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)

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI2 were studied. Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F 1 alpha, the stable end product of PGI2, was less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets circulating during evolving myocardial infarction ("ischemic platelets") were hyperaggregable in response to ADP and relatively resistant to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI2 were diminished. The platelet hyperreactivity, expressed by plasma beta-TG, platelet aggregation, and PGI2-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in "platelet fatigue," indicated by decreased contents of beta-TG of the ischemic platelet and decreased TxA2 production in response to collagen. However, the ischemic platelet produced twice normal TxA2 in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA2 was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI2 was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suppression of platelet function and requires significantly greater doses of PGI2 than normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Systemic and transcardiac platelet activity in acute myocardial infarction in man: resistance to prostacyclin. 293 81

Plasma prostanoids and levels of cyclic nucleotides were studied in forty-nine outpatients with precordial pains and subjected to the treadmill exercise test. Blood samples were drawn before, immediately after and 30 minutes after exercise, from antecubital veins. Plasma TXB2, 6-keto PGF1 alpha, cyclic AMP and cyclic GMP levels were measured by radioimmunoassay. The results of exercise tests were evaluated according to the treadmill exercise score (TES) of Hollenberg et al. Patients were divided into two groups; those with TES (-) with ischemic findings in exercise and those with TES (+) with normal exercise response. There were no differences in TXB2 levels between the two groups before exercise. Immediately after exercise statistically significant differences in TXB2 levels were present between the two groups. There were increased levels in the TES (-) group and decreased levels in the TES (+) group (p less than 0.01). Although the 6-keto PGF1 alpha levels were the same between the two groups before exercise, 6-keto PGF1 alpha levels in the TES (+) group increased significantly immediately after exercise. Similar changes were noted in the case of cyclic nucleotides, and the differences increased immediately after exercise. We conclude that high responses of cyclic nucleotides and PGI2 are required to counteract increases in levels of TXA2 and diminution of these responses may be an important phenomenon involved in the physiological status of ischemic heart disease.
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PMID:Plasma thromboxane B2, 6-keto PGF1 alpha and cyclic nucleotides levels as related to treadmill exercise test in patients with ischemic heart disease. 298 50

Calcium-channel blockers inhibit human platelet aggregation in vitro and ex vivo. To further evaluate the mechanism(s) responsible for the inhibition induced by this structurally heterogeneous group of compounds, we studied the effect of nifedipine and verapamil on human platelet aggregation in vitro. Neither 10 microM nifedipine nor 10 microM verapamil consistently inhibited the aggregation response of platelet-rich plasma to threshold concentrations of ADP, sodium arachidonate, epinephrine, or collagen. However, both 10 microM nifedipine and 10 microM verapamil epinephrine-potentiated, thromboxane A2 (TXA2)-induced aggregation of aspirin-incubated, gel-filtered platelets. Aggregation of similarly prepared platelets induced by TXA2 alone was abolished by 10 microM nifedipine but not by 10 microM verapamil. Even 100 microM verapamil gave only partial and inconsistent inhibition of aggregation. Both drugs had essentially the same effects on platelet aggregation induced by the stable endoperoxide and TXA2 mimic, U46619, with or without epinephrine. Neither 10 microM nifedipine nor 10 microM verapamil elevated platelet cyclic AMP. Verapamil (10 microM) inhibited binding of [3H]-yohimbine (an alpha 2-adrenergic receptor antagonist) to intact human platelets (KD 10.5 nM vs 2.4 nM for control platelets) without altering the number of binding sites. In contrast, 10 microM nifedipine had no effect on KD or number of binding sites. These results indicate that nifedipine and verapamil inhibit epinephrine-potentiated, TXA2-induced human platelet aggregation by different mechanisms. Verapamil inhibits the epinephrine contribution to the aggregation response by blocking alpha 2-adrenergic receptor binding. Nifedipine blocks the platelet response to TXA2 without affecting alpha-adrenergic receptor binding. These observations have potential clinical implications with regard to the mechanisms by which calcium-channel blockers inhibit vascular spasm and myocardial ischemia.
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PMID:Disparate effects of the calcium-channel blockers, nifedipine and verapamil, on alpha 2-adrenergic receptors and thromboxane A2-induced aggregation of human platelets. 300 84

To investigate whether slow Ca2+ channel blockers protect against development of changes in properties of the sarcolemma and in the tissue ultrastructure during myocardial ischemia, nifedipine was administered prior to occlusion (up to 3 hours) of the left anterior descending coronary artery in anesthetized pigs. Intravenous doses which reduced arterial blood pressure by 20-25%, had no effect on the time-dependent reduction of Ca2+-calmodulin and cyclic AMP-dependent 32P incorporation into sarcolemmal phospholamban-like protein. Nifedipine blocked the reduction in the activity of sarcolemmal 5'-nucleotidase. Nifedipine had no significant effect on the long-chain fatty acylcarnitine accumulation in sarcolemma. A marked delay in the appearance of ultrastructural indicators of irreversible tissue injury in subepicardial myocardium was observed, when nifedipine was infused. Particularly the reduced appearance of electron-dense bodies in mitochondria suggested a reducing effect of nifedipine on cellular net gain of Ca2+. Apparently, ischemia-induced loss of the ability of the proteinkinases to incorporate phosphate into sarcolemmal phospholamban-like protein is not a process secondary to Ca2+ overload of the myocardium. The involvement of accumulation of long-chain fatty acylcarnitine within the sarcolemma may also be excluded. The membrane defect as indicated by a change in phosphorylation-mediated control of Ca2+ transport may itself be associated with the development of ischemia (-reperfusion)-induced Ca2+ overload.
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PMID:The effect of nifedipine on ischemia-induced changes in the biochemical properties of isolated sarcolemmal vesicles and the ultrastructure of myocardium. 303 May 20

The effect of cibenzoline, an antiarrhythmic drug, on myocardial ischemia was studied in the anesthetized open-chest dog. Ischemia was induced by completely ligating or partially occluding the left anterior descending coronary artery. The levels of ATP and creatine-phosphate decreased, and the ADP and AMP levels increased during ischemia. The level of glycogen was also decreased, and that of lactate was increased by ischemia, resulting in myocardial acidosis. Pretreatment with either 2 mg/kg or 8 mg/kg of cibenzoline prevented the decrease in ATP level and the increase in lactate level. These results suggest that cibenzoline reduces the influence of ischemia on the myocardium.
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PMID:[Effects of cibenzoline on myocardial ischemia]. 324 14

When glucose-insulin-potassium (GIK) is infused, glucose supplies most of the energy demands of the heart. Fatty acid becomes the major substrate during fasting, pathologically increased work loads or insulin deficiency. Myocardial purine breakdown reflects myocardial energy status and influences coronary tone. Ischemia accelerates breakdown of ATP to AMP, which is further metabolized to adenosine, which causes vasodilatation and a blunted response to catecholamines. If normal circulation is restored, ADP and AMP are rapidly converted to ATP and purine metabolism is changed from degradation to salvage and de novo synthesis of purines. Ischemia impairs mitochondrial function, causing decreased capacity to oxidize fatty acids once aerobic conditions return. Thus, reperfusion with elevated plasma free fatty acids results in acyl-CoA accumulation in the heart. In diabetic animals, phosphorylation of AMP to ATP is defective in the heart, and AMP degradation is increased. Therefore, careful regulation of the blood sugar with concomitant lowering of plasma free fatty acids in diabetics with ischemic heart disease should improve myocardial salvage by preserving and repleting myocardial ATP. Thus, along with reestablishment of coronary flow and reduction in myocardial oxygen demands, may significantly reduce the morbidity of acute ischemia in diabetics.
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PMID:Myocardial fuel and energy balance, acute ischemia and diabetes. 328 57

Changes in compartmentation and specific mechanism in acute myocardial failure due to global ischemia and in regional myocardial ischemia in dog hearts are described. Ischemic failure was produced by periodic arrest of flow to supported heart preparations perfused with a fluorocarbon (FC-43). Sarcolemmal vesicles (SL) prepared from ischemic failing heart preparations exhibited diminished Ca++ binding and phosphorylation. TA-064, a beta-1-agonist partially abolished the reduction in Ca++ binding and phosphorylation of SL vesicles. The addition of cyclic-AMP (cAMP) and of protein kinase (PK) increased phosphorylation of SL vesicles obtained from non failing heart preparations. Combination of cAMP and of PK had the greatest effect. In contrast to myocardial failure, myocardial infarction is known to produce a large variety of specific disturbances in intermediary cardiac metabolism. Apparently in ischemic failing heart preparations, Ca++ binding and phosphorylation by SL are deficient. The results with TA-064 and isoproterenol suggest that phosphorylation of SL may play a role in the positive inotropic effect of beta-1-agonists.
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PMID:Compartmentation and functional mechanisms in myocardial failure and myocardial infarction. 352 63

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.
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PMID:Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses. 609 8

There is evidence that platelet activation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Since organic nitrate vasodilators are commonly used in coronary artery disease, we have studied the in vitro effects of these drugs on platelet function. Nitroglycerin, isosorbide dinitrate, and their biotransformation product, inorganic nitrite, inhibited platelet aggregation with collagen, epinephrine, arachidonate, and ionophore, and blocked both primary and secondary aggregation in response to ADP. Nitroglycerin was studied in more detail. Its inhibitory effect was reversible and not dependent on external calcium concentration. It inhibited arachidonic acid oxygenation as measured by the arachidonate-induced oxygen burst and malonaldehyde production. These effects were not due to an increase in intracellular cyclic AMP. This unusual generalized inhibition of platelet function by nitroglycerin possibly contributes to its beneficial effect in myocardial ischemia in part by attenuating platelet reactivity in the coronary circulation.
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PMID:Inhibition of platelet function by organic nitrate vasodilators. 624 16

The cause of death in patients who die suddenly or after an acute myocardial infarction is, in most cases, ventricular fibrillation. Most of these patients suffer from ischemic heart disease and atherosclerotic narrowing of the coronary arteries. Ischemic changes include hypoxia, accumulation of metabolites, depletion of energy-yielding substrates, ionic shifts and structural changes. There is an increased sympathetic activity and often a higher vagal tone. Recent observations support the idea that there is an elevated regional adrenergic activity in the ischemic area with increased tissue levels of cyclic AMP. This seems to be one of several important factors contributing to the occurrence of ventricular fibrillation. Increased sympathetic activity might mediate reentry mechanisms as well as enhanced automaticity.
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PMID:Myocardial metabolic changes related to ventricular fibrillation. 624 18


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