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)

Hyperacute renal allograft rejection is initiated by primary immune injury to vascular endothelium and is propagated by secondary vasoconstriction, platelet aggregation and intravascular coagulation. Previous dissociation of these primary and secondary events, with graft survival in one human, suggested that the more usual graft failure was due to secondary injury. As a basis for further modification studies, this primate model most closely resembled its counterpart in man, as the onset and intensity of functional, morphologic and biochemical alterations were similar. Unmodified allografts failed within 5 minutes. The earliest and most abnormal finding was marked reduction in renal blood flow affecting all compartments. By 5 minutes, histologic changes of hyperacute rejection as well as antibody and faint C3 deposits were noted, but biopsies suggested that the initial flow reduction was more likely due to vasoconstriction, which was then followed by vascular obstruction. Glomeruli appeared most damaged, but at the highest antibody titer arterial injury was more prominent. Early red cell sequestration and stasis was marked, followed by progressive platelet clumping and neutrophil infiltration. While the decline in renal venous C3 levels was prompt, as in man, early intrarenal activation of the coagulation, fibrinolytic and kinin-forming systems could not be demonstrated, and fibrin formation was sparse by light and fluorescence microscopy. Qualitatively similar histologic and functional alterations were noted in autograft controls. While the initiating event was unclear and may have been accentuated by the arteriovenous shunts utilized, the final mechanism was probably marked vasoconstriction with renal ischemia. Intrarenal C3 consumption was an important finding and was not associated with tissue deposits of antibody or complement; it may provide a parallel with the progressive complement-mediated injury associated with acute myocardial ischemia noted by others. Endothelial injury was not seen in arteries, and all alterations were delayed in onset and progressed more slowly than in allografts. These findings may elucidate the mechanism of early malfunction of most autografts. Treatment of additional autografts with increasing doses of heparin progressively reversed these changes and even prevented the initial reduction in blood flow. Therefore, many alterations consistent with hyperacute rejection which are probably immediately responsible for graft failure can also be initiated by nonspecific, nonimmunologic events and, where injury is less intense, can be prevented pharmacologically. This model provides a means of dissecting the injurious events and subsequent evaluation of the effectiveness and interaction of various agents on the damaging secondary alterations which occur during hyperacute rejection.
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PMID:A primate model of hyperacute renal allograft rejection. 109 89

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.
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PMID:Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion. 141 1

Oxygen free radicals are highly reactive compounds causing peroxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias. Free radical accumulation has been measured in ischemic and reperfused myocardium directly using techniques such as electron paramagnetic resonance spectroscopy and tissue chemiluminescence and indirectly using biochemical assays of lipid peroxidation products. Potential sources of free radicals during ischemia and reperfusion have been identified in myocytes, vascular endothelium, and leukocytes. In several different experimental models exogenous free radical-generating systems have been shown to produce alterations in cardiac function that resemble the various reperfusion abnormalities described above. Injury to processes involved in regulation of the intracellular Ca2+ concentration may be a common mechanism underlying both free radical-induced and reperfusion abnormalities. Direct effects of free radicals on each of the known Ca(2+)-regulating mechanisms of the cell as well as the contractile proteins and various ionic membrane currents have been described. Free radicals also inhibit critical enzymes in anaerobic and aerobic metabolic pathways, which may limit the metabolic reserve of reperfused myocardium and contribute to intracellular Ca2+ overload. Inhibiting free radical accumulation during myocardial ischemia/reperfusion with free radical scavengers and inhibitors has been demonstrated to reduce the severity of myocardial stunning, irreversible injury, and reperfusion arrhythmias in many, but not all, studies. This evidence strongly implicates free radical accumulation during myocardial ischemia/reperfusion as an important pathophysiological mechanism of reperfusion abnormalities, although many issues remain unresolved.
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PMID:Oxygen free radicals and cardiac reperfusion abnormalities. 161 47

The time course of the effects of permanent myocardial ischemia without reperfusion on the coronary vascular endothelium and myocardium were investigated in anesthetized cats. The left anterior descending (LAD) coronary artery was occluded for 1.5, 3.0, 4.5, or 6.0 h. Coronary rings from the ischemic LAD and the nonischemic left circumflex (LCX) arteries were tested for their responsiveness to the endothelium-dependent vasodilators acetylcholine (ACh, 0.1-100 nM) and the calcium ionophore A23187 (1-1,000 nM), and the endothelium-independent vasodilator sodium nitrite (NaNO2, 0.1-100 microM). Vasorelaxation was not significantly impaired in response to ACh after 1.5 h of ischemia and only moderately impaired after 3.0 h of ischemia (63 +/- 5% of control). However, after 4.5 h of ischemia the ACh-induced response was decreased to 33 +/- 4% of control and further declined to 31 +/- 4% of control after 6.0 h (P less than 0.001 from 1.5 h). There was no significant decrease in LCX ring vasorelaxant responses to vasodilators at all times, and the LAD rings only showed a moderately decreased response to NaNO2 after 6.0 h of ischemia (82 +/- 4% relaxation, P less than 0.05). Transmission electron microscopy revealed very little endothelial damage at 4.5 and 6.0 h, with only some subendothelial swelling noted. Damage to the myocardium did not become significant until after 4.5 h of ischemia, and cardiac myeloperoxidase activity, indicative of neutrophil accumulation, was not significant at any time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Time course of endothelial dysfunction and myocardial injury during coronary arterial occlusion. 165 39

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. 203 71

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

Recent investigations of the complex interactions among vascular endothelium, platelets and leukocytes have relevance to the pathogenesis of atherosclerosis and ischemic heart disease. Perturbations in the hemodynamic equilibrium maintained by these cellular elements may lead to vasospasm, in vivo thrombosis and a reduction in blood flow. Recent advances in the understanding of these interactions in health and disease states are summarized. The effect of pharmacologic agents on these cell-cell interactions are discussed to provide the reader with a general understanding of the relevance of these interactions in cardiovascular disease.
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PMID:Endothelial, platelet and leukocyte interactions in ischemic heart disease: insights into potential mechanisms and their clinical relevance. 201 65

The nature, mechanism of action, and roles of endothelium-derived relaxant factor (EDRF) are reviewed, particularly in relation to the coordination of vascular behavior in response to changes in flow, coronary spasm, and platelet aggregation. Vascular endothelium performs a multiplicity of roles. It is an active sieve for macromolecules and leukocytes, a negatively charged "lubricant" for passage of negatively charged red cells and platelets, and a factory for Von Willebrand factor, glycoaminoglycans, and plasminogen activator and its inhibitor. It is also a processing plant that metabolizes adenosine nucleotides to adenosine and activates angiotensin. Endothelium also produces prostacyclin and endothelium-derived relaxant factor, which act synergistically and through different pathways to the common ends of relaxing vascular smooth muscle and inhibiting platelet aggregation. Most recently it has been shown to also produce a constrictor agent called endothelin, a peptide whose structure has now been elucidated. This review will concentrate on EDRF, the recently discovered vasodilator agent that is continuously released by all vascular endothelium. It would be premature to define the role of EDRF in ischemic heart disease. It may, however, be timely to consider the ways in which EDRF might be relevant, based on a review of what is at present known.
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PMID:Vascular endothelium in ischemic heart disease: possible role for endothelium-derived relaxing factor. 248 97

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

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


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