Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study addresses the potential effects of pacing-induced myocardial ischemia on the secretion of coagulant and fibrinolytic factors within the coronary circulation. In 6 patients undergoing programmed ventricular stimulation with repeated induction of clinical ventricular tachycardia, the coronary release of tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI) capacity, von Willebrand factor antigen (WF:Ag), and prostacyclin (6-keto-PGF 1a) was measured. Blood samples were collected simultaneously from the ascending aorta and the coronary sinus at baseline and immediately after the induction of ventricular tachycardia. The occurrence of pacing-induced myocardial ischemia was established by myocardial net lactate production. Myocardial ischemia was induced in every patient by repeated pacing trials. Pacing-induced ischemia did not affect the coronary release of any of the above factors. Consequently, there was no alteration of transcardiac gradients of thrombin-antithrombin complexes and D-dimer. The present results indicate that pacing-induced myocardial ischemia does not affect the release of coagulant and fibrinolytic endothelial factors or prostacyclin into the coronary circulation.
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PMID:Pacing-induced myocardial ischemia does not affect the endothelial release of coagulant and fibrinolytic factors into the coronary circulation. 170 56

Intracoronary thrombosis is fundamental in the pathogenesis of acute coronary syndromes, although the causes of thrombosis are still unclear. As thrombin generation is crucial for thrombus formation, the inhibition of thrombin is a primary aim to prevent the evolution of an initial repair process into a pathological thrombus. Thrombin inhibition can be achieved by several drugs. Heparin is the principal antithrombin drug currently used in acute syndromes; it acts mainly by binding to antithrombin III and increasing its inhibitory effect on thrombin and other coagulation factors. The heparin-antithrombin III complex, however, does not inhibit thrombus-bound thrombin; moreover, iv heparin requires frequent laboratory monitoring and dose adjustments. Despite these limitations, continuous infusion of i.v. heparin has been found to be effective in unstable angina and in myocardial infarction, especially when treated with accelerated rt-PA. New antithrombin drugs that selectively and directly inhibit thrombin are hirudin, its synthetic derivate hirulog, and argatroban. These drugs have several theoretical advantages over heparin: greater stability of the aPTT--with the need for less laboratory monitoring--and greater efficacy--associated mainly with its capacity to inhibit clot-bound thrombin. Clinical pilot studies seem to indicate a greater antithrombotic efficacy compared with heparin, but a greater number of hemorrhagic events in patients with acute myocardial infarction receiving thrombolysis. In conclusion, the use of heparin is certainly indicated in patients with unstable angina and persistent ischemia and in acute myocardial infarction treated with accelerated rt-PA. The use of new antithrombin drugs, although promising, requires further clinical evaluation.
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PMID:[Antithrombin therapy in acute coronary syndromes]. 763 17

Evidence is presented that heparin pretreatment produces protective effects on myocardial tissue distinct from its anticoagulant activity. The present study examines the ability of heparin sulfate and N-acetyl heparin (a derivative of heparin devoid of anticoagulant effects) to protect the heart from injury associated with global ischemia and reperfusion. Male New Zealand White rabbits were administered either heparin sulfate (n = 7, 300 U/kg i.v.), N-acetyl heparin (n = 6, 1.73 mg/kg i.v.), or vehicle (n = 6). Two hours after treatment, the hearts were removed, perfused on a Langendorff apparatus, and subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. During reperfusion, creatine kinase concentrations in the coronary sinus effluent were greater in hearts from vehicle-treated rabbits compared with hearts from N-acetyl heparin-treated and heparin-treated rabbits. Left ventricular end-diastolic pressure after 45 minutes of reperfusion in the vehicle-treated group was 64 +/- 15 mm Hg compared with 17 +/- 4 and 10 +/- 3 mm Hg in the heparin-pretreated and N-acetyl heparin-pretreated groups, respectively. Heparin, but not N-acetyl heparin, increased the activated partial thromboplastin time, consistent with its known anticoagulant action. Heparin and N-acetyl heparin inhibited complement-mediated erythrocyte lysis in a concentration-dependent manner. The glycosaminoglycans, in contrast to r-hirudin, reduced complement activation-induced injury in the rabbit isolated heart. The results demonstrate that heparin or N-acetyl heparin, administered to the intact rabbit, protects the isolated heart from subsequent myocardial dysfunction secondary to ischemia/reperfusion. The cardioprotective effects of heparin and N-acetyl heparin are independent of an antithrombin mechanism.
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PMID:Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart. 792 16

We studied the effects of bolus injections and infusion of endothelin-1 (ET-1) in female rabbits by measuring serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactic dehydrogenase (LDH), antithrombin III (AT-III), thrombin antithrombin (TAT) complexes, platelet counts and indirect bilirubin. Two successive bolus doses of 0.125 and 0.25 nmol/kg of ET-1 with an interval of 30 min were given to conscious non-pregnant female rabbits (n = 8). GOT, GPT and LDH were found to be significantly increased after injections of ET-1 (p < 0.02, p < 0.04 and p < 0.05, respectively). The percent AT-III activity decreased significantly (p < 0.005). Vasospasm of the hepatic artery was demonstrated by angiography with the same bolus doses in rabbits. There was also an increase in GOT (p < 0.003), GTP (p < 0.05), LDH (p < 0.007), indirect bilirubin (p > 0.07) and TAT complexes (p < 0.02) and a decrease in AT-III (p < 0.03) and platelet counts (p < 0.02) in rabbits (n = 10) after 24 h of continuous infusion of ET-1 (0.6 nmol/kg/h). Histological examination of rabbit liver tissues showed varying degrees of ischemic necrosis of hepatocytes. Thus this study suggests that exogenously administered ET-1 causes vasospasm and liver ischemia resulting in HELLP syndrome-like blood parameters in rabbits.
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PMID:HELLP syndrome-like biochemical parameters obtained with endothelin-1 injections in rabbits. 833 Jul 62

Fifteen cases of traumatic thoracic aortic rupture (TAR) were treated at St. Marianna University Hospital from December 1980 to July 1995. Causes of TAR were due to vehicle accidents in 14 patients and fall in one patient. On diagnosis, contrast-enhanced CT scan was routinely performed in the patients with blunt chest trauma associated with superior mediastinal widening, loss of the aortic knob or right shift of the trachea on the initial roentgenogram. When CT scan demonstrated specific signs for TAR, pseudoaneurysm formation and/or extravasation of the contrast dye, aortography was eliminated before operation. As a role, operation was performed on an emergency basis as soon as the diagnosis was confirmed. Four cases died due to intrapleural rupture before or immediately after thoracotomy. Nine (82%) of the 11 patients in whom operation was completed survived and are doing well. In one of the 4 patients who underwent operation with simple aortic cross-clamping; paraplegia developed after 30 minutes of spinal ischemia. Left heart bypass with the Bio-Pump without heparin or with an antithrombin agent, argatroban, was used in recent 6 patients. Use of left heart bypass with the Bio-Pump without anticoagulant or with argatroban appears to be promising as a safe adjunct in the repair of TAR, preventing fatal bleeding of other injured organs.
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PMID:[Traumatic thoracic aortic rupture--diagnosis and surgical repair]. 874 50

Plasma antithrombin-III (AT-III), protein S, and protein C were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on their plasma levels were elucidated. Forty-nine open-chest swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. During MS an increase in the plasma AT-III (from 98.5 +/- 3.38% to 138.1 +/- 3.6%) during the early occlusion phase, without any further changes was observed. The profile of total protein S was not changed during MS. Protein C increased at the end of occlusion (from 45.3 +/- 1.8% to 55.7 +/- 1.4%) reaching a peak (64.5 +/- 1.4%) at the beginning of reperfusion. When compared with controls, no significant differences were found in the antithrombotics profile during MS after pretreatment with Mac-1 inhibitor. For the AMI, the AT-III decreased during occlusion (from 98.5 +/- 3.4% to 61.0 +/- 3.6%). The protein S decreased during occlusion with the lowest level at 1 h of reperfusion (from 71.8 +/- 2.2% to 46.7 +/- 1.0%), followed by an increase during late reperfusion (59.2 +/- 1.5%). Contrarily, protein C increased during occlusion and early reperfusion (from 44.7 +/- 2.6% to 79.4 +/- 2.4%), but declined to 49.6 +/- 2.5% thereafter. In both Mg and diltiazem-treated swine, protein C was higher at the end of occlusion and during the entire reperfusion period compared with controls. Mg and diltiazem therapy was associated with the slight elevation of plasma AT-III. The patterns for protein S level during ischemia-reperfusion were similar with the controls. Protein S was higher at the end of occlusion and through the entire reperfusion in the NPC 15669-treated animals when compared with the controls. Mac-1 inhibition was associated with the elevated protein C during late reperfusion. Ability of Mg, diltiazem, and Mac-1 inhibitor to favorably modulate the plasma level of antithrombotics have direct clinical implications for the use of these agents in patients with acute coronary artery syndromes.
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PMID:Serial changes of natural antithrombotics during myocardial ischemia-reperfusion in swine. Effects of magnesium, diltiazem, and a novel Mac-1 inhibitor. 889 53

Coagulation activation and fibrinolysis parameters were studied in eleven cases of thrombotic microangiopathy concerning eight adult patients. In addition to routine coagulation tests, antithrombin III, von Willebrand factor (vWF), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-dimer (DD), and plasminogen activator inhibitor type 1 (PAI-1) were measured in the plasma at the time of diagnosis and as soon as remission was achieved after therapy with plasma exchange and Iloprost. In the acute phase all patients showed normal aPTT, normal or slightly prolonged prothrombin time, normal or enhanced plasma levels of fibrinogen and antithrombin III, at variance with results in patients affected by disseminated intravascular coagulation. Mean F1+2, TAT, DD, vWF and PAI-1 were elevated in the acute phase, but decreased significantly in the early phase of remission. Our data provide evidence of increased thrombin generation rate which takes place in the acute phase of the disease and does not result in consumption coagulopathy, due to appropriate inhibition by antithrombin III; blood coagulation activation promptly decreased as soon as remission was achieved. Cross-linked fibrin deposition together with PAI-1 may consolidate the platelet plug, eventually resulting in microvascular occlusion and ischemia.
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PMID:Plasmatic parameters of coagulation activation in thrombotic microangiopathy. 895 55

We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.
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PMID:Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke. 914 22

The middle domain of plasma histidine-proline-rich glycoprotein (HPRG) contains unusual tandem pentapeptide repeats (consensus G(H/P)(H/P)PH) and binds heparin and transition metals. Unlike other proteins that interact with heparin via lysine or arginine residues, HPRG relies exclusively on histidine residues for this interaction. To assess the consequences of this unusual requirement, we have studied the interaction between human plasma HPRG and immobilized glycosaminoglycans (GAGs) using resonant mirror biosensor techniques. HPRG binding to immobilized heparin was strikingly pH-sensitive, producing a titration curve with a midpoint at pH 6.8. There was little binding of HPRG to heparin at physiological pH in the absence of metals, but the interaction was promoted by nanomolar concentrations of free zinc and copper, and its pH dependence was shifted toward alkaline pH by zinc. The affinity of HPRG for various GAGs measured in a competition assay decreased in the following order: heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate A. Binding of HPRG to immobilized dermatan sulfate had a midpoint at pH 6.5, was less influenced by zinc, and exhibited cooperativity. Importantly, plasminogen interacted specifically with GAG-bound HPRG. We propose that HPRG is a physiological pH sensor, interacting with negatively charged GAGs on cell surfaces only when it acquires a net positive charge by protonation and/or metal binding. This provides a mechanism to regulate the function of HPRG (the local pH) and rationalizes the role of its unique, conserved histidine-proline-rich domain. Thus, under conditions of local acidosis (e.g. ischemia or hypoxia), HPRG can co-immobilize plasminogen at the cell surface as well as compete for heparin with other proteins such as antithrombin.
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PMID:Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. 948 72

Acute inflammation, a localized response that occurs in various diseases, is characterized by neutrophil infiltration into tissues. This process requires neutrophils to initially tether and roll along the endothelium of postcapillary venules before undergoing firm adhesion and emigration out of the vasculature into the tissues. Recently, thrombin has been implicated at multiple sites in the inflammatory cascade, and may represent an important link between inflammation and thrombosis. Our recent studies demonstrate that thrombin is an important mediator of neutrophil-dependent injury in ischemia-reperfusion injury. Furthermore, antithrombin concentrate may be therapeutically efficacious in ischemia-reperfusion injury, as it is capable of attenuating the thrombin-mediated effects on neutrophil-endothelial interactions.
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PMID:Antithrombin and ischemia/reperfusion. 966 65


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