Weeks Of Streptozotocin Research Articles

Prevention of cardiovascular complications in aged diabetic rats by resveratrol

Reactive oxygen species are implicated in the generation of inflammation, decrease of vascular and tissue nitric oxide (NO) concentrations and damage to the cardiovascular system following diabetes. The aim of this study was to examine the antioxidant, anti-inflammatory and cardio-protective effects of resveratrol (Res) (2 mg/kg/day) in aged Wistar rats (6 months) following 8 weeks of streptozotocin (STZ)-induced diabetes. Rats were divided into control (C), control+Res (C+R), STZ and STZ+Res (STZ+R) treatment groups.

Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo

Albuminuria in diabetic nephropathy is due to endothelial dysfunction, a loss of negative charges in the basement membrane, and changes a of the slit-membrane diaphragm composition. We have recently shown that protein kinase C alpha (PKCalpha)-deficient mice are protected against the development of albuminuria under diabetic conditions. We here tested the hypothesis that PKCalpha mediates the hyperglycemia-induced downregulation of the slit-diaphragm protein nephrin. After 8 weeks of streptozotocin (STZ)-induced hyperglycemia the expression of glomerular nephrin was significantly reduced. In contrast, other slit-diaphragm proteins such as podocin and CD2AP were unaltered in diabetic state. In PKCalpha-/- mice, hyperglycemia-induced downregulation of nephrin was prevented. Podocin and CD2AP remained unchanged. In addition, the nephrin messenger RNA expression was also reduced in hyperglycemic wild-type mice but remained unaltered in PKCalpha-/- mice. We postulate that the underlying mechanism of the hyperglycemia-induced regulation of various proteins of the glomerular filtration barrier is a PKCalpha-dependent regulation of the Wilms' Tumor Suppressor (WT1) which previously has been shown to act as a direct transcription factor on the nephrin promoter. Our data suggest that PKCalpha activation may be an important intracellular signaling pathway in the regulation of nephrin expression and glomerular albumin permeability in the diabetic state.

Blood pressure fall and increased relaxation of aortic smooth muscle in diabetic rats

This study was designed to identify changes in endothelium-independent relaxation that could contribute to the depressed vascular reactivity and fall in blood pressure (BP) detected in rats after 5 weeks of streptozotocin (STZ)-induced (i.e. type 1) diabetes. Aortic rings were contracted by simultaneous activation of voltage-operated channels (KCl=80 mM) and alpha-adrenergic receptors (phenylephrine 1 microM) and then relaxed by simultaneous exposure to Ca2+-free PSS and 10 microM phentolamine. Additional relaxations were performed under conditions in which the plasma membrane Na-Ca exchanger (PMNaCa) or Ca-pump (PMCA), or the sarcoplasmic reticulum (SR) Ca-pump (SERCA) were blocked, to identify which mechanism(s) could modulate this process. The STZ-diabetic rats had a moderate but significant decrease of BP, and their aortic rings exhibited accelerated relaxation following a biexponential model, with a significantly decreased slow component. In control rats only the inhibition of the PMNaCa could slow down the fast component, while the slow component was insensitive to any blocking maneuver. In contrast, the diabetic animals' slow component was sensitive to the inhibition of both the PMNaCa and the SERCA. The SERCA-sensitive 45Ca2+ uptake by the SR was augmented in the aortas of STZ-treated animals. This hyperactivity of the SERCA, associated with augmented activity of the PMNaCa, at least partly induced by an increase of the plasma membrane Na+/K+-ATPase activity, could explain the decrease in BP and the accelerated aortic relaxation observed in the diabetic rats.

Endothelial F-actin Cytoskeleton in the Retinal Vasculature of Normal and Diabetic Rats

Purpose: The purpose of this study was to characterize the endothelial (EC) F-actin cytoskeleton at different orders of the retinal microvasculature in the normal and diabetic rat and determine if changes in F-actin are associated with different stages of diabetes. {Methods:} The EC F-actin cytoskeleton distribution, nuclei shape, and capillary diameter in the retinal vasculature of rats after 5 and 28 weeks of streptozotocin (STZ)-induced diabetes were compared to those in age-matched controls. The eyes were enucleated, arterially perfused, and labeled for F-actin cytoskeleton and nuclei (YO-PRO-1) or microvascular leakage (FITC-dextran). Retinal whole mounts were then examined by confocal microscopy. {Results:} The EC F-actin distribution and nuclear size and shape were highly dependent on the location down the vascular tree. The retinal arterial system in the rat shows a high level of F-actin stress fibre (SF) staining. Peripheral border (PB) staining was present in the ECs of all vessels. Diffuse F-actin staining was observed in endothelial cytoplasm in capillaries, venules, and veins. EC nuclei became distinctly less elongated down the vascular tree. In diabetic rats at 5 weeks, at the capillary level the F-actin staining was more diffuse, and areas of F-actin loss were evident. Both dot-like and diffuse leakage was detected in retinal capillaries, and these leakage types were closely associated with the degree of F-actin changes. In diabetic rats at 28 weeks, there was an increased level of SF staining in the arterial system in addition to capillary F-actin changes. {Conclusions}: The EC F-actin cytoskeleton and nuclei shape retinal microvasculature of the normal rat change with location along the vascular tree. In the early stages of diabetes, there are changes to the F-actin cytoskeleton that are clearly associated with microvascular leakage. F-actin distribution could indicate important structural changes in the pathogenesis of diabetic retinopathy.

Omega-3 polyunsaturated fatty acids inhibit the accumulation of PAS-positive material in the myocardium of STZ-diabetic wistar rats

This study was conducted to investigate the effect of Omega-3 PUFA on streptozotocin (STZ)-induced diabetic cardiomyopathy in wistar rats. After 4 weeks of STZ (60 mg/kg, i.v.) administration, the diabetic animals were randomly divided into two groups: Diabetic control and Omega-3 PUFA treated diabetic rats. Omega-3 PUFA (0.5 ml/kg) was administered to the latter group for 10 weeks. Age matched normal rats served as Normal controls. During the study, plasma glucose, glycosylated hemoglobin, plasma cholesterol, LDL and HDL cholesterol, triglyerides were evaluated in all the groups. Omega-3 PUFA treatment did not normalise but instead blunted the effect of diabetes with regards to the above parameters significantly ( P<0.01). At the end of the experiment, morphometric and histochemical studies were performed on heart and myocardial enzyme markers were studied. In the diabetic control group, diabetic cardiomyopathy was characerised by elevated CPK (DC 110±8.85 vs. NC 39±5.83) and morphological changes in heart. Gravimetric ratios showed increased heart-to-body weight ratio in diabetic control over normal control group. (DC 3.38±0.05 vs. NC 2.48±0.03). Histochemical evidence showed increased accumulation of PAS-positive material in myocardial interstitium (++++). The Omega-3 PUFA treatment blunted all these adverse effects of diabetes on heart significantly ( P<0.001). However, further studies are warranted to elucidate the mechanism by which Omega-3 PUFA decreases the accumulation of PAS-positive material in diabetic myocardium.

Extracellular matrix maturation in the left ventricle of normal and diabetic swine

The main objective of this study is to determine the transmural distribution of extracellular matrix (ECM) collagen and maturation in non-diabetic and diabetic hearts. The Yucatan miniature swine heart ECM was analyzed in eight streptozotocin (STZ) induced diabetic pigs (Diabetic-Swine) and age matched normal control pigs (Nondiabetic-Swine). After 12 weeks of STZ induced diabetes, transmural biopsies were obtained from the left ventricular free wall divided into subendocardial, mid- and subepicardial layers. Collagen concentration and maturation were measured by RP-HPLC determination of hydroxyproline (Hyp) and content of hydroxylysylpyridinoline (HP) cross-links, respectively. Results showed a significant elevation in arterial glucose ( P<0.05) and reduction in arterial plasma insulin levels in the Diabetic-Swine. Hyp concentration was significantly greater ( P<0.05) in the subendocardial layers in both the Diabetic and Nondiabetic animals. The HP cross-link content was significantly greater (17%) in the Diabetic-swine subendocardial layer compared to Nondiabetic-Swine ( P<0.05), but not in other layers. In summary, the accumulation and/or increase in HP cross-link content in the Diabetic-Swine subendocardial layer suggests that myocardial fibrosis may be greater in this specific region.

Decreased sensory neuropeptide release from trachea of rats with streptozotocin-induced diabetes

We studied the release of somatostatin, calcitonin gene-related peptide (CGRP) and substance P in response to electrical field stimulation from isolated tracheas of rats following 4 weeks of streptozotocin (50 mg/kg i.v.)-induced diabetes. Field stimulation (40 V, 0.1 ms, 10 Hz for 120 s) increased the release of somatostatin, CGRP and substance P from the baseline 0.18±0.029, 0.17±0.027, and 1.77±0.086 to 0.51±0.022, 0.69±0.115, and 5.96±0.377 in control preparations and 0.31±0.081, 0.41±0.142, and 3.14±0.443 fmol/mg wet tissue weight in preparations from diabetic rats as measured by radioimmunoassay (control vs. diabetic P<0.01 for each). The results show a simultaneous decrease in release of the three sensory neuropeptides and an enhanced plasma somatostatin level in rats with streptozotocin-induced diabetes.

Properties of Alpha-1-Adrenergic Receptors in the Rat Prostate: Effect of Experimental Diabetes

We studied the effects of 8 weeks of streptozotocin (STZ)-induced diabetes on the density and the pharmacological properties of α₁-adrenoceptors in the rat prostate using receptor-binding experiments with [¹²⁵I]iodo-2[β-(4-hydroxyphenyl)-ethylaminomethyl]tetralone [¹²⁵I]HEAT. Saturation experiments showed the presence of specific [¹²⁵I]HEAT-binding sites in the control and diabetic rat prostate and that the induction of diabetes significantly decreased the density of [¹²⁵I]HEAT-binding sites in the rat prostate. [¹²⁵I]HEAT-binding sites in the prostate of both groups were inhibited by prazosin (nonselective), spiperone (α_1B-selective), WB4101 and 5-methylurapidil (α_1A-selective) and BMY7378 (α_1D-selective) with the following rank order of K_i values: prazosin < WB4101 < 5-methylurapidil < spiperone < BMY7378, indicating a similar pharmacological profile of α₁-adrenoceptor in the 2 groups.Comparing the K_i values of the rat prostate with those obtained from the rat submaxillary gland (α_1A), rat spleen (α_1B), rat vas deferens (α_1A + α_1B) and those reported for cloned α_1D, indicates the predominance of the α_1A + α_1B or the α_1A subtype in the rat prostate. The present study demonstrates that STZ-induced diabetes downregulates the expression of α₁-adrenoceptor in the rat prostate, without significantly affecting the receptor subtype specificity.

Effects of streptozotocin-induced diabetes on dopaminergic functioning in the rat: Analysis of yawning behavior

Apomorphine, a dopamine receptor agonist, causes yawning in rats. It has been suggested that the analysis of yawning behavior provides an index of dopamine autoreceptor function. Dopamine turnover in the substantia nigra of diabetic rats has been shown to be decreased following administration of amphetamine or apomorphine (17, 21). Yawning behavior after 4 weeks of streptozotocin (STZ)-induced diabetes in Wistar rats was significantly lowered when compared with their age-matched normal controls. Yawning behavior was not further diminished after an 8-week duration of diabetes mellitus; however, a significant recovery in yawning was seen by 20 weeks of diabetes. Yawning in rats after 20 weeks of STZ-induced diabetes mellitus is not significantly different from that seen in normal control rats. The results suggest that in STZ-induced diabetes of only 4 weeks duration a measurable change in the substrate for yawning has occured.

Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.

In the present study, we have measured protein kinase C (PKC) specific activities and total diacylglycerol (DAG) level in the aorta and heart of rats, which showed that after 2 weeks of streptozotocin (STZ)-induced diabetes, membranous PKC specific activity and total DAG content were increased significantly by 88% and 40% in the aorta and by 21% and 72% in the heart, respectively. Hyperglycemia was identified as being a causal factor since elevated glucose levels increased DAG levels in cultured aortic endothelial and smooth muscle cells. Analysis by immunoblotting revealed that only alpha and beta II PKC isoenzymes are detected in these two tissues and vascular cells among those studied. In STZ-induced diabetic rats, beta II isoenzyme is preferentially increased in both aorta and heart, whereas PKC alpha did not change significantly. The increases in membranous PKC specific activity and DAG level are observed in both spontaneous diabetes-prone diabetic BB rats as well as in STZ-induced diabetic BB and Sprague-Dawley rats, which persisted for up to 5 weeks. After 2 weeks of diabetes without treatment, the normalization of blood glucose levels for up to 3 weeks with islet cell transplants in STZ-induced diabetic BB rats reversed the biochemical changes only in the heart, but not in the aorta. These results suggest that PKC activity and DAG level may be persistently activated in the macrovascular tissues from diabetic animals and indicate a possible role for these biochemical parameters in the development of diabetic chronic vascular complications.

Tissue-specific differences in the levels of proglucagon-derived peptides in streptozotocin-induced diabetes.

The synthesis and secretion of proglucagon-derived peptides are regulated in a tissue-specific manner in pancreas, intestine, and brain. We have examined the plasma and tissue levels of these peptides during the first 3 weeks of streptozotocin (STZ)-induced diabetes in the rat. Plasma glucose levels were markedly elevated (P less than 0.0001) within 24 h of STZ administration. The plasma levels of glucagon-like immunoreactive (GLI) peptides were significantly elevated on days 8-22 of diabetes (P less than 0.05-0.001). Ileal GLI peptide concentrations rose in parallel with the plasma levels (r = 0.39; P less than 0.006) to 250% of control levels (P less than 0.001); however, pancreatic GLI peptide content increased only transiently on day 1 (P less than 0.05). No significant differences in the posttranslational processing of proglucagon in normal or diabetic rats could be detected. The increment in ileal GLI peptide content was not associated with increases in intestinal proglucagon mRNA transcripts. In contrast, pancreatic, but not intestinal, somatostatin mRNA levels were increased on day 22 of diabetes. Diabetic rats were found to have small but significant changes in GLI and immunoreactive glucagon peptide content of the hypothalamus and medulla oblongata (P less than 0.05). These observations suggest that STZ-induced diabetes may produce tissue-specific perturbations in the biosynthesis and secretion of the proglucagon-derived peptides.

Early microvascular pathology during hyperglycemia in bats.

The microvascular changes in the wing of bats, Myoitis lucifugus, were observed during 3 weeks of normal life and 5 weeks of streptozotocin induced hyperglycemia (300-400 mg/dl, plasma). During normal life, week-to-week variations in diameter and blood flow in the same set of vessels were minor. After hyperglycemia was induced, the major initial response was dilation of all microvessels except the smallest arterioles which constricted. The dilation phase was followed by progressive constriction of all vessels. Blood flow was near normal during the dilation phase, but flow gradually decreased as hyperglycemia continued and vasoconstriction occurred. The ability to repeatedly observe the same set of microvessels on a week-to-week basis and the absence of anesthesia may make the diabetic bat a useful model in which to study the early phases of microvascular pathology during chronic hyperglycemia, which begins abruptly in adult life. In addition, the sequence of microvascular changes during chronic hyperglycemia in the bat are qualitatively similar to those in other diabetic mammals, including man.