glucuronyl-glucosamine-glycan-sulfate and Disease-Models--Animal

To assess the effects of different doses and routes of Sulodexide on leukocyte-endothelium interaction and tissue perfusion in a model of venous hypertension and low blood flow.. Subcutaneous and intramuscular treatments with Sulodexide after 2 and 4 weeks, significantly reduced leukocyte rolling and adhesion and increased FCD. Sulodexide did not affect venular diameter and intramuscular treatment was more effective in reducing leukocyte adhesion than the subcutaneous one.. This preliminary study demonstrated that Sulodexide significantly decreased leukocyte-endothelium interaction and improved tissue perfusion in hamsters subjected to venous hypertension and low blood flow.

Topics: Animals; Cricetinae; Disease Models, Animal; Endothelium; Hypertension; Leukocytes; Male; Mesocricetus; Microcirculation; Perfusion

Although the number of vascular surgeries performed is increasing, the incidence of complications associated with this surgery has not improved and re-operations are frequently required. Thrombosis in a vessel is the most hazardous postoperative complication.. The aim of this study was to evaluate the anti-thrombotic and anti-inflammatory effects of sulodexide compared to aspirin in a rat model.. We divided the animals into three groups (sham (saline), aspirin, and sulodexide). The abdominal aorta was surgically opened and closed, primarily with 8/0 Prolene sutures. Postoperatively, saline, aspirin, or sulodexide was administered by oral gavage for 14 days to the rats. The degree of neovascularization, thrombus, calcification, inflammatory infiltrates, and fibrosis were analyzed histopathologically by hematoxylin and eosin staining.. There was no significant difference in the incidence of postoperative thrombogenesis, but less calcification and inflammatory infiltrates were observed in the sulodexide group compared to the aspirin group. Histopathologic score revealed less infiltration of inflammatory cells and mild calcification for the sulodexide group (0.17±0.41 and 1.33±0.52, respectively) compared to the aspirin group (0.67±0.52 and 1.67±0.52, respectively) at days 14.. This study offers the possibility that sulodexide could be used as an aspirin substitute for the postoperative management of vascular patients, with low gastrointestinal discomfort. In addition, it may also offer reduced postoperative calcification and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Aspirin; Disease Models, Animal; Glycosaminoglycans; Humans; Inflammation; Male; Rats; Rats, Sprague-Dawley; Thrombosis

Acute myocardial ischaemia/reperfusion (MI/R) injury causes severe arrhythmias with a high rate of lethality. Extensive research focus on endoplasmic reticulum (ER) stress and its dysfunction which leads to cardiac injury in MI/R Our study evaluated the effects of sulodexide (SDX) on MI/R by establishing MI/R mice models and in vitro oxidative stress models in H9C2 cells. We found that SDX decreases cardiac injury during ischaemia reperfusion and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase and reduced malondialdehyde in mice plasm, increased Bcl-2 expression, decreased BAX expression in a mouse model of MI/R. In vitro, SDX exerted a protective effect by the suppression of the ER stress which induced by tert-butyl hydroperoxide (TBHP) treatment. Both of the in vivo and in vitro effects were involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. Inhibition of PI3K/Akt pathway by specific inhibitor, LY294002, partially reduced the protective effect of SDX. In short, our results suggested that the cardioprotective role of SDX was related to the suppression of ER stress in mice MI/R models and TBHP-induced H9C2 cell injury which was through the PI3K/Akt signalling pathway.

Topics: Animals; Apoptosis; Disease Models, Animal; Endoplasmic Reticulum Stress; Glycosaminoglycans; Heart; Male; Mice; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Sulodexide is a potent antithrombin agent, however, whether it has beneficial effects on renal ischemia-reperfusion injury (IRI) remains unknown. In the present study, we assessed the therapeutic effects of sulodexide in renal IRI and tried to investigate the potential mechanism. One dose of sulodexide was injected intravenously in Sprague-Dawley rats 30 min before bilateral kidney ischemia for 45 min. The animals were sacrificed at 3h and 24h respectively. Our results showed that sulodexide pretreatment improved renal dysfunction and alleviated tubular pathological injury at 24h after reperfusion, which was accompanied with inhibition of oxidative stress, inflammation and cell apoptosis. Moreover, we noticed that antithrombin III (ATIII) was activated at 3h after reperfusion, which preceded the alleviation of renal injury. For in vitro study, hypoxia/reoxygenation (H/R) injury model for HK2 cells was carried out and apoptosis and reactive oxygen species (ROS) levels were evaluated after sulodexide pretreatment. Consistently, sulodexide pretreatment could reduce apoptosis and ROS level in HK2 cells under H/R injury. Taken together, sulodexide pretreatment might attenuate renal IRI through inhibition of inflammation, oxidative stress and apoptosis, and activation of ATIII.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Antithrombin III; Apoptosis; Cell Hypoxia; Cell Line; Cytoprotection; Disease Models, Animal; Glycosaminoglycans; Humans; Kidney Diseases; Kidney Tubules; Male; Oxidative Stress; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. We previously showed that the inhibition of placental growth factor (PlGF) exerts antitumour effects and induces vessel normalisation, possibly reducing hypoxia. However, the exact mechanism underlying these effects remains unclear. Because hypoxia and endoplasmic reticulum stress, which activates the unfolded protein response (UPR), have been implicated in HCC progression, we assessed the interactions between PlGF and these microenvironmental stresses.. PlGF knockout mice and validated monoclonal anti-PlGF antibodies were used in a diethylnitrosamine-induced mouse model for HCC. We examined the interactions among hypoxia, UPR activation and PlGF induction in HCC cells.. Both the genetic and pharmacological inhibitions of PlGF reduced the chaperone levels and the activation of the PKR-like endoplasmic reticulum kinase (PERK) pathway of the UPR in diethylnitrosamine-induced HCC. Furthermore, we identified that tumour hypoxia was attenuated, as shown by reduced pimonidazole binding. Interestingly, hypoxic exposure markedly activated the PERK pathway in HCC cells in vitro, suggesting that PlGF inhibition may diminish PERK activation by improving oxygen delivery. We also found that PlGF expression is upregulated by different chemical UPR inducers via activation of the inositol-requiring enzyme 1 pathway in HCC cells.. PlGF inhibition attenuates PERK activation, likely by tempering hypoxia in HCC via vessel normalisation. The UPR, in turn, is able to regulate PlGF expression, suggesting the existence of a feedback mechanism for hypoxia-mediated UPR that promotes the expression of the angiogenic factor PlGF. These findings have important implications for our understanding of the effect of therapies normalising tumour vasculature.

Topics: Animals; Carcinoma, Hepatocellular; Cell Hypoxia; Diethylnitrosamine; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Glycosaminoglycans; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Knockout; Neovascularization, Pathologic; Placenta Growth Factor; Pregnancy Proteins; Tumor Microenvironment; Unfolded Protein Response

Substitution of drinking water for 1.8% NaCl in pregnant rats caused a pronounced increase in arterial pressure by 24,3% and urinary protein by 117% to day 21 of pregnancy. State 4 respiration of isolated placental mitochondria in the group of negative control was 3- and 1.5-fold higher with malate/glutamate and succinate as substrates than in placental mitochondria isolated from uncomplicated pregnant animals. This led to a decrease of the respiratory control ratio. These results suggest that development of experimental preeclampsia is accompanied by mitochondrial dysfunction through uncoupling of oxidative phosphorylation. Daily administration of sulodexide to females with experimental preeclampsia (EP) per os at a dose of 30 LE during the whole period of gestation decreased manifestations of the disease as evidenced by a slight increase in blood pressure (by 8,6%) and less pronounces increase in urinary protein (by 58,9%). Sulodexide decreased development of mitochondrial dysfunction in EP rats as shown a decrease of non-stimulated ADP respiration with malate/glutamate and succinate (4.5- and 2.5-fold, respectively) as compared with the negative control group and the corresponding increase in the respiratory control ratio (2.5- and 1.5-fold, respectively). Thus, sulodexide reduces uncoupling of oxidative phosphorylation and enhances the functional activity of mitochondria in EP animals, possibly due to its antioxidant and endotelioprotective effects.. U samok, poluchavshikh vo vremia beremennosti vmesto pit'evoĭ vody 1,8% r-r NaCl, obnaruzheno vyrazhennoe povyshenie k 21 dniu beremennosti arterial'nogo davleniia (AD) na 24,3% i belka v moche na 117%, v to vremia kak u zhivotnykh, kotorym davali pit'evuiu vodu, pokazateli izmenialis' v znachitel'no men'sheĭ stepeni. Skorost' dykhaniia V4 izolirovannykh mitokhondriĭ platsenty v gruppe negativnogo kontrolia vozrastala v 3 raza dlia substrata malat/glutamat i v 1,5 raza – dlia suktsinata po sravneniiu s pokazateliami zhivotnykh s neoslozhnennoĭ beremennost'iu. Éto privodilo k snizheniiu velichin dykhatel'nogo kontrolia. Poluchennye dannye ukazyvaiut, chto razvitie u samok éksperimental'noĭ preéklampsii (ÉP) soprovozhdaetsia disfunktsieĭ mitokhondriĭ, sviazannoĭ s razobshcheniem dykhaniia i okislitel'nogo fosforilirovaniia. Sulodeksid, vvodimyĭ samkam s ÉP odin raz v den' vnutrizheludochno v doze 30 LE ves' period gestatsii, sposobstvoval ogranicheniiu razvitiia patologii. Ob étom svidetel'stvuiut neznachitel'noe povyshenie AD (na 8,6%) i belka v moche (na 58,9%). Sulodeksid ogranichival razvitie mitokhondrial'noĭ disfunktsii v platsente u zhivotnykh s ÉP, o chem svidetel'stvuet snizhenie nestimulirovannogo dykhaniia po sravneniiu s pokazateliami u samok gruppy negativnogo kontrolia dlia malata/glutamata (v 4,5 raza) i suktsinata (v 2,5 raza) i uvelichenie dykhatel'nogo kontrolia v 2,5 i 1,5 raza sootvetstvenno. Takim obrazom, sulodeksid prepiatstvuet snizheniiu razobshcheniia okislitel'nogo fosforilirovaniia i sposobstvuet povysheniiu funktsional'noĭ aktivnosti mitokhondriĭ u zhivotnykh s ÉP, chto, vozmozhno, sviazano s ego antioksidantnym i éndotelioprotektornym éffektami.

Topics: Animals; Blood Pressure; Disease Models, Animal; Female; Glycosaminoglycans; Mitochondria; Oxidative Phosphorylation; Placenta; Pre-Eclampsia; Pregnancy; Rats

Sulodexide is a mixed glycosaminoglycan composed of heparin and dermatan sulfate. In this study, the anti-angiogenic effect of sulodexide was investigated using an oxygen-induced retinopathy (OIR) mouse model. The retinas of sham-injected OIR mice (P17) had a distinctive central area of nonperfusion, and this area was significantly decreased in sulodexide-injected mice. The number of neovascular tufts measured by SWIFT_NV and mean neovascular lumen number were significantly decreased in sulodexide-injected mice. Hyperbaric oxygen exposure resulted in increased levels of VEGF, MMP-2 and MMP-9, and when mice were treated with sulodexide, a dose-dependent reduction in VEGF, MMP-2 and MMP-9 levels was observed. Our results clearly demonstrate the anti-angiogenic effect of sulodexide and highlight sulodexide as a candidate supplementary substance to be used for the treatment of ocular pathologies that involve neovascularization.

Topics: Angiogenesis Inhibitors; Animals; Disease Models, Animal; Female; Fluorescein-5-isothiocyanate; Glycosaminoglycans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred ICR; Oxygen; Retina; Retinal Diseases; Retinal Neovascularization; Vascular Endothelial Growth Factor A

In the model of chronic obstructive pulmonary disease (COPD), produced in rats by 60-day exposure to nitrogen dioxide, the effect of drugs with endotelioprotector properties (sulodexide and rosuvastatin) on the functional state of small pulmonary arteries and bronchi was studied. We evaluated the contractile activity of smooth muscle strips of the bronchi caused by stimulation of the nerves or muscles, and changes in tone of isolated pulmonary artery rings at the application of reagents-vasodilators. The use of sulodexide promoted restoration NO-dependent mechanism of vasodilatation and improved β-adrenergic regulation of the pulmonary artery tone. The use of rosuvastatin had no effect on the dilator activity of pulmonary arteries. Both drugs improved the functional status of the bronchial smooth muscles and intrabronchial nervous system that controls the contractile activity of smooth muscle structures of the airways. The results of the study suggest that the one-way relaxing effect of sulodexide on pulmonary arterial and bronchial smooth muscles enables the recovery of coordinated regulation of the tone of these structures, which is essential for maintaining the optimal ratio of ventilation and pulmonary blood flow for efficient gas exchange.

Topics: Animals; Bronchi; Disease Models, Animal; Endothelium, Vascular; Fluorobenzenes; Glycosaminoglycans; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitrogen Dioxide; Protective Agents; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Rats; Rats, Wistar; Rosuvastatin Calcium; Sulfonamides; Vasodilation

The present study was undertaken to confirm whether sulodexide aleviates neointimal hyperplasia by regulating angiopoietin/Tie in a rat femoral arteriovenous fistula (AVF) model. Sprague Dawley rats were divided into four groups: sham, model, treatment and treatment control. An arteriovenous shunt model was created in the model and treatment groups. Sulodexide was subcutaneously administered (10 mg/kg/day) 6 times per week for 8 weeks in the treatment and treatment control groups. Histology and immunofluorescence were analyzed and the protein expression of angiopoietin‑1, angiopoietin‑2, Tie‑2, p‑ERK and total‑ERK were tested by ELISA and/or western blotting after 8 weeks. HE staining revealed that sulodexide was able to partially alleviate intimal hyperplasia of remodeled veins in the AVF model. Additionally, sulodexide was able to decrease angiopoietin‑2 and Tie‑2 expression while increasing angiopoietin‑1 expression in AVF tissue. Sulodexide was also able to decrease ERK phosphorylation which was increased in the model. Serum levels of soluble Tie-2 (sTie‑2) were also significantly decreased by sulodexide compared with the model. Immunofluorescent analysis also confirmed that sulodexide was able to decrease angiopoietin‑2 expression, possibly partially by inhibiting endothelial cell proliferation. Sulodexide may alleviate venous intimal hyperplasia by regulating the angiopoietin/Tie system, which may play a significant role in assisting remodeled veins to cope with their new biomechanical environment, but whether the angiopoietin/Tie system is beneficial or not requires further study.

Topics: Angiopoietin-1; Angiopoietin-2; Animals; Arteriovenous Fistula; Disease Models, Animal; Down-Regulation; Fibrinolytic Agents; Glycosaminoglycans; Hyperplasia; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, TIE-2; Tunica Intima; Up-Regulation

Peritoneal dialysis (PD) is associated with functional and morphological alterations of the peritoneal membrane (PM). It is hypothesized that vascular endothelial growth factor (VEGF) plays a role in this process. Sulodexide is a glycosaminoglycan with effects on vascular biology. Therefore, the impact of oral sulodexide on PM function and morphology in a rat model of peritoneal perfusion was evaluated.. Rats received 10 mL peritoneal dialysate fluid (PDF) twice daily via a tunnelled PD catheter. The test-PD group (Sul) received 15 mg/kg/day oral sulodexide versus none in the control-PD group (Con). A third group received no PDF (Sham). After 12 weeks, a peritoneal equilibration test was performed and the PM was sampled. Neo-angiogenesis was evaluated using immunostaining with von Willebrand, and epithelial-to-mesenchymal transition (EMT) using co-localization of cytokeratin and α-smooth muscle actin. VEGF was determined in the dialysate by enzyme-linked immunosorbent assay.. PD induced loss of ultrafiltration, also in the sulodexide group. Creatinine and glucose transport were better preserved, and sodium dip was more pronounced in the sulodexide group versus control. Submesothelial thickness, neo-angiogenesis and EMT were more pronounced in the Con versus Sul versus Sham group. VEGF in the dialysate, corrected for diffusion was higher in Con and Sul versus Sham.. Oral sulodexide administration diminishes neo-vascularization, submesothelial thickening and EMT induced by exposure to PDF in a rat model. As there was no difference in VEGF at the protein level in the dialysate, we hypothesize that oral sulodexide inhibits VEGF locally by binding.

Topics: Administration, Oral; Analysis of Variance; Animals; Biopsy, Needle; Dialysis Solutions; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glycosaminoglycans; Immunohistochemistry; Neovascularization, Pathologic; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum; Random Allocation; Rats; Rats, Wistar; Reference Values; Treatment Outcome; Vascular Endothelial Growth Factor A

Sulodexide, a glycosaminoglycan, could reduce albuminuria in diabetic patients. The aim of this study was to determine whether sulodexide could be used to treat chronic kidney failure in rats.. Sixty Wistar rats undergone 5/6 nephrectomy, then were randomly divided into 4 groups: the model group, sulodexide group (sulodexide 5 mg/kg per day, im), irbesartan group irbesartan (20 mg/kg per day, ig) and sulodexide plus irbesartan group. Another 12 rats were enrolled into the sham operation group. After the treatments for 4, 8 and 12 weeks, urinary protein and serum creatinine levels were measured. After 12 weeks, serum cholesterin and triglycerides levels were measured, and the degrees of glomerular sclerosis and renal tubulointerstitial fibrosis were scored. The expression of aminopeptidase P (JG-12) in the renal tissue was examined using immunohistochemical staining. The renal expressions of endothelial nitric oxide synthase (eNOS) and tissue type plasminogen activator (tPA) were detected with RT-PCR and Western blot.. Proteinuria was markedly attenuated in the sulodexide-treated groups. After 4 and 8 weeks only the sulodexide-treated groups showed significant reduction in serum creatinine; while after 12 weeks all the three treatment groups showed significant reduction in serum creatinine. Furthermore, all the three treatment groups showed significant reduction in the scores of glomerular sclerosis and tubulointerstitial fibrosis. The glomerular expression of JG-12 was increased in both the sulodexide group and the sulodexide plus irbesartan group, but not in the irbesartan group. The eNOS mRNA and protein expression was decreased and the tPA mRNA and protein expression was significantly increased in the model group compared with Sham group. Sulodexide, irbesartan, and their combination reversed the decrease of eNOS expression but increased the tPA expression much more compared with model group.. Sulodexide was similar to irbesartan that can decrease proteinuria and attenuate renal lesions in 5/6 nephrectomy rats. The renal protection by sulodexide might be achieved via its impact on renal vascular endothelial cells.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Biomarkers; Biphenyl Compounds; Blood Pressure; Blotting, Western; Body Weight; Creatinine; Disease Models, Animal; Fibrosis; Glycosaminoglycans; Immunohistochemistry; Irbesartan; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Nitric Oxide Synthase Type III; Proteinuria; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sclerosis; Tetrazoles; Time Factors; Tissue Plasminogen Activator; Triglycerides

Development of chronic obstructive pulmonary disease (COPD) involves not only the bronchial and respiratory areas of the lungs, but also the system of pulmonary circulation, which begins with the defeat of capillary blood flow. One of radiological methods of studying lung microcirculatory functions is perfusion scintigraphy. We designed the technique of radiological examination and identified its abilities in determination of the role of vascular dysfunctions in experimental model of development of COPD. We assessed the results of pharmacological agents that affect the microcirculatory bed of the lungs and smooth muscles of pulmonary arteries in rats. Studies have shown the promise of the possibility of using the drug sulodexide for studying impaired endothelial function in clinical practice.

Topics: Animals; Disease Models, Animal; Glycosaminoglycans; Lung; Male; Muscle Relaxation; Muscle, Smooth; Nitrogen Dioxide; Organ Culture Techniques; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Radiopharmaceuticals; Rats; Rats, Wistar; Technetium Tc 99m Aggregated Albumin

Sulodexide is a glycosaminoglycan with anticoagulant and antithrombotic activities. Although sulodexide reduced albuminuria in patients with type 1 and type 2 diabetes, long-term effects on chronic renal injury are not established. We investigated sulodexide effects and mechanisms in a rat radiation nephropathy model and in the db/db mouse model of diabetic kidney disease.. Sprague-Dawley rats received kidney radiation and were treated as follows: 15 mg/kg/day sulodexide s.c., 6 day/week (SUL) or no treatment (CONT). Subsets of animals were sacrificed after 8 weeks and 12 weeks. Blood pressure, serum creatinine, creatinine clearance (CrCl) and urinary protein excretion were measured every 4 weeks. Sclerosis and plasminogen activator inhibitor-1 (PAI-1) expression were assessed at 8 and 12 weeks, and collagen I, total collagen content and phospho-smad-2 expressions were determined at 12 weeks. Twelve-week-old db/db mice received sulodexide as above or vehicle. Albuminuria and CrCl were assessed at intervals till sacrifice at week 9 with assessment of urinary transforming growth factor-beta (TGF-beta) and glomerular lesions.. Blood pressure, serum creatinine and CrCl were not different in radiation rat CONT vs SUL at any time. Proteinuria was significantly lower in SUL compared to CONT at 4 and 8 weeks but not at 12 weeks. Sclerosis and PAI-1 expression trended lower in SUL vs CONT at 8 weeks. There was no difference between the groups in sclerosis, collagen I mRNA, total collagen content or PAI-1 expression at 12 weeks. Phospho-smad 2 expression was significantly decreased in SUL compared to CONT at 12 weeks. Db/db mice with or without SUL showed no difference in urinary albumin/creatinine ratio, urine TGF-beta or mesangial matrix expansion.. Our data show that sulodexide can reduce the early, but not late, proteinuria in radiation nephropathy in rats. In addition, sulodexide did not affect urine TGF-beta established albuminuria or mesangial matrix expansion in a chronic model of diabetic kidney disease in mice. Although sulodexide may affect TGF-beta activation in radiation nephropathy, this effect appeared insufficient in this model to inhibit the expressions of PAI-1 and collagen and reduce accumulation of extracellular matrix. These results may explain in part its lack of efficacy in recent clinical trials of chronic kidney disease.

Topics: Animals; Anticoagulants; Collagen; Diabetic Nephropathies; Disease Models, Animal; Fibrinolytic Agents; Glycosaminoglycans; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Transforming Growth Factor beta

Dermatan sulphates have been shown to inhibit thrombus formation and thrombus growth in different experimental model of venous thrombosis. At variance with heparins, they show a remarkably low haemorrhagic potential. On the other hand, very few data are available on the effect of dermatan sulphates on arterial thrombus formation. We evaluated the effects of a low molecular weight (LMW)-dermatan sulphate, a high molecular weight (HMW)-dermatan sulphate and sulodexide (a mixture of fast-moving heparin fraction and dermatan sulphate) in comparison with LMW- and HMW-heparin, in a model of arterial thrombosis in rats. The insertion of an artificial prosthesis into the abdominal aorta of the animals induced the formation of an occluding thrombus within 2-5 days. The time in which 50% of the loops became occluded (OT50) was also calculated and used to compare the efficacy of the different drug treatments. This was 2.84 days for control animals and 4.25 and 5.80 days for HMW- and LMW-dermatan sulphate, respectively. Neither drug changed the "template" bleeding time, even at higher doses. In contrast, HMW-heparin at doses (8 mg/kg, sc, twice a day) inducing an antithrombotic activity comparable to that of dermatan sulphates, dramatically prolonged the bleeding time. LMW-heparin at the same doses was ineffective. Sulodexide (10 mg/Kg, sc, twice a day) prolonged the occlusion time to the same extent as HMW-heparin (OT50 5.10 vs. 4.14 days), with less an effect on the bleeding time (144 +/- 6 s vs. > 300 s, respectively). Histological examination confirms that the prolongation of occlusion time induced by the drugs is really related to thrombus formation inhibition at the site of arterial wall injury. Acetyl salicylic acid (ASA) (100 mg/kg/day in drinking water as lysine acetylsalicylate) did not modify the effect of Desmin 370 and Sulodexide on both occlusion and bleeding time. However, while it did not increase the antithrombotic activity of HMW-heparin, it significantly prolonged its haemorrhagic effect. In conclusion, dermatan sulphates are effective inhibitors of arterial thrombosis in rats, without inducing bleeding complications.

Topics: Animals; Anticoagulants; Dermatan Sulfate; Disease Models, Animal; Drug Therapy, Combination; Glycosaminoglycans; Heparin; Male; Rats; Thrombosis

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation Tests; Disease Models, Animal; Fibrinolytic Agents; Glycosaminoglycans; Heparitin Sulfate; Humans; Injections, Intravenous; Macaca mulatta; Male; Rabbits

We evaluated the ability of sulodexide, an extracted glycosaminoglycan, to prevent thrombus formation and to reduce a stabilized thrombus in a rat venous thrombosis model (vena cava ligature). Injection of sulodexide 10 min before induction of venous stasis, prevented thrombus formation in a dose-dependent manner (median effective dose 0.55 mg/kg). When given to rats with 6-h-old thrombi, sulodexide caused a marked reduction in thrombus size which reached 70% after 2 h with the highest dose tested (2 mg/kg). The effect of sulodexide on established thrombi appears to be due, at least in part, to a fibrinolysis-mediated mechanism, since it was significantly inhibited by epsilon-aminocaproic acid, a well-known antifibrinolytic drug. Treatment with sulodexide did not noticeably affect plasma levels of plasminogen activator and its specific inhibitor. We also showed that fluorescein-labelled sulodexide, when given to animals with 6-h-old thrombi, was present within the thrombi harvested 2 h later, but was then absent from blood. The fluorescence was mainly located in areas filled with amorphous material, that was identified as fibrin by staining with phosphotungstic acid-hematoxylin. No fluorescein-labelled material could be detected in rats treated with fluorescein alone. These findings indicate that, besides preventing venous thrombus formation, sulodexide is able to promote thrombus dissolution by a mechanism that is partly related to local fibrinolysis stimulation.

Topics: Animals; Disease Models, Animal; Fibrinolytic Agents; Glycosaminoglycans; Hypolipidemic Agents; Male; Rats; Rats, Inbred Strains; Thrombophlebitis