UMLS:C0151744 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since serotonin (5-HT) is implicated in exacerbating acute coronary syndromes, we studied the reactivity of atrial coronary arterioles (70-140 microm) of atherosclerotic patients undergoing cardiac surgery to 5-HT, substance P (Sub P), and sodium nitroprusside by video-microscopy. Before ischemia, 5-HT-induced relaxation was not affected by NS398 (cyclooxygenase inhibitor), H2O2 or U63557A (thromboxane A2 synthase inhibitor), but was reduced by L-NNA. 5-HT elicited a potent contractile response after ischemia that was inhibited by NS398, Indo, and U63557A. While Sub P relaxation was decreased after ischemia, SNP relaxation was unchanged. The mRNA steady-state levels of NOS-3, NOS-2, prostacyclin synthase, and COX- 1 were not altered by ischemia. COX-2 mRNA and protein levels (Westernblotting), however, were increased (mean +/- SEM) 2.4 +/- 0.4 and 3.2 +/- 0.7 fold, respectively, in ischemic atrium corroborating with the immunohistochemistry of atrial tissue. It is concluded that myocardial ischemia enhanced contractile response of coronary arterioles to 5-HT maybe due to the stimulated prostaglandin release (likely thromboxane A2) secondary to induction of COX-2 expression. These findings may have implications regarding the cause of coronary spasm during acute myocardial ischemia.
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PMID:Serotonin-induced human coronary microvascular contraction during acute myocardial ischemia is blocked by COX-2 inhibition. 1121 33

Slow, time-dependent, irreversible, highly selective inhibitors of COX-2 such as celecoxib, etoricoxib, rofecoxib and valdecoxib, so-called coxibs, are a new group of drugs widely used in rheumatology as well as in other fields of medicine. The tolerability of these drugs is at least equivalent to that of commonly used non-selective COX inhibitors (e.g. diclofenac, ibuprofen, naproxen). The unquestionable superiority of selective COX-2 blockade includes a low risk of gastrointestinal side effects. However, similarly to the other COX inhibitors, coxibs must be carefully administered to patients with coexistent liver and renal disease, generalised atherosclerosis, ischaemic heart disease, and to the elderly and children. Pregnancy and lactation require precise monitoring of adverse effects on the fetus, neonate and infant, or discontinuation of therapy with the drug.
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PMID:[Coxibs: highly selective cyclooxygenase-2 inhibitors. Part II. Side effects]. 1286 1

There is increasing evidence that cyclooxygenase (COX)-2 possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic cardiac myocytes (H9c2 cells) on COX-2 expression in human umbilical vein endothelial cells (HUVECs) to determine the pathway involved in COX-2 regulation. The medium from hypoxic (<1% O2) cardiac myocytes (HMCM) or normoxic cardiac myocytes (21% O2) was added to HUVEC cultures. HMCM induced a transient increase of COX-2 mRNA expression at 1 and 3 h without affecting the COX-1 mRNA level. A similar effect also observed in HMCM from cultured primary cardiac myocytes (rat neonatal cardiac myocytes). The increased COX-2 mRNA was associated with a time-dependent increase in COX-2 protein expression. COX-2 was significantly induced by VEGF (4.86 +/- 1.03-fold) and IL-1beta (3.93 +/- 0.89-fold) and slightly increased by TNF-alpha but not by FGF2, IGF-1, or PDGFs. Analysis of proteins secreted in HMCM showed increased levels of VEGF but not IL-1 beta or TNF-alpha. The HMCM-induced COX-2 expression was inhibited by the addition of an anti-VEGF neutralizing antibody. VEGF induced endothelial cell COX-2 expression by both increasing COX-2 transcription and prolonging the COX-2 mRNA half-life. Furthermore, staurosporine, a nonselective PKC inhibitor, prevented the induction of VEGF by hypoxia. Both a selective PKC-alpha and -beta inhibitor and an inducible nitric oxide synthase (NOS) inhibitor decreased the induction of COX-2 by HMCM and VEGF. Finally, HMCM-induced upregulation of COX-2 was accompanied by upregulation of PGI2 and PGE2. These results suggest that VEGF is one of the principal factors produced by hypoxic myocytes that is responsible for the induction of endothelial cell COX-2 expression. This process likely involves both PKC and NOS pathways. Our findings have important implications regarding the cardiac protection of COX-2 in ischemic heart disease.
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PMID:Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF. 1288 Dec 20

Opioids have been shown to confer late preconditioning against ischemia/reperfusion injury in several species. However, it is unknown whether gender or aging affects opioid-induced cardioprotection. Isolated perfused hearts from Fischer 344 rats were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW373U86, a delta-opioid receptor agonist, was administered s.c. at varying doses (0.1, 0.33, 1.0 mg/kg) 24 h before (BW0.1, BW0.33 and BW1.0, respectively). In 12-week-old male (YM) rats, the recovery of LV developed pressure (LVDP) after ischemia/reperfusion improved significantly in BW0.33 and BW1.0, compared with the control (C). In 78-week-old male (OM) rats, the recovery of LV function after ischemia/reperfusion improved and the total release of CK and LDH during reperfusion was attenuated in BW1.0. In 12-week-old female (YF) rats, the recovery of LV function improved only in BW0.33 but not in BW0.1 and BW1.0. The cardioprotective effect afforded by BW373U86 was completely abolished by NS-398, a COX-2 selective inhibitor, in YM, YF, and OM, although NS-398 in itself did not affect myocardial ischemia/reperfusion injury. The levels of 6-keto-PGF(1alpha) (a stable metabolite of PGI(2)) in coronary effluent during reperfusion were higher in the BW373U86-pretreated group that showed cardioprotection than in C and this increase in PGI(2) production was also inhibited by NS-398 in YM, YF, and OM. In conclusion, BW373U86-induced late preconditioning can be observed in aged and female hearts. A COX-2-dependent increase in PGI(2) production is essential for BW373U86-induced late PC in both sexes and in both young and old rats.
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PMID:Gender and aging do not impair opioid-induced late preconditioning in rats. 1468 5

The use of specific COX-2 inhibitors in place of standard nonsteroidals for the treatment of arthritis appears to reduce the risk of serious gastrointestinal toxicity in this group of patients. However, the role played by these inhibitors in the generation or exacerbation of ischaemic cardiovascular disease is less clear. Clinical studies demonstrate that hypertension can be induced or aggravated by COX-2 inhibitors to a degree similar to that which occurs with standard nonsteroidals. Endothelial dysfunction, an indicator of cardiac ischaemia, may also be exacerbated by specific COX-2 inhibition and there is much debate as to whether these changes lead to an absolute increase in ischaemic cardiac events. These effects on cardiovascular risk factors appear all the more important in patients with rheumatoid arthritis where there is an increase in the incidence of ischaemic heart disease. Here we review the available data on COX-2 inhibition and cardiovascular disease and conclude that all patients who started these agents should have a careful assessment and modification of any cardiovascular risk factors.
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PMID:Cardiovascular risk and COX-2 inhibition in rheumatological practice. 1538 47

p38 mitogen-activated protein (MAP) kinase is activated during ischemic/hypoxic myocardial injury. However, the role of activated p38 MAP kinase on cardiac function after myocardial injury is not well understood. In the present study, we investigated the cardioprotective effects of p38 MAP kinase inhibition in a rat model of acute myocardial injury, induced by subcutaneous injection of isoproterenol (ISO, 20 mg/kg/d for 3 days). A synthetic p38 alpha MAP kinase inhibitor, SD-282 (40 mg/kg) or vehicle (0.25% Tween 80 in saline) was given intraperitoneally twice a day for 3 days, concomitant with ISO treatment. Cardiac function, systolic blood pressure, gene expression including collagen I and III, fibronectin and COX-2, and the myocardial injury were analyzed. Results showed that administration of SD-282 remarkably improved ISO-induced reduction of cardiac function with increases in ejection fraction (P < 0.001), cardiac output (P < 0.05), stroke volume (P < 0.001), and cardiac index (P < 0.01). SD-282 abolished ISO-induced reduction of systolic blood pressure (106.7 +/- 2.2 versus 123.1 +/- 5.3 mm Hg, P < 0.05). The ISO-induced expression of COX-2, collagen I and III, and fibronectin genes was reduced significantly (P < 0.05 in all cases) by administration of SD-282. The myocardial injury induced by ISO was significantly reduced by the treatment of SD-282 as judged by the reduction of myocardial necrosis. Data suggest that p38 alpha MAP kinase may be involved in the pathogenesis of cardiac dysfunction in ischemic myocardial injury. Inhibition of this enzyme may improve cardiac function and protect myocardium from ischemic/hypoxic injury that occurs during ischemic heart disease.
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PMID:p38 alpha mitogen-activated protein kinase inhibition improves cardiac function and reduces myocardial damage in isoproterenol-induced acute myocardial injury in rats. 1545 58

The two cyclooxygenase isoforms (COX-1 and COX-2--coxibs) have overlapping functions and both are involved in the regulation of homeostatic and inflammatory processes in the various tissues. Treatment with highly selective COX-2 inhibitors is associated with significantly fewer serious adverse gastrointestinal events than is treatment with the dual inhibitors--the non-selective NSAIDs. Of the two coxibs, rofecoxib was shown to be much more selective than celecoxib and with less interaction with other drugs. Various clinical studies have demonstrated that the coxibs are equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator non-selective NSAIDs in osteoarthritis, rheumatoid arthritis, post surgery pain and dysmenorrhea. Perioperative use of coxibs reduces pain, opioid consumption and the risk of bleeding caused by the non-selective NSAIDs. The coxibs show similar tolerability for renal, liver and cardiothrombotic events as compared to the non-selective NSAIDs. Coxibs are contraindicated in pregnancy, in nursing mothers and pediatric patients and should be used with caution in patients with asthma. The impact of the coxibs on the cardiovascular system is controversial. However, coxibs should be used in caution and at the lowest recommended dose in patients with hypertension, ischemic heart disease and heart failure. These drugs do not interfere with the aspirin anti-platelet aggregation activity. Emerging evidence suggest that the coxibs may also find potential use as supportive therapy in various malignant tumors and intestinal polyps where COX-2 is overly expressed.
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PMID:[Is there a future for COX-2 inhibitors?]. 1560 72

CD44 is a receptor for hyaluronic acid and is found on the surface of hematopoetic cells and in mesenchymal tissue. It is also expressed on endothelial cells (EC). Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins in EC. Here we show that engagement of CD44 with signaling monoclonal antibodies (mAbs) or its natural ligand hyaluronic acid induces COX-2 and prostacyclin (PGI2) formation in human EC. This induction was blocked by mAbs that have been shown to inhibit CD44-mediated intracellular signaling. COX-1 induction was not observed after CD44 ligation. CD44-stimulated COX-2 activation/PGI2 production was accompanied by the production of the potent endothelial mitogen, vascular endothelial growth factor (VEGF) and was inhibited by a neutralizing VEGF antibody. Moreover, this COX-2 induction was also associated with an increase in EC proliferation that was inhibited by the blocking anti-CD44 mAbs and a COX-2-specific inhibitor. This is the first study to show that engagement of CD44 with mAbs or its natural ligand induces COX-2, generates VEGF, and thus leads to an increase in EC proliferation. Results from this study may have important and widespread implications for the development of novel therapeutic agents for modulating blood vessel growth during ischemic heart disease, during inflammation, or around solid tumors.
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PMID:Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and proliferation in human vascular endothelial cells. 1564 Feb 81

Owing to the selective inhibition of PGI2 synthesis, treatment with COX-2 inhibitors constitutes a potential risk for the increased occurrence of thrombotic cardiovascular incidents and of the first-time occurrence or a deterioration in pre-existing heart failure. Elderly patients, particularly those with a history of ischemic heart disease, hypertension or heart failure, are at risk. One key indication for selective COX-2 inhibitors is the chronic treatment of patients suffering from rheumatoid arthritis or osteoarthritis. However, these patients have an excess cardiovascular mortality, which relates particularly to cardiovascular incidents or heart failure. The use of nonselective antiphlogistic drugs and COX-2 inhibitors is associated with a higher potential risk in these patient groups. In essence, more than 80 million patients worldwide were treated with rofecoxib up to its voluntary withdrawal. The high number of patients who are still being treated with COX-2 inhibitors or for whom the use of COX-2 inhibitors is planned justifies the use of a biochemical marker which, as a screening instrument, is initially designed to recognize the patients who are "ill" despite the lack of symptoms. In asymptomatic patients with NT-proBNP levels below the cut-off, high-risk patients require further work-up. Recognition of these risk factors is easily accomplished considering the case history and the results of an established cardiovascular risk score (e.g. PROCAM score). These risk patients should then also be referred for intensive diagnostic work-up. On the other hand, symptomatic patients or those with high NT-proBNP levels should primarily be referred for more extensive cardiovascular diagnosis before a decision is taken concerning the use of COX-2 inhibitors. As an integral part of this extensive work-up the determination of NT-proBNP can help to improve the accuracy of diagnosis and prognostic assessment. With the exception of patients showing symptoms of an unstable coronary heart disease, imminent cerebral ischemia, uncontrolled arterial hypertension or decompensated heart failure, the use of a COX-2 inhibitor is possible provided special caution is exercised. Termination of treatment is advisable if there is a clinical deterioration of specific symptoms or signs in those patients (product information). Follow-up with NT-proBNP (monitoring) can be helpful in detecting imminent cardiac decompensation at an earlier stage in order to take suitable countermeasures.
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PMID:Rationale for testing the cardiovascular risk for patients with COX-2 inhibitors on the basis of biomarker NT-proBNP. 1571 8

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.
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PMID:Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? 1581 52

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