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)

The effects of arachidonic acid (AA) and its metabolites on the conductance (gj) of the gap junctions between neonatal rat myocardial cells was investigated. AA reduced gj in a dose- (2, 5, and 20 microM) and time-dependent fashion. Pretreatment of the cells with an inhibitor of the 5-lipoxygenase pathway, U-70344A, shifted the dose-response curve to the right; pretreatment with indomethacin, an inhibitor of the cyclooxygenase pathway, had no effect. The mean time to uncoupling was 3.7 +/- 0.3, 3.8 +/- 0.9, and 4.6 +/- 0.6 min (means +/- SE, P less than 0.05) for 5 microM AA, 5 microM AA + indomethacin, and 5 microM AA + U-70344A, respectively. Incorporation of AA into membrane phospholipids was not affected by the inhibitor. These studies suggest that complete uncoupling of the cells occurred at membrane concentrations of 3-4 mol%. The data indicate that AA and a 5-lipoxygenase metabolite uncouple neonatal rat heart cells. The data are discussed with respect to the possible underlying mechanism of uncoupling and the potential role of gap junctions in arrhythmia formation in ischemic heart disease.
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PMID:Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte pairs. 151 93

Polymorphonuclear granulocytes PMN) are suggested mediators of myocardial ischemia-reperfusion injury. We have previously shown that activated PMN producing oxygen free radicals (OFR) in the coronary circulation are cardiodepressive. OFR may induce lipid peroxidation and production of eicosanoids. We have investigated the influence of cyclo-oxygenase and lipoxygenase inhibitors on the effects of activated, OFR producing PMN in the Langedorff rat heart model. Left ventricular developed pressure (LVDP) was measured by a balloon in the left ventricle. Human PMN and drugs were given into the aortic cannula for 10 min and the hearts were observed for 30 min thereafter. After infusion for 5 min OFR production in the cellular infusate was measured at the level of the aortic cannula by a chemiluminescence (CL) technique. Phorbol 12-myristate 13-acetate (PMA)-activated PMN (n = 8), produced a CL response of 27649 +/- 11048 counts (mean +/- S.E.M.), and reduced coronary flow (CF) to 53 +/- 6% (mean +/- S.E.M.) and LVDP to 38 +/- 9% of baseline values at the end of the observation period. Ibuprofen (n = 6), a cyclooxygenase (CO) inhibitor, neither influenced the CL response (31915 +/- 7563) of activated PMN, nor the reduction of CF and LVDP at this time. Although both BW 755C (n = 7), a dual inhibitor of CO and lipoxygenase (LO) (CF:90 +/- 4%, LVDP:99 +/- 6%) and diethylcarbamazine (DCM) (n = 8), a LO inhibitor (CF:88 +/- 11%, LVDP:87 +/- 4%), significantly inhibited the cardiodepressive effects of activated PMN. BW 755C alone abolished the CL response (431 +/- 158 counts), whereas DCM had no effect on CL (30105 +/- 1698 counts).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen free radical producing leukocytes cause functional depression of isolated rat hearts: role of leukotrienes. 211 68

The activation and accumulation of leukocytes during inflammatory processes such as that initiated by myocardial ischemia and reflow appear to be major determinants of irreversible tissue injury. Myocardial salvage by dual cyclooxygenase/lipoxygenase inhibitors and selective 5-lipoxygenase inhibitors has suggested a role for lipoxygenase (LOX) products, such as the potent chemotactic factor leukotriene B4, in ischemia-reflow injury. However, many LOX inhibitors are antioxidants and several have been shown to directly inhibit neutrophil function in vitro, thereby questioning the role of LOX products in reperfusion injury. To clarify further the protective mechanism of lipoxygenase inhibitors, we have examined the effects of two nonantioxidant inhibitors, SK&F 86002 and REV-5901, on human neutrophil activation and function in vitro. The antioxidant LOX inhibitor nordihydroguiaretic acid, which served as a positive control, exhibited a concentration-dependent inhibition of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and recombinant C5a-induced neutrophil bipolarization, fMLP-induced upregulation of the adherence glycoprotein Mac-1 (CD11b/CD18), fMLP-induced aggregation and neutrophil adherence to and migration through interleukin-1-stimulated human endothelial monolayers. In contrast, neither SK&F 86002 nor REV-5901 (in concentrations up to 50 microM) had any effect on these functions, nor did they inhibit neutrophil oxidative metabolism (phorbol myristate acetate-induced chemiluminescence). Inasmuch as both of these agents have been observed to reduce myocardial ischemia-reflow injury in vivo, their failure to directly inhibit neutrophil function further supports an important role for chemotactic LOX products in the pathogenesis of reperfusion injury.
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PMID:Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. 215 49

Neutrophils have been implicated in the genesis of myocardial ischemia-reperfusion injury, and their mechanism of action has been linked to the production of reactive oxygen species, fatty acid-derived prostanoids, and leukotrienes. In this study, we examined the potential relation between production of reactive oxygen species and cyclooxygenase-derived autacoids by studying the effects of superoxide dismutase (SOD) and catalase (CAT) on the rise in thromboxane formation observed with myocardial ischemia and reperfusion. Immunoreactive thromboxane B2 was measured in cardiac lymph from conscious dogs during reperfusion after a 60-minute occlusion in the presence of infusions of SOD alone, CAT alone, and a combination of SOD and CAT. Reperfusion after 60 minutes of ischemia causes an immediate elevation in thromboxane B2. SOD and CAT infusion prevented this rise in thromboxane B2 as did infusion of SOD alone. The ability of SOD-CAT to suppress thromboxane B2 production dissipated within 3 hours after the cessation of infusion, at which time thromboxane B2 excretion increased. The modulation of fatty acid oxygenases by reactive oxygen species may be a very important pathogenic factor in considering the origin of the protective effect of antioxidants in the setting of myocardial ischemia-reperfusion injury.
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PMID:Thromboxane B2 in cardiac lymph. Effect of superoxide dismutase and catalase during myocardial ischemia and reperfusion. 231 86

The anti-ischemic effects of nafazatrom (10 mg/kg intraduodenally) have been studied in a canine model of myocardial infarction. Nafazatrom was given 30 min before and 2 h after occlusion of the left anterior descending coronary artery (LAD). Effects were compared with those after intravenous indomethacin (10 mg/kg) treatment. Infarct size was measured at 6 h of coronary occlusion by postmortem tetrazolium staining. Myocardial ischemia was reduced after nafazatrom administration, whether related to total left ventricle (18 +/- 3.3 vs. 30.7 +/- 4.8%; p less than 0.05) or to the LAD vessel area at risk for infarction (51.4 +/- 4.0 vs. 82.5 +/- 4.5%; p less than 0.01). Salvage with nafazatrom occurred in the subepicardial and endomural tissues without lateral protection. Indomethacin had no effects on infarction. The LAD occlusion-induced hemodynamic consequences were reduced at 15 min by nafazatrom and remained unchanged by indomethacin. During the following experimental course, no differences were noted between the groups. At 6 h, blood flow in the nonoccluded circumflex artery increased by 12.6 +/- 3.2 ml/min (p less than 0.05) following nafazatrom treatment. Thus, nafazatrom reduced ischemia by a mechanism unrelated to changes in hemodynamics. Most likely, this was due to 5-lipoxygenase inhibition. This may shift arachidonic acid metabolism to cyclooxygenase products and prevent release of deleterious lipoxygenase products by neutrophils during ischemic injury.
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PMID:Effects of nafazatrom and indomethacin on experimental myocardial ischemia in the anesthetized dog. 241 12

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

Eicosanoids represent a family of compounds derived primarily from arachidonic acid. It is now known that arachidonic acid can undergo metabolism via at least three distinct pathways, although the most readily understood are those resulting in prostaglandin or leukotriene formation via cyclooxygenase and 5-lipoxygenase, respectively. These products can be synthesized by the heart or can be released from accumulating neutrophils under various pathological conditions. Eicosanoids possess a wide array of pharmacological actions that could be of importance either in the initiation or modulation of various cardiac diseases. Here, we review the potential importance of eicosanoids to ischemic heart disease. Data are cited that examine the potential importance of these compounds to experimentally induced cardiac injury as well as clinically observed ischemic heart disease. Particular emphasis is placed on recent studies that document the relevance of endogenously synthesized arachidonic acid metabolites as well as the consequence of modulating eicosanoid synthesis through pharmacological or dietary means on cardiac injury under experimental or clinical situations.
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PMID:Synthesis and relevance of cardiac eicosanoids with particular emphasis on ischemia and reperfusion. 268 54

A simple method of measuring the biological effect of acetylsalicylic acid (ASA), based on the determination of the disaggregation rate (DR) of platelet aggregation induced by adenosine diphosphate (ADP), is described. The DR was found to correlate with the inhibition of the production of malondialdehyde (MDA) by platelets (r = 0.66, P less than 0.001). Therefore, the DR was used for laboratory monitoring of the ASA effect. The study included 63 arteriosclerotic patients--patients with ischemic heart disease (IHD), peripheral arterial disease (PAD), or cerebrovascular insufficiency (CVI) -- who were analyzed before treatment and after receiving ASA in an individually controlled dosage. Before treatment the authors found an increased level of MDA and a longer euglobulin clot lysis time in patients when compared with healthy volunteers (n = 16). Extremely different doses of ASA were required to normalize initially elevated MDA levels in patients. Normalization of the MDA level corresponds to a DR of at least 50% (in comparison with 0-13% without treatment). When judging the ASA dose individually from the 50% DR, the authors demonstrated that there were no differences in the levels of cyclooxygenase- and lipoxygenase-derived eicosanoids between healthy volunteers (n = 16) and arteriosclerotic patients receiving 100-250 mg (n = 18), 500 mg (n = 17), or 750-1500 mg ASA per day (n = 6). Thus, their results support the idea of using individually controlled ASA as the most promising way of resolving the "aspirin dilemma" and provide a simple and reproducible method of measuring the biological effect of ASA.
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PMID:Individually controlled aspirin in the long-term treatment of patients with chronic arterial diseases. 270 48

Dietary intake of unsaturated fatty acid of eicosapentaenoic acid (EPA) is thought to reduce the size and incidence of myocardial infarction. These beneficial effects are postulated to be due to chronic antithrombotic properties of EPA itself. We studied the possible direct effects of EPA on vascular smooth muscle as well as the ability of EPA to modify the vasoactivity of constrictor mediators in rabbit and cat aortic rings and isolated cat coronary arteries. EPA concentration-dependently (30 to 300 microM) relaxed rabbit and cat aortic rings having an intact endothelium, while EPA did not show any significant vasodilator effects on rings without an endothelium. This EPA-induced vasorelaxation was not altered by the cyclooxygenase inhibitor ibuprofen, but was totally abolished by the guanylate cyclase inhibitor methylene blue, indicating an endothelium-dependent smooth muscle relaxation mechanism. In isolated perfused cat coronary arteries, EPA (3 to 300 microM) exerted a dilator effect which was endothelium-independent and not affected by ibuprofen. The response was attenuated by propyl gallate, a lipoxygenase inhibitor. EPA also inhibited leukotriene (LT) C4, (50 nM) and LTD4 (50 nM)-induced vasoconstriction of isolated cat coronary arteries ranging from a blockade of 10% to 15% (P less than 0.05) at 3 microM of EPA to a blockade of 89% to 93% (P less than 0.01) at 300 microM. In contrast, the thromboxane analog, CTA2, induced coronary constriction was not significantly altered by EPA. Thus, EPA produces endothelium-dependent relaxation in rabbit and cat aorta and endothelium-independent vasodilation in cat coronary arteries (i.e., intact vessels or helical strips). Moreover, EPA exerts acute anti-leukotriene actions in coronary arteries. In the case of long-term dietary intake of EPA, these actions may contribute to the protective action of EPA in myocardial ischemia.
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PMID:Vasoactive effects of eicosapentaenoic acid on isolated vascular smooth muscle. 303 70

In the present studies, we demonstrate in buffer-perfused isolated working guinea pig hearts that indometacin reduces coronary flow rate in a dose-dependent manner (max 56.7 +/- 5.5%, SEM, n = 6, of control at 5 x 10(-6) mol/l of indometacin, P less than 0.01), and that this leads to a development of heterogeneous patterns of myocardial ischemia (elevated myocardial levels of reduced pyridine nucleotide, NADH) and depressed cardiac work (64.7 +/- 11.7%, SEM, of control at 5 x 10(-6) mol/l of indometacin, P less than 0.05). The effect of indometacin on coronary flow rate and consequently on myocardial tissue oxygenation was completely prevented by the preferential 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) (1 x 10(-6) mol/l), or the sulfidopeptide leukotriene receptor antagonist FPL 55712 (2 x 10(-5) mol/l), indicating that the isolated working guinea pig heart, even when deprived of blood, is able to produce vasoactive sulfidopeptide leukotrienes at significant levels. At higher concentrations of indometacin (5 x 10(-5) mol/l, 1 x 10(-4) mol/l), coronary flow rate returned to initial levels while cardiac work became further depressed despite normoxic levels of NADH. These data support that indometacin also has a direct suppressive effect on the myocardium independent of its coronary vascular effect. This conclusion is supported by the observation that addition of sodium arachidonate (6 x 10(-5) mol/l) completely inhibited the vascular effect of indometacin, but not the depressive effect on the myocardium. The divalent cation ionophore A23187 (6 x 10(-6) mol/l) had a strong positive chronotropic effect on the heart and a biphasic effect on coronary flow rate. After a brief period of increased coronary flow rate, presumably due to coronary vasodilatation, the ionophore caused a sustained reduction in coronary flow, and this was accompanied by high myocardial levels of NADH fluorescence of characteristically heterogeneous pattern. This is presumably caused by vasoconstrictory effects of elevated levels of intracellular Ca2+ of vascular smooth muscle, independent of stimulation of 5-lipoxygenase or cyclooxygenase pathways, since neither indometacin nor nordihydroguaiaretic acid modified the effect of A23187.
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PMID:Modulation of coronary flow rate and cardiac contractility by the divalent cation ionophore A23187 and inhibitors of the cyclooxygenase and 5-lipoxygenase pathways: development of heterogeneous patterns of myocardial ischemia. 313 May 82


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