CO2 artificial pneumothorax on coagulation and fibrinolysis during thoracoscopic esophagectomy.

BACKGROUND: CO2 artificial pneumothorax creates a sufficient operative field for thoracoscopic esophagectomy. However, it has potential complications and continuous CO2 insufflation may impede coagulation and fibrinolysis. We sought to compare the effects of CO2 artificial pneumothorax on perioperative coagulation and fibrinolysis during thoracoscopic esophagectomy. METHODS: We investigated patients who underwent thoracoscopic esophagectomy with (group P, n = 24) or without CO2 artificial pneumothorax (group N, n = 24). The following parameters of coagulation-fibrinolysis function: intraoperative bleeding volume; serum levels of tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thromboelastogram (TEG), D-Dimer; and arterial blood gas levels were compared with two groups. RESULTS: Group P showed higher levels of PaCO2, reaction time (R) value and kinetics (K) value, but significantly lower pH value, alpha (α) angle and Maximum Amplitude (MA) value at 60 minutes after the initiation of CO2 artificial pneumothorax than group N ((P < .05, all). The t-PA level after CO2 insufflation for 60 minutes was significantly higher in group P than in group N (P < .05), but preoperative levels were gradually restored on cessation of CO2 insufflation for 30 min (P > .05). There was no significant difference in D-dimer. CONCLUSION: CO2 artificial pneumothorax during thoracoscopic esophagectomy had a substantial impact on coagulation and fibrinolysis, inducing significant derangements in pH and PaCO2. TRIAL REGISTRATION: The study was registered at the Chinese clinical trial registry (ChiCTR1800019004).

Antithrombotic Agents for tPA-Induced Cerebral Hemorrhage: A Systematic Review and Meta-Analysis of Preclinical Studies.

Background tPA (tissue-type plasminogen activator) remains the only approved drug for acute ischemic stroke, with a potentially serious adverse effect: hemorrhagic transformation. The effects of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke are not clearly defined. We performed a systematic review and meta-analysis in preclinical studies aiming to evaluate the efficacy of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke. Methods and Results We conducted a systematic review and meta-analysis of studies testing antithrombotic agents in animal models of tPA-induced hemorrhagic transformation. The pooled effects were calculated using random-effects models, and heterogeneity was explored through meta-regression and subgroup analyses. Publication bias was assessed using trim and fill method and the Egger test. The efficacy of 18 distinct interventions was described in 22 publications. The pooled data showed a significant improvement in cerebral hemorrhage, infarct size, and neurobehavioral outcome in treated compared with control animals (standardized mean difference, 0.45 [95% CI, 0.11-0.78]; standardized mean difference, 1.18 [95% CI, 0.73-1.64]; and standardized mean difference, 0.91 [95% CI, 0.49-1.32], respectively). Subgroup analysis indicated that quality score, random allocation, control of temperature, anesthetic used, stroke model used, route of drug delivery, time of drug administration, and time of assessment were significant factors that influenced the effects of interventions. Conclusions Administration with antiplatelet agents revealed statistically significant improvement in all the outcomes. Anticoagulant agents showed significant effects in infarct size and neurobehavioral score, but fibrinolytic agents did not show any significant improvement in all the outcomes. The conclusions should be interpreted cautiously given the heterogeneity and publication bias identified in this analysis.

[Time is brain : Time management in acute stroke treatment]. / "Time is brain" : Zeitmanagement in der akuten Schlaganfallversorgung.

BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rt-PA) and interventional thrombectomy are evidence-based causative therapies in acute stroke; however, the clinical benefit for the patient has been proven to be highly time-dependent. METHODS: A review of critical time intervals in acute stroke management and possibilities for modification is presented. RESULTS: Both prehospital and in-hospital times can be reduced with proven clinical benefits. The means to achieve time reductions are diverse and require clear workflow guidelines and continuous training. CONCLUSION: Optimization of time management during the complete acute diagnostics and treatment procedure by avoiding specific delays and streamlining universal workflow is of utmost importance regarding the efficiency and safety of treatment.

SmSP2: A serine protease secreted by the blood fluke pathogen Schistosoma mansoni with anti-hemostatic properties.

BACKGROUND: Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting. CONCLUSIONS/SIGNIFICANCE: The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.

Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

Regulatory effects of estetrol on the endothelial plasminogen pathway and endothelial cell migration.

BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17ß-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u-PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early-immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration.

Epigallocatechin Gallate Extends Therapeutic Window of Recombinant Tissue Plasminogen Activator Treatment for Brain Ischemic Stroke: A Randomized Double-Blind and Placebo-Controlled Trial.

OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a safe and effective treatment for acute brain ischemia stroke, albeit with a narrow therapeutic window. We aimed to assess the effect of epigallocatechin gallate (EGCG) in extending the rt-PA treatment window in this clinical trial among stroke patients. METHODS: Patients were randomly assigned according to their onset-to-treatment time (OTT) and were then treated with rt-PA simultaneously with EGCG or placebo. Treatment outcome was assessed by the National Institutes of Health stroke scale (NIHSS) and plasma levels of matrix metalloproteinases (MMP)-2 and 9. RESULTS: Administration of EGCG significantly improved treatment outcomes of patients in the delayed OTT strata, as evidenced by improved NIHSS scores. This improved treatment outcome was likely attributed to reduction in plasma levels of both MMP-2 and 9, as indicated by strong linear correlations between both MMPs and NIHSS scores in all patients. CONCLUSIONS: Epigallocatechin gallate could potentially be used as a supplement of traditional rt-PA treatment among stroke patients, particularly those with delayed OTT, to extend the otherwise narrow therapeutic window and improve the outcome in late stroke treatment.

Focal cerebral ischemia and neurovascular protection: a bench-to-bedside update.

PURPOSE OF REVIEW: To date, many pharmacological approaches, or combination of approaches, have been applied to experimental models of focal cerebral ischemia (FCI), but their translation to clinically effective agents has proved unsuccessful. To date, only thrombolysis with recombinant tissue-type plasminogen activator, or other 'clot-breaking' or 'clot-removal' approaches, have proved effective for acute stroke. This review, therefore, focuses on the 'vascular' phenomena involved in the development of FCI. RECENT FINDINGS: Recent advances in the experimental literature on FCI describe the microvascular characteristics of the ischemic penumbra, the consequences of cortical spreading depression on impairing cerebral perfusion, and the potential neuroprotective mechanisms of ischemic preconditioning via antithrombotic effects on the neurovascular unit. SUMMARY: This review provides a perspective about the neurovascular components contributing to the pathophysiology of FCI, and some relevant clinical strategies available on the horizon that hold promise for improved cerebral perfusion in FCI.

Hemostatic and fibrinolytic changes are related to inflammatory conditions in patients with psoriatic arthritis--effect of different treatments.

OBJECTIVE: To prospectively evaluate the effect of tumor necrosis factor (TNF)-α inhibitors on hemostatic and fibrinolytic variables in subjects with psoriatic arthritis (PsA). METHODS: Among subjects with PsA who were taking traditional disease-modifying antirheumatic drugs (DMARD), 98 patients with active disease who switched to treatment with TNF-α inhibitors were enrolled in this study (Group 1). In parallel, 98 matched subjects with minimal disease activity (MDA) and treated with DMARD were enrolled (Group 2). In all patients, hemostatic and fibrinolytic variables were evaluated at enrollment and after a 6-month followup. Results were stratified according to treatment and to MDA achievement. RESULTS: Seventy-six Group 1 and 80 Group 2 subjects completed the 6-month followup. During the followup, significant changes in hemostatic and fibrinolytic variables were found in Group 1, but not in Group 2 subjects. At the end of the followup, patients treated with TNF-α inhibitors showed significantly lower levels of hemostatic and fibrinolytic variables as compared to those treated with traditional DMARD. Among Group 1 subjects, changes in hemostatic and fibrinolytic variable levels were significantly higher in those who achieved MDA versus in those who did not. Multivariate analyses showed that a treatment with TNF-α blockers affected fibrinolytic variables [plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA)] and some acute-phase proteins (D-dimer, coagulation factor VIII, and von Willebrand factor). In contrast, the MDA achievement during treatment with TNF-α blockers maximally affected fibrinolytic variables (PAI-1 and t-PA). CONCLUSION: TNF-α inhibitors brought about a significant improvement of hemostatic and fibrinolytic balance in subjects with PsA. Maximal changes were found in patients achieving MDA.

A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C.

The incidence of disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction and high mortality, has remained constant in recent years. At present, treatments of DIC have focused on preventing cytokine induction, inhibiting coagulation processes and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC. To better understand the mechanism of treatment on DIC, we here report a novel fibrinogenase from Agkistrodon acutus (FIIa) that effectively protected against LPS-induced DIC in a rabbit model, and detected the tissue factors expression in HUVE cells after using FIIa. In vivo, administration of FIIa reduced hepatic and renal damage, increased the concentration of fibrinogen, the activities of protein C, the platelet count, APTT, PT, FDP, the level of AT-III and t-PA, decreased the level of PAI-1, and increased survival rate in LPS-induced DIC rabbits. In vitro experiments, we further confirmed that FIIa up-regulated the expression of t-PA and u-PA, down-regulated the expression of PAI-1, and directly activated protein C. Our findings suggest that FIIa could effectively protect against DIC via direct degradation of microthrombi and activation of protein C as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.

[Effects of metformin therapy on markers of coagulation disorders in hyperinsulinemic women with polycystic ovary syndrome]. / Wplyw leczenia metformina na wykladniki zaburzen krzepniecia u kobiet z zespolem policystycznych jajników i insulinoopornoscia.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and oligo-/anovulation and is associated with risk factors for cardiovascular disorders, such as insulin resistance and central adiposity. All these factors can lead to endothelial dysfunction and impaired coagulation processes. Metformin effectively treats hyperinsulinemia in women with PCOS. However, clinical trials assessing influence of metformin on endothelium and fibrinolysis are limited. Therefore, the objective of this study was to prospectively assess the effects of a 6-month metformin therapy on body mass index (BMI), insulin sensitivity and coagulation/fibrinolysis markers in hyperinsulinemic women with PCOS. MATERIALS AND METHODS: Thirty hyperinsulinemic PCOS women (aged 26.0 +/- 3.7 [mean +/- SD]) without any additional disorders were included into the study. Metformin was administered at a dose of 1700 mg daily for 6 months. Serum plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) concentrations and von Willebrand factor (vWf) levels were measured with specific assays, together with glucose and insulin concentrations. Insulin sensitivity index (ISI) and BMI were calculated. RESULTS: All patients completed the study and no side effects were reported. BMI decreased significantly (by 8.5%, p < 0.0001). The metformin therapy improved insulin sensitivity as evidenced by an increase in ISI by 41.5% (p = 0.0005). A marked reduction in PAI-1 (by 26%, p < 0.005) concentrations was observed. No significant changes were noted for t-PA and vWf. CONCLUSIONS: Metformin administration decreases the circulating PAI-1 concentration and simultaneously improves insulin sensitivity and BMI in PCOS women with hyperinsulinemia. Long-term metformin administration may be a new prophylactic measure for the prevention of cardiovascular disorders in such patients.

The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering.

The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8 pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n = 9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n = 3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P < 0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P < 0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low-pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P = ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein.

The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity.

Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients.

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats.

Tissue plasminogen activator (TPA) showed brain-protective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.

Plasma BDNF and tPA are associated with late-onset geriatric depression.

AIMS: Studies in the recent decade have shown that brain-derived neurotrophic factor (BDNF) may play an important role in the pathogenesis of major depressive disorder (MDD). Tissue-type plasminogen activator (tPA) has been implicated in the control of the direction of BDNF action. The aim of the study was therefore to investigate the changes of BDNF/tPA levels and their clinical meanings in geriatric depression. METHODS: Plasma BDNF and tPA levels were measured in late-onset geriatric depression (LGD) before treatment (n = 24) and after 6 weeks of antidepressant treatment (n = 24) compared with control subjects (n = 30) using enzyme-linked immunosorbent assay. The severity of depression was assessed with the Hamilton Depression Rating Scale. RESULTS: Baseline plasma BDNF and tPA levels were significantly lower in LGD patients compared to controls (P = 0.037 and P = 0.000, respectively). There was a heightening tendency of plasma BDNF level after treatment. CONCLUSIONS: Plasma BDNF and tPA levels are associated with LGD. The complex mechanism of BDNF and tPA in LGD should be further explored in future studies.

Up-regulation of osteolytic mediators in human osteosarcoma cells stimulated with nicotine.

BACKGROUND AND OBJECTIVE: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. However, little is known about how nicotine influences the expression of osteolytic mediators in cigarette smoking-associated periodontal diseases. The aim of this study was to investigate the expression of interleukin-1, interleukin-8, receptor activator of nuclear factor-kappaB ligand (RANKL), gelatinases and tissue-type plasminogen activator in U2OS cells (from the human osteosarcoma cell line) stimulated with nicotine. MATERIAL AND METHODS: Differences in the expression of interleukin-1, interleukin-8 and RANKL mRNAs, in response to exposure to various concentrations of nicotine (0, 0.125, 0.25, 0.5 and 1 mm) were evaluated in U2OS cells using the reverse transcription-polymerase chain reaction.In addition, the levels of interleukin-1, interleukin-8 and RANKL proteins were determined using enzyme-linked immunosorbent assays. The gelatinolytic and caseinolytic activities in nicotine treated-U2OS cells were demonstrated using gelatin and casein zymography, respectively. RESULTS: Nicotine was found to increase the expression of interleukin-1, interleukin-8 and RANKL mRNA and protein in U2OS cells (p < 0.05). The gelatin zymograms revealed that matrix metalloproteinase (MMP)-2 and MMP-9 were secreted by U2OS cells. The secretion of MMP-2 and MMP-9 occurred in a dose-dependent manner that was dependent on the concentration of nicotine (p < 0.05). Casein zymography exhibited a caseinolytic band with a molecular weight of 70 kDa, indicative of the presence of tissue-type plasminogen activator. Tissue-type plasminogen activator was also found to be up-regulated by nicotine in a dose-dependent manner (p < 0.05). CONCLUSION: Taken together, the results of the present study indicated that smoking modulation of bone destruction in periodontal disease may involve various osteolytic mediators, such as interleukin-1, interleukin-8, RANKL, MMP-2, MMP-9, and tissue-type plasminogen activator.

Effect of sulfaphenazole on tissue plasminogen activator release in normotensive subjects and hypertensive patients.

BACKGROUND: A nitric oxide-independent response, possibly mediated by hyperpolarization, regulates vascular tone, acting as a compensatory mechanism in the presence of impaired nitric oxide availability. Cytochrome P450 2C9 (CYP 2C9) is a source of endothelium-derived hyperpolarizing factors and modulates tissue-type plasminogen activator (tPA) release from endothelial cells; however, no effect of hyperpolarization on fibrinolysis has been documented in humans. We aimed to assess the effect of sulfaphenazole, a specific CYP 2C9 inhibitor, on tPA release in normotensive subjects and patients with essential hypertension. METHODS AND RESULTS: tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 microg x 100 mL(-1) x min(-1)) and acetylcholine (1.5 microg x 100 mL(-1) x min(-1)) infusions, with or without sulfaphenazole (0.03 microg x 100 mL(-1) x min(-1)). Bradykinin and acetylcholine infusions were repeated with N(G)-monomethyl-l-arginine (L-NMMA; 100 microg x 100 mL(-1) x min(-1)) and/or sulfaphenazole. tPA release by bradykinin and acetylcholine was higher in normotensive subjects than in patients with essential hypertension (P<0.01). Sulfaphenazole (P<0.01) blunted bradykinin-induced but not acetylcholine-induced tPA release in both groups. In normotensive subjects, L-NMMA infusion reduced tPA release (P<0.01). When L-NMMA was coinfused with sulfaphenazole, tPA release induced by bradykinin, but not by acetylcholine, was further reduced (P<0.01). In patients with essential hypertension, tPA release by both agonists was unaffected by L-NMMA, but only bradykinin-induced tPA release was blunted by sulfaphenazole, alone or with L-NMMA (P<001). CONCLUSIONS: Sulfaphenazole inhibits bradykinin-induced tPA release, which suggests a modulatory role of CYP 2C9-derived endothelium-derived hyperpolarizing factors in tPA release in humans. In patients with essential hypertension, tPA release depends exclusively on endothelium-derived hyperpolarizing factor, which is an ineffective compensatory mechanism in the presence of impaired nitric oxide availability.

Short term effects of GnRH agonists on plasma fibrinolytic balance in patients with advanced prostate cancer.

BACKGROUND: Gonadotropin releasing hormone (GnRH) agonists are the cornerstone of metastatic prostate cancer treatment. Cardiovascular effects of GnRH agonists are unclear. In this study, we investigated the short term effects of GnRH agonists on plasma fibrinolytic parameters in patients with metastatic prostate cancer. METHODS: Eleven patients (mean age 69.3 +/- 6.5) with metastatic prostate cancer and a clinical indication for GnRH agonist therapy were selected. Plasma plasminogen activator inhibitor (PAI-1) antigen (Ag), tissue plasminogen activator (t-PA) Ag and thrombin-activatable fibrinolysis inhibitor (TAFI) activity levels were measured at baseline and at 4 weeks after the first dose of GnRH agonist, Goserelin Acetate (Zoladex, subcutaneous administration, 10.8 mg). RESULTS: Serum prostate specific antigen (PSA) levels significantly decreased from 36.6 +/- 19.3 to 1.1 +/- 0.3 ng/ml after Goserelin acetate treatment (P = 0.005). Significant changes occurred in the fibrinolytic parameters. GnRH agonists decreased plasma t-PA Ag levels (16.3 +/- 4.9 vs. 12.2 +/- 2.8 ng/ml, P = 0.047) and increased PAI-1/t-PA molar ratio (4.8 +/- 3.6 vs. 6.6 +/- 3.4, P = 0.16), on the other hand, plasma PAI-1 Ag (59.0 +/- 48.5 vs. 56.4 +/- 30.5 ng/ml, P = 0.8), and TAFI levels (130.6 +/- 9.5 vs. 124.2 +/- 26.5% activity, P = 0.3) did not change significantly. CONCLUSION: This study provides evidence that GnRH agonists may inhibit fibrinolytic system by decreasing t-PA levels.

The effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on cardiovascular metabolic risk factors.

OBJECTIVES: Hormone treatment (HT) after the menopause affects lipid and carbohydrate metabolism and inflammation and may modify risk factors relevant for the clinical expression of the metabolic syndrome and cardiovascular disease. Tibolone has pharmacodynamic properties different from other hormone preparations. Here, we compare the effect of combined HT and tibolone on metabolic risk markers for the development of cardiovascular disease. METHODS: Postmenopausal women were randomly assigned to 1.25 or 2.5 mg/day of tibolone or oral continuous combined conjugated equine estrogen plus medroxyprogesterone acetate (CEE/MPA). Cardiovascular risk factors were determined at baseline and after 12 months of treatment. RESULTS: Body mass index and blood pressure were unaffected by the HT. HOMA-IR decreased in the CEE/MPA group (3.69 vs. 3.38; p = 0.02). Treatment with tibolone increased tissue-type plasminogen activator activity (0.87 IU/ml vs. 1.21 IU/ml; p = 0.005) and C-reactive protein (0.83 mg/l vs. 1.88 mg/l; p < 0.001), and decreased plasminogen activator inhibitor activity (6.9 IU/ml vs. 2.0 IU/ml; p < 0.001) and triglycerides (0.99 vs. 0.87 mmol/l; p = 0.004). Both treatments decreased total cholesterol significantly. CONCLUSIONS: CEE/MPA and tibolone have comparable effects on most metabolic risk factors investigated. The effect of tibolone on fibrinolysis and triglycerides suggests that tibolone has a favorable pharmacological profile on these risk factors when compared to CEE/MPA.