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)

Myocardial ischemia inhibits endothelium-dependent relaxation stimulated by the coagulant peptide, thrombin. To investigate whether activation of endogenous thrombin contributed to this reduction in relaxant sensitivity, the effects of pretreatment of dogs with the coumarin anticoagulant, brodifacoum, were studied. Experiments were performed in both normal coronary vasculature and coronary vasculature exposed to 90 min of myocardial ischemia, with or without 60 min of subsequent reperfusion. Ischemia was induced in the left anterior descending artery (LAD); nonischemic vessels from the left circumflex (LCX) artery of the same animals were used as control. Thrombin caused dose-dependent relaxation in isolated LCX preconstricted with prostaglandin F2 alpha (Emax of 89.1 +/- 2.33%). Relaxation was reduced by 90 min of ischemia (Emax of 27.5 +/- 8.0%; p less than 0.05), and further reduced after subsequent reperfusion (Emax of 8.7 +/- 8.7%). However, maximum relaxations to acetylcholine, calcimycin, and isoproterenol were unchanged after ischemia (Emax greater than 90% in all groups). Brodifacoum had no effect on thrombin-induced relaxation in control vessels (Emax of 83.0 +/- 3.5%), or on relaxation in response to acetylcholine, calcimycin, or isoproterenol (Emax greater than 90%). In contrast, brodifacoum markedly reduced thrombin-induced relaxation after ischemia (Emax of 3.3 +/- 3.3%; p less than 0.05) yet significantly preserved the relaxant response to thrombin after ischemia and reperfusion (Emax of 36.6 +/- 4.3%). Infusion of the thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK), during ischemia and reperfusion also preserved in part the relaxant response induced by thrombin (Emax of 30.0 +/- 5.1%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of thrombin-induced endothelium-dependent relaxation after coronary ischemia in the dog: possible role of the coagulation cascade. 171 94

Thrombin stimulates phosphoinositide hydrolysis and increases cytosolic calcium in several types of cells. To determine whether thrombin exerts similar stimulatory actions in the heart and whether this mechanism is linked to changes in cardiac electrical activity, the effects of thrombin on several biochemical and electrophysiological parameters were examined. In neonatal rat ventricular myocyte cultures freed of fibroblast contamination by irradiation, thrombin rapidly induced the breakdown of phosphoinositides. Formation of inositol trisphosphate was detectable within 5 seconds and was followed by the sequential accumulation of inositol bisphosphate and inositol monophosphate. The effect of thrombin to stimulate phosphoinositide hydrolysis was inhibited by hirudin, but not by propranolol, prazosin, or pretreatment with pertussis toxin. The inositol phospholipid response was unassociated with changes in intracellular cAMP levels. To determine the electrophysiological effects of thrombin, we used microelectrode techniques to study canine Purkinje fibers. Thrombin increased the beating rate of fibers depolarized using barium, but not those at normal maximal diastolic potential. In addition, thrombin prolonged the action potential duration in fibers driven at a constant cycle length. This response was inhibited by hirudin and nisoldipine, but not by propranolol, prazosin, or pretreatment with pertussis toxin. Thrombin also augmented cesium-induced early afterdepolarizations. Using the fluorescent calcium indicator fura-2, we demonstrated that thrombin increased the beating rate, diastolic calcium, and peak systolic calcium of spontaneously contracting cultured ventricular myocytes. Cytosolic calcium also increased in both rat ventricular myocytes and canine Purkinje myocytes that were electrically driven at a constant basic cycle length, indicating that thrombin modulates cellular calcium metabolism independent of its actions to enhance automaticity. Taken together, these findings demonstrate several novel biological actions of thrombin in the mammalian heart that may be functionally related. The actions of thrombin to enhance automaticity and prolong repolarization may contribute to the electrical abnormalities observed in the setting of myocardial ischemia and infarction.
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PMID:Thrombin modulates phosphoinositide metabolism, cytosolic calcium, and impulse initiation in the heart. 185 Mar 29

Platelet aggregation and its relation to fatty acid composition of platelets, plasma and adipose tissue was determined in 196 randomly selected, free-living, 40-49-year-old men in two regions of Finland (east and southwest) with a nearly twofold difference in the IHD rate. There were no significant east-southwest differences in platelet aggregation induced with ADP, thrombin or epinephrine. ADP-induced platelet secondary aggregation showed significant negative associations with all C20-C22 omega 3-fatty acids in platelets (r = -0.26- -0.40) and with the platelet 20: 5 omega 3/20: 4 omega 6 and omega 3/omega 6 ratios, but significant positive correlations with the contents of 18:2 in adipose tissue (r = 0.20) and plasma triglycerides (TG) (r = 0.29). Epinephrine-induced aggregation correlated negatively with 20: 5 omega 3 in plasma cholesteryl esters (CE) (r = -0.23) and TG (r = -0.29), and positively with the total percentage of saturated fatty acids in platelets (r = 0.33), but had no significant correlations with any of the omega 6-fatty acids. Thrombin-induced aggregation correlated negatively with the omega 3/6 omega ratio in adipose tissue (r = -0.25) and the 20: 3 omega 6/20: 4 omega 6 ratio in plasma CE (r = -0.27) and free fatty acids (FFA) (r = -0.23), and positively with adipose tissue 18:2 (r = 0.23) and 20:4 omega 6 (r = 0.22) in plasma phospholipids (PL). The percentages of prostanoid precursors in platelet lipids, i.e. 20:3 omega 6, 20:4 omega 6 and 20:5 omega 3, correlated best with the same fatty acids in plasma CE (r = 0.32 - 0.77) and PL (r = 0.28 - 0.74). Platelet 20:5 omega 3 had highly significant negative correlations with the percentage of 18:2 in adipose tissue and all plasma lipid fractions (r = -0.35 - -0.44).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet aggregation in Finnish men and its relation to fatty acids in platelets, plasma and adipose tissue. 408 91

Aspirin (ASA) is widely used in the treatment of cardiovascular diseases. Recently, we have found that aspirin decreases not only platelet aggregation but also thrombin generation. This effect, however, was seen only in certain subjects. Therefore we decided to examine influence of a single dose of aspirin (500 mg) on thrombin generation in healthy volunteers. Thrombin genesis was assessed by serial measurements of fibrinopeptide A concentration in blood emerging from standardised forearm skin incisions. Aspirin reduced thrombin generation in persons with normal serum level of lipids. This effect was lost, however, in subjects with high level of cholesterol and lipoprotein (a)--well known risk factors of ischaemic heart disease. While the mechanism by which aspirin affects thrombin generation remains to be elucidated, our data indicate that hypercholesterolemic subjects might benefit less than others from preventive aspirin treatment.
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PMID:[High levels of cholesterol and lipoprotein (A) in serum decreases the inhibitory effect of aspirin on generation of thrombin]. 749 48

Thrombin's cellular actions are mediated by a novel G-protein coupled transmembrane receptor. We infused SFLLRN, a peptide that directly activates thrombin receptors, into the left circumflex coronary artery (CFX) of anesthetized dogs to evaluate the cardiovascular effects of thrombin receptor activation in vivo. Intracoronary SFLLRN, 0.9, 9 and 90 nmol/min, produced transient, dose-related increases in CFX blood flow, followed by sustained decreases in CFX and left anterior descending (LAD) blood flow. SFLLRN also decreased positive and negative dP/dtmax, arterial pressure, cardiac output and heart rate. Peripheral vascular resistance transiently decreased and then increased. SFLLRN decreased systolic wall thickening (WT) and increased ST segment level within the CFX perfusion area. In contrast, WT was increased, and ST segment was unchanged in the LAD perfusion area. CFX flow, but not LAD flow, increased transiently above control after SFLLRN infusion. FSLLRN, a peptide that does not activate thrombin receptors, had no effect at 90 nmol/min. The response to intravenous SFLLRN was greatly attenuated when compared with intracoronary infusion, and regional changes in coronary flow and function were absent. Decreases in arterial pressure, heart rate, coronary blood flow, and positive and negative dP/dtmax, were inhibited after bilateral vagotomy. Moreover, arterial pressure and peripheral resistance increased in response to SFLLRN after vagotomy. Initial CFX flow increase, regional dysfunction, ST level changes and hyperemic response were comparable but attenuated after vagotomy. Ex vivo platelet function was not affected by SFLLRN up to 100 microM. We conclude that regional myocardial ischemia and cardiac dysfunction result from thrombin receptor-mediated local coronary vasoconstriction. Thus, thrombin generation at a site of vascular injury or thrombus may significantly affect vascular tone and myocardial perfusion.
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PMID:Cardiovascular actions of thrombin receptor activation in vivo. 896 61

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

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.
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PMID:Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. 957 50

Background: Myocardial ischemia at rest is typically associated with atherosclerotic coronary artery disease, atherommous plaque rupture, and intracoronary thrombosis. In areas of advanced disease and vascular injury, the extent of thrombus is influenced largely by a delicate balance of procoagulant factors, favoring thrombus initiation, growth, and development, and anticoagulant factors, attempting to limit potentially flow-limiting coronary thrombosis. Thrombin, a 308 amino acid serine pretense, is considered the most patent procoagulant factor in the setting of acute vessel wall injury, playing an essential role in the conversion of fibrinogen to fibrin, accelerating the prothrombinase complex, activating platelets, and stabilizing fibrin polymers. The purpose of this study was to determine the relationship between electrocardiographic abnormalities and markers of thrombin activity and generation among patients with unstable angina and non-Q.wave myocardial infarction. Mehtods and Results: In a study of 36 patients (59.1+/- 11.0 years) with myocardial ischemia at rest participating in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB trial, thrombin activity in plasma, as determined by fibrinopeptide A (FPA), prothrombin fragment 1.2 (F 1.2), and thrombin-antithrombin III complexes (TAT) concentrations, were found to be increased significantly when compared with healthy volunteers (p < 0.004). Thrombin generation was also increased modestly compared with age-matched patients with stable coronary artery disease undergoing elective cardiac catheterization. Given that,he surface 12-lead electrocardiogram (ECG) is frequently abnormal in patients with ischemic chest pain at rest and represents a readily available, first-line diagnostic test for assessing disease activity and treatment response, we investigated whether ECG abnormalities and thrombin activity/generation in plasma were correlated. Twenty-six patients (72%) had ECG changes compatible with myocardial ischemia at the time of study entry, including 18 (50%) with newly inverted T waves (or pseudonormalization), 14 (39%) with reversible ST-segment depression, and 4 (11%) with transient (<30 minutes) ST-segment elevation. Within the predefined ECG groups there were no differences in plasma thrombin activity between patients with and those without confirmed abnormalities. Similarly, there were no differences in either plasma thrombin activity or generation between the predefined ECG groups. Conclusion: Although ECG abnormalities supporting the presence of myocardial ischemia occur commonly in patients with chest pain at rest, they do not correlate closely with markers of thrombin activity and generation in plasma. The diagnostic and prognostic capabilities of these diagnostic tools, considered either alone or together, require further investigation.
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PMID:Surface 12-Lead Electrocardiographic Findings and Plasma Markers of Thrombin Activity and Generation in Patients with Myocardial Ischemia at Rest. 1060 19

Thrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications. Methods: Fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet alpha-granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial. Results: Thrombin generation (TAT 12.1 +/- 17.8 ng/ml vs. 3.4 +/- 1.0 ng/ml; F1.2 0.19 +/- 0.14 nmol/l vs. 0.12 +/- 0.8 nmol/l), fibrin formation (FPA 15.8 +/- 23.5 ng/ml vs. 7.5 +/- 2.3 ng/ml), and platelet activation) 10.6 +/- 2.4% vs. 2.5 +/- 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r = -.10, p = 0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r =.42, p = 0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold. Conclusions: Thrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of di sease and response to treatment observed commonly in clinical practice.
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PMID:Dynamic Nature of Thrombin Generation, Fibrin Formation, and Platelet Activation in Unstable Angina and Non-Q-Wave Myocardial Infarction. 1063 14

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.
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PMID:Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. 1110 58


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