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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of phospholipases during prolonged myocardial ischemia could contribute to the functional derangement of myocardial cells by altering the phospholipid environment of a number of membrane bound proteins including receptors. The present study examined the kinetics of muscarinic receptor antagonist [3H]quinuclidinyl benzilate binding ([3H]QNB) to muscarinic receptors of highly purified sarcolemmal membranes under control conditions and after treatment with phospholipase A2 (PLA2; EC 3.1.1.4). Initial binding rates of QNB exhibited saturation kinetics, when plotted against the ligand concentration in control and PLA2 treated sarcolemmal membranes. This kinetic behaviour of QNB-binding is consistent with at least a two step binding mechanism. According to this two step binding hypothesis an unstable intermediate receptor-QNB complex (R*QNB) forms rapidly, and this form undergoes a slow conversion to the high affinity ligand-receptor complex R-QNB. The Michaelis constant Km of R-QNB formation was 1.8 nM, whereas the dissociation constant Kd obtained from equilibrium measurements was 0.062 nM. After 5 min exposure of sarcolemmal membranes to PLA2QNB binding capacity (Bmax) was reduced by 62%, and the affinity of the remaining receptor sites was decreased by 47% (Kd = 0.116 nM). This PLA2-induced increase of Kd was accompanied by a corresponding increase of Km, whereas the rate constants k2 and k-2 of the hypothetical slow conversion step (second reaction step) remained unchanged. These results suggest that binding of QNB to cardiac muscarinic receptors induces a transition in the receptor-ligand configuration, which is necessary for the formation of the final high affinity R-QNB complex. PLA2-induced changes of the lipid environment result in the inability of a part of the receptor population to undergo this transition, thereby inhibiting high affinity QNB-binding.
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PMID:Effect of phospholipid hydrolysis by phospholipase A2 on the kinetics of antagonist binding to cardiac muscarinic receptors. 794 23

Myocardial calcium-independent phospholipase A2 (PLA2) activity is mediated by a 400 kDa catalytic complex comprised of a tetramer of phosphofructokinase (PFK) and a 40 kDa catalytic subunit [1,2]. During myocardial ischemia, calcium-independent PLA2 activity rapidly and reversibly translocates from the cytosol to a membrane-associated compartment where it has been implicated as a mediator of ischemic damage [3,4]. Herein we demonstrate that the majority of both PFK mass and activity is translocated from the cytosol to a membrane-associated compartment prior to the onset of irreversible myocytic injury and that translocated PFK is catalytically inactive while membrane-associated. Furthermore, reperfusion of ischemic myocardium, or treatment of membranes derived from ischemic myocardium with ATP results in the conversion of both PFK mass and activity from its membrane-associated state to a soluble, catalytically-competent form. Collectively, these studies demonstrate that the concomitant changes in glycolysis and phospholipid hydrolysis during early myocardial ischemia result, at least in part, from the translocation of a common regulatory polypeptide critical in both processes.
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PMID:The rapid and reversible association of phosphofructokinase with myocardial membranes during myocardial ischemia. 811 58

A high-performance liquid chromatographic method for the assay of diacyl and plasmalogen (alk-1-enyl) phospholipid content and the determination of their fatty acid content from tissue homogenates is described. Myocardial phospholipids are rich in plasmalogens and have a high content of unsaturated fatty acids, including arachidonic acid, esterified in the sn-2 position. Using a three-stage HPLC assay we have analyzed the phospholipid subclass content and the amount of arachidonic acid esterified to these fractions extracted from isolated perfused rat hearts. After HPLC separation of total myocardial phospholipids, the phosphatidylcholine and phosphatidylethanolamine peak fractions are treated with phospholipase C to remove polar head groups and ultraviolet-absorbing benzoate derivatives are made. Separation and quantification of diacyl and plasmalogen content of the total phospholipids with nanomolar sensitivity is then achieved using isocratic elution with a silicic acid HPLC column. The separated plasmalogen and diacyl glycerobenzoates are then subjected to alkaline hydrolysis to remove fatty acids from the sn-2 position. The 2-(2,3-napthalimino)ethyltrifluoromethanesulfonate esters of the free fatty acids are then prepared and analyzed with subnanomolar sensitivity using reverse-phase chromatography with gradient elution. As plasmalogen-specific phospholipase A2 is activated during myocardial ischemia and comprises the majority of total phospholipase A2 activity in the heart, this methodology allows for a sensitive and complete determination of the changes in the mass of these phospholipids and their arachidonic acid content.
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PMID:Analysis of myocardial plasmalogen and diacyl phospholipids and their arachidonic acid content using high-performance liquid chromatography. 823 66

Myocardial ischemia in vivo is associated with dramatic electrophysiologic alterations that occur within minutes of cessation of coronary flow and are rapidly reversible with reperfusion. This suggests that subtle and reversible biochemical alterations within or near the sarcolemma may contribute to the electrophysiologic derangements. Our studies have concentrated on two amphipathic metabolites, long-chain acylcarnitines and lysophosphatidylcholine (LPC), which have been shown to increase rapidly in ischemic tissue in vivo and to elicit electrophysiologic derangements in normoxic tissue in vitro. Incorporation of these amphiphiles into the sarcolemma at concentrations of 1 to 2 mole%, elicits profound electrophysiologic derangements analogous to those observed in ischemic myocardium in vivo. The pathophysiological effects of the accumulation of these amphiphiles are thought to be mediated by alterations in the biophysical properties of the sarcolemmal membrane, although there is a possibility of a direct effect upon ion channels. Inhibition of carnitine acyltransferase I (CAT-I) in the ischemic cat heart was found to prevent the increase in long-chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmias including ventricular tachycardia and fibrillation. This review focuses on the electrophysiologic derangements that are observed during early ischemia and presents data supporting the concept that accumulation of these amphiphiles within the sarcolemma contributes to these changes. The potential contribution of these amphiphiles to the increases in extracellular potassium and intracellular calcium are examined. Finally, recent data pertaining to the accumulation of long-chain acylcarnitines on cell-to-cell uncoupling are presented. In addition to the events reviewed here, there are many other alterations that occur during early myocardial ischemia, but the results from multiple studies over the past two decades indicate that the accumulation of these amphiphiles contributes importantly to arrhythmogenesis and that development of specific inhibitors of CAT-I or phospholipase A2 may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.
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PMID:Recent insights pertaining to sarcolemmal phospholipid alterations underlying arrhythmogenesis in the ischemic heart. 826 1

Haloenol lactones are potent mechanism-based inhibitors of a novel class of calcium-independent phospholipases A2 which have been implicated as the enzymic mediators of membrane dysfunction during myocardial ischemia (Hazen, S. L.; et al. J. Biol. Chem. 1991, 266, 7227-7232). Herein we demonstrate that the ring size, hydrophobic group, and cryptic electrophile in the haloenol lactone moiety are important and modifiable determinants of the inhibitory potency of haloenol lactone-mediated inhibition of calcium-independent phospholipase A2. Direct comparisons between haloenol lactone-mediated inhibition of calcium-independent phospholipase A2 and the absence of inhibition with calcium-dependent phospholipase A2 further underscore the marked differences in the catalytic strategy employed by these two classes of intracellular phospholipases A2.
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PMID:Structural determinants of haloenol lactone-mediated suicide inhibition of canine myocardial calcium-independent phospholipase A2. 842 Dec 94

Myocardial ischemia, as well as angiotensin-converting-enzyme-inhibitors, increase cardiac concentrations of the non-apeptide bradykinin. Cardiac effects of bradykinin are potentially mediated by modulation of sympathoadrenergic neurotransmission. Accordingly, the present study was designed to examine the influence of bradykinin on exocytotic noradrenaline release from rat isolated perfused heart. Exocytotic noradrenaline release was induced by electrical field stimulation (1 min, 5 V, 6 Hz) twice to compare the effect of intervention (S2) with respective control stimulation (S1). The overflow of endogenous noradrenaline was determined by high pressure liquid chromatography and electrochemical detection. The results are expressed as the mean S2/S1 ratio+/-S.E.M. Bradykinin (1 micromol/l) evoked a significant increase in noradrenaline release (S2/S1: 1.60+/-0.12; P<0.01), which was even more pronounced after inhibition of neuronal reuptake of noradrenaline by desipramine (0.1 micromol/l: S2/S1: 1.83+/-0.15; P<0.01) excluding interference of bradykinin with the noradrenaline uptake1 carrier. The concentration-response curve for bradykinin (0.1 nmol/l to 10 micromol/l) revealed a maximum effect at 1 micromol/l and an EC50-value of 7.5 nmol/l. The effect of bradykinin was unaltered by the B1-receptor antagonist des-Arg9 (Leu8)-bradykinin (1 micromol/l; S2/S1: 1.69+/-0.17), whereas it was reduced significantly by the B2-receptor antagonist Hoe 140 (1 micromol/l; S2/S1: 1.14+/-0.11; P<0.05). Des-Arg9-bradykinin (1 micromol/l), a specific B1-agonist, had no effect on stimulation-induced noradrenaline release (S2/S1: 0.94+/-0.08). Utilizing pharmacological interventions, we attempted to characterize the intraneuronal signal transduction pathway mediating the effect of bradykinin on exocytosis. Neither inhibition of cyclooxygenase nor blockade of nitric oxide synthesis affected bradykinin-induced stimulation of noradrenaline release. Likewise, inhibition of protein kinase C by bisindolylmaleimide (1 micromol/l) or tyrosine kinase by genistein (10 micromol/l) had no effect on the promoting action of bradykinin. In contrast, inhibition of cytosolic phospholipase A2 activity by the specific inhibitor AACOCF3 (1 micromol/l) prevented bradykinin-induced increase in noradrenaline release (S2/S1: 1.09+/-0.15; P<0.01). In conclusion, bradykinin increases exocytotic release of endogenous noradrenaline from cardiac sympathetic neurons via activation of presynaptic B2-receptors. Intraneuronal coupling of B2-receptors to phospholipase A2 appears to mediate the facilitatory effect of bradykinin on noradrenaline release in rat heart.
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PMID:Bradykinin B2-receptor-mediated stimulation of exocytotic noradrenaline release from cardiac sympathetic neurons. 929 78

Activation of phospholipase A2 (PLA2) and accumulation of lysophosphatidylcholine contribute importantly to arrhythmogenesis during acute myocardial ischemia. We examined thrombin stimulation of PLA2 activity in isolated ventricular myocytes. Basal and thrombin-stimulated cardiac myocyte PLA2 activity demonstrated a distinct preference for sn-1 ether-linked phospholipids with arachidonate esterified at the sn-2 position. The majority of PLA2 activity was calcium independent and membrane associated. Thrombin stimulation of membrane-associated PLA2 occurs in a time- and concentration-dependent fashion. An increase in PLA2 activity was also observed using the synthetic peptide SFLLRNPNDKYEPF (the tethered ligand generated by thrombin cleavage of its receptor). Bromoenol lactone, a selective inhibitor of calcium-independent PLA2, completely blocked thrombin-stimulated increases in PLA2 activity and arachidonic acid release. No significant inhibition of thrombin-induced PLA2 was observed following pretreatment with mepacrine or dibucaine. These data confirm the presence of high-affinity thrombin receptors on isolated cardiac myocytes and demonstrate the specific activation of a unique membrane-associated, calcium-independent PLA2 following thrombin receptor ligation.
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PMID:Thrombin activates a membrane-associated calcium-independent PLA2 in ventricular myocytes. 948 35

Accelerated phospholipid catabolism occurs early after the onset of myocardial ischemia and is likely to be mediated by the activation of one or more phospholipases in ischemic tissue. We hypothesized that hypoxia increases phospholipase A2 (PLA2) activity in isolated ventricular myocytes, resulting in increased lysophospholipid and arachidonic acid production, contributing to arrhythmogenesis in ischemic heart disease. The majority of ventricular myocyte arachidonic acid was found in plasmalogen phospholipids. Hypoxia increased membrane-associated, Ca2+-independent, plasmalogen-selective PLA2 activity, resulting in increased arachidonic acid release and lysoplasmenylcholine production. Pretreatment with the specific Ca2+-independent PLA2 inhibitor bromoenol lactone blocked hypoxia-induced increases in PLA2 activity, arachidonic acid release, and lysoplasmenylcholine production. Lysoplasmenylcholine produced action potential derangements, including shortening of action potential duration, and induced early and delayed afterdepolarizations in normoxic myocytes. The electrophysiological alterations induced by lysoplasmenylcholine would likely contribute to the initiation of arrhythmogenesis in the ischemic heart.
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PMID:Selective hydrolysis of plasmalogen phospholipids by Ca2+-independent PLA2 in hypoxic ventricular myocytes. 961 Nov 39

Recent clinical trial evidence supports an inflammatory etiology in acute ischemic heart disease. When a segment of coronary artery becomes inflamed, important cytokines, such as tissue factor, are released, facilitating thrombosis. Serum inflammatory markers are elevated in most acute coronary syndrome patients at presentation. Mortality risk has been shown to be associated with increased levels of high-sensitivity C-reactive protein (CRP), interleukin 6, and serum vascular cell adhesion molecule. Platelets, which are rich in inflammatory mediators (CD40 and its ligand thrombospondin, and phospholipase A2), also supply important triggers for the inflammatory cascade. In addition, more than 35 platelet-associated messenger ribonucleic acid mediators involved in arterial injury and inflammation have been found. The use of biomarkers of inflammation, such as CRP, and of the sequelae of embolization, such as troponin, provide a window into the underlying pathophysiology of acute ischemic heart disease. New agents from three distinct drug classes have recently flooded the therapeutic armamentarium. Decision-making is further complicated by the choice of an invasive (aggressive) or a medical (conservative) strategy of management with respect to coronary revascularization. For patients at highest risk, aspirin, beta-blockers, nitrates, and a statin should be given, and clopidogrel, enoxaparin, a glycoprotein (GP) IIb/IIIa inhibitor, plus an invasive strategy should be considered. For intermediate- and low-risk patients, a "sliding-scale" approach may be best. Decisions about the three classes of antithrombotics--low-molecular-weight heparins, GP IIb/IIIa inhibitors, and thienopyridines--along with whether to adopt an early invasive strategy, should be made on an individual basis.
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PMID:A guide to therapeutic decision-making in patients with non-ST-segment elevation acute coronary syndromes. 1264 50

As detailed in previous reviews, phospholipase A2 (PLA2) enzymes belonging to the secretory PLA2 (sPLA2), cytosolic PLA2 (cPLA2), and Ca2+-independent PLA2 (iPLA2) families may play specific physiologic and pathologic roles. In the past two years, there have been considerable advances in the understanding of the regulatory functions of individual PLA2s. This short article focuses on the latest topics in the PLA2 field, which have offered new insights into this intriguing enzyme family. Specifically, I describe a novel cellular action and unexplored in vivo functions of sPLA2, expanding regulatory aspects of cPLA2, and unique functional roles of iPLA2 in apoptosis, Ca2+ homeostasis, and myocardial ischemia.
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PMID:Hot topics in phospholipase A2 field. 1530 17


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