Effects of dual endothelin receptor antagonist on antiapoptotic marker Bcl-2 expression in streptozotocin-induced diabetic rats

Erectile dysfunction (ED) affects approximately 50% of male patients with diabetes mellitus (DM) and is possibly due to the vascular and neuropathic complications of DM. Recently, apoptosis has been regarded as a downstream event in ED. More recently, the importance of alterations in apoptosis-related molecules in the mechanism of DM-induced ED has begun to be appreciated. Endothelin-1 (ET-1) plays a role via ET(A) and ET(B) receptors in the regulation of cavernosal smooth-muscle tone in penile tissues. We found that the ET-1 level in the penis of rats with DM was higher than that in the penis of control animals. The present study investigated a rat model in which DM was induced by a 3-week regimen of streptozotocin (STZ) to assess the expression of several apoptosis-related molecules in penile tissue and, concomitantly, the effects of ET antagonism on these changes. Male Sprague-Dawley rats (weight [+/-SD], 450 +/- 26 g) received a citrate saline vehicle or STZ (65 mg/kg ip). DM was confirmed by the presence of hyperglycemia. Diabetic animals were further separated into two treatment groups 1 week after onset of disease: one group received ET(A/B) dual receptor antagonist (SB209670) by means of osmotic minipump at a dosage of 1 mg/day, and the other group received saline. Rats in both groups were treated for 2 weeks and then sacrificed. Plasma glucose levels (+/-SD) in rats with DM were significantly higher than those in rats without DM (506 +/- 70 vs. 111 +/- 11 mg/dl). In the penile tissue of rats with DM, a 35% decrease in the expression of Bcl-2 protein (an important antiapoptotic marker detectable by immunoblotting) was seen, and ET(A/B) dual antagonist was observed to significantly counteract this decrease. Real-time polymerase chain reaction revealed that the expression of Bcl-2 mRNA was consistent with Bcl-2 protein expression. Levels of Bax and caspase-3, two important proapoptotic markers, were not significantly altered in the present study. Thus, we conclude that, in the penis of rats with early stage DM, the protection against apoptosis has decreased but can be improved by ET antagonism.     

Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart

Cardiovascular complications are an important feature of diabetes mellitus (DM). Abnormal and decreased coronary collateral development has been implicated in the pathogenesis of cardiac complications in DM. More recently, decreased expression of vascular endothelial growth factor (VEGF) and its receptors has been found in diabetic heart. To our knowledge, no study has focused on the therapeutic improvement associated with VEGF in diabetic heart. DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control rats received only citrate buffer. After 1 week, the streptozotocin-treated rats were randomly divided into two groups: one group received the selective endothelin (ET) type A receptor antagonist TA-0201 at a dose of 1 mg/kg/day for 2 weeks by osmotic mini-pump, and the vehicle group received saline only. The plasma glucose level was 504 +/- 75 mg/dl in the diabetic rats and was unchanged by treatment with ET antagonist. The body weight was decreased in the diabetic rats compared with the control rats, but the left ventricular (LV)-body weight ratio was increased in the diabetic group and was unaffected by treatment with ET antagonist. mRNA expression of VEGF and its receptors (Flt-1 and Flk-1) in the LV tissues was assessed using real-time polymerase chain reaction. VEGF expression was significantly decreased in diabetic heart and was greatly improved by treatment with ET antagonist. The expression of VEGF receptors was down-regulated in early diabetic heart but was not recovered by treatment with ET antagonist. ET and its receptor A might have differential regulation on the gene expressions of VEGF and its receptors in early diabetic heart.     

Effect of endothelin dual receptor antagonist on VEGF levels in streptozotocin-induced diabetic rat retina

Diabetic retinopathy (DR), one of the most serious causes of blindness, is often associated with the upregulation of vascular endothelial growth factor (VEGF) in retina. Recently, leukocyte adhesion (leukostasis) is blamed for the occlusion of retinal capillary vascularity, which ultimately contributes to the progression of diabetic retinopathy. In addition, intercellular adhesion molecule-1 (ICAM-1), a representative factor for leukostasis, is increased in the diabetic retina. Endothelin (ET)-1, a potent vasoconstrictor peptide, is deeply linked to the pathogenesis of diabetic retinopathy. Different therapeutic interventions concerning VEGF have already been proposed to prevent diabetic retinopathy. However, no study yet has reported whether ET-1 dual receptor antagonist could alter the upregulated VEGF and ICAM-1 levels in the diabetic retina. The present study investigated the effect of ET(A/B) dual receptor antagonist (SB209670; 1 mg/rat/day) on the expression of VEGF and ICAM-1 in the diabetic rat retina. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in Sprague-Dawley rats, whereas control rats (non-DM control) received only citrate buffer. After 1 week, the STZ-administered rats were randomly divided into two groups: one group (DM+SB209670) received ET(A/B) dual receptor antagonist for 2 weeks, and a vehicle group (DM+vehicle) was treated only with saline. After the treatment period, the retinas were removed from the eyeballs. In DM+vehicle group, the VEGF expression of the retinas was significantly increased (32.8 pg/mg) in comparison to that in the non-DM control group (26.2 pg/mg); this upregulation of VEGF was reversed in the DM+SB209670 group (28.6 pg/mg). The expression of retinal ICAM-1 was increased in the DM+vehicle group (152.2 pg/mg) compared with the non-DM control group (121.6 pg/mg). However, SB209670 treatment did not alter the expression of retinal ICAM-1 level (154.8 pg/ml) in DM rats. Thus we conclude that an ET(A/B) dual receptor antagonist could reverse the expression level of VEGF in the diabetic retina while failing to normalize the upregulated ICAM-1 expression.     

Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats

AimsOxidative stress-induced cell damage is reported to contribute to the pathogenesis of cerebral ischemia/reperfusion injury. This study investigated the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult in rats.Main methodsThe model adopted was that of surgically-induced forebrain ischemia, performed by means of bilateral common carotid artery occlusion for 1 h, followed by reperfusion for 24 h. The effects of 5 and 10 mg/kg nebivolol, treated for 7 days prior to ischemia/reperfusion insult, were investigated by estimating endothelial and inducible nitric oxide synthases (eNOS and iNOS) protein expressions and assessing oxidative stress-related biochemical parameters in the rat forebrain. Also, infarct volume measurement and histopathological study of the forebrain were examined.Key findingsAdministration of nebivolol increased eNOS expression with simultaneous decrease in iNOS expression in a dose dependent manner. Moreover, nebivolol inhibited ischemia/reperfusion-induced depletion of reduced glutathione level and decreased the elevated total nitric oxide end production and malondialdehyde levels, superoxide dismutase and lactate dehydrogenase activities. A notable finding is that catalase activity was not changed in response to either ischemia/reperfusion insult or nebivolol treatment. However, the results confirmed that nebivolol significantly reduced infarct volume and alleviated ischemia/reperfusion-induced histopathological changes.SignificanceThe present study demonstrates the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult. Neuroprotection observed with nebivolol may possibly be explained by regulating eNOS and iNOS expressions and by inhibition of oxidative stress-induced injury. Thus, nebivolol may be considered as a potential candidate for treatment in patients who are prone to stroke.     

Lipoprotein lipase activities in heart muscle of streptozotocin-induced diabetic rats

Triglyceride lipase (TGL) activities in the homogenates of the rat heart muscle were studied. TGL activity per mg protein of heart muscle was the highest in heart muscle homogenate utilizing 2.1 M glycine buffer, pH 8.3 among the assays investigated. The effects of NaCl, serum and heparin on TGL activities in heart muscle homogenates indicated the characteristics of lipoprotein lipase (LPL). Twelve-hour fasting increased heart muscle LPL activity, while enzyme activities in 48 hour- and 72 hour-fasted rats were lower than those in fed rats. LPL activities in heart muscle homogenates in streptozotocin (STZ)-induced diabetic rats either 3 days or 4 weeks after STZ injection, were decreased significantly as compared with those of control rats.     

Effects of sleeve gastrectomy in neonatally streptozotocin-induced diabetic rats

Background

Sleeve gastrectomy (SG) has emerged recently as a stand-alone bariatric procedure to treat morbid obesity and enhance glucose homeostasis. The aim of the study was to evaluate its effects in neonatally streptozotocin (STZ)-induced diabetic rats (n-STZ diabetic rats).

Methodology and Principal Findings

To induce diabetes, STZ (90 mg/kg) was administered intraperitoneally to 2-day-old male pups. When 12 weeks old, diabetic rats were randomized into sleeve operation group (SLG, n = 6) and sham operation group (SOG, n = 6). Body weights were monitored weekly, and daily consumption of water and food were followed for eight consecutive weeks postoperatively. Serum glucose levels were measured periodically at the 4th and 8th week after surgery. Insulin, ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) levels were assayed at the end of the study. Our data showed that SLG rats exhibited significantly lower body weight gain in addition to reduced food and water intakes postoperatively compared to their sham-operation counterparts. However, resolution of diabetes was not observed in our study. Correspondingly, there were no significant differences between SOG rats and SLG rats in glucose metabolism-associated hormones, including insulin, GIP and GLP-1. In contrast, ghrelin level significantly decreased (P<0.01) in SLG group (58.01±3.75 pg/ml) after SG surgery compared to SOG group (76.36±3.51 pg/ml).

Conclusions

These observations strongly suggest that SG is effective in controlling body weight. However, SG did not achieve resolution or improvement of diabetes in n-STZ diabetic rats.     

Effect of cobalt on the oxidative status in heart and aorta of streptozotocin-induced diabetic rats

Effects of cobalt on the antioxidant status of control and streptozotocin diabetic rat heart and aorta were examined at the second, fourth and sixth week of treatment. Rats were divided into four groups: control, diabetic, control treated with cobalt chloride and diabetic treated with cobalt chloride. Diabetes was induced by tail vein injection of streptozotocin (STZ). Cobalt treatment groups were given 0.5 mM of CoCl(2) in drinking water. The rats in both groups were further subdivided into three groups of six rats each. Rats in these subgroups were studied at 2-week intervals up to 6 weeks. At the end of the experiment, all animals were sacrificed by decapitation, heart and aorta samples were removed for determination of thiobarbituric acid reactive substance (TBARS) level and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities. It was found that lipid peroxidation levels and antioxidant enzyme activities were increased in the streptozotocin-induced diabetic rats at all times studied. Cobalt treatment of diabetic rats (0.5 mM in drinking water) resulted in attenuation of the increased levels of TBARS and antioxidant enzyme activities in heart and aorta. Thus, the effect of oral administration of cobalt at this dose during the early stage of experimental diabetes can be considered as a consequence of altered endogenous defence mechanisms in heart and aorta.     

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats

Free radicals and oxidative stress have been implicated in the etiology of diabetes and its complications. This in vivo study has examined whether subacute administration of pycnogenol, a French pine bark extract containing procyanidins that have strong antioxidant potential, alters biomarkers of oxidative stress in normal and diabetic rats. Diabetes was induced in female Sprague-Dawley rats by a single injection of streptozotocin (90 mg/kg body weight, ip), resulting (after 30 days) in subnormal body weight, increased serum glucose concentrations, and an increase in liver weight, liver/body weight ratios, total and glycated hemoglobin, and serum aspartate aminotransferase activity. Normal and diabetic rats were treated with pycnogenol (10 mg/kg body weight/day, ip) for 14 days. Pycnogenol treatment significantly reduced blood glucose concentrations in diabetic rats. Biochemical markers for oxidative stress were assessed in the liver, kidney, and heart. Elevated hepatic catalase activity in diabetic rats was restored to normal levels after pycnogenol treatment. Additionally, diabetic rats treated with pycnogenol had significantly elevated levels of reduced glutathione and glutathione redox enzyme activities. The results demonstrate that pycnogenol alters intracellular antioxidant defense mechanisms in streptozotocin-induced diabetic rats.     

Effects of quercetin on antioxidant defense in streptozotocin-induced diabetic rats.

In light of evidence that some complications of diabetes mellitus may be caused or exacerbated by oxidative damage, we investigated the effects of subacute treatment with the antioxidant quercetin on tissue antioxidant defense systems in streptozotocin-induced diabetic Sprague-Dawley rats (30 days after streptozotocin induction). Quercetin, 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one, was administered at a dose of 10mg/kg/day, ip for 14 days, after which liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione content, and activities of the free-radical detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Treatment of normal rats with quercetin increased serum AST and increased hepatic concentration of oxidized glutathione. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Quercetin treatment of diabetic rats reversed only the diabetic effects on brain oxidized glutathione concentration and on hepatic glutathione peroxidase activity. By contrast, a 20% increase in hepatic lipid peroxidation, a 40% decline in hepatic glutathione concentration, an increase in renal (23%) and cardiac (40%) glutathione peroxidase activities, and a 65% increase in cardiac catalase activity reflect intensified diabetic effects after treatment with quercetin. These results call into question the ability of therapy with the antioxidant quercetin to reverse diabetic oxidative stress in an overall sense.     

Effects of vanadyl sulfate on liver of streptozotocin-induced diabetic rats

The aim of this study was to investigate the microscopic and biochemical effects of vanadyl sulfate on liver tissue of normal and streptozotocin (65 mg/kg) diabetic rats. Vanadyl sulfate was administered by gavage at a dose of 100 mg/kg. Degenerative changes were observed in diabetic animals by light and transmission electron microscopes. Although there were individual differences in diabetic animals to which vanadium was given, some reduction of degenerative changes were detected. After 60 d of treatment, serum aspartate and alanine transaminase, alkaline phosphatase, blood glucose levels, liver lipid peroxidation, and nonenzymatic glycosylation significantly increased, but liver glutathione levels significantly decreased in the diabetic group. On the other hand, treatment with vanadyl sulfate reversed these effects. As a result, it might be concluded that vanadyl sulfate has a protective effect on damage of liver of streptozotocin-induced diabetic rats.     

Effects of resveratrol on nucleotide degrading enzymes in streptozotocin-induced diabetic rats

AimsDiabetes mellitus is associated with platelet alterations that may contribute to the development of cardiovascular complications. The present study investigates the effects of resveratrol (RSV), an important compound with cardioprotective activities, on NTPDase, ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), 5′-nucleotidase and adenosine deaminase (ADA) activities in platelets from streptozotocin (STZ)-induced diabetic rats.Main methodsThe animals were divided into six groups (n = 8): control/saline; control/RSV 10 mg/kg; control/RSV 20 mg/kg; diabetic/saline; diabetic/RSV 10 mg/kg; diabetic/RSV 20 mg/kg. RSV was administered during 30 days and after this period the blood was collected for enzymatic assay.Key findingsThe results demonstrated that NTPDase, E-NPP and 5′-nucleotidase activities were significantly higher in the diabetic/saline group (P < 0.05) compared to control/saline group. Treatment with RSV significantly increased NTPDase, 5′-nucleotidase and E-NPP activities in the diabetic/RSV10 and diabetic/RSV20 groups (P < 0.05) compared to diabetic/saline group. When RSV was administered per se there was also an increase in the activities of these enzymes in the control/RSV10 and control/RSV20 groups (P < 0.05) compared to control/saline group. ADA activity was significantly increased in the diabetic/saline group (P < 0.05) compared to control/saline group. The treatment with RSV prevented this increase in the diabetic/RSV10 and diabetic/RSV20 groups. No significant differences in ADA activity were observed in the control/RSV10 and control/RSV20 compared to control/saline group.SignificanceThe present findings demonstrate alterations in nucleotide hydrolysis in platelets of STZ-induced diabetic rats and treatment with RSV was able to modulate adenine nucleotide hydrolysis, which may be important in the control of the platelet coagulant status in diabetes.     

Alterations in Fc receptor function of macrophages from streptozotocin-induced diabetic rats

The presence of elevated levels of circulating immune complexes in diabetic humans and animals suggests impaired phagocyte function. To evaluate FcR-mediated phagocytosis, resident peritoneal macrophages were harvested from control, streptozotocin-induced diabetic, and insulin-treated diabetic rats. FcR number and avidity were determined from Scatchard analysis of binding of 125I-labeled aggregated rat IgG (ARG) to macrophages. The total and fractional catabolic capacity were determined by quantitating the digestion of ARG as a percent of the total ARG added and as a percent of ARG bound. Insulin-deficient diabetic rats had an increase in the number of FcR per cell (26.8 +/- 3.5 X 10(4)) as compared with control animals (13.1 +/- 1.2 X 10(4)) (p less than 0.01). In contrast, insulin-treated diabetic animals had a reduction in the number of FcR per cell (9.8 +/- 1.4 X 10(4)) (p less than 0.01). FcR of macrophages from insulin-deficient diabetic rats had a lower avidity (Kd = 6.9 +/- 1.8 X 10(-10)M) when compared with control (3.7 +/- 0.6 X 10(-10)M) and insulin-treated diabetic rats (3.6 +/- 0.9 X 10(-10)M) (p less than 0.01). Total catabolism of ARG by macrophages from both insulin-deficient and insulin-treated diabetic rats was reduced (31.0% +/- 3.4 and 17.5% +/- 3, respectively) when compared with controls (49.6% +/- 5.2) (p less than 0.01). Fractional catabolism by macrophages from insulin-deficient diabetic rats was significantly reduced (21% +/- 1.9 and 4.6% +/- 0.9/10(4) FcR) when compared with results from control rats (26% +/- 1.3 and 6.7% +/- 0.7/10(4) FcR) (p less than 0.01), whereas the results from insulin-treated diabetic rats (32% +/- 2.4 and 10.8% +/- 1.0/10(4) FcR) (p less than 0.01) were greater than those from controls. These studies demonstrate that FcR-mediated phagocytosis of soluble, "model" immune complexes is impaired in macrophages from both insulin-deficient and insulin-treated diabetic rats; however, different mechanisms account for this impairment in phagocytosis. Despite an increase in FcR number of macrophages from insulin-deficient diabetic rats, the depression of post-receptor-mediated catabolism results in a net depression in phagocytic activity. In contrast, macrophages from insulin-treated diabetic rats display augmented post-receptor-mediated catabolism; however, this does not overcome the low initial binding of ARG to the cell that results from the depression of FcR number.     

Alteration of antioxidants during the progression of heart disease in streptozotocin-induced diabetic rats

Involvement of oxidative stress is implicated in the progression of complication of diabetes mellitus. With respect to heart diseases, we have studied role of oxidative stress/antioxidants using rats treated with streptozotocin to induce diabetes (DM). Hemodynamic and echocardiographic measurements showed thickening of the wall and an increase in the internal dimension of the left ventricle (LV) in DM rats at 8th week. Decrease in diastolic posterior wall velocity and rate of LV pressure change, and increase in LV end diastolic pressures also proved cardiac dysfunction. These changes were further developed in DM rats after 12 weeks. Utilizing rat hearts at 8th and 12th weeks, the following estimations were performed. There was a decrease in the activity of Mn-superoxide dismutase (SOD), suggesting abnormal mitochondrial metabolism of reactive oxygen species. The level of glutathione (GSH) decreased concomitant with a decrease in the expression of γ-glutamylcysteine synthetase (γ-GCS). The expression of transforming growth factor-β1 (TGF-β1), known as a growth factor and a suppressor of GSH synthesis, elevated in DM rat hearts. Immunohistochemical estimation showed an increase in type IV collagen in DM hearts. Collectively, it was suggested a linkage between mitochondrial damage to generate reactive oxygen species and inactivation of Mn-SOD and elevation of the expression of TGF-β1 to lead suppression of GSH synthesis and induction of fibrous change for the consequent cardiac dysfunction in DM.     

Effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin-induced diabetic rats

In view of the antioxidant properties of melatonin, the effects of melatonin on the oxidative-antioxidative status of tissues affected by diabetes, e.g. liver, heart and kidneys, were investigated in streptozotocin (STZ)-induced diabetic rats in the present study. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tissues were compared in three groups of 10 rats each (control non-diabetic rats (group I), untreated diabetic rats (group II) and diabetic rats treated with melatonin (group III)). In the study groups, diabetes developed 3 days after intraperitoneal (i.p.) administration of a single 60 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mg kg(-1) i.p. dose of melatonin per day. After 6 weeks, the rats in groups II and III had significantly lower body weights and higher blood glucose levels than the rats in group I (p < 0.001 and p < 0.001, respectively). MDA levels in the liver, kidney and heart of group II rats were higher than that of the control group (p < 0.01, p < 0.05, p < 0.01, respectively) and diabetic rats treated with melatonin (p < 0.05). The GSH, GSH-Px and SOD levels increased in diabetic rats. Treatment with melatonin changed them to near control values. Our results confirm that diabetes increases oxidative stress in many organs such as liver, kidney and heart and indicate the role of melatonin in combating the oxidative stress via its free radical-scavenging and antioxidant properties.     

Alteration of antioxidants during the progression of heart disease in streptozotocin-induced diabetic rats

Involvement of oxidative stress is implicated in the progression of complication of diabetes mellitus. With respect to heart diseases, we have studied role of oxidative stress/antioxidants using rats treated with streptozotocin to induce diabetes (DM). Hemodynamic and echocardiographic measurements showed thickening of the wall and an increase in the internal dimension of the left ventricle (LV) in DM rats at 8th week. Decrease in diastolic posterior wall velocity and rate of LV pressure change, and increase in LV end diastolic pressures also proved cardiac dysfunction. These changes were further developed in DM rats after 12 weeks. Utilizing rat hearts at 8th and 12th weeks, the following estimations were performed. There was a decrease in the activity of Mn-superoxide dismutase (SOD), suggesting abnormal mitochondrial metabolism of reactive oxygen species. The level of glutathione (GSH) decreased concomitant with a decrease in the expression of γ-glutamylcysteine synthetase (γ-GCS). The expression of transforming growth factor-β1 (TGF-β1), known as a growth factor and a suppressor of GSH synthesis, elevated in DM rat hearts. Immunohistochemical estimation showed an increase in type IV collagen in DM hearts. Collectively, it was suggested a linkage between mitochondrial damage to generate reactive oxygen species and inactivation of Mn-SOD and elevation of the expression of TGF-β1 to lead suppression of GSH synthesis and induction of fibrous change for the consequent cardiac dysfunction in DM.     

Prostatic androgen receptor and plasma testosterone levels in streptozotocin-induced diabetic rats.

Diabetes was induced in male Sprague-Dawley (S-D) rats by streptozotocin (STZ) administration. Following STZ injection, plasma glucose levels in the treated rats were significantly elevated from values of untreated controls. Over the experimental period (140 days) plasma testosterone (T) levels, prostatic nuclear androgen receptor (AR) contents and prostatic weights declined with increasing age in the rats. The declines in both STZ-treated and untreated rats were similar in manner and no notable differences were discerned in the data obtained from the two groups. On the contrary, prostatic cytosolic AR contents in untreated rats remained unchanged with advancing age, but was reduced to 50% of normal control values in diabetic rats following STZ treatment. Correlation analyses revealed that prostatic nuclear AR contents correlated positively with plasma T levels while prostatic cytosolic AR contents correlated negatively with plasma glucose levels. These data support former claims that prostatic nuclear AR content is dependent on circulating T level and suggest a possible link between prostatic cytosolic AR content and plasma glucose concentrations.     

Enhanced dermal and retinal vascular permeability in streptozotocin-induced type 1 diabetes in Wistar rats: blockade with a selective bradykinin B1 receptor antagonist

The vascular complications associated with type 1 diabetes are to some extent related to the dysfunction of the endothelium leading to an increased vascular permeability and plasma extravasation in the surrounding tissues. The various micro- and macro-vascular complications of diabetes develop over time, leading to nephropathy, retinopathy and neuropathy and cardiomyopathy. In the present study, the effect of a novel selective bradykinin B1 receptor (BKB1-R) antagonist, R-954, was investigated on the changes of vascular permeability in the skin and retina of streptozotocin (STZ)-induced type 1 diabetic rats. Plasma extravasation increased in the skin and retina of STZ-diabetic rats after 1 week and persisted over 4 weeks following STZ injection. Acute treatment with R-954 (2 mg/kg, bolus s.c.) highly reduced the elevated vascular permeability in both 1- and 4-week STZ-diabetic rats. These results showed that the inducible BKB1-R subtype modulates the vascular permeability of the skin and retina of type 1 diabetic rats and suggests that BKB1-R antagonists could have a beneficial role in diabetic neuropathy and retinopathy.     

Effects of alpha-lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats

Increased oxidative stress and impaired antioxidant defense mechanisms are important factors in the pathogenesis and progression of diabetes mellitus and other oxidant-related diseases. This study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (10 mg/kg ip) once daily for 14 days to normal and diabetic female Sprague-Dawley rats would prevent diabetes-induced changes in biomarkers of oxidative stress in liver, kidney and heart. Serum glucose concentrations, aspartate aminotransferase activity, and glycated hemoglobin levels, which were increased in diabetes, were not significantly altered by alpha-lipoic acid treatment. Normal rats treated with a high dose of alpha-lipoic acid (50 mg/kg) survived but diabetic rats on similar treatment died during the course of the experiment. The activity of glutathione peroxidase was increased in livers of normal rats treated with alpha-lipoic acid, but decreased in diabetic rats after alpha-lipoic acid treatment. Hepatic catalase activity was decreased in both normal and diabetic rats after alpha-lipoic acid treatment. Concentrations of reduced glutathione and glutathione disulfide in liver were increased after alpha-lipoic acid treatment of normal rats, but were not altered in diabetics. In kidney, glutathione peroxidase activity was elevated in diabetic rats, and in both normal and diabetic animals after alpha-lipoic acid treatment. Superoxide dismutase activity in heart was decreased in diabetic rats but normalized after treatment with alpha-lipoic acid; other cardiac enzyme activities were not influenced by either diabetes or antioxidant treatment. These results suggest that after 14 days of treatment with an appropriate pharmacological dose, alpha-lipoic acid may reduce oxidative stress in STZ-induced diabetic rats, perhaps by modulating the thiol status of the cells.     

Effects of piperine on antioxidant pathways in tissues from normal and streptozotocin-induced diabetic rats

Using diabetes mellitus as a model of oxidative damage, this study investigated whether subacute treatment (10 mg/kg/day, intraperitoneally for 14 days) with the compound piperine would protect against diabetes-induced oxidative stress in 30-day streptozotocin-induced diabetic Sprague-Dawley rats. Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione (GSH and GSSG, respectively) content, and activities of the free-radical detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Piperine treatment of normal rats enhanced hepatic GSSG concentration by 100% and decreased renal GSH concentration by 35% and renal glutathione reductase activity by 25% when compared to normal controls. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Treatment with piperine reversed the diabetic effects on GSSG concentration in brain, on renal glutathione peroxidase and superoxide dismutase activities, and on cardiac glutathione reductase activity and lipid peroxidation. Piperine treatment did not reverse the effects of diabetes on hepatic GSH concentrations, lipid peroxidation, or glutathione peroxidase or catalase activities; on renal superoxide dismutase activity; or on cardiac glutathione peroxidase or catalase activities. These data indicate that subacute treatment with piperine for 14 days is only partially effective as an antioxidant therapy in diabetes.