variety of ischemic disorders including circulatory shock, myocardial ischemia, and sudden cardiopulmonary death. Moreover, inasmuch as early work indicates that these agents are both safe and effective in humans, Tx receptor antagonists may be employed as therapeutic agents in several cardiovascular disease states. Further investigation is necessary to clarify the role of TxRA as therapeutic agents.
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PMID:A pharmacological approach to thromboxane receptor antagonism. 294 38

Thromboxane A2 (TXA2) receptor antagonists can limit infarct size in models of coronary occlusion and reperfusion, but it was unknown if these compounds can mitigate reperfusion injury. Anesthetized open chest dogs were subjected to left circumflex coronary (LCX) occlusion for 90 min. Two minutes before reperfusion, the dogs were given iv saline (0.9% NaCl) or the TXA2 antagonist SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/hr). Reperfusion was instituted for 5 hr at which time infarct size was determined. Regional myocardial blood flow was determined before, during, and after occlusion. SQ 29,548 treatment resulted in a significant reduction in infarct size (57 +/- 7 and 34 +/- 8% of the left ventricular area at risk infarcted in the saline and SQ 29,548 groups, respectively). No differences in collateral flow during occlusion were observed between groups, but SQ 29,548 treatment resulted in a significantly higher subendocardial reperfusion flow (54 +/- 10 and 93 +/- 14 ml/min/100g for the saline and SQ 29,548 groups, respectively). Thus, TXA2 seems to play a role in exacerbating reperfusion injury and TXA2 receptor blockade may have potential as a mode of therapy for ischemia-reperfusion damage.
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PMID:The role of thromboxane A2 in reperfusion injury. 297 Dec 19

A variety of eicosanoids are produced in ischemic and circulatory shock. Many of these constrict arteries, induce platelet aggregation or adherence of other blood cells to the vasculature, and contribute to increased membrane permeability. Thromboxane A2, leukotriene C4, and leukotriene D4 fulfill all the criteria stipulated for humoral mediators of ischemia and shock. Moreover, pharmacologic modulation of these mediators by either specific inhibition of their synthesis or antagonism of their arteries at their receptor sites protects against tissue and cell damage during ischemia and shock as well as enhances survival in these life-threatening states.
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PMID:Eicosanoids as mediators of ischemia and shock. 298 45

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction, and has a direct cytolytic effect, thromboxane receptor antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.5 hours. ST segment elevation declined significantly (p less than 0.02) after BM-13,177 treatment, suggesting a reduction in cellular ischemia. The loss in myocardial creatine kinase (CK) activity and in free amino-nitrogen concentration in the ischemic area was also significantly reduced (p less than 0.01). No significant changes in blood pressure or heart rate were seen with BM-13,177 during myocardial ischemia or in nonischemic control cats. Blood levels of BM-13,177 were sufficient to inhibit ex vivo platelet aggregation induced by the prostaglandin endoperoxide analog, U-46,619. Data from isolated cat coronary arteries suggest that BM-13, 177 antagonizes the thromboxane/endoperoxide receptor in coronary vascular smooth muscle. These experiments indicate that TxA2 plays a significant role in propagating the extension of ischemic damage, and that thromboxane receptor antagonism is an effective means of reducing the damage provoked by TxA2 in acute myocardial ischemia.
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PMID:Anti-ischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats. 300 Jan 59

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.
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PMID:Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia. 300 26

The aim of this chapter was to highlight the major components of PAF actions which lead to a state of shock, i.e. inadequate perfusion of essential organs which if sustained over a critical period of time, leads to irreversible damage in essential organs and eventually death. The heart, the pulmonary vessels and the microcirculation seem to be the primary target organs to PAF-induced hypotension. The effects of PAF on the pulmonary airways in some species (bronchoconstriction) might lead to hypoxemia and further exacerbate organ function. Thrombocytopenia, leukopenia and activation of the complement system are also important in PAF-induced shock by promoting thrombi formation and generation of multiple secondary mediators (e.g. histamine kinins, TXA2, leukotrienes, oxygen radicals). Identification of PAF production during specific or generalized pathophysiological processes is a critical step to implicate this vasoactive lipid in disease processes. So far, only limited information has been derived from studies involving immune responses (anaphylaxis) or bacterial endotoxins. Yet, the growing number of selective and potent PAF antagonists provide important information on the potential role of PAF in shock states. Such evidence, summarized in table I, is of great importance in designing new therapeutic strategies to a highly complex and lethal disease such as septicemia. However, the data summarized in table I clearly show that little is known on the mechanism of action of the various PAF antagonists. It is also important to note that PAF-induced shock and death can be prevented by drugs which are not necessarily PAF antagonists. For example, dexamethasone is extremely efficient in preventing PAF-induced shock and death in the mouse [24, 39] and thyrotropin releasing hormone in the guinea pig [15]. Therefore, it is conceivable that pathological conditions in which PAF might play a fundamental role might be reversed by pharmacological interventions which activate physiological mechanisms which can overcome and reverse the pathological processes activated by PAF. In conclusion, PAF is a powerful vasoactive lipid which can produce severe derangements in essential biological functions which can lead to death. The role of PAF in pathological processes in vivo is well supported in conditions such as anaphylaxis and endotoxemia. Yet, direct proof for PAF production in other shock states, such as multiple trauma, ischemia, inflammation and hemorrhage, is still missing. Furthermore, it is important to keep in mind that in shock, trauma or inflammation, multiple mediators in addition to PAF are formed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Platelet-activating factor and shock. 304 32


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