Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats

The present study was designed to examine whether astaxanthin (ASX, 3,3-dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, has a protective effect on endothelial dysfunction of aortas in diabetic rats and the possible molecular mechanism involved. Male Wistar rats were randomly divided into four groups: control rats, diabetic rats, diabetic rats treated with ASX (10 mg/kg/d), and control rats treated with ASX. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/ kg). STZ-induced diabetes in rats was complicated with excessive oxidative stress and endothelial dysfunction, increased serum oxidized low-density lipoprotein (ox-LDL) and aortic malondialdehyde (MDA) levels, inhibited endothelium-dependent vasorelaxation to acetylcholine (ACh) and unaffected endothelium-dependent vasorelaxation to sodium nitroprusside (SNP). Simultaneously, lectin-like oxLDL receptor-i (LOX-1) expression was enhanced and endothelial nitric oxide (NO) synthase (eNOS) expression was reduced in the aortas of diabetic rats. ASX treatment could significantly decrease serum oxLDL and aortic MDA levels, attenuate blunted endothelium-dependent vasodilator responses to ACh, upregulate eNOS expression, and decrease LOX-1 expression. These results indicated that ASX could ameliorate diabetic endothelial dysfunction by inhibiting the ox-LDLLOX-1-eNOS pathway. Treatment with ASX might be clinically useful for diabetic complications associated with endothelial dysfunction.     

Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocin

Berberine can improve insulin resistance, lower blood glucose, and regulate lipid metabolism disorders which cause endothelial dysfunction, leading to vascular complications of type 2 diabetes mellitus. The aim of the present study was to investigate the effects of berberine on endothelial dysfunction of aortas in type 2 diabetes mellitus rats and its mechanism. Wistar rats were randomly divided into four groups: diabetic rats, control rats, diabetic rats treated with berberine (100 mg/kg), and control rats treated with berberine. The serum fasting blood glucose, insulin, total cholesterol, triglyceride and nitric oxide (NO) levels were tested. Acetylcholine-induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estimating endothelial function. The expression of endothelial nitric oxide synthase (eNOS) mRNA was measured by RT-PCR, and the protein expressions of eNOS and NADPH oxidase (NOX4) were analyzed by western blot. The results showed that berberine significantly decreased fasting blood glucose, and triglyceride levels in diabetic rats. Berberine also improved endothelium-dependent vasorelaxation impaired in aorta. The expressions of eNOS mRNA and protein were significantly increased, while NOX4 protein expression was decreased in aortas from diabetic rats with berberine treatment. Moreover, serum NO levels were elevated after berberine treatment. In conclusion, berberine restores diabetic endothelial dysfunction through enhanced NO bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase.     

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a relevant target for diabetic vasculopathy?

Mechanisms through which major risk factors accelerate diabetic angiopathy include low density lipoprotein (LDL) oxidation and advanced glycation end products (AGEs) formation. Lectin-like oxidized LDL receptor (LOX-1) is a newly identified vascular receptor for oxidized LDL (oxLDL) and AGEs. LOX-1 is up-regulated in vascular endothelium of diabetic animals and thus may be relevant to the development and progression of human diabetic vasculopathy. The mechanisms responsible for LOX-1 induction in diabetes remain unclear but appear to involve metabolic and inflammatory stimuli relevant to diabetes. Such factors may impact on LOX-1-mediated pro-atherogenic events, including endothelial dysfunction and plaque destabilization. Previous studies have shown that drugs commonly used in the treatment of type 2 diabetic patients, including statins and antidiabetic agents, inhibit endothelial LOX-1 expression. This review summarizes recent advances related to the role of LOX-1 in macrovascular diseases, its regulation by some derangements commonly found in diabetic patients and its modulation by vasculoprotective drugs.     

Interleukin-2 protects against endothelial dysfunction induced by high glucose levels in rats

AIMS: Interleukin-2 (IL-2) can modulate cardiovascular functions, but the effect of IL-2 on vascular endothelial function in diabetes is not known. We hypothesized that IL-2 may attenuate endothelial dysfunction induced by high glucose or diabetes. So the aim of this study was to investigate the effect of IL-2 on endothelium-response of aortas incubated with high glucose or from diabetic rats and its underlying mechanism. METHODS: Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EIR), superoxide dismutase (SOD) and nitric oxide synthase (NOS) were measured in aortas isolated from non-diabetic rats and exposed to a high glucose concentration and from streptozotocin-induced diabetic rats. RESULTS: Incubation of aortic rings with high glucose (44 mM) for 4 h resulted in a significant inhibition of EDR, but had no effects on EIR. Co-incubation with IL-2 for 40 min prevented the inhibition of EDR caused by high glucose in a concentration-dependent manner. Similarly, high glucose decreased SOD and NOS activity in aortic tissue. IL-2 (1000 U/ml) significantly attenuated the decrease of SOD and NOS activity caused by high glucose. In addition, EDR declined along with the decrease of serum NO level in aortas from STZ-induced diabetic rats. Injection of IL-2 (5000 and 50,000 U kg(-1) d(-1), s.c.) for 5 weeks prevented the inhibition of EDR and the decrease of serum NO levels caused by diabetes. CONCLUSIONS: IL-2 significantly ameliorated the endothelial dysfunction induced by hyperglycemia, in which the activation of the NO pathway and SOD may be involved.     

Effect of hyperoxia and metformin on vascular responses to vasoactive compounds in rats.

Exposure of cells to oxygen concentrations higher than normal (hyperoxia) damages the molecular components of cells, resulting in cellular dysfunction and death. Metformin, a biguanide molecule used for treating non-insulin-dependent diabetes, been shown to lower blood pressure. The aim of this study was to investigate the possible effects of hyperoxia and metformin on the vascular responses of thoracic aorta to vasoactive compounds, using an in vitro rat model. In the hyperoxia-control (HC) group, the response to acetylcholine was completely abolished, but metformin treatment before (MH) or after (HM) exposure to 100% oxygen restored the response to acetylcholine to near-control values. In aortas from HC, MH, or HM groups, no significant differences were found in pD2 values to the endothelium-dependent vasodilator sodium nitroprussiate. In aortic strips from metformin-treated rats, the pD2 values for noradrenaline in the presence of endothelium were significantly smaller than those in the normal control group. The maximal contractile responses to KCl were not significantly different among all experimental groups. The results of the present study show that in hyperoxia-exposed rats, metformin treatment reverses the abolished vascular relaxation to AChe.     

野黄芩甙元对糖尿病大鼠主动脉的影响

目的：研究野黄芩甙元对糖尿病大鼠血管合并症的预防作用。方法：利用平滑肌条离体研究装置。结果：在第六周的糖尿病大鼠主动脉：1）乙酰胆碱引起的内膜依赖性舒张作用较对照明显减弱（P＜0．01）;2）苯肾上腺素引起的收缩反应较对照明显增加,最大收缩增加约40％（P＜0．01）;3）糖尿病大鼠服用含0．5％的野黄芩甙元的饮水后,乙酰胆碱引起的内膜依赖性舒张作用较糖尿病组明显增加（P＜0．01）。但是,苯肾上腺素引起的收缩反应增加更显著,最大收缩较对照加约80％（P＜0．01）。结论：野黄芩甙元对糖尿病引起的血管内膜功能损害有防护作用,也可增强苯肾上腺素引起的收缩。     

Inhibition of protein tyrosin phosphatase improves vascular endothelial dysfunction

The study has been designed to investigate the effect of Bis-(maltolato) oxovanadium (BMOV), an inhibitor of protein tyrosin phosphatase (PTPase), in diabetes mellitus and hyperhomocysteinemia induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >140 mg dl(-1)) and hyperhomocysteinemia (serum homocysteine>10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard drug to improve vascular endothelial dysfunction. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. BMOV or atorvastatin markedly improved acetylcholine induced endothelium dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of BMOV has been prevented by l-NAME (25 mg kg(-1), i.p.), an inhibitor of NOS or by glibenclamide (5 mg kg(-1), i.p.), a blocker of ATP sensitive K(+) channels. Therefore, it may be concluded that BMOV induced inhibition of PTPase may activate eNOS due to opening of ATP sensitive K(+) channels and consequently reduce oxidative stress to improve vascular endothelial dysfunction.     

Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level

1. Oxide low-density lipoprotein (ox-LDL) is believed to play an important role in early events of atherogenesis, and asymmetric dimethylarginine (ADMA) is associated with the development of endothelial dysfunction. The present study examined the effect of a single injection of native low-density lipoprotein (LDL) on endothelium function and the serum level of ADMA and the effect of probucol on endothelium function and ADMA level in rats. 2. Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg(-1) for 24, 48, or 72 h, and vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA, nitrite/nitrate (NO) and malondialdehyde (MDA) were determined. 3. Pretreatment with LDL markedly reduced endothelium-dependent relaxation in a concentration-dependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence of L-arginine (3 x 10(-4) M). Serum levels of ADMA and MDA were significantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4. Pretreatment with probucol significantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar effect was seen in the rats pretreated with an antioxidant vitamin E. 5. These results suggest that a single injection of native LDL causes endothelial dysfunction by elevation of ADMA levels and that the protective effect of probucol on endothelial cells is related to reduction of ADMA concentration.     

Endothelial dysfunction in diabetes

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.     

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300–350 g, n = 6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1–0.8 μg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1–4 μg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.     

Endothelium-dependent relaxation in isolated renal arteries of diabetic rabbits

1 In this study, we have investigated the vasodilator response to acetylcholine under diabetes conditions in isolated renal arteries of rabbits. We have also examined the contribution of endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF) to the endothelium-dependent relaxation caused by acetylcholine in the renal arteries of alloxan-induced diabetic rabbits. 2 Acetylcholine (10(-10) - 10(-4) M) produced cumulative concentration-response curve in the renal arteries of both control and diabetic rabbits. The EC50 values and maximal responses to acetylcholine were not significantly different relative to diabetic conditions. In order to isolate the EDHF component of acetylcholine-induced vasodilator response, L-nitro-methyl arginine ester (L-NAME, 10(-4) M) and indomethacin (10(-6) M) were added to the Krebs' solution throughout the experiment. Under these conditions, acetylcholine induced vasodilatation in the isolated renal arteries from both control and diabetic rabbits. The vasodilator response to acetylcholine was not affected under diabetic conditions. 3 Sodium nitroprusside (SNP)-induced relaxation was increased in the diabetic rabbits compared with the control animals. 4 Tetrabutyl ammonium (TBA, 0.5 mM) produced a significant reduction in acetylcholine-induced vasodilatation in both preparations from control and diabetic animals, consistent with involvement of K+ channels in mediating this response. Glibenclamide (1 microM) attenuated acetylcholine-induced vasodilatation in preparations from control animals only, while iberiotoxin (0.05 microM) significantly reduced the vasodilator response to acetylcholine in preparations from both control and diabetic animals. 5 The role of EDNO in mediating acetylcholine-induced vasodilatation was examined. The vascular preparations were incubated with 20 mM K(+)-Krebs' solution to inhibit the EDHF contribution to acetylcholine-induced vasodilatation. Under this condition, acetylcholine induced a vasodilator response in both preparations from control and diabetic rats. Pretreatment with L-NAME (10(-4) M) attenuated acetylcholine-induced vasodilatation in both preparations, indicating an nitric oxide-mediated vasodilator response. 6 Our results indicated that acetylcholine-induced vasodilatation in the isolated renal arteries of alloxan-induced diabetic rabbits was not affected under diabetic conditions. Acetylcholine-induced vasodilatation is mediated by two vasodilator components; namely, EDHF and EDNO. The contribution of EDHF and EDNO to acetylcholine-induced vasodilatation was not affected under diabetic conditions and there was no indication of endothelial dysfunction associated with diabetes. EDHF component was found to act mainly through high conductance Ca(2+)-activated K+ channels under normal and diabetic conditions, while the adenosine triphosphate-dependent K+ channels were involved in mediating acetylcholine vasodilator response in the control preparations only.     

Gender differences in vascular reactivity of aortas from streptozotocin-induced diabetic mice

The aim of the present study was to assess gender differences in diabetes-related vascular reactivity in murine aortas. Diabetes is a risk factor for ischemic heart disease, cerebral ischemia, and atherosclerosis, conditions in which endothelial dysfunction plays a pathogenetic role. We examined vascular responses in aortas isolated from streptozotocin (STZ)-induced type 1 diabetic mice and age-matched control mice, and looked for gender differences in the diabetes-induced changes in these responses. For each gender, the plasma adiponectin levels were lower in diabetic mice than in the controls, and they were significantly higher in females than in males. The acetylcholine (ACh)-induced endothelium-dependent relaxation of aortic rings was impaired (vs. that in the age-matched controls) in diabetic male mice, but not in diabetic female mice. The sodium nitroprusside-induced endothelium-independent aortic relaxation was not altered by diabetes in either male or female mice. The norepinephrine-induced aortic contraction was enhanced (vs. that in the control group) in diabetic female mice, but not in diabetic male mice, whereas in the presence of N(G)-nitro-L-arginine neither gender exhibited a significant diabetes-induced change in this contraction. The clonidine-induced and insulin-induced endothelium-dependent aortic relaxations were impaired only in the diabetic female group (vs. the age-matched controls). These results suggest that: a) in male diabetic mice, which exhibited low adiponectin levels, these were impairments of both the aortic relaxation and nitric oxide (NO) production induced by ACh, whereas b) in female diabetic mice, there were impairments of the aortic relaxations induced by both insulin and clonidine.     

Protective Effect of Sitagliptin and Rosuvastatin Combination on Vascular Endothelial Dysfunction in Type-2 Diabetes

The present investigation aimed to evaluate the protective effects of sitagliptin, glimepiride, rosuvastatin and their combinations on oxidative stress and endothelial dysfunction in the aortic tissues in fructose-fed type-2 diabetic rats. Sitagliptin (20 mg/kg, p.o.), glimepiride (2 mg/kg, p.o.), rosuvastatin (5 mg/kg, p.o.) and their combinations were administered for 6 w after induction of diabetes by fructose (66%, w/v solution, p.o. for 8 w) in wistar rats. The effects were examined on body weight, serum glucose, triglyceride, cholesterol, blood pressure, heart rate, nitric oxide and antioxidant defensive enzymes. After completion of treatment schedule, the blood pressure was determined by invasive method and vascular reactivity was tested with adrenaline, noradrenaline and phenylephrine. Endothelial dysfunction was determined by acetylcholine and sodium nitroprusside-induced vasorelaxation studies on isolated rat aortas. Long term treatments significantly decreased body weight gain, serum glucose, triglyceride and cholesterol levels; normalize the heart rate, and blood pressure in fructose fed rats. The treatments significantly improved vascular reactivity to catecholamines with reduction in elevated blood pressure in type-2 diabetic rats. The significant improvement in the relaxant response to acetylcholine and sodium nitroprusside was obtained on isolated aortas. All the treatments were effective in restoring defensive antioxidant enzymes. Sitagliptin and rosuvastatin were able to reverse endothelial dysfunction in type-2 diabetes, but better ameliorating potential was found when used in combination.     

烟酸对幼年肥胖大鼠血脂及血管内皮粘附功能的影响

目的研究烟酸对幼年肥胖大鼠血脂及血管内皮粘附功能的影响,探讨烟酸防治动脉粥样硬化(AS)的作用机制。方法Wistar大鼠随机分为对照组和试验组,分别饲予基础饲料和高脂饲料,8周后肥胖大鼠造模成功。肥胖大鼠再随机分为3组:A组:单纯控制食谱,B组:控制食谱+烟酸,F组:继续高脂饮食。原对照组继续饲予基础饲料,为N组。干预12周后,处死全部大鼠,测定血脂指标:总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、计算动脉粥样硬化指数(AI);血管内皮粘附因子:血清可溶性细胞间粘附分子1(sICAM-1),免疫组化法检测腹主动脉ICAM-1蛋白的表达,RT-PCR法检测腹主动脉ICAM-1mRNA的表达。结果与F组比较,B组的TC、TG、LDL、AI、sICAM-1、ICAM-1蛋白和mRNA表达水平显著降低,HDL显著升高,且均与N组无显著差异。结论控制食谱联合烟酸可以改善血脂、血管内皮粘附功能,因此调节血脂紊乱和血管内皮粘附功能障碍是烟酸类药物改善AS预后的可能机制。     

盐酸二甲双胍对2型糖尿病大鼠波动性高血糖状态下血管内皮功能的影响

目的观察盐酸二甲双胍(metformin hydrochloride,MH)对2型糖尿病大鼠波动性高血糖状态下血管内皮功能的影响。方法采用高脂饲料喂养加链脲佐菌素(streptozo-tocin,STZ)35 mg.kg-1腹腔注射建立2型糖尿病(T2DM)大鼠模型,并依照空腹血糖变异系数将造模成功的T2DM大鼠分为波动高糖组和稳定高糖组,并将波动高糖组随机分为3组:MH 150 mg.kg-1.d-1组、300 mg.kg-1.d-1组和波动高糖对照组。药物干预8周,观察盐酸二甲双胍对波动性高血糖大鼠主动脉内皮,血浆肝细胞生长因子(HGF)、血浆糖基化终末产物(AGEs)、氧化型低密度脂蛋白受体-1(LOX-1)含量及血清抗氧化能力、TNF-α、sICAM-1的影响。结果盐酸二甲双胍组大鼠血浆HGF、AGEs、LOX-1及血清TNF-α、sICAM-1均较波动高糖组降低,血清抗氧化能力改善。结论二甲双胍具有减轻血糖波动T2DM大鼠血管内皮损伤的作用,其保护作用可能与其减少脂质过氧化产物的产生,增强机体的抗氧化能力,减轻炎症反应,减少细胞黏附因子表达及糖基化终末产物的蓄积有关。     

Carvedilol ameliorates endothelial dysfunction in streptozotocin-induced diabetic rats

The beta-blocker, carvedilol has an additional endothelium-dependent vasodilating properties in patients with hypertension or heart failure. Whether carvedilol can improve endothelium-dependent relaxation in a diabetic animal model and its mechanism of action are unknown. The aim of this study was to investigate the effect of carvedilol on the endothelial-response of aortas from diabetic rats and the underlying mechanism. Acetylcholine-induced endothelium-dependent relaxation, sodium nitroprusside (SNP)-induced endothelium-independent relaxation, and expression of nitric oxide synthase 3 (NOS3) mRNA were measured in aortas isolated from both non-diabetic and streptozotocin-induced diabetic rats. The level of NO in serum was also measured 5 weeks after carvedilol administration (1 or 10 mg/kg/day). Endothelium-dependent relaxation declined along with the decrease of serum NO level in aortas from diabetic rats. Treatment with carvedilol for 5 weeks prevented the inhibition of endothelium-dependent relaxation and the decrease of serum NO levels caused by diabetes. The expression of NOS3 mRNA, protein expression and NOS3 phosphorylation at Ser1177 in diabetic rat aorta was very low in untreated diabetic aortas compared with the healthy group. Administration of carvedilol not only significantly increased the expression of NOS3 mRNA but also protein expression and NOS3 phosphorylation at Ser1177 in the healthy and diabetic groups. In conclusion, chronic carvedilol administration significantly ameliorated the endothelial dysfunction in diabetic rat aortas, in which increased NO level, up-regulated NOS3 mRNA and phosphorylation at Ser1177 may be involved.     

糖尿病大鼠血管内皮依赖性舒张与降钙素基因相关肽的关系

在糖尿病大鼠，检测血浆降钙素基因相关肽(CGRP)含量的变化，并探讨其与血管内皮舒张功能的关系. 糖尿病大鼠血浆CGRP的含量显著低于对照组(0.22±0.08 vs 0.37±0.13 μg·L^-1, P<0.01), 但丙二醛含量显著增加；糖尿病大鼠胸主动脉对乙酰胆碱诱导内皮依赖性舒张反应显著降低. 结果提示：糖尿病大鼠血管内皮舒张功能的削弱与血浆CGRP含量的下降有关.     

Endothelin-1-induced impairment of endothelium-dependent relaxation in aortas isolated from controls and diabetic rats

An accumulating body of evidence indicates that an increased endothelin-1 level is related to endothelial dysfunction in cardiovascular diseases. In this study, we tested whether prolonged treatment of aortas with endothelin-1 induces endothelial dysfunction. When isolated aortas from control rats were cultured with endothelin-1, at levels above the plasma concentration, the acetylcholine-induced endothelium-dependent relaxation was significantly decreased (as compared with endothelin-1-nontreatment). This endothelin-1-induced endothelial dysfunction was more marked in aortas obtained from rats with streptozotocin-induced diabetes than in those from the controls. The endothelin-1- induced attenuation was very strongly suppressed by co-incubation with J-104132, endothelin receptor A/B antagonist, or polyethylene-glycolated superoxide dismutase, a cell-permeant superoxide anion scavenger or LY294002, phosphoinositide 3-kinase inhibitor. These results indicate that endothelin-1 can induce endothelial dysfunction, and that this may be related to superoxide generation and to PI3-kinase activity.     

Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes

This study was designed to determine the relationship between elevated levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), and metabolic control in rats with streptozotocin-induced diabetes. Serum levels of ADMA were measured by high-performance liquid chromatography at 8 weeks after diabetes was induced. Endothelium-dependent relaxation to acetylcholine was tested in aortic rings from nondiabetic age-matched control, untreated diabetic, and insulin-treated diabetic rats to evaluate endothelial function. Serum concentrations of glucose, glycosylated serum protein, and malondialdehyde were examined to estimate metabolic control. Serum levels of ADMA increased dramatically in untreated diabetic rats compared with control rats. This elevation in ADMA levels was accompanied by impairment of the endothelium-dependent relaxation response to acetylcholine in aortic rings. Long-term insulin treatment not only prevented the elevation of serum ADMA levels, but also improved the impairment of endothelium-dependent relaxation in diabetic rats. Serum levels of glucose, glycosylated serum protein, and malondialdehyde were significantly increased in parallel with the elevation of ADMA in untreated diabetic rats compared with control rats. These parameters were normalized after diabetic rats received insulin treatment for 8 weeks. These results provide the first evidence that an elevation in the concentration of ADMA in rats with streptozotocin-induced diabetes is closely related to metabolic control of the disease.