Hyperglycemic Animals Research Articles

Differential Neuropathies in Hyperglycemic and Hypoglycemic Diabetic Rats

We investigated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic BB/Wor rats. The animals were maintained in a hyper- or hypoglycemic state by treatment with insulin for 3 months. Nondiabetic siblings served as controls. Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. Degeneration was more common in the gastrocnemius nerve than in the sural nerve. In hypoglycemic rats, myelinated fibers in both the gastrocnemius and sural nerves had significantly shorter internodes and smaller diameters. The decreased fiber diameter was related (r = -0.9) to the duration of severe hypoglycemia (</=2.5 mmol/L). Myelinated fiber occupancy was also decreased without any significant changes in fiber counts in both the gastrocnemius and sural nerves. In hyperglycemic rats, myelinated fibers in the sural nerve but not the gastrocnemius nerve had smaller diameters compared with controls. We conclude that hypoglycemia has a more severe impact on somatic motor nerves than on somatic sensory nerves, whereas hyperglycemia affects only somatic sensory nerves.

Efeito da goma guar parcialmente hidrolisada no metabolismo de lipídeos e na aterogênese de camundongos

OBJETIVO: Observar os efeitos da goma guar parcialmente hidrolisada no metabolismo de colesterol e na formação de placa aterosclerótica em aorta de camundongos deficientes no receptor LDL, euglicêmicos ou com hiperglicemia induzida por estreptozotocina. MÉTODOS: Trinta e seis camundongos deficientes para o receptor de LDL foram divididos em quatro grupos de nove animais: grupos euglicêmicos, alimentados com dieta aterogênica padrão (controle euglicêmico) ou suplementada com 7,5% de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada euglicêmico) e grupos hiperglicêmicos alimentados com dieta aterogênica padrão (controle hiperglicêmico) ou suplementada com 7,5% de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada hiperglicêmico). Após quatro semanas de experimento foram medidos: ingestão alimentar, ganho de peso, glicemia, colesterol plasmático e hepático, assim como lesão aterosclerótica na aorta torácica e abdominal. RESULTADOS: Os resultados mostram que a suplementação de goma guar parcialmente hidrolisada levou ao aumento do colesterol hepático e plasmático em animais euglicêmicos, mas sem aumento na área de lesão aterosclerótica na aorta. Em animais hiperglicêmicos, a redução no colesterol plasmático não foi estatisticamente significante, mas no que se refere à lesão da aorta, observou-se redução significante. CONCLUSÃO: Os resultados sugerem que a goma guar parcialmente hidrolisada pode reduzir a aterosclerose associada ao Diabetes Mellitus tipo 1.

Expression and localization of MT1-MMP and furin in the glomerular wall of short- and long-term diabetic rats

Diabetic glomerulopathy has been linked to shifts in balance between the synthetic and degradative pathways of the glomerular basement membrane (GBM), a key player in the permselectivity properties of the glomerular wall. The goal of this study was to trace the expression and localization of membrane type-1 metalloprotease (MT1-MMP) and its activating enzyme furin, key proteins involved in basement membrane turnover, in short- and long-term diabetic rat renal tissues. Quantitative immunogold was carried out for MT1-MMP and furin and their expression was evaluated in renal tissues of young and old, control and diabetic rats. To corroborate immunocytochemical findings, Western blots were performed on glomerular lysates. Electron microscopy revealed that the overall expression of MT1-MMP and furin is reduced in plasma membranes of all glomerular cell types of old normoglycemic animals, a phenomenon that is exacerbated in long-term diabetic animals. This observation supports the prevailing theory that diabetes fosters acceleration in the aging process. Interestingly, while biochemical results confirmed a decrease in MT1-MMP expression, an increase in furin was observed. Immunocytochemical studies resolved this discrepancy by tracing the increased furin expression in endoplasmic reticulum and Golgi membranes of podocytes, indicating that furin is retained in the secretory pathway in a diabetic environment. Disturbances at the molecular level of the otherwise tightly regulated MT1-MMP/furin interactions found at the cell surface must account for a lack in extracellular matrix remodeling, increased deposition of GBM material, and loss of glomerular filtration integrity.

Effects of Hyperglycemia and Insulin Therapy on Outcome in a Hyperglycemic Septic Model of Critical Illness

The effects of hyperglycemia and insulin therapy on septic outcome have not been well studied. Septic hyperglycemia was induced by infusion of TPN (254 kcal/kg x d) immediately following cecal ligation and puncture (CLP) surgery in rats. Animals (N = 109) were monitored for blood glucose and followed for survival for 4 days. Separate cohorts (N = 36) were sacrificed at 22 hours post-CLP and analyzed for cytokines/chemokines, hormones, and organ damage markers. The effects of insulin treatment on 4 day survival were also examined (N = 60). Hyperglycemic septic animals had significantly higher blood glucose (p < 0.0001), plasma proinflammatory cytokine levels, serum organ damage markers (p < 0.05) and reduced mean survival time (p < 0.001). Insulin treatment (2 IU/kg/hr) resulted in significantly lower blood glucose (p < 0.01) and improved 4 day survival (p < 0.03). Hyperglycemia is associated with greater morbidity and mortality in sepsis. Insulin therapy significantly improved survival suggesting that management of hyperglycemia with insulin may improve outcome in septic patients.

Role of insulin in the progression of ovarian sex cord stromal tumors in rats

This study examined the effect of insulin on sex cord stromal tumors in the rat. Sex cord stromal tumors were induced by transplantation of ovaries under the splenic capsule of ovariectomized rats (Lewis-inbred). These tumors were then transplanted into new inbred rats. Hyperglycemic conditions were induced by treatment with streptozotocin (STZ, which selectively destroyed pancreatic islet cells) and hypoglycemic conditions by treatment with a subcutaneously implanted insulin pump (Alzet). The animals were killed 28, 56, and 84 days later. Tumor growth, animal weight, food and water consumption, and serum concentrations of glucose, FSH, LH, and estradiol were measured. Treatment with STZ and insulin with osmotic Alzet pumps induced continuous hypoglycemic and hyperglycemic conditions, respectively. No significant influence of the hypoglycemic or hyperglycemic status on tumor growth was measured during the first 28 and 56 days. Eighty-four days after transplantation and substitution of 1 or 2 IU/100 g body weight/d insulin, there was a significant stimulation of tumor growth (2.2-fold and 2.7-fold, respectively). In hyperglycemic animals (treated with STZ), no influence on tumor growth was found in comparison with the controls. This study confirms that hyperinsulinemic conditions contribute to the progression of tumors.

Hyperglycemia Induced by Pharmacological Activation of Central Serotonergic Pathways Depends on the Functional Integrity of Brain CRH System and 5-HT3 Receptors

In the present study, we investigated the effect of central serotonergic pathway activation achieved through third ventricle injections of quipazine, a serotonergic agonist, on plasma glucose levels of fasted and fed adult Wistar male rats, whose third ventricles were canulated 7 days before the experiments. Central quipazine administration induced a significant increase in plasma glucose levels in fasted animals, but was unable to modify plasma glucose concentrations in fed rats. Pretreatment with alpha-helical CRH, a CRH antagonist, significantly attenuated quipazine-induced hyperglycemia. Pretreatment with two different 5-HT3 receptor antagonists, LY-278,584 and ondansetron, was also able to produce a significant reduction in the hyperglycemic response evoked by central administration of quipazine. None of the antagonists used was capable of modifying plasma glucose concentrations when injected alone into the third ventricle. Quipazine-treated, hyperglycemic animals did not show any increase in plasma insulin levels. We conclude that acute pharmacological serotonergic stimulation by quipazine produces hyperglycemia by mechanisms that require the functional integrity of both CRH and 5-HT3 receptors, and that impairment in insulin secretion and/or activity may explain hyperglycemia induced by third ventricle injections of quipazine.

Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats

The aim of this study was to investigate whether hyperglycemia enhances the systemic inflammatory response and oxidative stress induced by endotoxin. Laboratory investigation. University medical school. Forty-one male Sprague-Dawley rats. A hyperglycemic condition was produced in rats by glucose clamp for 3 hrs. Immediately on stopping the glucose infusion, animals received different doses of endotoxin injection (0, 0.2, or 1 mg/kg), and then blood glucose concentration was monitored over the ensuing 2 hrs. At the end of 2 hrs, levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, corticosterone, and alpha-1 acid glycoprotein were determined in serum, and malondialdehyde and total glutathione content were determined in the liver. Over the 2-hr period, blood glucose concentrations returned to normal in initially hyperglycemic rats. However, the levels of cytokines, corticosterone, and alpha-1 acid glycoprotein were significantly higher in these animals compared with nonhyperglycemic controls, demonstrating an extended effect of prior hyperglycemia on markers of systemic inflammation. With low-dose (0.2 mg/kg) but not high-dose (1 mg/kg) endotoxin administration, hyperglycemic animals had significantly higher levels of cytokines compared with controls, indicating that prior hyperglycemia can enhance the systemic inflammatory response to a moderate endotoxin dose, but that the maximum effects of endotoxin on production of inflammatory cytokines are not altered by transient high glucose exposure. Systemic inflammation persists for a period following hyperglycemia, and this can enhance the systemic inflammatory response to a subsequent moderate stress.

Antioxidative and anti-inflammatory effects of repaglinide in plasma of diabetic animals

Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense, is considered to be an important pathogenic factor in diabetes mellitus and its complications. In diabetic state, ROS might also be implicated in promoting a state of systemic inflammation. Recently, it was demonstrated that antioxidant therapy could be used to stop the initiation and propagation of this inflammatory response. Repaglinide is a new oral antidiabetic agent with a possible antioxidant activity. Therefore, in the present study, a possible therapeutic value of repaglinide in ameliorating the oxidative and inflammatory processes was tested in diabetic animals. In the study, the levels of total antioxidant status (TAS), ascorbic acid (AA), protein carbonyl groups (PCG) and interleukin-6 (IL-6) were determined in plasma of diabetic rabbits after 4 and 8 weeks of repaglinide treatment (1 mg daily). Ex vivo analysis revealed that there were significant differences in these markers between hyperglycemic and control animals ( P < 0.05). Some of these parameters were ameliorated by repaglinide treatment. In diabetic rabbits treated with repaglinide, protein oxidation was diminished by 17.8% after 8 weeks of experiment. The level of AA in plasma of diabetic treated animals was higher than in non-treated diabetic groups (by 9.4 and 22.6% after 4 and 8 weeks, respectively). In diabetic treated animals, the TAS level was also significantly increased (by 23.6 and 16.7%). However, in diabetic rabbits, repaglinide did not affect the concentration of IL-6.

Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat

We investigated the effect of dehydroascorbic acid (DHA), the oxidized form of vitamin C which is a superoxide scavenger, on manganese superoxide dismutase (MnSOD), copper–zinc SOD (CuZnSOD), cyclooxygenase-2 (COX-2) and interleukin-1beta (IL-1β) expression in a rat model of focal cerebral ischemia under normo- and hyperglycemic conditions. Edema formation was also assessed. MnSOD, CuZnSOD, COX-2 and IL-1β mRNA and protein expression were studied 3 h post-ischemia. No changes were observed in MnSOD and CuZnSOD mRNA expression among the groups. COX-2 and IL-1β mRNA expression were upregulated by ischemia but were not influenced by the glycemic state. At the protein level, hyperglycemic cerebral ischemia increased MnSOD and CuZnSOD [Bémeur, C., Ste-Marie, L., Desjardins, P., Butterworth, R.F., Vachon, L., Montgomery, J., Hazell, A.S., 2004a. Expression of superoxide dismutase in hyperglycemic focal cerebral ischemia in the rat. Neurochem. Int. 45, 1167–1174] and IL-1β expression compared to normoglycemic ischemia. COX-2 protein expression was also significantly higher following hyperglycemic ischemia compared to hyperglycemic shams. DHA administration did not change the pattern of COX-2 or IL-1β mRNA expression, but normalized the increased protein expression following hyperglycemic ischemia. DHA administration also normalized MnSOD and CuZnSOD protein expression to the levels observed in normoglycemic ischemic animals. Edema formation was significantly reduced by DHA administration in hyperglycemic ischemic animals. The DHA-induced post-transcriptional normalization of MnSOD, CuZnSOD, COX-2 and IL-1β levels and the decreased edema formation suggest that hyperglycemia accelerates superoxide formation and the inflammatory response, thus contributing to early damage in hyperglycemic stroke and strategies to scavenge superoxide should be an important therapeutic avenue.

Cardiac Mitochondrial Alterations Observed in Hyperglycaemic Rats - What Can We Learn From Cell Biology?

Diabetes mellitus is one of the most common metabolic diseases in the world. The complications associated with this disease are often responsible for a decreased quality of life in many patients. For example, the diabetic population has a greater probability to suffer from cardiovascular problems and heart failure than the general population. Due to the importance heart mitochondria have in the context of the bioenergetics of the myocardium, it appears logical to explore mitochondrial dysfunction as an important link between hyperglycaemia and heart alterations observed during diabetes. One important factor that can lead to mitochondrial dysfunction is the mitochondrial permeability transition (MPT), caused by the formation of poly-protein pores (MPT pores), occurring with mitochondrial calcium overload and increased oxidative stress, conditions already described to exist in myocytes exposed to hyperglycaemia. The MPT has been involved as determinant in the survival of myocytes after anoxia and reoxigenation, as well as in triggering cell death. The present review deals with cardiac mitochondrial alterations observed in drug-induced hyperglycaemic animals or in the GK rat, a hereditary model of hyperglycaemia. Respiration rates, susceptibility to oxidative stress, protein expression and MPT induction are altered in hyperglycaemic animals, which in extreme conditions can alter the bioenergetics of the diabetic myocardium and even cause myocardial cell death. The study of the cardiac mitochondrial function of hyperglycaemic animals offer an important insight, not only to explain cardiac alterations found in diabetic patients, but also in the design of new therapeutic approaches to reduce mitochondrial dysfunction and cell death typically associated with diabetes.

Gymnemic Acids from Gymnema sylvestre. Potentially Regulates Dexamethasone-Induced Hyperglycemia in Mice

ABSTRACTEffects of three different doses (6.7, 13.4, and 26.8 mg/kg body wt., i.p.) of gymnemic acids (GA) from the leaves of Gymnema sylvestre. R. Br. in the regulation of dexamethasone induced hyperglycemia have been investigated in mice. Simultaneously, thyroid hormone levels were estimated by radioimmunoassay (RIA) in order to find out whether the effects are mediated through alteration in the thyroid function or not. While the prestandardized dose (1 mg/kg body wt., i.m.) of dexamethasone administration for 22 days increased the serum glucose concentration, it decreased serum concentration of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Although the administration of all three different doses of gymnemic acid decreased the serum glucose concentration in dexamethasone-induced hyperglycemic animals, the decrease was significant only in groups receiving the two higher doses, 13.4 and 26.8 mg/kg. These effects were comparable to a standard corticosteroid-inhibiting drug, ketoconazole. However, the percentage reduction was greater in the 13.4 and 26.8 mg/kg of gymnemic acids–treated groups (28.76% and 21.71% respectively) as compared to that of ketoconazole, where it was only 9.07%. As no significant changes in thyroid hormone concentrations were observed by the administration of any of the doses of GA in dexamethasone-treated animals, it further appears that the effects of the tested material might not have been mediated through alterations in the thyroid function. The changes in hepatic lipid peroxidation (LPO), superoxide dismutase (SOD), and catalase (CAT) activity revealed a toxic effect at the highest dose (26.8 mg/kg body wt.) as evidenced by increased LPO, whereas the medium dose (13.4 mg/kg body wt.) was found to be safe and antiperoxidative. It is suggested that 13.4 mg/kg of gymnemic acids may prove to be potentially effective in the amelioration of corticosteroid-induced diabetes mellitus/hyperglycemia.

Intraretinal pH in Diabetic Cats

Purpose: To examine intraretinal extracellular H+ concentration ([H+]O) in diabetic cats. Methods: Double-barreled H+-selective microelectrodes were used to measure [H+]O as a function of retinal depth ([H+]O profiles) in four cats with different stages of diabetic retinopathy. Profiles from “normal” and “damaged” areas of the retina were compared to profiles previously obtained from healthy cats. Results: In the healthy retina, [H+]O is generally highest in the middle of the retina and decreases toward the choroid and the vitreous. In 48% of the profiles from diabetic animals with visible retinopathy, the inner retinal gradient was reversed so that the vitreous was more acidic than the middle of the retina. The profiles with reversed inner retinal gradients were classified as damaged. On the average, the inner retina tended to be 0.07–0.08 pH units more acidic in diabetic animals than in healthy normoglycemic animals, but of similar acidity to healthy hyperglycemic animals. In areas with damaged inner retinal gradients, net H+ production in the outer retina was also impaired. Conclusions: While the number of animals is small, we conclude that the [H+]O distribution varied from normal to damaged in the same retina. Diabetes seems to lead to an acidification of the inner retina that appears to be at least partly related to hyperglycemia and which may be important in the progression of retinopathy.

Hyperglycemia does not alter state 3 respiration in cardiac mitochondria from type-I diabetic rats

Cardiovascular complications are the primary cause of death for diabetic patients. Clinically, the development of dysfunctional cardiomyopathy is one of the main complications of diabetes. Experimental evidence indicates that the mitochondrion is one of the main sites implicated in the development of cardiac dysfunction. Yet, the precise cause and mechanisms involved in the process are largely debated. We report here that heart mitochondria from streptozotocin-induced diabetic Sprague-Dawley rats present a gradual reduction in state 3 oxygen consumption that reaches 35% by the fourth week following diabetes onset. Rats presenting a level of hyperglycemia similar to diabetic animals, but not showing the marked weight loss or appearance of urinary ketones typical of the later group present no decline in state 3 mitochondrial oxygen consumption, the values being indistinguishable from those of mitochondria from control animals. Mitochondria from hyperglycemic non-ketotic rats, however, show a 15-20% increase in state 4 respiration, but only when glutamate is used as energetic substrate. Mitochondria from diabetic rats, instead, show a 40-50% increase in state 4 respiration with glutamate and 20-25% with succinate as energetic substrate. Interestingly, hyperglycemic non-ketotic animals present a level of serum insulin intermediate between those of controls and diabetic animals. These functional modifications are unrelated to the time elapsed since the onset of diabetes, as they are observed at 2, 4, 6 as well as 8 and 12 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats. Rather, they point to insulin level and subsequent metabolic alterations as a possible cause for the insurgence of mitochondrial dysfunction.

Effects of Experimental Diabetes on Endothelin-induced Ventricular Arrhythmias in Dogs

Endothelin-1 (ET-1) is known to have a direct arrhythmogenic effect in the mammalian heart. Diabetes mellitus is accompanied by a series of endothelial and cardiac disfunctions; however, little is known about ET-1-induced direct arrhythmias in diabetes mellitus. Therefore, we infused ET-1 (33 pmol/min) into the left anterior descending coronary artery of 28 mongrel dogs, and measured basic hemodynamic parameters, coronary flow and an electrocardiogram. Diabetes mellitus was induced by alloxan (Group 4) and experiments were carried out 8 weeks later. Metabolically healthy dogs served as controls (Group 2). In a further control group, local hyperglycemia was induced by intracoronary glucose infusion (Group 3). ET-1 infusion induced prolongation of the QT-time and frequency-adjusted QT-time in all groups. Other electrophysiological parameters were comparable between the groups. This was followed by the occurence of ventricular premature beats, coupled extra-beats and later sustained ventricular tachycardia. Most of the experiments were terminated by ventricular fibrillation. The onset of arrhythmias was shorter in diabetic dogs as compared with control and locally hyperglycemic animals (18 +/- 8 minutes versus 24 +/- 8 minutes and 30 +/- 28 minutes, P < 0.05). However, there was no difference in the number of ventricular fibrillations, and the total elapsed time until the termination of the experiments. Therefore, the diabetic heart seems to be more prone to ET-1-induced arrhythmias and this is probably not a result of locally high glucose concentrations.

Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes.

Heme oxygenase (HO)-1 represents a key defense mechanism against oxidative injury. Hyperglycemia produces oxidative stress and various perturbations of cell physiology. The effect of streptozotocin (STZ)-induced diabetes on aortic HO activity, heme content, the number of circulating endothelial cells, and urinary 8-epi-isoprostane PGF2alpha (8-Epi) levels in control rats and rats overexpressing or underexpressing HO-1 was measured. HO activity was decreased in hyperglycemic rats. Hyperglycemia increased urinary 8-Epi, and this increase was augmented in rats underexpressing HO-1 and diminished in rats overexpressing HO-1. The number of detached endothelial cells and O2- formation increased in diabetic rats and in hyperglycemic animals underexpressing HO-1 and decreased in diabetic animals overexpressing HO-1 compared with controls. These data demonstrate that HO-1 gene transfer in hyperglycemic rats brings about a reduction in O2- production and a decrease in endothelial cell sloughing. Upregulation of HO-1 decreases oxidant production and endothelial cell damage and shedding and may attenuate vascular complications in diabetes.

Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice.

Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-alpha is activated in the kidneys of hyperglycemic animals. We now used PKC-alpha(-/-) mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-alpha(-/-) mice. However, the development of albuminuria was almost absent in the diabetic PKC-alpha(-/-) mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-alpha(-/-) mice, compared with controls. We then asked whether transforming growth factor-beta1 (TGF-beta1) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-alpha-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-alpha(-/-) mice, whereas expression of TGF-beta1 was not affected by the lack of PKC-alpha. Our findings indicate that two important features of diabetic nephropathy-glomerular hypertrophy and albuminuria-are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC-alpha via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-alpha is a possible therapeutic target for the prevention of diabetic albuminuria.

Influence of platelet-derived growth factor on microcirculation during normal and impaired wound healing.

The aim of the current study was to evaluate the influence of platelet-derived growth factor (PDGF) on skin microcirculation during normal and impaired wound healing. Secondary healing wounds were created on the ears of hairless mice and treated once with 3 microg of PDGF-BB immediately after wound creation. Intravital fluorescence microscopy was used to quantify reepithelialization, revascularization, vessel diameters, vascular permeability, and leukocyte-endothelium interactions up to 24 days after wound creation. Microvascular perfusion was assessed by laser Doppler flowmetry. Wound healing was studied in normal (n = 15) and ischemic skin tissue (n = 15) as well as in mice (n = 17) rendered hyperglycemic by an intravenous injection of streptozotocin 7 days prior to wound creation. Treatment with PDGF accelerated reepithelialization and reduced the time for complete wound closure in ischemic skin from 14.9 +/- 2.5 (control) to 12.3 +/- 1.8 days (p < 0.03), and in hyperglycemic animals from 15.0 +/- 2.4 (control) to 12.0 +/- 3.0 days (p < 0.04). Revascularization of these wounds was also significantly enhanced after PDFG application. No other parameters were influenced by the treatment. Normal wound healing was not affected. This study confirms the positive influence of PDGF on wound healing under pathophysiological conditions. The effects in this model seem to be primarily due to the mitogenic potency of PDGF on keratinocytes and endothelial cells. A significant effect on leukocyte activation during the inflammatory process was not observed.

Effect of testosterone and endurance training on glycogen metabolism in skeletal muscle of chronic hyperglycaemic female rats

Objectives: To investigate in glycolytic and oxidative muscles of trained (nine weeks) and untrained hyperglycaemic female rats the effect of hyperandrogenicity and/or endurance training on energy metabolic properties. Methods: Glycogen...

Effects of the nitric oxide donor 3-morpholinosydnonimine (SIN-1) in focal cerebral ischemia dependent on intracellular brain pH.

A nitric oxide (NO) donor that has been successfully used in the treatment of myocardial infarction, 3-morpholinosydnonimine (SIN-1), may be a potential neuroprotective agent. Production of NO in brain microsomes is dependent on the pH. The purpose of this study was to determine the efficacy of SIN-1 and its dependence on pH in vivo during periods of focal cerebral ischemia. At 0.1 or 1 mg/kg, SIN-1 was administered to 54 Wistar rats 30 minutes before a 2-hour period of focal cerebral ischemia under moderate hypo-, normo-, and hyperglycemic conditions. Measurements of brain intracellular pH (pHi); regional cortical blood flow, and the redox state of nicotinamide adenine dinucleotide were obtained in three additional animals to confirm the effects of the serum glucose manipulations. The animals were killed at 72 hours after the ischemic period to obtain infarction volumes. Administration of SIN-1 significantly reduced infarction in normoglycemic animals and, to a lesser extent, in hyperglycemic animals, indicating that SIN-1 was less effective under hyperglycemic conditions. At either dose SIN-1 had no significant effect on infarction volume in moderately hypoglycemic animals because moderate hypoglycemia in itself significantly (p < 0.005) reduced infarction volume. The NO donor SIN-1 may be a useful intraoperative cerebral protective agent. Furthermore, it is hypothesized that a mechanism that could explain the published discrepancies regarding the effects of NO donors in vivo may be affected by differences in ischemic brain acidosis.

Is neuroprotective efficacy of nNOS inhibitor 7-NI dependent on ischemic intracellular pH?

The purpose of this study was to test the hypothesis that the efficacy of 7-nitroindazole (7-NI), a selective neuronal nitric oxide (NO) synthase (NOS) inhibitor, is pH dependent in vivo during focal cerebral ischemia. Wistar rats underwent 2 h of focal cerebral ischemia under 1% halothane anesthesia. 7-NI, 10 and 100 mg/kg in 0.1 ml/kg DMSO, was administered 30 min before occlusion. Ischemic brain acidosis was manipulated by altering serum glucose concentrations. Confirmation of the effects of these serum glucose manipulations on brain intracellular pH (pH(i)) was confirmed in a group of acute experiments utilizing umbelliferone fluorescence. The animals were euthanized at 72 h for histology. 7-NI significantly (P < 0.05) reduced infarction volume in both the normoglycemic by 93.3% and hyperglycemic animals by 27.5%. In the moderate hypoglycemic animals, the reduction in infarction volume did not reach significance because moderate hypoglycemia in itself dramatically reduced infarction volume. We hypothesize that a mechanism to explain the published discrepancies on the effects of neuronal NOS inhibitors in vivo may be due to the effects by differences in ischemic brain acidosis on the production of NO.