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Biomedical subjects

M Buerke

Publications and source records attributed to M Buerke.

At least 19 recordsLinked to original sources
PubMed2006

Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia: diagnosis and treatment.

Thrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte aggregation. The inhibition of thrombocyte activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI). Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without thrombocytopenia. Advanced age (> 65 years), low BMI and a low initial thrombocyte count (<180,000/microl) are independent risk factors of thrombocytopenia. The risk of bleeding is higher with this form of thrombocytopenia not only due to the low thrombocyte count but also to the impaired function of the remaining thrombocytes. It is important to closely monitor platelet count during GP IIb/IIIa antagonist treatment. Platelet count monitoring two, six, twelve and 24 hour after starting the treatment reveals most cases of acute thrombocytopenia. Side effects can be avoided by the early discontinuation of the GP IIb/IIIa antagonist treatment. This article reviews the diagnosis and treatment of glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia and summarizes the differential diagnosis from heparin-induced thrombocytopenia and laboratory-related pseudothrombocytopenia.

Acute Disease↗
PubMed2005

[Reversible autonomic dysfunction in a young woman with septic multiple organ dysfunction syndrome].

HISTORY: A 24-year-old woman was admitted for treatment of a meningococcal infection accompanied by fulminant autonomic dysfunction. INVESTIGATIONS: Laboratory tests indicated acute renal failure and disseminated intravascular coagulopathy (creatinine 183 mmol, D-dimer 1.52 mg/l). The initial central venous oxygen saturation was 60-65%. The diagnosis of severe septic shock was supported by a high procalcitonin level of 66.7 ng/ml, CRP of 79.8 mg/l, and a WBC count of 12.2 Gpt/l. TREATMENT AND COURSE: Treatment of sepsis with antibiotics (ciprofloxacin, penicillin G, ceftriaxon and erythromycin in standard dosages), activated protein-C, hydrocortisone and GMA-embedded immunoglobulin led to complete cure and restoration of normal autonomic function. CONCLUSIONS: This case shows that even in multiple organ dysfunction syndrome autonomic dysfunction can occur which is improved by adequate treatment.

Adult↗
PubMed2004

[S2 guideline for infectious endocarditis].

Microbe-induced (infectious) endocarditis is an endovascular infection, caused mainly by bacteria, of cardiovascular structures. The major predilection site are the native heart valves, but involvement of implanted intracardiac foreign material is increasingly being seen. The mortality rate of infectious endocarditis depends on clinical factors and the causal agent, but also on the time of the establishment of the diagnosis and the initiation of appropriate treatment. In Germany, the current mortality rate ranges up to 18%. Between January 2003 and July 2004, with the aim of improving patient care and thus the outcome of this condition, a guideline commission worked out recommendations for the diagnosis, treatment and management of the disease for the use of general practitioners and hospital physicians, in particular microbiologists, infectiologists, cardiologists and cardiac surgeons. The basis for this guideline was the systematic search through the literature of the European guideline. On the 16th and 28th of June 2004, the entire guideline was formerly approved in a nominal group process.

Anti-Bacterial Agents↗
PubMed2004

[Catecholamine therapy in cardiogenic shock: helpful, useless or dangerous?].

Cardiogenic shock is characterized by inadequate organ and tissue perfusion, due to cardiac dysfunction, predominantly following acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain high, ranging from 50-70 % despite effective therapy. Rapid diagnostics, aggressive therapeutic approach (invasive or surgical revascularisation) and pharmacological support are currently used to improve the clinical outcome and survival. In the first line commonly sympathomimetics like dopamine, dobutamine, epinephrine and norepinephrine are used for the pharmacological treatment. They have a high affinity for alpha- and beta adrenergic receptors, leading to a positive inotropic cardiac function, an increase in heart rate, oxygen enhanced demand, and an increase in vasoconstriction. However, there are also some disadvantages in the use of sympathomimetics in patients with cardiogenic shock. Clearly, metabolic acidosis due to the increased oxygen demand can be observed. Vasoconstriction induced by sympathomimetics can lead to perfusion mismatch or even deficit within the microcirculation. Additionally, in some studies which give evidence that the use of sympathomimetics can directly lead to enhanced systemic inflammatory response due to an increased IL-6 expression. However, sympathomimetics are still first line therapeutics for treatment of cardiogenic shock -- with respect to dosage and duration of treatment.

Age Factors↗
PubMed2004

[Recommendations for statin therapy in the elderly].

Elderly patients are significantly less likely to receive statins than younger patients possibly because of doubts regarding compliance or concerns regarding the increased likelihood of adverse events and drug interactions. Poor compliance can be expected especially in patients suffering from dementia or depression as well as those whose stage of cardiovascular disease exhibits few symptoms. On the other hand, the clinical significance of CHD events is high in the elderly, and 80% of coronary deaths occur in patients aged over 65 years. The average statistical life expectancy of elderly and old patients is often underestimated. The HPS and PROSPER studies showed that statins reduce mortality and morbidity even in very elderly individuals with a high global cardiovascular risk and/or CAD. Patients up to the age of 79 years should be treated according to the same guidelines as younger patients. Statin therapy should only be considered for patients aged 80 years and older who are at a very high risk for cardiovascular events.

Aged↗
PubMed2004

[Cardiogenic shock: pathophysiology, clinics, therapeutical options and perspectives].

Documented mortality from myocardial infarction (MI) has significantly decreased from around 30% in the 1960s to 6-7% currently, following the introduction of intensive care treatment, thrombolysis, effective antithrombotic therapy and coronary angioplasty. However, the approximate mortality of 70-80% of patients with cardiogenic shock following acute MI has hardly improved despite the introduction of modern treatment strategies. The major cause of in-hospital MI mortality remains myocardial failure with consecutive cardiogenic shock and multi-organ failure. Prompt coronary revascularisation by "facilitated" or "adjunctive" percutaneous coronary intervention (PCI), is currently considered the best method to reduce the high mortality in these patients. Facilitated PCI includes administration of glycoproteine receptor antagonists, mechanical circulation support strategies, such as, intraaortic balloon counterpulsation and potentially prehospital thrombolysis.

Angioplasty, Balloon, Coronary↗
PubMed2003

Rapamycin reduces neointima formation during vascular injury.

BACKGROUND: Proliferation and migration of vascular smooth muscle cells (SMCs) mark the key processes in the development of bypass graft disease and during neointima formation in restenosis after angioplasty. Growth factors are potent SMC mitogens as they are involved in SMC proliferation and in extracellular matrix (ECM) synthesis. Based on these premises, we examined the effect of the proliferation inhibitor rapamycin in human SMC culture and in a rabbit vascular injury model. MATERIALS AND METHODS: Injection of rapamycin or its vehicle was performed with an infusion-balloon catheter directly into the vessel wall during vascular injury. The intima/media ratio was determined histologically whereas the protein expression was analysed using the powerful two-dimensional gel electrophoresis (2D page) technique. Inhibition of proliferation after rapamycin application was estimated in a human SMC culture for time and dose dependent effects. RESULTS: Rapamycin treatment resulted in a significant reduction of intima media ratio compared to vehicle treated animals after three weeks (0.65 +/- 0.1 vs. 1.2 +/- 0.2 intima-media-ratio, p < 0.05). 2D electrophoresis analysis proved increased ECM synthesis following angioplasty (i.e., lamin, vimentin) in vehicle treated animals. Local rapamycin administration resulted in profound reduction of ECM synthesis after vascular injury. In in-vitro experiments exposure of cultured human SMCs to rapamycin resulted in a significant and dose-dependent (1 nm-100 nm) reduction of human smooth muscle cell proliferation measured by cell counting. CONCLUSION: These above mentioned results suggest that protein synthesis in addition to reduction of cellular proliferation plays an important role following vascular injury, since application of rapamycin resulted in the reduction of SMC proliferation and ECM-synthesis.

Angioplasty, Balloon↗
PubMed2002

Effects of combined therapy of clopidogrel and aspirin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model.

BACKGROUND: The aim of our study was to investigate the efficacy of the combination of clopidogrel and aspirin in the prevention of thrombus formation on artificial heart valves in an experimental rabbit model as compared to anticoagulation with warfarin. METHODS: Studies were performed after oral administration of clopidogrel and aspirin in group I (n=9) for 5 days, after 5+/-2 days treatment with warfarin in group II (n=9) and without medication in group III (n=9). Leaflets from Sulzer Carbomedics bileaflet valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein. RESULTS: In group III, the flow chamber was clotted after a median of 15 min of circulation. Weight analysis before and after 1 h of perfusion showed that the median thrombus weight was 9.1 mg in group I, 14.4 mg in group II and 33.7 mg in group III. Further analysis by electron microscopy showed fewer platelets and erythrocytes on leaflets in group I than on leaflet surfaces in group II. CONCLUSION: Clopidogrel and aspirin were more effective than warfarin in preventing thrombus formation on artificial heart valve leaflets in our investigation. This rabbit model with a high dosage of clopidogrel and aspirin, and a short-time exposure of the heart valve leaflets to rabbit blood under laminar flow, should be further evaluated with respect to whether it can give information about antithrombotic regimens in patients after mechanical heart valve replacement.

Animals↗
PubMed2002

Bypass graft disease: analysis of proliferative activity in human aorto-coronary bypass grafts.

BACKGROUND: Aortocoronary bypass graft disease with its increasing clinical signification represents an unsolved problem in cardiological and heart surgery practice. Late occlusion of autologous saphenous vein grafts occurs against a background of medial and neointimal thickening due to migration and proliferation of smooth muscle cells and the later appearance of atherosclerotic plaques. To clarify the role of cellular proliferation in humans we characterized the cellular composition and proliferative index in 30 stenotic saphenous vein grafts. METHODS: 30 stenotic vein grafts and 25 control veins were explantated during redo heart surgery procedures. Time between initial surgical intervention and explantation was 3-168 month (mean 94,8 month). The total area and cell count of the neointima, media and adventitia was calculated computer assisted. Actively proliferating cells were identified using antibody to Ki-67 and by double-lable immuncytochemistry with alpha SMC actin, CD 31 (endothelial cells), CD 68 lpar;makrophages) and CD 45 (T-lymphocytes). RESULTS: Active proliferation was detected in different cell typs with a mean proliferation index of 0.15%,0.18% and 0.086% for the neointima, media and adventita. Only 9% of the proliferating cells in the neointima were SMC (not identified cells 40%); corresponding 14% SMC (not identified cells 33%) were detected in the media. Endothelial cells were the predominante proliferating cell type in all sites of the vessel wall. CONCLUSION: 1. Proliferation occured at low level. While proliferation may play an important role in early lesions our data imply low proliferation activity in advanced graft lesions. Other mechanism like production and deposition of extracellular matrix (ECM) in the neointima are responsible for the lumen reduction of bypass grafts. 2. The high portion of unidentified cells may represent SMC or other cell types at different stages of differentiation; this requires further investigation. 3. The identification of proliferating macrophages and T-lymphocytes implicate an inflammatory component in the development of human bypass graft lesions.

Biomarkers↗
PubMed2001

Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

Animals↗
PubMed2001

Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.

Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate-labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.

Animals↗
PubMed2001

Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma.

BACKGROUND: The c-kit ligand, stem cell factor (SCF), is an important activating and chemotactic factor for both mast cells and eosinophils. These cells are known to play a fundamental role in the pathogenesis of asthma. OBJECTIVE: Our goal was to analyze the functional role of SCF in the pathogenesis of asthma. METHODS: The expression of SCF was targeted in fibroblasts, epithelial cells, and locally in a murine model of asthma in mice induced by ovalbumin sensitization with an antisense DNA strategy. RESULTS: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 epithelial cells by a specific antisense phosphorothioate oligonucleotide overlapping the translation start site of SCF, whereas control oligonucleotides were virtually inactive. We then focused on the role of SCF in a murine model of asthma associated with late-phase allergic inflammation in ovalbumin-sensitized mice: Local intranasal administration of FITC-labeled SCF antisense oligonucleotides led to strong DNA uptake in interstitial lung cells associated with a striking reduction of intracellular SCF expression. Such intrapulmonary blockade of SCF expression after repeated allergen challenges suppressed various signs of lung inflammation including IL-4 production and infiltration of eosinophils. SCF antisense DNA treatment was at least as effective as corticosteroid treatment. CONCLUSION: These data indicate a critical role for SCF in a murine asthma model and suggest that local delivery of SCF antisense oligonucleotides may be a novel approach for the treatment of inflammatory lung disorders such as asthma.

3T3 Cells↗
PubMed2001

Expression of the proto-oncogene c-myc in human stenotic aortocoronary bypass grafts.

Proliferation and differentiation of vascular smooth muscle cells (VSMC) are central events in vascular pathobiology and play a major role in the development of stenotic and restenotic lesions. The proto-oncogene c-myc and other early cell cycle-regulating genes have been implicated in the induction of cell proliferation and differentiation under diverse pathophysiological conditions. In the present study we analyzed c-myc mRNA expression by indirect nonradioactive in situ hybridization technique (NISH) in human stenotic venous bypass grafts (n = 32) retrieved during re-do operations of coronary artery disease and compared the results with 28 native veins (vena saphena magna) from the same patients. Stenotic bypass grafts showed enhanced c-myc expression located predominantly in VSMC in the media and neointima (severity score: ++-+++, 32/32 stenotic veins). In native veins we observed only low levels of c-myc mRNA (severity score: +, 28/28 native veins), all signals were restricted to endothelial cells of either the innermost intimal layer or of the vasa vasorum. Our in situ hybridization studies demonstrate enhanced mRNA expression of the proto-oncogene c-myc in stenotic venous bypass grafts. These results suggest that--in analogy to other pathophysiological conditions--c-myc exerts essential regulatory functions in cellular events operative during the initiation and progression of venous bypass graft disease.

Adult↗
PubMed2001

Biosynthesis of constitutive nitric oxide synthase-derived nitric oxide attenuates coronary vasoconstriction and myocardial depression in a model of septic heart failure induced by Staphylococcus aureus alpha-toxin.

OBJECTIVE: Myocardial depression, which frequently occurs in the course of septic shock, has been attributed to the cardiodepressant properties of nitric oxide (NO) generated by either the inducible NO synthase (iNOS) or the constitutive isoform (cNOS). We have previously demonstrated that alpha-toxin from Staphylococcus aureus induces thromboxane-mediated vasoconstriction accompanied by severe cardiodepression in isolated rat hearts. In the present study, we investigated the role of NO in the alpha-toxin-induced vascular and contractile abnormalities. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university hospital. SUBJECTS: Isolated hearts from male Wistar rats. INTERVENTIONS: Isolated hearts were perfused with purified staphylococcal alpha-toxin for 60 mins. MEASUREMENTS AND MAIN RESULTS: At a concentration of 0.25 and 0.5 microg/mL, alpha-toxin induced a rise in coronary perfusion pressure, depressed myocardial contractility, and caused edema formation. Simultaneously, a time- and dose-dependent rapid release of NO into the perfusate was noted as quantified by a chemiluminescence technique. L-NMMA, a nonselective inhibitor of NOS, but not PBITU, an iNOS-selective inhibitor, blocked NO synthesis, markedly increased the rise in coronary perfusion pressure and the loss in contractility, and enhanced edema formation in response to alpha-toxin. In contrast, zaprinast, a selective inhibitor of phosphodiesterase type V that is used for stabilization of cyclic guanosine monophosphate, attenuated the toxin-induced coronary vasoconstrictor response and the myocardial depression. L-arginine, the substrate of NOS, had similar, yet less potent, effects as zaprinast and slightly increased the release of NO caused by alpha-toxin. Immunohistochemical analysis of the myocardium at the end of the perfusion period demonstrated a positive staining for cNOS but not for iNOS. In addition, no up-regulation of iNOS mRNA was detected in the tissue of toxin-exposed hearts. CONCLUSIONS: Staphylococcal alpha-toxin provokes NO biosynthesis via activation of cNOS in rat hearts. NO partly antagonizes the deleterious effects of this pathogenicity factor on coronary vasoregulation and myocardial performance.

Animals↗
PubMed2001

Involvement of PKC and NF-kappaB in nitric oxide induced apoptosis in human coronary artery smooth muscle cells.

Apoptosis of vascular smooth muscle cells is critically involved in progression of atherosclerosis and may prevent intimal hyperplasia in restenosis and vascular remodeling. Nitric oxide (NO) is known to induce apoptosis, but the signaling pathways still remain unclear. We investigated p53 accumulation, protein kinase C (PKC) activation and nuclear transcription factor (NF-kappaB) binding activity as possible signaling mechanisms of NO-induced apoptosis. Apoptosis was induced dose-dependently with the NO-donors sodiumnitroprusside (SNP: 232+/-48%) and SIN-1 (241+/-90% of actinomycin D induced apoptosis; means +/- SEM, *p< or =0.05 vs. control) in HSMC. Inhibition of PKC significantly attenuated NO-induced apoptosis. Staurosporine reduced SIN-1/SNP-mediated DNA fragmentation by 55.3+/-13.8% and 38.3+/-13.9% respectively. Comparable results were obtained for calphostin C. However, NO-mediated induction of apoptosis was not preceded by p53 accumulation. SNP decreased NF-kappaB binding activity in HSMC. These results suggest that induction of apoptosis by exogenous NO in HSMC is not dependent on p53 accumulation but involves protein kinase C signaling and regulation of NF-kappaB binding activity. This opens a new therapeutical approach in preventing restenosis after angioplasty.

Apoptosis↗
PubMed2001

In vitro investigation of prosthetic heart valves in magnetic resonance imaging: evaluation of potential hazards.

BACKGROUND AND AIM OF THE STUDY: Magnetic resonance (MR) imaging is used in an increasing number of patients, and not only after cardiac valve replacement. However, ferromagnetic biomedical implants are often considered a contraindication for MR imaging because of the potential hazards with respect to their movement, dislodgement, or heating effects during the procedure. The purpose of this study was to assess ferromagnetism, attraction forces, heating effects, and artifacts associated with prosthetic heart valve implants. METHODS: Seventeen common heart valve prostheses (12 mechanical, five biological) were examined in vitro using a high-field-strength 1.5 Tesla (T) MR system. Attractive forces, temperature changes and the amount of artifacts were assessed by applying turbo-spin and gradient-echo sequences. RESULTS: The maximal calculated corresponding ferromagnetic force was (0.22 x 10(-3) N) in the static magnetic field. The temperature changes ranged from 0 to 0.5 degrees C maximum. Artifacts produced by the presence of the heart valve prostheses were less evident using a spin-echo sequence than a gradient-echo sequence. CONCLUSION: MR imaging exerted no significant force on the examined heart valve prostheses, and did not result in significant biological relevant temperature increase. None of the associated artifacts is considered to pose a substantial risk on MR imaging. MR procedures performed with a 1.5 T MR system can be applied safely in patients with heart valve prostheses evaluated in this study.

Artifacts↗
PubMed2000

Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts: evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production.

BACKGROUND: Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated. METHODS AND RESULTS: Perfusion of isolated rat hearts with LPS for 180 minutes resulted in a decline of left ventricular contractility after 90 minutes, whereas coronary perfusion pressure remained unaffected. This cardiodepression was paralleled by a release of tumor necrosis factor (TNF)-alpha into the perfusate and preceded by myocardial TNF-alpha mRNA upregulation as quantified by real-time polymerase chain reaction. The cardiodepression was abrogated when LPS was perfused with a TNF-alpha antiserum or the ceramidase inhibitor N:-oleoylethanolamine. In contrast, the cardiac release of nitric oxide (NO) was not augmented by LPS. Immunohistochemical studies of LPS-perfused hearts revealed a positive staining for the constitutive (NOSIII) but not for the inducible NO synthase (NOSII). Accordingly, NOSII mRNA levels commenced to increase only at the very end of the LPS perfusion period. Progressive liberation of thromboxane (Tx) A(2) and prostacyclin was induced by LPS together with myocardial cyclooxygenase (Cox)-2 mRNA expression. Both nonselective inhibition of Cox by indomethacin and selective inhibition of the inducible Cox-2 by NS-398 abolished prostanoid release. Interestingly, the generation of TNF-alpha and the associated cardiodepression caused by LPS were reduced by indomethacin, NS-398 and the Tx-receptor antagonist daltroban. CONCLUSIONS: LPS depresses contractility of isolated rat hearts by inducing TNF-alpha synthesis and subsequently activating the sphingomyelinase pathway, whereas no evidence for a role of NOSII- or NOSIII-generated NO was found. Moreover, Cox-2-derived TxA(2) appears to facilitate TNF-alpha synthesis in response to LPS.

Animals↗