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)

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. Granulocytes can release a variety of molecules mediating tissue injury which act synergistically with other molecules and cells. The aim of our investigation was to evaluate the granulocyte function in patients affected by coronary artery disease (CAD) and during coronary angioplasty (PTCA). We studied 20 patients suffering from CAD. The PMN's aggregating activity was greater in the coronary sinus than in the aorta (P < 0.01). The increase in aggregating activity was evident in patients who were smokers: their cells release significantly lower quantities of leukotriene C4 (P < 0.025). In the 20 patients who underwent coronary angioplasty we analyzed superoxide release after stimulation with phorbol-myristate-acetate (PMA). The results showed a greater decrease of PMN's superoxide production in the coronary sinus than in the aorta (P < 0.05). In all patients affected by CAD we evaluated the PMN's expression of CD11b/CD18 membrane integrins. In these patients the increase in expression of CD11b/CD18 was statistically significant in comparison with the controls (P < 0.01). This increase in expression correlates with a higher aggregation (r = 0.87, P < 0.001). The potential role of leukocytes, oxygen radicals, leukotrienes and granulocyte enzymes in the pathophysiology of myocardial injury due to regional ischemia and reperfusion is an area of intense investigation. This paper presents studies carried out in vivo which have been instrumental in demonstrating the role of granulocytes as mediators of myocardial ischemia.
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PMID:Phagocyte activation in coronary artery disease. 136 45

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. Rabbit-derived antiserum-dependent reduction of circulating PMNs in the dog or using monoclonal antibody anti-CD11b/CD18 of PMNs resulted in smaller myocardial infarcts. Experience in humans shows the modification of PMN function in angina and during myocardial ischemia. In our studies, patients affected by coronary artery disease presented an increase in granulocyte aggregability in coronary sinus and showed a related higher expression of CD11b/CD18 in coronary sinus with respect to aorta leukocytes. The potential role of this modification of PMNs was analyzed.
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PMID:Correlation between CD11b/CD18 and increase of aggregability of granulocytes in coronary artery disease. 152 63

Although previous studies have demonstrated that complement (C)5a causes myocardial ischemia and mechanical dysfunction, the cardiac response of endogenously produced C5a and C5a des-Arg in zymosan-activated serum (ZAS) and the critical role of granulocytes in this process are poorly understood. Therefore, we compared the coronary and cardiac effects of ZAS and purified C5a and investigated the role of leukocyte adhesion-promoting receptors (i.e., CD11/CD18). Like purified C5a, ZAS (0.5 ml) significantly reduced coronary artery blood flow and regional segment shortening, whereas coronary venous granulocyte concentration and myocardial lactate extraction were significantly decreased. A monoclonal antibody (MoAb) to C5a/C5a des-Arg attenuated ZAS-induced cardiac alterations. Three minutes of continuous infusion of C5a or ZAS induced sustained decreases in coronary venous granulocyte concentrations, although coronary flow and segment shortening returned to control levels after 2 min. Another MoAb, IB4, directed against CD18, significantly inhibited ZAS-induced granulocyte extraction and associated cardiac effects. Thus, cardiac dysfunction occurs after activation of the complement cascade with zymosan resulting in extraction of granulocytes mediated by the CD18 adherence glycoprotein. Furthermore, intramyocardial retention of granulocytes appears necessary for the initial and full ZAS-induced cardiac dysfunction.
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PMID:Role of granulocytes and C5a in myocardial response to zymosan-activated serum. 167 37

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. A positive correlation was also found between leukocyte count and severity of coronary artery disease. Rabbit derived antiserum dependent-reduction of circulating PMNs in the dog or using monoclonal antibody anti-CD11b/CD18 of PMNs resulted in smaller myocardial infarcts. Granulocytes can release a variety of mediators tissue injury and synergize with these different mediators and other cells resulting in amplification of neutrophil stimulation and rising to additional products with enhanced endothelial injury. This paper reviews "in vivo" studies that have been instrumental in demonstrating this role of granulocytes as a mediator of myocardial ischemia. Experience in humans shows the modification of PMNs function in angina and during myocardial ischemia, and data from our group demonstrated that their aggregability is increased in the coronary sinus of patients with angiographically documented coronary disease. Upon re-perfusion PMNs accumulate and produce an inflammatory response resulting in endothelial injury. Free radicals formed during ischemia or re-perfusion produce deleterious effects on cell membranes, endothelial cell and myocardium. On the other hand the PMNs activation occurring during coronary angioplasty (PTCA) by the release of proteolytic enzymes and the generation of oxygen-free radicals, may aggravate the endothelial damage induced by PTCA and further stimulate platelets having potential implications in subsequent development of restenosis. An other aspect of PMNs function is related to leukotriene C4 release; the vasoconstrictor effect of this leukotriene on coronary arteries is synergistic with that induced by platelet-released thromboxane A2, as well as the decrease in coronary flow produced by the combination of both substances is greater than the sum of changes caused by the two eicosanoids separately administered. The potential role of leukocytes, oxygen radicals, leukotrienes and granulocyte enzymes in pathophysiology of myocardial injury due to a regional ischemia and reperfusion is an area of intense investigation. Experimental and clinical studies to elucidate these events should not only provide insights into acute and chronic pathologic tissue damage, but may also lead to the identification of important new targets of pharmacologic intervention.
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PMID:Role of granulocytes in endothelial injury in coronary heart disease in humans. 181 45

The contribution of the leukocyte, particularly the granulocyte, to the tissue injury resulting from the inflammatory response accompanying organ ischemia is a subject of intense, current interest. Leukocytes are large and viscous cells which adhere to vascular endothelium, and are a source of a variety of toxic and vasoactive substances. There are several lines of evidence indicating their involvement in the development of abnormal and heterogeneous tissue perfusion in a wide variety of pathologic states. They have been implicated in the capillary stasis and no-reflow following hemorrhagic shock, and in ischemia and reperfusion of skeletal muscle, brain, and heart. The mechanisms responsible for the detrimental influence of the granulocyte on tissue perfusion include their inherent rheologic properties, their role in the generation of vascular smooth muscle-constricting substances, and their potential for damaging vascular endothelium. One contributing aspect of the inflammatory response is leukocyte activation by products of the complement cascade. In our in vivo model system, stimulation of the granulocyte with activated complement C5a (intracoronary) is associated with myocardial ischemia and a transient myocardial accumulation of granulocytes. The enhanced generation of thromboxane A2 and leukotrienes appears to be primarily responsible for this increase in coronary vascular resistance.
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PMID:Effects of leukocyte activation on myocardial vascular resistance. 211 13

To determine if alterations in regional coronary vascular resistance could occur in the type of myocardial ischemia present in severe angina pectoris, regional perfusion and function were studied in 35 conscious sedated dogs. A stenosis producing severe hypokinesia of the perfused segment was created for 2 h on the left anterior descending coronary artery and 10 episodes of 1 min of high demand ischemia (atrial pacing at a rate sufficient to induce dyskinesia in the hypoperfused segment) were superimposed before reperfusion. The dogs were randomized into three treatment groups: control (n = 13), dipyridamole (n = 10) or WEB-2086 (n = 12), an antagonist of the effects of the endogenous platelet-activating factor. During stenosis, residual endocardial blood flow in the ischemic but nonnecrotic area averaged 0.72 +/- 0.14, 0.38 +/- 0.13 and 0.68 +/- 0.17 ml/min per g in the control, WEB-2086 and dipyridamole groups, respectively. Twenty-four hours after reperfusion, endocardial blood flow in the ischemic area was significantly lower in control dogs (1.04 +/- 0.15 ml/min per g) than in dogs treated with WEB-2086 (1.44 +/- 0.28 ml/min per g; p less than 0.03) or dipyridamole (3.00 +/- 0.83 ml/min per g; p less than 0.01). Accordingly, in control dogs, endocardial coronary vascular resistance in the ischemic area was increased after reperfusion from 85 +/- 11 to 124 +/- 27 mm Hg/(ml/min per g) (p less than 0.05) after 24 h. In contrast, coronary vascular resistance in the ischemic area remained unchanged in dogs receiving WEB-2086 (77 +/- 8 to 79 +/- 9 mm Hg/(ml/min per g); p = NS) and it decreased significantly in dogs receiving dipyridamole (72 +/- 8 to 44 +/- 8 mm Hg/(ml/min per g); p less than 0.01). Regional function after 24 h remained depressed in all three groups. These data indicate that low flow, high demand ischemia induces alterations in the subendocardial microvasculature. Such alterations in regional coronary vascular resistance might play a role in several forms of ischemic heart disease such as in severe angina, but they appear susceptible to improvement by therapeutic interventions that influence granulocyte and platelet activation.
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PMID:Alterations in endocardial vascular resistance after reperfusion in a low flow, high demand model of ischemia: effects of dipyridamole and WEB-2086, a platelet-activating factor antagonist. 225 62

Morbidity and mortality from acute coronary artery occlusion may be reduced if local myocardial adenosine concentration is augmented because 1) coronary collateral blood flow during ischemia increases with adenosine infusion, and 2) granulocytes that accumulate in the microcirculation during ischemia are, to a large extent, inhibited by adenosine from generating superoxide anion free radicals, from adhering to vascular endothelium, and from damaging endothelial cells in culture. Using a cultured lymphoblast model system, we found that 5-amino-4-imidazole carboxamide (AICA) riboside enhanced adenosine accumulation during ATP catabolism. Therefore, AICA riboside pretreatment was used in canine myocardium to selectively increase adenosine concentration in the ischemic area during 1 hour of ischemia. At 5 minutes of ischemia, endocardial flow to ischemic myocardium in saline-treated and AICA riboside-treated dogs was 0.06 +/- 0.03 and 0.34 +/- 0.11 ml/min/g, respectively (p less than 0.01); flow to nonischemic myocardium was not affected. Ventricular tachycardia and premature ventricular depolarizations were significantly attenuated in the AICA riboside-treated dogs. Blood pressure and heart rate were not affected by AICA riboside. In venous blood from ischemic tissue, adenosine increased from undetectable levels (less than 0.01 microM) to 0.22 +/- 0.08 microM in saline and 1.79 +/- 0.06 microM in AICA riboside-treated dogs, respectively (p less than 0.001). Coronary vein inosine concentrations were greater in saline than in AICA riboside-treated dogs. In separate in vitro studies, AICA riboside did not alter the removal rate of adenosine from canine blood. Indium-labeled granulocyte accumulation was significantly less in ischemic myocardium in AICA riboside-treated compared with saline-treated dogs. In addition, adenosine, but not AICA riboside, inhibited in vitro canine granulocyte superoxide production. We conclude that AICA riboside given before myocardial ischemia augments adenosine concentration, decreases arrhythmias, decreases granulocyte accumulation, and improves collateral flow to ischemic myocardium. One of the beneficial mechanisms could be an increased production of adenosine rather than inosine from ATP catabolism that causes vasodilation and inhibition of granulocytes. We propose a new hypothesis regarding regulation of the inflammatory reaction to ischemia in the microcirculation. Adenosine, in addition to its vasodilator action, is an anti-injury autacoid that links ATP catabolism to inhibition of granulocyte adherence, microvascular obstruction, and superoxide anion formation.
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PMID:Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. 255 98

Myocardial ischemia is associated with endothelial injury and an apparently insufficient generation of endothelium-derived vasodilating and platelet and white cell inhibitory mediators, such as prostacyclin (PGI2) and EDRF. This paper reviews some recent findings of our laboratory on cardioprotective effects of defibrotide, a PGI2 stimulating agent, in experimental myocardial ischemia and its possible sites of action in several in vitro assay systems. Defibrotide (32 mg/kg x h) reduced the infarct size by 50% in pigs, subjected to 1 h of coronary artery ligation followed by 3 h of reperfusion. This was associated with significant inhibition of neutrophil activation during the reperfusion period and a two-to threefold increase in cardiocoronary PGI2 generation. In vitro studies on PAF- and calcium ionophore-stimulated human granulocytes confirmed a dose-dependent (10-1000 micrograms/ml) antineutrophil effect of defibrotide (inhibition of lysosomal enzyme release) which was independent of the type of stimulus. Defibrotide (0.1 mg/ml) also inhibited superoxide anion generation from PAF stimulated neutrophils in Langendorff-perfused guinea pig hearts and was equipotent to a specific PAF antagonist (BN 52021). Defibrotide (0.1 mg/ml) did not stimulate PGI2 release from cultured porcine aortic endothelial cells but enhanced PGI2 release four- to fivefold above control if endothelial cells were coincubated with platelets. These data demonstrate a considerable cardioprotective potential of defibrotide which appears to involve endothelial protection from granulocyte-derived noxious compounds and a long-lasting stimulation of PGI2 production.
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PMID:Endothelial protection by defibrotide--a new strategy for treatment of myocardial infarction? 255 54

The influence of isosorbide dinitrate on polymorphonuclear neutrophils migration into a sterile inflammatory focus was evaluated in 12 patients with ischemic heart disease. The number of neutrophils migrated into the "skin window" increased significantly during treatment with isosorbide. Also granulocyte clearance increased in comparison with control investigation. Possible clinical implications of this phenomenon are discussed.
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PMID:[Effect of isosorbide dinitrate on neutrophil migration in vivo]. 269 25

Recent evidence indicates that mechanical obstruction of capillaries by leukocytes plays an important role in the "no-reflow" phenomenon in the heart. This entrapment of leukocytes in the microcirculation precedes their recognized role in an inflammatory reaction following ischemia. It is a fundamental rheological mechanism that may be associated with ischemic injury and reflow injury and it has not been elucidated. To explore the accumulation of granulocytes during myocardial ischemia we studied the accumulation of 111Inlabeled autologous granulocytes in acutely ischemic myocardium during 3 h of flow reduction with and without a subsequent period of reflow in open-chest dogs. Granulocytes accumulated in the ischemic endocardium of all animals and, for the majority of dogs, also in the epicardium. Accumulation in the endocardium was enhanced by reperfusion. The entrapped leukocytes may have an influence on the increase in resistance, since regional accumulation of leukocytes in the endocardium inversely correlated with ischemic blood flow during 3 h of ischemia. The tissue water content measured from the wet and dry weights of biopsies showed a significant positive correlation with the number of entrapped granulocytes. These results suggest that collateral flow is an important mechanism of leukocyte arrival early in ischemic myocardium and that reperfusion enhances granulocyte accumulation.
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PMID:Accumulation of polymorphonuclear leukocytes during 3-h experimental myocardial ischemia. 308 32


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