endothelin-1 and Pulmonary-Embolism

Chronic thromboembolic pulmonary hypertension may occur in the context of incomplete lysis of acute pulmonary emboli, resulting in the obstruction of pulmonary blood flow, as well as progressive right ventricular dysfunction and failure. The treatment of choice for this condition is surgical removal of the obstructing material. However, in many patients, surgery is not possible due to either an unfavourable distribution of the disease, the development of a concurrent small vessel pulmonary arteriopathy, or the presence of significant comorbid conditions. There is increasing evidence that the medical therapies that are used in other forms of pulmonary hypertension may also be effective in inoperable chronic thromboembolic pulmonary hypertension. This article examines the rationale for the use of the oral dual endothelin receptor antagonist bosentan in this life-threatening condition.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Drug Administration Schedule; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Receptors, Endothelin; Sulfonamides

To investigate the effects of thrombolysis and anticoagulation on the functions of vascular endothelial cells and coagulation and fibrinolysis in patients with pulmonary thromboembolism.. Twenty-four patients with documented pulmonary thromboembolism and 20 normal subjects were included. Of the 24 patients with pulmonary thromboembolism, 7 were treated with recombinant tissue-type plasminogen activator intravenously, and 17 with low molecular weight heparin. The plasma levels of endothelin 1 (ET-1), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), antithrombin III (AT-III) and D-dimer and the blood serum levels of nitrogen monoxide (NO) were measured in the control group and in the patients at different time points before and after therapies.. In patients receiving thrombolytic therapy, ET-1 [(103.7 +/- 26.6) ng/L] and D-dimer [(5.0 +/- 1.7) mg/L] increased significantly at 4 h after the treatment, and were higher than those at other time points (P < 0.05 and P < 0.01, respectively). The level of ET-1 was correlated positively with PaO(2) and D-dimer (r = 0.751, and 0.782 respectively, P < 0.05). In patients receiving anticoagulation therapy, compared with pretreatment data, NO and AT-III increased and ET-1 decreased significantly at 14 d after the start of low molecular weight heparin therapy, (48 +/- 14) micromol/L vs (66 +/- 24) micromol/L for NO, (90 +/- 7)% vs (99 +/- 4)% for AT-III, (72.0 +/- 18.3) ng/L vs (52.8 +/- 13.9) ng/L for ET-1, all P < 0.05.. ET-1 and D-dimer changed significantly after thrombolytic therapy, while ET-1, NO and AT-III showed dramatic change after anticoagulation therapy. The change of ET-1 and D-dimer reflects the therapeutic effects. Thrombolytic and anticoagulation therapies are beneficial in keeping the balance between coagulation and fibrinolysis and protecting the functions of vascular endothelial cells in patients with pulmonary thromboembolism.

Topics: Adult; Aged; Blood Coagulation; Endothelial Cells; Endothelin-1; Female; Fibrin Fibrinogen Degradation Products; Hematologic Tests; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Pulmonary Embolism; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. Increased plasma ET-1 levels are observed in pulmonary arterial hypertension (PHT) and may contribute to the regulation of pulmonary vascular resistance, as well as to proliferative changes in the pulmonary vascular bed.. We prospectively assessed changes in plasma big ET-1 levels and changes in ET(A) and ET(B) receptor gene expression in 14 consecutive patients undergoing pulmonary thromboendarterectomy for thromboembolic PHT. Plasma big ET-1 levels were higher in patients with PHT (median, 2.2 pg/mL; 25th to 75th percentile, 1.5 to 3.0 pg/mL) compared with age-matched controls (median, 1.2 pg/mL; 25th to 75th percentile, 1.0 to 1.4 pg/mL; P=0.002). In addition to increased plasma big ET-1 levels, selective upregulation of ET(B) receptor mRNA transcripts and immunoreactive protein in the pulmonary artery was observed in the patients; however, ET(A) receptor gene expression was unaffected.. These data suggest that changes in the ET signaling system in PHT caused by thromboembolic disease are not limited to an increased production of ET-1: they also affect ET receptor gene expression.

Topics: Endarterectomy; Endothelin-1; Endothelins; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Protein Precursors; Pulmonary Artery; Pulmonary Embolism; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition with a poor prognosis in which the pulmonary arteries are occluded by organized thrombi. Pulmonary thromboendarterectomy (PEA) is an effective treatment for CTEPH; however, the literature on its histopathological examination is lacking. This study aimed to investigate the histopathological findings and protein and gene expression in PEA specimens, establish an optimal histopathological evaluation method, and clarify the mechanisms of thrombus organization and disease progression in CTEPH.. In total, 50 patients with CTEPH who underwent PEA were analyzed. The patients were categorized according to their clinical data into two groups: good and poor postoperative courses. The relationship between their histopathological findings and the clinical course was examined. Immunohistochemical studies confirmed the expression of oxidants, antioxidants, and smooth muscle cell (SMC) differentiation markers and their changes during the progression of thrombus organization. The mRNA expression analysis of 102 samples from 27 cases included oxidants, antioxidants, and vasoconstrictor endothelin-1.. In the PEA specimens, colander-like lesions (aggregations of recanalized blood vessels with well-differentiated SMCs) were significantly more common in the good postoperative course group than in the poor postoperative course group; analysis of proteins and genes proposed that oxidative and antioxidant mechanisms were involved. In the colander-like lesions, there was an increase in endothelin-1 mRNA and protein expression of endothelin receptor A.. Colander-like lesions in PEA specimens must be identified. Additionally, SMC differentiation in recanalized vessels and the expression of vasoconstrictors and their receptors may contribute to the progression of CTEPH.

Topics: Chronic Disease; Endarterectomy; Endothelin-1; Humans; Hypertension, Pulmonary; Oxidants; Pulmonary Embolism; RNA, Messenger; Thrombosis

The purpose of this study was to report the characteristics and long-term survival of patients with CTEPH treated in three distinct ways: PEA, BPA and medical therapy.. Patients diagnosed with CTEPH were included in the registry that was set up in 18 centres from August 2009 to July 2018. The characteristics and survival of patients with CTEPH receiving the different treatments were reported. Prognostic factors were evaluated by Cox regression model.. A total of 593 patients with CTEPH were included. Eighty-one patients were treated with PEA, 61 with BPA and 451 with drugs. The estimated survival rates at 1, 3, 5 and 8 years were, respectively, 95.2%, 84.6%, 73.4% and 66.6% in all patients; 92.6%, 89.6%, 87.5% and 80.2% in surgical patients; and 95.4%, 88.3%, 71.0% and 64.1% in medically treated patients. The estimated survival rates at 1, 3, 5 and 7 years in patients treated with BPA were 96.7%, 88.1%, 70.0% and 70.0%, respectively. For all patients, PEA was an independent predictor of survival. Other independent risk factors were CHD, cardiac index, PVR, big endothelin-1, APE and 6MWD.. This is the first multicentre prospective registry reporting baseline characteristics and estimated survival of patients with CTEPH in China. The long-term survival rates are similar to those of patients in the international and Spanish registries. PEA is an independent predictor of survival.

Topics: Angioplasty, Balloon; China; Chronic Disease; Endarterectomy; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Pulmonary Embolism; Registries; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome

To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices.. A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline).. In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups.. Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

Topics: Acute Disease; Administration, Inhalation; Animals; Bronchodilator Agents; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Male; Nitric Oxide; Pulmonary Embolism; Rabbits; Random Allocation; Reference Values; Reproducibility of Results; Thromboxane A2; Time Factors; Treatment Outcome; Troponin I

The only curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). PEA requires cardiopulmonary bypass (CPB) which is associated with a high acute kidney injury (AKI) risk. Circulating endothelin-1 (ET-1) levels are elevated in CTEPH, and ET-1 plays a pivotal role in AKI. Because AKI is burdened by high morbidity and mortality, we aimed to evaluate the association between preoperative ET-1 and the risk to develop AKI in CTEPH individuals who undergo PEA. We also evaluated the association of AKI and ET-1 with kidney function and mortality at 1 year after PEA.. In 385 consecutive patients diagnosed with CTEPH who underwent PEA at the Foundation IRCC Policlinico San Matteo (Pavia, Italy) from January 2009 to April 2015, we assessed preoperative circulating ET-1 by ELISA and identified presence of AKI based on 2012 KDIGO criteria.. AKI occurred in 26.5% of the 347 patients included in the analysis, and was independently associated with preoperative ET-1 (p = 0.008), body mass index (BMI) (p = 0.022), male gender (p = 0.005) and duration of CPB (p = 0.002). At 1-year post PEA, estimated glomerular filtration rate (eGFR) significantly improved in patients who did not develop AKI [ΔeGFR 5.6 ml/min/1.73 m. Perioperative AKI is associated with higher preoperative circulating ET-1 and it negatively influences long-term kidney function in patients with CTEPH who undergo PEA.

Topics: Acute Kidney Injury; Aged; Biomarkers; Endarterectomy; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Italy; Kidney; Male; Middle Aged; Predictive Value of Tests; Pulmonary Embolism; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Up-Regulation

Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor N

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin-1; Hypertension, Pulmonary; Lung; Microvessels; Nitric Oxide; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; rho-Associated Kinases; Swine; Vasoconstriction

To establish the rat model of acute pulmonary embolism, and study the changes of vascular active substances in pulmonary embolism rats, and investigate the interventive effect of anticoagulant drugs on vascular active substances.. One hundred and twenty-eight rats were randomly divided into four groups: control group, model group, low-molecular-weight heparin and warfarin treated group and rivaroxaban-treated group (n = 32 in each group). The method of autologous thrombosis was used to establish the animal model of acute pulmonary embolism. The animals were treated with saline or different anticoagulant drugs. The physiological and biochemical parameters were detected at different time points after embolization. The rats were killed after embolism of 24 h, 3 d, 5 d or 1 week respectively and the pathologic samples of lung tissues were collected to analyze the pulmonary pathological changes in different groups.. Rats in embolization group after blood clots injection showed shortness of breath, oral cyanosis; quicken heart rates and other symptoms. All embolization groups had pulmonary hypertension, the levels of type B natriuretic peptide (BNP) were increased significantly. The ratio of endothelin-1 (ET-1)/NO and thromboxane (TXB2) and prostacyclin (6-k-PGFla) were abnormal. After treated with effective anticoagulant drugs, the levels of BNP, ET-1, NO, TXB2 and 6-k-PGF1a were tended to the normal levels in the control group. The pulmonary hypertensions were gradually decreased. The efficacy of rivaroxaban on pulmonary embolism was the same as that of the low molecular weight heparin or warfarin.. Anticoagulation therapy can effectively improve endothelial function after pulmonary embolism, reduce pulmonary hypertension, and revise the increased BNP levels to normal levels. The efficacy of rivaroxaban is not inferior to that of low molecular weight heparin and warfarin.

Topics: Animals; Anticoagulants; Disease Models, Animal; Endothelin-1; Heparin, Low-Molecular-Weight; Hypertension, Pulmonary; Lung; Morpholines; Pulmonary Embolism; Rats; Rivaroxaban; Thiophenes; Warfarin

Besides the established biomarker NT-proBNP, the new cardiovascular biomarkers MR-proANP, MR-proADM, Copeptin, and CT-proET-1 are promising to evaluate hemodynamics, exercise parameters, and prognosis in patients with pulmonary hypertension (PH).. 125 consecutive patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were prospectively enrolled at five German PH centers. Blood samples were taken during right heart catheterization. The primary study endpoint was the correlation between biomarkers and hemodynamic and exercise parameters. As secondary endpoint, prediction of 1-year mortality was evaluated.. MR-proADM showed the strongest correlations with 6MWD and VO2peak, whereas NT-proBNP showed the strongest correlations with PVR, PAPm, and CI. In multivariate analysis, only MR-proADM was independently associated with exercise variables, whereas only NT-proBNP independently predicted hemodynamic parameters. All biomarkers were associated with 1-year survival, with MR-proADM showing the highest C index of 0.78. In multivariate analysis, MR-proADM predicted survival independent of age, 6-MWD, CI, RAP, and NT-proBNP. The cut-off of 1.08 nmol/l provided a sensitivity of 83 % and specificity of 66 %.. Different biomarkers reflect distinctive disease aspects in PH. NT-proBNP best predicts hemodynamic impairment while MR-proADM strongly correlates with exercise capacity. Additionally, MR-proADM represents a promising new marker to evaluate prognosis in patients with PAH and CTEPH. Multi-marker strategies should further be evaluated.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Chronic Disease; Endothelin-1; Exercise Tolerance; Female; Germany; Glycopeptides; Heart Atria; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Pulmonary Embolism; Pulmonary Wedge Pressure; Vascular Resistance

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.

Topics: Adult; Case-Control Studies; Cell Movement; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelin-1; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Male; MicroRNAs; Middle Aged; Myocytes, Smooth Muscle; Protein Binding; Protein Serine-Threonine Kinases; Pulmonary Artery; Pulmonary Embolism; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Transcriptome

Acute pulmonary embolism (PE) is a severe and potentially fatal disease which acutely augments the right ventricle (RV) strain. Development of RV dysfunction (RVD) in the disease process is synonymous with an overall poor prognosis. The diagnosis of PE is usually established by a combination of clinical assessment, D-dimer test and medical imaging with either lung scintigraphy or pulmonary multidetector computer tomography (MDCT) angiography. Which of the two methods to use in PE diagnostic has not been determined and very limited data comparing these modalities are available. Assessment of RV function is cumbersome due to complex geometry. RVD is usually established by echocardiography which is observer dependent, has low reproducibility, and requires expertise. Therefore, a simple and reproducible biochemical method to assess RVD in patients with PE would be desirable. Brain natriuretic peptide (BNP), pro-atrial natriuretic peptide (pro-ANP), cardiac troponin I (TnI), and endothelin-1 (ET-1) have been the most studied plasma biomarkers in the context of risk stratification in PE. BNP is mainly produced in the ventricles of the heart. It is released from the left ventricle in response to increased filling pressure and is increased in chronic left heart failure. Pro-ANP is primarily produced in the atria, is released by atrial distention and is elevated in chronic pulmonary hypertension and could be an early marker for RVD. Plasma level of ET-1 has been shown to correlate with pulmonary pressure and is released from endothelial cells in the pulmonary vessels. Additionally, increases in circulating levels of ET-1 have been reported in an experimental animal model of PE. TnI is part of a complex of regulatory proteins in the cardiac myofilaments and is released upon myocyte injury. It is related to short term clinical outcome, prolonged hypotension, and cardiogenic shock after myocardial infarction and is a predictor of 30-day mortality and RVD using echocardiography in patients with PE. Our hypothesis was therefore that the neuroendocrine activation of BNP, pro-ANP, ET-1, and TnI alone or in combination could serve as markers of RVD in patients with PE. The use of plasma biomarkers would be much simpler than reproducible medical imaging methods such as magnetic resonance imaging (MRI), radionuclide based methods etc.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Humans; Natriuretic Peptide, Brain; Prospective Studies; Pulmonary Artery; Pulmonary Embolism; Radiography; Rats; ROC Curve; Sensitivity and Specificity; Tomography Scanners, X-Ray Computed; Tomography, Emission-Computed, Single-Photon; Troponin I; Ventricular Dysfunction, Right

Topics: Adult; Endothelin-1; Female; Humans; Male; Middle Aged; Pulmonary Embolism

Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 microm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 +/- 1.6 vs. 32.9 +/- 7.5 mmHg). Arterial oxygen tension was lower (92.3 +/- 12.5 vs. 66.0 +/- 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 +/- 3.8 vs. 36.5 +/- 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase alpha expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 +/- 3.7, 17.1 +/- 3.2, 14.3 +/- 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 +/- 16.2, 94.9 +/- 23.0, 89.1 +/- 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

Topics: Acute Disease; Animals; Blood Gas Analysis; Blood Pressure; Endothelin-1; Hemodynamics; Injections, Intravenous; Lung; Male; Microspheres; Nitric Oxide Synthase Type III; Polystyrenes; Protein Kinase Inhibitors; Pulmonary Artery; Pulmonary Embolism; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Vascular Cell Adhesion Molecule-1

It has been shown that neurohumoral factors other than mechanical obstruction are involved in the pathophysiology of acute pulmonary thromboembolism (APTE). The aim of this study was to investigate the effects of thrombolytic drugs, a selective endothelin-1 receptor (ET-1R) antagonist alone or their combination on APTE in a canine model.. Twenty dogs were randomly assigned to five groups: sham, model, urokinase (UK), BQ123, and combination (UK plus BQ123). The dogs in the sham group underwent sham surgery. APTE was induced in the other four groups by intravenous injection of autologous blood clots. Dogs in the UK, BQ123 and combination groups received UK, BQ123 (a selective ET-1R antagonist), or UK plus BQ123, respectively. The dogs in the model group were given saline. Mean pulmonary artery pressure (mPAP), serum concentrations of ET-1, thromboxane (TXB2), and tumor necrosis factor (TNF)-alpha were determined at different time points following the induction of APTE.. UK and BQ123 alone markedly decreased mPAP in APTE. By comparison, the reduction was more significant in the combination group. Compared with the sham group ((-0.90 +/- 0.61) mmHg), mPAP increased by (7.44 +/- 1.04), (3.42 +/- 1.12) and (1.14 +/- 0.55) mmHg in the model group, UK alone and BQ123 alone groups, respectively, and decreased by (2.24 +/- 0.67) mmHg in the combination group (P < 0.01). Serum ET-1 concentrations in the BQ123 and combination groups were (52.95 +/- 8.53) and (74.42 +/- 10.27) pg/ml, respectively, and were significantly lower than those in the model and UK groups ((84.56 +/- 7.44) and (97.66 +/- 8.31) pg/ml respectively; P < 0.01). Serum TNF-alpha concentrations were significantly lower in the BQ123 group than in the model, UK and combination groups (P < 0.05).. Our results indicate that the selective ET-1R antagonist BQ123 not only reduces the increase of mPAP and serum ET-1 level, but also inhibits the production of TNF-alpha, and attenuates the local inflammatory response induced by APTE. Selective ET-1R antagonists may be beneficial to the treatment of APTE, particularly when used in combination with a thrombolytic agent.

Topics: Animals; Dogs; Endothelin A Receptor Antagonists; Endothelin-1; Fibrinolytic Agents; Peptides, Cyclic; Pulmonary Embolism; Random Allocation; Thromboxanes; Tumor Necrosis Factor-alpha

Atrial natriuretic petide (ANP), brain natriuretic peptide (BNP) and endothelin-1 (ET-1) may reflect the severity of right ventricular dysfunction (RVD) in patients with pulmonary embolism (PE). The exact nature and source of BNP, ANP and ET-1 expression and secretion following PE has not previously been studied.. Polystyrene microparticles were injected to induce PE in rats. Gene expression of BNP, ANP and ET-1 were determined in the 4 cardiac chambers by quantitative real time polymerase chain reaction (QPCR). Plasma levels of ANP, BNP, ET-1 and cardiac troponin I (TNI) were measured in plasma. PE dose-dependently increased gene expression of ANP and BNP in the right ventricle (RV) and increased gene expression of ANP in the right atrium (RA). In contrast PE dose-dependently decreased BNP gene expression in both the left ventricle (LV) and the left atrium (LA). Plasma levels of BNP, TNI and ET-1 levels dose-dependently increased with the degree of PE.. We found a close correlation between PE degree and gene-expression of ANP, and BNP in the cardiac chambers with a selective increase in the right chambers of the heart. The present data supports the idea of natriuretic peptides as valuable biomarkers of RVD in PE.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; DNA Primers; Endothelin-1; Gene Expression; Male; Myocardium; Natriuretic Peptide, Brain; Polymerase Chain Reaction; Pulmonary Embolism; Rats; Rats, Sprague-Dawley

In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions.. Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5).. High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05).. Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

Topics: Angiopoietin-1; Animals; Animals, Newborn; Antihypertensive Agents; Aorta; Apoptosis; Cell Proliferation; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Hemodynamics; Hypertension, Pulmonary; Hypertrophy; Isoxazoles; Muscle, Smooth, Vascular; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Receptor, Endothelin A; Receptor, TIE-2; RNA, Messenger; Sulfones; Swine; Time Factors

The aim of this study was to predict right ventricular dysfunction (RVD) using plasma concentration of D-dimer, pro-atrial natriuretic peptide (pro-ANP), brain natriuretic peptide (BNP), endothelin-1 (ET-1) and cardiac troponin I (TNI) in patients with pulmonary embolism (PE).. Patients suspected of PE had a ventilation/perfusion-single-photon emission-tomography (V/Q-SPECT), pulmonary multidetector computer tomography (MDCT) angiography, blood samples and ECG-gated cardiac CT performed the same day.. Pro-ANP, BNP and D-dimer are associated with significantly elevated levels in PE patients with RVD. ROC curves demonstrated that D-dimer, pro-ANP and BNP were accurate for detection of RVD.. Because measurements of cardiac biomarkers are inexpensive and easily obtained they may prove useful in the clinical diagnosis of RVD. However because of the small sample size, the results need to be confirmed in larger studies.

Topics: Acute Disease; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Denmark; Endothelin-1; Female; Fibrin Fibrinogen Degradation Products; Humans; Linear Models; Logistic Models; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Perfusion Imaging; Predictive Value of Tests; Prognosis; Prospective Studies; Pulmonary Embolism; ROC Curve; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Troponin I; Up-Regulation; Ventricular Dysfunction, Right; Ventricular Function, Right

Chronic thromboembolic pulmonary hypertension is due to partial obstruction of the pulmonary arterial bed and may resolve after pulmonary thromboendarterectomy. Persistent pulmonary hypertension, the main complication after pulmonary thromboendarterectomy, may reflect vessel alterations induced by high flow in unobstructed lung territories. The aim of this study was to determine whether correcting high flow led to reversal of the vasculopathy in piglets.. The effects of high pulmonary blood flow were investigated 5 weeks after creation of an aortopulmonary shunt (n = 10), and reversibility of vessel disease was evaluated at 1 week (n = 10) and 5 weeks after shunt closure (n = 10), compared to sham-operated animals (n = 10). Hemodynamic variables, pulmonary artery reactivity, and morphometry were recorded. We also investigated the endothelin, angiopoietin, and nitric oxide synthase pathways.. High flow increased medial thickness in distal pulmonary arteries (55.6% +/- 1.2% vs 35.9% +/- 0.8%; P < .0001) owing to an increase of smooth muscle cell proliferation (proliferating cell nuclear antigen labeling). The endothelium-dependent relaxation was altered (P < .05). This phenomenon was associated to an overexpression of endothelin-1, endothelin-A, angiopoietin 1, angiopoietin 2, and Tie-2 (P < .05). After 1 week of shunt closure, all overexpressed genes returned to control values, the proliferation of smooth muscle cells stopped, and smooth muscle cell apoptosis increased (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), preceding the normalization of the wall thickness hypertrophy and the pulmonary artery vasoreactivity observed at 5 weeks after shunt closure.. These results demonstrate that endothelin-1 and angiopoietin pathways are involved in vasculopathy development and may be important therapeutic targets for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

Topics: Acetylcholine; Angiopoietin-1; Animals; Apoptosis; Cell Proliferation; Collagen; Cyclic Nucleotide Phosphodiesterases, Type 5; Endarterectomy; Endothelin-1; Hypertension, Pulmonary; Lung; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Receptor, TIE-2; Receptors, Endothelin; Tunica Media; Vasoconstriction; Vasodilation

During orthopedic surgery, embolization of bone marrow fat can lead to potentially fatal, intra-operative cardiovascular deterioration. Vasoactive mediators may also be released from the bone marrow and contribute to these changes. Increased plasma levels of endothelin-1 (ET-1) have been observed after pulmonary air and thrombo-embolism. The role of ET-1 in the development of acute cardiovascular deterioration as a result of bone marrow fat embolization during vertebroplasty was therefore investigated.. Bone cement was injected into three lumbar vertebrae of six sheep in order to force bone marrow fat into the circulation. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output, arterial and mixed venous blood gas parameters and plasma ET-1 concentrations were measured at selected time points. Post-mortem, lung biopsies were taken for analysis of intravascular fat.. Cement injections resulted in a sudden (within 1 min) and severe increase in pulmonary arterial pressure (>100%). Plasma concentrations of ET-1 started to increase after the second injection, but no significant changes were observed. Intravascular fat and bone marrow cells were present in all lung lobes.. Cement injections into vertebral bodies elicited fat embolism resulting in subsequent cardiovascular changes that were characterized by an increase in pulmonary arterial pressure. Cardiovascular complications as a result of bone marrow fat embolism should thus be considered in patients undergoing vertebroplasty. No significant changes in ET-1 plasma values were observed. Thus, ET-1 did not contribute to the acute cardiovascular changes after fat embolism.

Topics: Animals; Bone Marrow; Disease Models, Animal; Embolism, Fat; Endothelin-1; Lumbar Vertebrae; Pulmonary Embolism; Sheep; Time Factors

Topics: Benzamides; Cell Division; Drug Therapy, Combination; Endothelin-1; Endothelium, Vascular; Fibromuscular Dysplasia; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyrimidines; Vasodilator Agents

In non-thromboembolic pulmonary hypertension, endothelin (ET)-1 levels are increased and correlate with the hemodynamic severity of the disease. Whether such correlations exist in chronic thromboembolic pulmonary hypertension (CTEPH) is unknown, nor whether ET-1 levels correlate with hemodynamic outcome after pulmonary endarterectomy (PEA).. ET-1 levels were determined by ELISA. ET-levels were increased in 35 CTEPH patients (1.62+/-0.21 pg/ml) compared with healthy controls (n=11: 0.75+/-0.06 pg/ml, p<0.02). ET-1 levels correlated (all p<0.0001) with mean pulmonary artery pressure (mPAP) (r=0.70), cardiac index (r=-0.76), total pulmonary resistance (r=0.72), mixed venous oxygen saturation (r=-0.87), and the distance walked in the 6-min walk test (r=-0.59; p<0.005; n=23). Three months after PEA, ET-1 levels had decreased (p<0.002), and were similar between patients with and without residual pulmonary hypertension (p=0.4). Preoperative ET-1 levels, however, were higher in patients with bad postoperative outcome; that is, patients who either died because of persistent pulmonary hypertension or had residual pulmonary hypertension after PEA (2.68+/-0.48 pg/ml, and 1.13+/-0.15 pg/ml, respectively; p<0.002). The levels also correlated with hemodynamic outcome after PEA (mPAP: r=0.67, p<0.0001). By receiver-operator characteristic curve analysis, ET-1>1.77 pg/ml detected a bad postoperative outcome with a sensitivity and specificity of 79% and 85%, respectively, and a likelihood ratio of 5.2.. ET-1 levels in CTEPH closely correlated with the hemodynamic and clinical severity of disease in a large cohort of patients. Preoperative ET-1 levels may be useful for better identification of patients at risk for persistent pulmonary hypertension after PEA.

Topics: Adolescent; Adult; Aged; Endarterectomy; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Embolism; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome; Vascular Resistance

To study the expression levels of endothelin-1(ET-1) and nuclear factor-kappaB (NF-kappaB) in lung vascular endothelium, bronchial and alveolar epithelia in acute pulmonary thromboembolism (APTE), and to explore the effects of thrombolytic (urokinase, UK) or ant-inflammatory therapy (dexamethasone, Dex) on their expressions.. Forty rabbits were randomly divided into a control (C) group, a pulmonary thromboembolism (PTE) model group, an UK therapy group, a Dex therapy group, and an UK + Dex therapy group, with 8 rabbits each. The PTE model was established by intravenous injection of autologous blood clots. The pathological changes of the lung were examined with light microscope. By using immunohistochemistry, the expression levels of ET-1 and NF-kappaB P65 in lung vascular endothelium, bronchial and alveolar epithelia were examined.. Histopathological study showed that lung injury was evident in the PTE, UK and Dex groups, but was mild in the UK + Dex group. In the PTE group, the expression levels of ET-1 in lung vascular endothelium, bronchial and alveolar epithelia were 0.331 +/- 0.036, 0.229 +/- 0.014 and 0.191 +/- 0.046, respectively, while the expression levels of NF-kappaB P65 were 0.245 +/- 0.036, 0.190 +/- 0.040 and 0.204 +/- 0.054, respectively. Their levels were significantly higher as compared to those of the control group and the UK + Dex group (all P < 0. 01). In the UK group, the ET-1 expression in lung vascular endothelium, bronchial and alveolar epithelia were 0.204 +/- 0.020, 0.163 +/- 0.017 and 0.137 +/- 0.013 respectively, significantly lower as compared to the PTE group (all P < 0. 05). In the Dex group, the NF-kappaB P65 expression was 0.175 +/- 0.024, 0.104 +/- 0.022 and 0.144 +/- 0.022 respectively, the difference being significant as compared with the PTE group (all P < 0. 05). In the UK + Dex group, the ET-1 expression was 0.186 +/- 0.033, 0.107 +/- 0.012 and 0.098 +/- 0.026 respectively, significantly different from the PTE group (all P < 0.05); the NF-kappaB P65 expression was 0.109 +/- 0.018, 0.062 +/- 0.023 and 0.093 +/- 0.019 respectively, significantly lower as compared with the PTE and the UK groups (all P < 0. 01).. After APTE, thrombolytic and anti-inflammatory treatment could decrease acute lung injury induced by ET-1 and NF-kappaB activation. Thus, anti-inflammatory therapy and the use of ET-1 inhibitor or receptor antagonist should be considered in APTE.

Topics: Animals; Dexamethasone; Endothelin-1; Fibrinolytic Agents; NF-kappa B; Pulmonary Embolism; Rabbits

To study the functional changes and the significance of coagulation, fibrinolysis and pulmonary vascular endothelium before and after experimental pulmonary thromboembolism in rabbits.. Rabbit pulmonary thromboembolism models by injection of auto-blood clots into femoral vein were used to observe the dynamical changes of activity of coagulation and fibrinolysis and endothelin-1 (ET-1), nitrogen monoxide (NO), von Willebrand factor (vWF) in blood.. Petechial and patchy hemorrhages were observed on the surfaces of embolic lungs. The injected blood clots and secondary thrombosis in the pulmonary arteries, inflammatory cell infiltration around alveoli, local hemorrhages in the alveoli and interstitial tissue could be found by microscopy. The concentration of D-dimer, ET-1 and vWF in blood were significantly elevated, and the tissue-type plasminogen activator (t-PA), NO and antithrombin III (AT-III) decreased significantly after embolism (P < 0.05). After administration of urokinase, the pathological injuries relieved, and the concentration of D-dimer was higher at 1 h and 2 h after embolization than that before embolization (P < 0.05), and reduced to the level of pre- embolization at 4 h after embolization. The levels of t-PA, NO and AT-III after embolization were lower than those before embolization (P < 0.05). The level of ET-1 was higher at 2 h after embolization (P < 0.05) and reduced to the level of pre-embolization at 4 h.. PTE has important impacts on coagulation, fibrinolysis and pulmonary vascular endothelial function. Thrombolysis with urokinase could keep the balance between coagulation and fibrinolysis and protect pulmonary vascular endothelial function.

Topics: Animals; Antithrombin III; Blood Coagulation; Endothelin-1; Endothelium, Vascular; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Male; Nitric Oxide; Pulmonary Embolism; Rabbits; Urokinase-Type Plasminogen Activator; von Willebrand Factor

Acute pulmonary air embolism (APAE) was induced in nine piglets by repeated intravenous bolus injection of room air into a large bore central venous catheter at time=0 min so that the mean pulmonary artery pressure (MPAP) was maintained at two times the baseline value for 4 h. Another five animals served as controls. At time=0, 30, 60, 120, 240 min, circulating arterial plasma levels of endothelin-1 (ET-1), its precursor big ET-1, and thromboxane (Tx), were measured by RIA and EIA, respectively, along with hemodynamics and blood gases. The data showed that following APAE, there was a rapid increase in MPAP and a persistent decrease in Pa(O(2)), while the mean arterial blood pressure and cardiac output remained comparable. Plasma levels of ET-1, big ET-1 and Tx were also increased steadily in these first 4 h. These results showed that during APAE, the resulted changes in the pulmonary vascular and airway tones mediated by these potent mediators could explain the observed pulmonary hypertension and the deterioration of gas exchange.

Topics: Acute Disease; Animals; Disease Models, Animal; Embolism, Air; Endothelin-1; Hemodynamics; Pulmonary Embolism; Random Allocation; Swine; Thromboxanes

Acute pulmonary air embolism (APAE) injures the vascular endothelium in the lung and results in pulmonary hypertension (PH). Endothelins (ETs), a family of potent vasoactive peptides, are known to be associated with PH of various aetiologies. We evaluated the effects of ABT-627, a selective ET(A) receptor (ET(A)-R) antagonist in a rat model of APAE over 3 h. APAE rats developed a higher right ventricular systolic pressure (RVSP), lower mean arterial blood pressure (MABP), and had lower PaO(2). At 3 h, arterial plasma levels of ET-1 were increased. ABT-627-treated controls showed no effects. However, ABT-627 significantly lowered RVSP during APAE, abolished the short recovery phase (within 10-25 min) of MABP without affecting the subsequent lowering of MABP, and improved oxygen saturation in APAE rats. These results show that ET(A)-R subtype is involved in the pathogenesis of APAE since a blockade of this receptor subtype attenuated the cardiopulmonary deterioration and improved blood gas exchanges in rats with this disease.

Topics: Acute Disease; Animals; Atrasentan; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Gene Expression; Lung; Male; Models, Animal; Oxygen; Pulmonary Embolism; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

To investigate the role of blood vessel active substances, such as endothelin-1 (ET-1), thromboxane B(2) (TXB(2)), and 6-keto-prostaglandin F(1alpha) (6-K-PGF(1alpha)) in a rabbit model of acute pulmonary embolism induced by echinococus granulous cyst.. Catheters were placed into the femoral artery and the femoral vein. Saline, fresh clear cyst fluid or sand containing cyst fluid in a volume of 2 ml/kg were infused through the femoral vein catheter. Changes of ET-1, TXB(2) and 6-K-PGF(1alpha) were measured; PaO(2), PaCO(2), pH, MAP, heart rate, and respiration rate were recorded; and radionuclide lung perfusion scan and the change of heart and lung pathology were studied.. The changes of the studied parameters were not remarkable in the saline treated animals (P > 0.05). TXB(2) and 6-K-PGF(1alpha) were elevated in the cyst fluid treated animals (P < 0.05). PaO(2), PaCO(2), and MAP declined in the clear cyst fluid group (P < 0.05), but their changes were more significant in animals treated with sand containing cyst fluid. Radionuclide lung perfusion scan showed radioactivity defect or attenuation. Histological examination of the lungs revealed diffuse alveolar damage.. Sand containing cyst fluid caused a more severe disease in this rabbit model of acute pulmonary embolism, suggesting that it played an important role in the induction of lung damage.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Blood Pressure; Echinococcosis; Endothelin-1; Female; Lung; Male; Myocardium; Pulmonary Embolism; Rabbits; Radionuclide Imaging; Thromboxane B2

The plasma endothelin-1 (ET-1) level is elevated in patients with acute pulmonary thromboembolism (APE). Whether ET-1 is a pathogenic mediator or a simple marker of APE is not known. We investigated the role of ET-1 in hemodynamic dysfunction in APE through evaluating the effects of ET(A) receptor antagonist in an experimental APE model. We also examined ET-1 expression in embolized lungs. In a canine autologous blood clot pulmonary embolism model, ET(A) receptor antagonist ZD2574 (10 mg/kg, intravenous; ZD2574 group; n = 6) or vehicle (control group; n = 5) was administered. Hemodynamic and gas exchange parameters and plasma levels of ET-1 were serially measured. Prepro-ET-1 mRNA expression and the distribution of ET-1 peptide in lung tissues were also examined. With ZD2574 pulmonary arterial pressure and pulmonary vascular resistance significantly decreased, and were lower compared with the control group. The decrease in cardiac output was also less in the ZD2574 group. Plasma ET-1 levels increased after embolization. Prepro-ET-1 mRNA expression increased in embolized lungs and ET-1 peptide expression also increased in embolized lungs, particularly in the muscular pulmonary arteries, compared with normal lungs. These findings suggest that ET-1 partially contributes to hemodynamic derangements of APE, and that ET(A) receptor antagonists might constitute a useful therapeutic tool for APE.

Topics: Acute Disease; Animals; Dogs; Endothelin-1; Hemodynamics; Pulmonary Embolism

It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Bosentan; Chronic Disease; Culture Techniques; Disease Models, Animal; Dogs; Endothelin-1; Female; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Lung; Male; Probability; Pulmonary Artery; Pulmonary Circulation; Pulmonary Embolism; Reference Values; Sulfonamides; Tomography, Emission-Computed; Vascular Resistance

To evaluate the effects of nonselective endothelin (ET)-receptor antagonism on the hemodynamic changes and serum thromboxane (TX)-A(2) levels after a massive pulmonary air embolism (PAE) in dogs.. Prospective trial.. University laboratory.. Anesthetized mongrel dogs (ET-receptor antagonist group; n = 6) received a bolus injection of 1 mg of the nonselective ET-A/ET-B-receptor antagonist PD 145065 (Sigma Chemical; St. Louis, MO), and dogs in the control group (n = 6) received saline solution. Hemodynamic data were recorded 5 min after the administration of antagonist or saline solution. Subsequently, each dog received 2.5-mL air/kg via the right femoral vein (the PAE), and the hemodynamic data were recorded for up to 60 min thereafter. Arterial blood samples were drawn at baseline and 15 min after PAE for the determination of plasma TX-A(2), measured by enzyme-linked immunosorbent assay as TX-B(2) (the stable metabolite of TX-A(2)).. PD 145065 alone produced no hemodynamic effects. However, dogs pretreated with PD 145065 had significantly lower increases in mean pulmonary arterial pressure and in pulmonary vascular resistance after the PAE (116% and 165%, respectively) compared to the control dogs (187% and 367%, respectively). The mean arterial pressure (MAP), cardiac index (CI), and plasma TX-B(2) levels were unaltered after PAE in the presence of ET-receptor antagonist, whereas CI and MAP decreased 5 to 10 min after PAE, and TX-B(2) concentrations increased 15 min after PAE in control dogs (p < 0.05 in all cases).. Nonselective antagonism of ET receptors attenuates the pulmonary hypertension and blunts the TX-A(2) release caused by massive PAE in dogs.

Topics: Animals; Dogs; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Male; Oligopeptides; Prospective Studies; Pulmonary Embolism; Thromboxanes

Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung.. Controlled experiment using isolated organs.. Experimental laboratory.. Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis).. Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg.. Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups.. We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Aspartic Acid Endopeptidases; Atrasentan; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Myocardial Contraction; Oligopeptides; Peptides, Cyclic; Protein Precursors; Pulmonary Embolism; Pyrrolidines; Rabbits; Thromboxane B2; Vasoconstriction

It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. 36 adult rabbits of either sex.. The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.. PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).. The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.

Topics: Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Perfusion; Phenylpropionates; Piperidines; Pulmonary Artery; Pulmonary Embolism; Pyrimidines; Rabbits; Radioimmunoassay; Thromboxane A2; Time Factors; Vascular Resistance