Repairing effect of sulodexide on diabetic retinopathy and the regulation of MAPK pathway in rats / 解剖学报

[ Abstract] Objective To study the effect of sulodexide on the repair of diabetic retinopathy and the regulation of MAPK pathway in rats. Methods Totally 72 rats were randomly divided into normal control group, diabetic retinopathy group, low, middle and high dose of sulodexide group and metformin hydrochloride group. Except normal control group, other rats were intraperitoneally injected with streptozotocin to establish the rat model of diabetic retinopathy. Rats in the low, middle and high dose sulodexide groups were given sulodexide by intragastric administration of 10 mg / kg,20 mg / kg and 40 mg / kg, respectively. Metformin hydrochloride group was given metformin hydrochloride of 200 mg / kg, once a day for 12 weeks. The levels of fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c) and serum levels of advanced glycation end products (AGEs), interleukin-6 (IL-6), IL-1β, and levels of glucose transporter 1 (GLUT-1), glucose transporter 3(GLUT-3), superoxide dismutase (SOD) and malondialdehyde (MDA) in retina were detected. The levels of p38 MAPK and phosphorylated p38 MAPK (p-p38 MAPK) in retina were detected by immunohistochemistry and Western blotting. Retinal pathological changes and ganglion cell count were examined by HE staining. Results The levels of FBG and HbA1c, serum AGEs, IL-6, IL-1 β, GLUT-1, GLUT-3, MDA and p38 MAPK mRNA, p38 MAPK, p-p38 MAPK / p38 MAPK and immunohistochemical integral optical density of retina in sulodexide group were significantly lower than those in diabetic retinopathy group (P < 0. 05), while the SOD level and ganglion cell number in retinal tissue were significantly higher than those in diabetic retinopathy group (P < 0. 05) . Conclusion Sulodexide can regulate blood glucose level and retinal glucose metabolism in diabetic retinopathy rats, and repair retinal pathological damage, and its mechanism may be related to the regulation of MAPK pathway.

The protective effect of sulodexide on endothelial damage induced by pregnancy serum of preeclampsia / 医学研究生学报

ObjectiveThe relationship between glycosaminoglycans sulodexide (SDX) and HDP such as preeclampsia (PE) has not been reported. The purpose of this study is to observe the protective effect and molecular mechanism of SDX on the function damage of human umbilical vein endothelial cells induced by pregnancy serum of PE.Methodsthe indicated concentrations of SDX (0, 0.1, 0.3, 1, 3, 10, 30 LSU/mL) were used to interfere with HUVEC and Ea.hy926 cells. CCK8 and Matrigel methods were used to detect cell proliferation and tube formation. The normal pregnant women serum (NPS) or PE patients serum (PES) which collected at the 12 th week of pregnancy and the effective concentration of SDX were used to intervene the cells. Matrigel methods were used to observe the protective effect of SDX on endothelial function damage which induced by pathological serum. The secretion level of sFLT-1 and PlGF in supernatant were determined by ELISA.ResultsCompared with the control group, high concentration of SDX inhibited the proliferation of endothelial cells. SDX significantly promoted the tube formation activity wiht a peak at 0.3 LSU/mL (P<0.01). PES damaged the tube formation activity. 0.3 LSU/mL SDX protected cells from tube formation damage which induced by PES (P<0.01). PES promoted the secretion of sFLT-1 and inhibit the secretion of PlGF, while 0.3 LSU/mL SDX reversed the secretion of sFLT-1 and PlGF induced by PES (P<0.01).Conclusion0.3 LSU/mL SDX can protect endothelial cells from PES induced endothelial dysfunction, which is associated with the secretion balance regulation of sFLT-1 / PlGF.

Effect of sulodexide on apoptosis of human dermal microvascular endo-thelial cells exposed to hypoxia / 中国病理生理杂志

AIM:To investigate the effect of sulodexide(SDX)on the apoptosis of human dermal microvascu-lar endothelial cells(HDMECs)exposed to hypoxia and its underlying mechanism.METHODS:The HDMECs were cul-tured and divided into normoxia control group cultured under normoxic condition;hypoxia control group cultured in a humid incubator maintained at 37 ℃with 5% CO2and 1% O2for 24 h;treatment groups treated with SDX at 0.25,0.5 and 1 LSU/mL for 24 h under hypoxic condition.The cell viability was measured by CCK-8 assay.The apoptotic rate of the HD-MECs was analyzed by flow cytometry.The activity of caspase-3 in HDMECs was examined by caspase-3 activity assay kit. The expression of pro-apoptotic factor P53,caspase-3,Bax and anti-apoptotic factor Bcl-2 at mRNA and protein levels was determined by real-time PCR and Western blot.RESULTS:SDX increased the viability of HDMECs exposed to hypoxia, but also decreased the apoptosis.Furthermore, SDX down-regulated the expression of pro-apoptotic factor P53, Bax and caspase-3 at mRNA and protein levels as well as the activity of caspase-3,while the expression of anti-apoptotic factor Bcl-2 was up-regulated.CONCLUSION:SDX significantly increases the viability and decreases the apoptosis of HDMECs ex-posed to hypoxia.Inhibition of the mitochondrial apoptosis pathway may be involved in the underlying mechanism.

Perioperative implication of the endothelial glycocalyx / 대한마취과학회지

The endothelial glycocalyx (EG) is a gel-like layer lining the luminal surface of healthy vascular endothelium. Recently, the EG has gained extensive interest as a crucial regulator of endothelial funtction, including vascular permeability, mechanotransduction, and the interaction between endothelial and circulating blood cells. The EG is degraded by various enzymes and reactive oxygen species upon pro-inflammatory stimulus. Ischemia-reperfusion injury, oxidative stress, hypervolemia, and systemic inflammatory response are responsible for perioperative EG degradation. Perioperative damage of the EG has also been demonstrated, especially in cardiac surgery. However, the protection of the EG and its association with perioperative morbidity needs to be elucidated in future studies. In this review, the present knowledge about EG and its perioperative implication is discussed from an anesthesiologist's perspective.

Protective effect of sulodexide on ox-LDL induced damage to human umbilical vein endothelial cells and its mechanism / 介入放射学杂志

Objective To investigate the protective effect of sulodexide (SDX) on oxidized low density lipoprotein (ox-LDL) induced damage to human umbilical vein endothelial cell (HUVEC),and to discuss its mechanism.Methods By using CCK-8 method,the ox-LDL intervention HUVEC dose and the concentration of SDX were determined.The reactive oxygen species (ROS) assay kit was used to verify the protective effect of SDX on HUVEC.Real time fluorescent quantitation-polymerase chain reaction (RT-PCR) was employed to test the endothelial nitric oxide synthase (eNOS) and caveolin-1 mRNA expression;immunoblot assay was adopted to check the protein expression of phosphorylated eNOS (p-eNOS) and caveolin-1.The ability of cell migration was assessed by Transwell assay.Results Stimulated by 100 μg/ml concentration of ox-LDL,the cell viability of HUVEC decreased significantly (P＜0.01).After adding 125 LRU/ml concentration of LDX,the cell viability of HUVEC was remarkably improved (P＜0.01) and the production of ROS was strikingly decreased (P＜0.01).SDX could down-regulate the expression of caveolin-1 (P＜0.05) and up-regulate the expression of eNOS mRNA and p-eNOS (P＜0.05) for ox-LDL-damaged HUVEC,and markedly improve the migration ability of damaged HUVEC (P＜0.01).Conclusion By regulating the caveolin-1/eNOS signal route,SDX can improve impaired HUVEC cell migration ability,thus,to protect endothelial cells.

Efficacy Observation of Candesartan Combined with Sulodexide Soft Capsules in the Treatment of Persistent Proteinuria of Diabetic Nephropathy / 中国药房

OBJECTIVE:To observe therapeutic efficacy of candesartan combined with Sulodexide soft capsules in the treatment of persistent proteinuria of diabetic nephropathy. METHODS:180 patients with persistent proteinuria of diabetic ne-phropathy were randomly divided into control group and trial group,with 90 cases in each group. Control group was given can-desartan,8 mg/time,once a day;trial group was additionally given Sulodexide soft capsules on the basis of control group,250 LSU/time,twice a day. The indexes levels of both groups were compared before and after treatment,including systolic blood pressure(SBP),diastolic blood pressure(DBP),serum creatinine(Scr),blood urea nitrogen(BUN),urinary albumin excre-tion rate (UAER),24 hour urinary albumin (24hU-Alb) and urinary 2-microglobulin (β2-MG),α1 microglobulin (α1-MG), urine N-acetyl-β-D glucoside enzyme(NAG)and serum cystatin C(Cys-C). RESULTS:After treatment,there was no statisti-cal significance in the levels of SBP,DBP,Scr,BUN and UAER between 2 groups(P>0.05);24hU-Alb level of observation group was significantly betRter than that of control group,with statistical significance (P<0.05);after treatment,β2-MG,α1-MG,NAG and Cys-C of 2 groups were all improved significantly,and the trial group was more significant then the control group,with statistical significance (P<0.05). CONCLUSIONS:Candesartan combined with Sulodexide soft capsules in the treatment of persistent proteinuria of diabetic nephropathy can effectively improve renal function and reduce urinary microalbu-min.

The clinical observation of the effects of sulodexide and tripterygium glycosides on the idiopathic membranous nephropathy in stage Ⅰ ~Ⅱ / 中国基层医药

Objective To observe the effect of sulodexide and tripterygium glycosides on the idiopathic membranous nephropathy in stage Ⅰ ~Ⅱ.Methods 52 adult patients with idiopathic membranous nephropathy (pathologic stage Ⅰ -Ⅱ stage,24 h urinary protein 4 -8 g/d)were randomly divided into the control group and observation group,with 26 cases in each group.The cases in the control group were treated by conventional treatment and tripterygium glycosides tablet,and the observation group were treated with sulodexide based on the therapy of con-trol group.Six months was a course.24 h urinary protein excretion(24hUpro),serum creatinine(CR),alanine amin-otransferase(ALT),albumin(ALB),activated partial thromboplastin time(APTT),fibrinogen(Fbg)and total choles-terol(TC)were compared before and after treatment.The clinical efficacy and adverse reactions of the two treatments were observed.Results After 6 months of treatment,24hUpro,Fbg and TC of the two groups were significantly decreased than those before treatment(control group:t =3.754,2.096,3.781,observation group:t =5.412,5.043, 6.200,all P 0.05).APTT was significantly longer than that before treatment(t =5.115,P 0.05 ).Both groups had no serious adverse reactions.Conclusion The clinical efficacy of sulodexide and tripterygium glycosides tablet may be more precise than alone tripterygium for IMN,which is safety.

Importancia médica del glucocáliz endotelial: Parte 2: su papel en enfermedades vasculares y complicaciones de la diabetes mellitus / Medical significance of endothelial glycocalyx: Part 2: Its role in vascular diseases and in diabetic complications

El glucocáliz endotelial es una capa constituida por glucosaminoglicanos, proteoglicanos y glucoproteínas que cubre al endotelio en su cara luminal. La participación del deterioro del glucocáliz endotelial parece esencial en los pasos iniciales de la fisiopatología de la aterosclerosis, de las complicaciones microangiopáticas de la diabetes mellitus y de la enfermedad venosa crónica. Los factores de riesgo de la aterosclerosis como la hipercolesterolemia, la hiperglucemia, la inflamación, el exceso de sodio y las fuerzas de tensión alteradas causan deterioro del glucocáliz. Esto provoca disfunción endotelial y permite la filtración de lipoproteínas (LDL) y de leucocitos al espacio subendotelial, iniciando la formación de la placa de ateroma. En la diabetes el glucocáliz adelgazado, principalmente por estrés oxidativo, posibilita la filtración de proteínas (albuminuria) y el trastorno endotelial de la microangiopatía. La hipertensión venosa crónica altera las fuerzas de tensión y daña el glucocáliz, lo que permite la filtración de leucocitos a las partes más profundas de la pared venosa, iniciando la inflamación y el deterioro morfológico y funcional de las venas que lleva a la enfermedad venosa crónica. El tratamiento con glucosaminoglicanos (sulodexida) logra prevenir o revertir el daño al glucocáliz endotelial y algunas de sus consecuencias; es eficaz en la enfermedad venosa crónica, especialmente con úlceras venosas. También ha sido útil en aterosclerosis obliterante de miembros inferiores y en la nefropatía diabética con albuminuria.

Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. Shredding of glycocalyx appears as an essential initial step in the pathophysiology of atherosclerosis and microangiopathic complications of diabetes mellitus, as well as in chronic venous disease. Atherosclerosis risk factors, as hypercholesterolemia (LDL), hyperglycemia, inflammation, salt excess and altered shear stress can damage glycocalyx. This lead to endothelial dysfunction and allows LDL and leukocytes to filtrate to the subendothelial space initiating atheroma plaque formation. Degradation of glycocalyx in diabetes mellitus is mainly due to oxidative stress and enables protein filtration (albuminuria) and endothelial disorder of microangiopathy. Chronic venous hypertension brings to altered shears stress which results in shredded glycocalyx, this allows leukocytes to migrate into venous wall and initiate inflammation leading to morphologic and functional venous changes of the chronic venous disease. Treatment with glycosaminoglycans (sulodexide) prevents or recovers the damaged glycocalyx and several of its consequences. This drug improves chronic venous disease and promotes healing of chronic venous ulcers. It has also been useful in peripheral arterial obstructive disease and in diabetic nephropathy with albuminuria.

Effect of sulodexide combined with dipyridamole on postoperative period of internal arteriovenous fistulae in patients with chronic renal failure complicating diabetes / 重庆医学

Objective To observe the effect of sulodexide combined with dipyridamole on postoperative period of internal arterio‐venous fistula in the patients with chronic renal failure complicating diabetes .Methods 72 cases of chronic renal failure complica‐ting diabetes were randomly divided into two groups :sulodexide combined with dipyridamole group(group A) and dipyridamole group (group B) .Platelet ,fibrinogen(FIB) ,prothrombin time ,activated partial thromboplastin time ,triglyceride ,total cholesterol and hemortheological indexes were tested at different time points .The internal fistula patency ,blood flow volume after internal fis‐tula maturation and time of initial internal fistula use after internal arteriovenous fistula operationwere observed .‐Results (1)The patency rate of internal arteriovenous fistula in the group A was higher than that in the group B .(2) Compared with the group B , FIB and low‐shear rate of whole blood viscosity in the group A were decreased .(3)The time of internal fistula maturation in the group A was shortened ,but the blood flow volume had no significant difference between the two groups .Conclusion Sulodexide combined with dipyridamole is safe and effective for preventing the thrombogenesis after internal arteriovenous fistula operation ,its effect is superior to single dipyridamole .

Importancia médica del glucocáliz endotelial / Medical significance of endothelial glycocalyx

El glucocáliz endotelial es una capa constituida por glucosaminoglicanos, proteoglicanos y glucoproteínas que cubre al endotelio vascular en su cara luminal. Tiene múltiples funciones: transducción de las fuerzas mecánicas de tensión, regulación de la permeabilidad vascular de líquidos y moléculas y de la activación de la coagulación y de la fibrinólisis, protege de la adhesión de leucocitos y plaquetas al endotelio. En general, el glucocáliz protege a la pared vascular de ataques patogénicos. La lesión del glucocáliz puede ocurrir por fuerzas de tensión anormales, especies reactivas de oxígeno, hipernatremia, hiperglucemia, hipercolesterolemia y moléculas inflamatorias, lo que causa disfunción endotelial, incremento en la permeabilidad, filtración de lipoproteínas al subendotelio, activación de la coagulación e incremento de la adherencia de leucocitos y plaquetas al endotelio vascular. La participación del deterioro del glucocáliz endotelial puede ser importante en la fisiopatología de diversas enfermedades vasculares.

Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. It has several physiological roles: shear stress mechanotransduction to the endothelial cells, regulation of fluids and macromolecules vascular permeability, of coagulation cascade activation and fibrinolysis, and protects the endothelium from platelets and leukocytes adhesion. In general, glycocalyx protects vascular wall against pathogenic insults. The glycocalyx may be damaged by abnormal shear stress, reactive oxygen species, hypernatremia, hyperglycemia, hypercholesterolemia and inflammatory molecules, resulting in endothelial dysfunction, enhanced vascular permeability, lipoproteins leakage to subendothelial space, activation of plasma coagulation, and increased adherence of platelets and leukocytes to the endothelial cells. Shredding of glycocalyx appears as an important initial step in the pathophysiology of vascular diseases.

Sulodexide prevents diabetic nephropathy through inhibiting renal NF-κB activation and MCP-1 expression / 中华肾脏病杂志

Objective To study the effects of sulodexide on renal NF-κB activation and monocyte chemotactic protein 1 (MCP-1) expression in diabetic rats and elucidate the possible mechanism of sulodexide in preventing diabetic nephropathy (DN). Methods Wistar rats were fed with high-sucrose-high-fat diet and injected with a low dose of STZ (streptozotocin,35 mg/kg) into abdominal cavity to induce diabetes.DM rats were randomly divided into non-treated group of treatment,blood glucose (BG),triglyceride (TG),cholesterol,serum creatinine (Scr),urea nitrogen (BUN),24 h urinary albumin excretion (UAE) were measured.HE staining was performed in renal tissues for light microscopy examination of mean glomerular volume (MGV).MCP-1 expression was detected by immunohistochemical method.NF-κB activation was determined by Western blot. Results Compared with NC group,DM group and DMS group had significant elevated BG,TG and TC levels (all P＜0.01).There were no significant differences of BG,TG or TC levels between DM group and DMS group.Compared with NC group,DM group and DMS group had significant increased Scr,BUN,UAE levels (all P＜0.01).Scr,BUN,UAE levels were significantly lower in DMS group than those in DM group [(39.1±0.88) μmol/L vs (41.0±2.16) μmol/L,(9.12±1.06) mmol/L vs (9.87±0.19) mmol/L； (19.92±0.96) mg/24 h vs (25.99±0.52)mg/24 h,all P＜0.05].Compared with NC group,the MGV of DM group was significantly increased [(7.47±1.11)×105 μm3 vs (4.22±1.09)×105 μm3,P＜0.01].Compared with DM group,the MGA of DMS group was significantly reduced [(6.64±0.71)×105 μm3 vs (7.47±1.11)×105 μm3,P＜0.05],but was still increased compared with that of NC group (P＜0.01).Compared with NC group,the MCP-1 expression of DM group was significantly higher [(12.17±1.94)/HPF vs (1.19±0.70)/HPF,P＜0.01].MCP-1 expression in DSM group was significantly lower than that of DM group [(9.22± 1.61)/HPF vs (12.17±1.94)/HPF,P＜0.01],but still higher than that of control group (P＜0.01).Compared with NC group,the NF-κB activity was significantly higher in DM group [(0.89±0.07) vs (0.24±0.03),P＜0.01].Compared with DM group,NF-κB activity of DMS group was significantly lower [(0.27±0.01) vs (0.89±0.07),P＜0.01].There was no significant difference of NF-κB activity between DMS group and NC group. Conclusion Sulodexide has protective effects on diabetic nephropathy,and one of the mechanisms may involve the inhibition of NF-κB activation as well as the suppression of MCP-I expression.

Use of low-dose sulodexide in IgA nephropathy patients on renin-angiotensin system blockades

BACKGROUND: Despite using renin-angiotensin system (RAS) blockades, some of the patients with immunoglobulin A (IgA) nephropathy often had persistent proteinuria of more than 500mg/d. They need to be managed further by alternative methods to halt the progression of the disease; these methods could also be applied safely over a long period of time. In this context, sulodexide has been studied for the management of diabetic nephropathy. METHODS: A retrospective review was carried out involving 20 patients with IgA nephropathy who had been taking sulodexide (50mg daily) as an add-on therapy together with an optimal dose of RAS blockades during 2008-2009. We evaluated the proteinuria reduction rates and renal function changes. RESULTS: During 11.1+/-72.7 months of follow-up duration, urinary protein-to-creatinine ratio (UPCR) decreased for 1.57+/-0.6 to 1.17+/-0.7 g/g (P=0.032). Twenty-five percent of the patients showed a greater than 50% reduction of UPCR, and 40% had a UPCR of less than 1.0g/g at their final observations. The analysis of the factors contributing to the effect found that a higher pretreatment UPCR showed a significant correlation with the UPCR decrease (r=0.45, P=0.047). Neither the adverse effects nor the renal function impairments were documented during the management. CONCLUSION: Low-dose sulodexide has an additional modest antiproteinuric effect on IgA nephropathy undergoing RAS blockade therapy.

Anti-Proteinuric Effect of Sulodexide in Immunoglobulin A Nephropathy

PURPOSE: We conducted a multi-center randomized double-blind study to determine the effects of 6-month therapy with sulodexide on urinary protein excretion in patients with idiopathic Immunoglobulin A (IgA) nephropathy. MATERIALS AND METHODS: A total of seventy-seven patients participated in the study. They were randomly allocated to one of three groups: sulodexide 75 mg or 150 mg daily or the placebo for 6 months. The primary end point was the achievement, at 6 months, of at least 50% reduction in urine protein/creatinine ratio (UPCR) from the baseline value. RESULTS: At 6 months, the primary end point was achieved by 12.5% of the patients assigned to the placebo, 4.0% of the patients assigned to sulodexide 75 mg daily and 21.4% of those assigned to 150 mg (p=0.308). Treatment with sulodexide 150 mg daily for 6 months significantly reduced log UPCR from 6.38+/-0.77 at baseline to 5.98+/-0.94 at 6 months (p=0.045), while treatment with sulodexide 75 mg daily and placebo did not. CONCLUSION: A 6-month treatment with sulodexide did not achieve 50% reduction of urinary protein excretion in IgA nephropathy patients, but showed a tendency to increase the time-dependent anti-proteinuric effect. Therefore, long-term clinical trials on a larger scale are warranted to elucidate the hypothesis that sulodexide affords renal protection in IgA nephropathy patients.

Efecto del sulodexide sobre la capacidad de relajación y alteraciones estructurales de la arteria aorta en ratas diabéticas por estreptozotocina / Effect of sulodexide on aortic vasodilation capacity and associated morphological changes in rats with streptozotocin-induced diabetes

La disfunción endotelial (DE) se presenta en pacientes con hipercolesterolemia, hipertensión arterial, obesidad y diabetes mellitus. Evidencias sugieren un papel de los glicosaminoglicanos en la DE. Evaluamos el efecto del sulodexide (SLD), un glicosaminoglicano utilizado en el tratamiento de la albuminuria y la enfermedad isquémica en pacientes diabéticos, sobre la relajación arterial y los cambios morfológicos en un modelo experimental de diabetes tipo 1. La diabetes se indujo a ratas Sprague Dawley administrando estreptozotocina (STZ), 60 mg/kg, i.v. Los animales fueron distribuidos en los siguientes grupos: I= control, II= diabéticas, III: control + sulodexide, IV= diabéticas + sulodexide (15 mg/kg/día s.c). A los 3 meses fueron sacrificados, las aortas extraídas para evaluar la relajación vascular inducida por acetilcolina (Ach) y nitroprusiato de sodio en anillos precontraídos con fenilefrina. Fueron evaluadas histológicamente mediante microscopía de luz y coloraciones diversas. El SLD in vitro no modificó la tensión basal de los anillos arteriales en reposo o precontraídos con fenilefrina. La diabetes disminuyó la capacidad de relajación arterial en respuesta a la Ach en un 28,8-35,1% vs control, efecto que fue prevenido por SLD. No se observó diferencia significativa en la relajación inducida por nitroprusiato sódico entre los grupos. El estudio histológico en los animales diabéticos mostró alteraciones estructurales, particularmente en la íntima y la adventicia, cambios que fueron prevenidos por el tratamiento con SLD. Nuestros resultados apoyan la potencial utilidad terapéutica del SLD en el tratamiento de la disfunción endotelial.

Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans(GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, iv. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.

Effect of sulodexide on islet β-cell function in streptozocin induced diabetic rats / 中国综合临床

Objective To study the effects of sulodexide on islet B-cell function in streptozocin induced di-abetic rats. Methods Sprague-Dawley(SD) rats were randomly divided into normal control group (group C), dia-betic group without treatment(group D), and suledexide treatment group(group S), a single dose of streptozotocin were abdominally injected to establish the diabetic rat models. Each animal in sulodexide treated group was addition-ally fed with sulodexide of 10 mg/(kg·d) for 12 weeks,while the remained group (group C and D) were given normal water in the same period. After 12 weeks of treatment, fasting plasma glucose(FPG),fasting plasma insulin (FINS), activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), triglyceride (TG), Low-density lipoprotein cholesterol (LDL-C), serum creatinine rates (SCr) and alanine aminotransferase (ALT) were measured. Insulin sensitivity index(ISI) and insulin resistant index (HOMA-IR) were calculated. Results After 12 weeks, the levels of TG, LDL-C and ALT had no significant difference between group D and group S, but were higher than those in group C (P <0.05);There were no significant difference of SCr levels among the three groups. Compared with the group C, APTT, PT, TT and ISI in group D and S were significantly decreased, HOMA-IR were significantly increased (P < 0.05). APTT, PT, TT and ISI in group S had significantly increased compared with that in group D, HOMA-IR was significantly decreased in group S compared with that in group D (P < 0.01). Conclusions Sulodexide can reduce insulin resistant, improve hypercoagulability and insulin sensitiv-ity in streptozocin induced diabetic rats. The effects to blood lipid, liver and renal functions in diabetic rats are not obvious.

Sulodexide-induced Hyperkalemia: A Case Report / 대한신장학회지

Sulodexide is composed of two glycosaminoglycans (fast-moving heparin 80%, dermatan sulfate 20%) that are capable of preventing diabetic nephropathy by correcting abnormal glycosaminoglycan metabolism. Considering heparin-like propertyof sulodexide, side effect profiles of sulodexide are expected to be similar with those of heparin. Among those side effects, we remarked on heparin-induced hyperkalemia and hereby report a case of severe hyperkalemia during the use of sulodexide. A 52-year-old man with diabetic nephroapthy and hypertension was admitted to our hospital because of severe hyperkalemia up to 7.5 meq/L. His clinical condition was stable and medications including losartan and furosemide had not been changed for last 6 months except the addition of sulodexide, which was started 30 days prior to admission. Despite intensive use of Kayexalate and immediate discontinuation of losartan, hyperkalemia aggravated up to 8.0 meq/L. After recognition of possible sulodexide-induced hyperkalemia, sulodexide was discontinued, which resulted in rapid correction of hyperkalemia. In view of the above discussed clinical consideration, we suspect sulodexide as a major cause of hyperkalmia and report this case with a review of literature.

Protective Effect of Sulodexide on Podocyte Injury in Adriamycin Nephropathy Rats / 华中科技大学学报（医学）（英德文版）

This study examined the effect of sulodexide on podocyte injury in rats with adriamycin nephropathy (AN). A total of 36 healthy male SD rats were randomly assigned to three groups:control group,AN group and sulodexide treatment group. Rat models of AN were established by a single tail intravenous injection of adriamycin (6.5 mg/kg) in both AN group and sulodexide treatment group. Sulodexide (10 mg/kg) was administered the rats in the treatment group once daily by garage from the fast day of model establishment until the 14th day or the 28th day. Samples of 24-h urine and renal cortex tissues were harvested at day 14,28 after the model establishment. Excretion of 24-h urinary protein was measured by Coomassie brilliant blue method. The pathological changes in renal tissues were observed by light microscopy and electron microscopy respectively. Heparanase mRNA was detected by RT-PCR. Expressions of desmin,CD2AP and heparanase were determined by immunohistological staining. The results showed that the expressions of heparanase mRNA and proteinwere increased in the glomeruli of AN rats at day 14 and 28 after the model establishment,which was accompanied by the increased expression of desmin and CD2AP. The mRNA and protein expression of heparanase was decreased in the sulodexide-treated rats as compared with AN rats at day 14 and 28. And,the protein expression of desmin and CD2AP was reduced as with heparanase in the sulodexide-treated rats. Proteinuria and podocyte foot process effacement were alleviated in the AN rats after sulodexide treatment. There was a positive correlation between the expression of heparanase and the expression of desmin and CD2AP (as well as 24-h urinary protein excretion). It was concluded that increased heparanase is involved in podocyte injury. Sulodexide can maintain and restore podocyte morphology by inhibiting the expression of heparanase in AN.

Effect of sulodexide on podocalyxin expression of podocytes in streptozotocin diabetic desoxycorticosterone acetate-hypertensive rats / 中华肾脏病杂志

Objective To explore the effect of suledexide on renal injury and podocalyxin expression of podocytes in STZ diabetic desoxycorticosterone acetate (DOCA)-hypertensive rats. Methods Wistar rats were subjected to subcutaneous injection of streptozotocin(STZ), followed by uninephrectomy and subcutaneous administration of DOCA. Diabetic and hypertensive rats were randomly allocated to treatment with sulodexide or a combination of sulodexide and telmisartan for 8 weeks. Blood pressure (BP), 24-hour urinary albumin were measured every 2 weeks. Blood and urinary samples were collected to detect biochemical indexes of plasma and urinary β-acetyl-β-D-glucosaminidase (NAG) at the end of the study. Immunohistochemistry (IHC), RT-PCR and Western blot were performed to examine the expression and distribution of podocalyxin. Results STZ +DOCA-treated rats progressively developed hypertension, albuminuria and hyperglycemia. Hyperlipidemia and hypoinsulinemia were found in diabetic and hypertensive rats compared with controls. Albuminuia was significantly reduced in sulodexide group at week 8 and sulodexide plus telmisartan group at week 6 and week 8. Blood pressure decreased in sulodexide plus telmisartan group. No significant effects on lipid and glucose metabolism were observed in all treated groups. Histopathological index increased in STZ+DOCA-treated rats, but was significantly lower in sulodexide group as well as sulodexide plus telmisartan group. The number of podocytes on glomerular cross-section of the four groups were comparable. Segmental loss and down-regulation of podocalyxin were detected in STZ+DOCA-treated rats, which were greatly attenuated by sulodexinde, meanwhile, combination treatment preserved more podocalyxin expression in glomeruli than sulodexide monotherapy. Conclusion Sulodexide effectively reduces albuminuria, prevents loss of podocyte podocalyxin and alleviates renal damage in STZ diabetic DOCA-hypertensive rats.

A Prospective, Randomized, Comparative Clinical Investigation of the Effects of Sulodexide on Restenosis after Percutaneous Transluminal Coronary Balloon Angioplasty

BACKGROUND: Restenosis remains as the major limitation of percutaneous translumainal coronary balloon angioplasty (PTCA). Although its mechanism remains incompletely understood, proliferative action of arterial smooth muscle cells has been found to play an important role on restenosis by neointimal formation after PTCA. Glycosaminoglycan-containing compounds, including Sulodexide (Vessel Due , ALFA, Wasserman, S.p.A, Italy), inhibit the proliferation and maigration of vascular smooth muscle cells in vitro. OBJECTIVES: This study was performed to assess the efficacy of Sulodexide, a glycosaminoglycan compound with antithrombotic and antiproliferative properties, in preventing restenosis after PTCA. METHOD: Two hundred eighty-four patients with ischemic heart disease were randomized to receive either the standard PTCA without Sulodexide in 144 patients (control group, M : F = 99 : 45, Age = 58 +9 or -9), 160 lesions or the standard PTCA with Sulodexide in 140 patients (treated group, M : F = 89 : 51, age = 58 +10 or -10), 158 lesions. Successful angioplasties were performed in 258 atheromatous coronary lesions in 224 patients for whom follow-up angiographic data were obtained 6 month later. Quantitative coronary angiographic analysis (QCA) was performed before , immediate after PTCA and 6-month later. Angiographic restenosis (>50% diameter stenosis at follow-up) was the primary end point : miniamal luminal diameter at follow-up angiogram was the secondary end point. RESULT: Successful PTCA was 97.6% and 97.5% in the standard PTCA with Sulodexide and the standard PTCA without Sulodexide, respectively. Although reference vessel size and minimal luminal diamater after PTCA were larger in the control group than in the Sulodexide group(2.94+0.11 or-0.11 vs 2.83+0.13 or -0.13 mm and 2.26+0.12 or -0.12 vs 2.18+0.08 or -0.08 mm, respectively, p=NS), there was a increased tendency of minimal lumen diameter at 6 months angiogram in the Sulidexide group than in the control group (1.12+0.50 or -0.50 vs 1.07 + 0.53 or -0.53 mm, respectively, p=NS). Angiographic restenosis occured in 42% of lesions in the Sulodexide group and 52% of the control group (p=NS). CONCLUSIONS: Sulodexide treatment had a tendency to reduce restenosis rate in 6 months after coronary angioplasty. However, further study is necessary to verify the antiproliferative effect of Sulodexide with much larger number of patients.