Diabetes-related changes in contractile responses of stomach fundus to endothelin-1 in streptozotocin-induced diabetic rats.

The contractile response of the stomach fundus to endothelin-1 (ET-1) was examined in streptozotocin (STZ)-induced diabetic rats. In STZ-diabetic rats (versus age-matched control rats) (a) ET-1 caused a longer-lasting contraction of stomach fundus strips, and (b) in the dose-response curve, the ET-1-induced contraction was significantly greater for a given concentration (3 x 10(-7) to 10(-7) M). Although repeated application of ET-1 led to desensitization, the desensitization was less pronounced in STZ-diabetic rats than in the controls. The density of the binding sites for [(125)I]-ET-1 was increased in the diabetic stomach fundus (versus the controls), but Kd values were similar between the two groups. The ET(B) receptor mRNA expression level was significantly increased in the diabetic stomach fundus. These results suggest that the diabetes-related enhancement of the ET-1-induced contraction of the stomach fundus may be due to an increase in the ET(B) receptor population.     

Effects of prolonged exendin-4 administration on entero-insular axis of normal and streptozotocin-induced diabetic rats

The effects of the glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (EX4) and antagonist EX4(9-39) EX4-A on entero-insular axis have been investigated in normoglycemic and streptozotocin (STZ)-induced diabetic rats. Rats were administered daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A for 7 days, and were decapitated 3 h after the last injection. In STZ-untreated rats, EX4 reduced body-weight (BW) gain and raised glycemia, and the effects were prevented by EX4-A; conversely, EX4 did not alter plasma concentrations of insulin, glucagon and leptin. STZ-treated rats displayed body and hematochemical alterations typical of experimental diabetes: decrease in BW and insulin blood level, coupled with normal glucagon plasma concentration and marked hyperglycemia. In diabetic rats, both EX4 and EX4-A decreased BW gain, thereby suggesting a mechanism at least in part independent of GLP-1 receptors. EX4 did not alter glucagon blood level, but decreased glycemia and raised insulin and leptin plasma levels. These effects were annulled by EX4-A, which indicates that they occur through the activation of GLP-1 receptors. Collectively, our findings add support to the view that EX4 can be considered an important therapeutical tool to improve glucose metabolism in diabetes.     

性别对L-精氨酸诱发的昆明小鼠慢性胰腺炎的影响

目的:通过比较雌雄小鼠L-精氨酸诱发的慢性胰腺炎(CP)程度的差异,探讨性别对CP模型形成的影响。方法:健康昆明小鼠雌雄各42只,分为雌性对照组、雌性CP组、雄性对照组和雄性CP组(对照组n=18,每时点6只;CP组n=24,每时点8只)。CP模型组小鼠腹腔注射20%L-精氨酸(3 g/kg,每周1次,每次2轮,间隔1 h)诱发CP。分别于造模后第2、4、6周处死动物,取小鼠胰腺组织,HE及Masson染色检测各组小鼠胰腺形态学改变及纤维化程度;免疫组织化学观察胰腺组织F4/80的阳性染色率;real-time PCR检测胰腺组织白细胞介素6(interleukin-6,IL-6)、α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)及纤维连接蛋白(fibronectin,FN)的mRNA表达;Western blot检测胰腺组织α-SMA及FN蛋白的表达。结果:20%L-精氨酸腹腔注射后的第2、4和6周,HE及Masson染色显示雌雄CP组胰腺组织均可见病理损伤,但是同一时点雌雄小鼠胰腺损伤程度存在明显差异,雄性小鼠胰腺病变程度明显较重;胰腺F4/80染色显示雄性小鼠胰腺F4/80的表达水平在造模后各时点均明显高于同一时点的雌性小鼠;造模后第2和4周胰腺IL-6的mRNA表达在雌雄CP组均有所升高,但是雄性组表达水平明显高于雌性组(P0.05)。造模后α-SMA和FN在mRNA水平和蛋白质水平均可见高表达,但雄性小鼠表达时点更早,水平更高(P0.05)。结论:采用腹腔注射20%L-精氨酸可成功复制小鼠CP模型,但复制的模型在雌雄小鼠存在病变程度差异。L-精氨酸诱导的CP模型在雄性小鼠成模更早、纤维化程度更明显,其原因可能与雄性小鼠对L-精氨酸更敏感,引发的炎症反应程度更明显有关。雄性小鼠更适合于复制CP动物模型。     

Effects of chronic prednisolone administration on plasma copper in rats with adjuvant arthritis.

Copper metabolism is known to be significantly affected by inflammation or by glucocorticoid administration. We have previously demonstrated that acute prednisolone administration induces a moderate but sustained increase in plasma copper in healthy rats while it induces a more pronounced but shorter increase in rats with adjuvant arthritis. In the present study we have investigated the effects of chronic prednisolone administration (around 0.65 mg/kg daily in food) in both healthy rats and rats with adjuvant arthritis at various stages of the disease. In healthy rats, a slight but significant increase of 11% was observed in plasma copper after 3 weeks of treatment. This modification was no longer apparent after 5 weeks of treatment. In arthritic rats, plasma copper was, as expected, higher than in healthy rats and reached a maximum 3 weeks after adjuvant injection. In prednisolone-treated arthritic rats, there was a sustained decrease in plasma copper starting after 2 weeks of treatment which could be correlated with an improvement of the clinical and biochemical signs of inflammation. In conclusion, chronic prednisolone treatment only slightly increases plasma copper in healthy rats while in arthritic rats plasma copper is dependent on the severity of the disease which is improved by the treatment.     

Effects of melatonin on streptozotocin-induced diabetic liver injury in rats

This study investigated the possible protective effects of melatonin as an antioxidant against streptozotocin (STZ)-induced diabetic liver injury in rats. Wistar rats were divided into four groups: untreated control (UC), melatonin-treated control (MC), untreated diabetic (UD), and melatonin-treated diabetic (MD). Experimental diabetes was induced by a single-dose (60 mg/kg, intraperitoneally (ip)) STZ injection, and melatonin was injected (200 microg/kg/day, ip) for 4 weeks. Upon light and electron microscopic examination, we observed that melatonin improved the morphological and histopathological changes of the liver caused by diabetes. Malondialdehyde levels in the liver homogenates of UD rats were higher than those of controls and were markedly reduced after melatonin treatment. Although no significant difference was observed with respect to antioxidant status, the superoxide dismutase activity tended to be higher in the UD rats than in the treated rats. Our findings showed that melatonin administration partially reduced liver injury in STZ-induced diabetic rats.     

Effects of insulin on food intake and plasma glucose level in fat-fed diabetic rats

Schedules of insulin treatment which reliably increased eating in fat-fed diabetic rats were studied for their effect on plasma glucose concentrations. An inverse correlation between intake and plasma glucose was observed in fat-fed diabetics given long-term treatment with protamine-zinc insulin (PZI); however changes in glucose did not account for the differential effect of insulin on food intakes in normal controls or normal and diabetic rats fed a low-fat food. A single injection of 1 U PZI which increased eating in fat-fed diabetics but not normal controls 17–23 hr later did not reduce glucose concentrations from hyperglycemic levels in diabetics during the same time period. Injections of regular insulin increased eating in fat-fed diabetic and normal rats in a comparable fashion, but did not reduce plasma glucose in diabetics as low as in normal animals. The results show that the effect of exogenously administered insulin on food intake in fat-fed diabetics is largely unrelated to changes in circulating glucose levels and suggest that metabolic consequences of insulin treatment other than hypoglycemia may underlie the effect of the hormone on feeding in these animals.     

Increased amyloid beta-peptide (1-40) level in brain of streptozotocin-induced diabetic rats

The aims of the study were to investigate whether the level of amyloid β-peptide (Aβ) (1–40) was increased in brain of diabetic rats and whether the increase was associated with dysfunction of P-glycoprotein at the blood–brain barrier. A diabetes-like condition was induced by single administration of 65 mg/kg streptozotocin via i.p. injection. Aβ (1–40) levels in brain of the diabetic rats were measured using an enzyme linked immunosorbent assay (ELISA) kit. The in vivo brain-to-blood efflux and blood-to-brain influx transport of [¹²⁵I]-labeled human amyloid-β-peptide (hAβ) (1–40) were measured using the brain efflux index and brain permeability coefficient-surface area product, respectively. [¹⁴C]inulin served as a reference compound. The results showed that Aβ (1–40) levels significantly increased in temporal cortex and hippocampus of the diabetic rats. The brain remaining percentage of [¹²⁵I]hAβ (1–40) in diabetic rats significantly increased at 30 min after intracerebral microinjection, accompanied by decrease of the brain efflux index. Pretreatment of P-glycoprotein inhibitors verapamil or cyclosporin A significantly increased the brain remaining percentage of [¹²⁵I]hAβ (1–40). The brain permeability coefficient-surface area product of [¹²⁵I]hAβ (1–40) was increased in diabetic rats, accompanied by increased Aβ (1–40) levels in plasma. The present study demonstrated that a diabetic state could increase Aβ (1–40) levels in brain, which might be explained, at least in part, by the decline in brain-to-blood efflux of Aβ (1–40) due to deficient cerebral P-glycoprotein function in diabetic rats.     

Investigations of the mechanism of the reduction of plasma glucose by cold-stress in streptozotocin-induced diabetic rats.

Exposure to a cold environment may increase the activity of the sympathetic nervous system inducing an elevation of plasma norepinephrine and may result in hyperglycemia. In the present study, we found that a hypoglycemic effect was produced in streptozotocin-induced diabetic rats after cold-exposure at 4 degrees C for 1 h. In addition to the blockade of this hypoglycemic effect by guanethidine (a ganglion-blocking agent) and prazosin (an alpha1-adrenoceptor antagonist), an increase of plasma norepinephrine was also observed in streptozotocin-induced diabetic rats receiving this cold-stress. Participation of sympathetic hyperactivity can thus be considered. Furthermore, naloxone, in a dose (0.5 mg/kg, i.p.) sufficient to block opioid receptors, reversed this hypoglycemia. Also, an increase of plasma beta-endorphin-like immunoreactivity was observed in streptozotocin-induced diabetic rats receiving this cold-stress. Intravenous injection of beta-endorphin into streptozotocin-induced diabetic rats produced a lowering of plasma glucose. Administration of methoxamine at a dose sufficient to activate the alpha1-adrenoceptors produced hypoglycemia and a similar increase of plasma beta-endorphin-like immunoreactivity in streptozotocin-induced diabetic rats. However, plasma beta-endorphin-like immunoreactivity level was not modified by similar treatment with methoxamine or cold-stress in normoglycemic rats. Therefore, beta-endorphin appears to be responsible for the induction of hypoglycemic effects in streptozotocin-induced diabetic rats after cold exposure which is different to the response in normal rats.     

Effects of chronic treatment with the spontaneous nitric oxide releaser FK409 on vascular responses in established streptozotocin-induced diabetic rat.

Experiments were designed to investigate the effects of chronic administration of an NO donor, (+/-)-(E)-ethyl-2-[(E)-ethylhydroxyimino]-5-nitro-3-hexeneamide (FK409), on the impairment of the acetylcholine-induced endothelium-dependent relaxations of the aorta, perfused mesenteric arterial bed and perfused kidney that seen in streptozotocin-induced diabetic rats. In aortic strips and in the perfused kidney, the decreased acetylcholine-induced relaxation seen in diabetes was restored to normal by chronic (daily for 4 weeks) administration of FK409 (20 mg/kg or 10 mg/kg, respectively). Acetylcholine increased the NOx (NO2- and NO3-) level in the perfusates from aortic strips, the perfused kidney and the perfused mesenteric arterial bed. These increases were significantly weaker for diabetic rats than for the controls. This effect of diabetes was ameliorated by chronic administration of FK409 (20 mg/kg) in aortic strips and perfused kidney, but not in the perfused mesenteric arterial bed. These results demonstrate that chronic administration of the novel NO releaser FK409 can improve diabetes-impaired endothelium-dependent vasodilatation in the rat aorta and perfused kidney.     

Alteration of the responses of gastric smooth muscle to endothelin in streptozotocin-induced diabetic rats.

Diabetic gastropathy is suggested to be the result of not only an autonomic neuropathy but also to disorder of the spontaneous rhythmic motility of the gastric smooth muscle. Attempts were made to investigate the alteration of the effects of endothelin-1 (ET-1), which is known to enhance the spontaneous activity of gastrointestinal smooth muscle, on gastric activity in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were prepared by the injection of Sprague-Dawley (SD) rats with STZ (i.p.). Isometric mechanical responses were recorded in isolated circular smooth muscle strips of the stomach antrum, to measure changes in the rhythmicity of the smooth muscle. ET-1 (10 nM) significantly elevated the resting tension and the frequency of spontaneous contraction, but did not alter the amplitude of the spontaneous oscillatory contractions in normal rats. In diabetic rats, ET-1 elevated the resting tension, and spontaneous contractions were increased in frequency, however they were decreased in amplitude. In normal rats, sarafotoxin S6c (S6c, 10 nM), a selective ET(B) receptor agonist, elevated the resting tension slightly and increased both the frequency and amplitude of the spontaneous contractions. However, S6c significantly elevated the resting tension alone in STZ-induced diabetic rats. Selective stimulation of endothelin type A (ET(A)) receptors with ET-1, in the presence of a selective antagonist of ET(B) receptors, produced similar responses in the gastric muscle of both normal and diabetic rats. These results indicate that ET-1 elevates the resting tension and increases the frequency of the spontaneous oscillatory contractions in both normal and STZ-induced diabetic rats, to a similar extent. However, the specific actions on ET(B) receptors were quite different between the two: the elevating actions on the resting tension were much greater in STZ-diabetic rats than in normal rats. The results suggested the facilitation of ET(B) receptor signaling in the antrum during the pathogenesis of diabetic gastropathy.     

Effects of physical and psychological stress on 5-HT2A receptor-mediated wet-dog shake responses in streptozotocin-induced diabetic rats

Several epidemiological and clinical studies have indicated that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. In the present studies, we examined the behavioral changes in streptozotocin-induced diabetic rats, and investigated the effects of physical and psychological stress on the hippocampal BDNF levels and on the serotonin 2A (5-HT(2A)) receptor-mediated wet-dog shake responses. The streptozotocin (60 mg/kg, i.p.)-induced diabetes had no significant effects on the immobility time in the forced swim test or on locomotor activity in the open-field test. Moreover, there was no significant difference in the wet-dog shake responses induced by DOI, a 5-HT(2A) receptor agonist, between nondiabetic and diabetic rats. Five-day exposure to physical (electric footshock) and psychological (non-footshock) stress had no significant effect on the hippocampal BDNF level in diabetic or nondiabetic rats. The 2 types of stress had no significant effect on the DOI-induced wet-dog shake responses in nondiabetic rats. In diabetic rats, the repeated exposure to physical stress markedly increased the DOI-induced wet-dog shake responses, but the repeated exposure to psychological stress had no effect. These results suggest that exposure to physical stress augmented the susceptibility to the wet-dog shake responses to 5-HT(2A) receptor stimulation in streptozotocin-induced diabetic rats.     

内皮素性大鼠门静脉高压模型的建立

目的： 建立内皮素-1(ET-1)引起门静脉压力升高的动物模型。方法: 正常雄性SD大鼠48只，随机分为生理盐水组、ET-1低剂量组(0.3 μg/kg)，ET-1中剂量组(1.0 μg/kg)和ET-1高剂量组(3.0 μg/kg)。生理盐水组大鼠经股静脉注入生理盐水，其余各组大鼠按相应剂量经股静脉注入ET-1溶液，观察门静脉压力和颈动脉压力的变化情况,并筛选出能使门静脉压力升高最适宜的剂量；另取15只大鼠随机分为对照组、ETAR阻断剂(BQ-123)组和ETBR阻断剂(BQ-788)组，实验开始前30 min经各组大鼠股静脉分别注入生理盐水、ETR阻断剂BQ-123(给药剂量为12.5 μg/kg)和BQ-788(给药剂量为15 μg/kg)，然后以选定的适宜剂量匀速注入ET-1溶液，观察各组大鼠门静脉压力变化。结果: 不同剂量的ET-1均能使门静脉压力升高，尤以高剂量组最为明显；而提前注入ETR阻断剂之后，再注入ET-1溶液门静脉压力虽然升高，但升高的幅度较小。结论: 成功创建了内皮素性大鼠门静脉高压模型，此模型可用于研究ET-1在PHT发病机制中的作用和药物对PHT时血中ET-1的影响。     

Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats

Previous studies have shown an association between diabetes mellitus and impairments in learning and memory. These deficits were partially reversed by the use of insulin. Due to the fact that exercise has positive effects on many physiological systems, including the central nervous system, the present study, evaluated the effects of treadmill running on spatial learning and memory in streptozotocin (STZ)-induced diabetic rats. The exercise program was treadmill running at 17 meters per minute (m/min) at 0° inclination for 40 minutes per day (min/day), 7 days/week, for 12 weeks. Experimental groups were: the control-rest, the control-exercise, the diabetes-rest and the diabetes-exercise. Spatial learning and memory was investigated by Morris water maze test in the rats after 12 weeks of diabetes induction and the exercise period. Our data showed that spatial learning and memory was significantly impaired in the diabetes-rest group with respect to the control-rest group. However, there were no differences between the other groups. The present results suggest that spatial learning and memory is affected under diabetic conditions and that treadmill running prevents these effects. The data correspond to the possibility that treadmill running is helpful in the prevention and alleviation of the cognitive decline in diabetes mellitus.     

Prolonged exendin-4 administration stimulates pituitary-adrenocortical axis of normal and streptozotocin-induced diabetic rats

Evidence is available that exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist acutely stimulates hypothalamo-pituitary-adrenal (HPA) axis in the rat. EX4 is a potent insulinotropic agent, which is currently under clinical trial for treatment of type 2 diabetes. Since diabetes is known to affect adrenal function, we investigated the effects of the prolonged administration of EX4 and/or the GLP-1R antagonist EX4(9-39) (EX4-A) (daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A, for 7 days) on the HPA axis of normoglycemic and streptozotocin (STZ)-induced diabetic rats. In STZ-untreated rats, chronic EX4 treatment did not change the blood level of ACTH. In contrast, it evoked a marked rise in the plasma concentrations of aldosterone and corticosterone, these effects being reversed by EX4-A. In STZ-induced diabetic rats, prolonged EX4 administration increased the plasma levels of ACTH, aldosterone and corticosterone. EX4-A did not prevent the first two effects of EX4, and annulled the latter one. These findings allow us to draw the following conclusions: i) EX4 prolonged exposure desensitizes hypothalamo-hypophyseal GLP-1R in normal rats, and exerts an ACTH-independent GLP-1R-mediated aldosterone and corticosterone secretagogue effect; and ii) experimental diabetes induces the expression of EX4 receptors other than the classic GLP-1R, whose activation mediate the ACTH and aldosterone, but not corticosterone, secretagogue effects. Our study provides evidence that metabolic dysregulations occurring in STZ-induced diabetic rats are able to profoundly affect the response of the HPA axis to GLP-1.     

Pinacidil对低氧性肺动脉高压大鼠肺动脉压和血浆内皮素-1的影响

目的：探讨钾通道开放剂pinacidil对低氧性肺动脉高压（HPH）及对血浆内皮素-1（ET-1）含量的影响。方法：将45只雄性Wistar大鼠分为3组：①对照组;②低氧组,每天低氧8 h,共4周;③治疗组,每天低氧前半小时腹腔注射pinacidil 3 mg/kg,共4周,4周后观察3组平均肺动脉压（mPAP）,右心室肥厚指标、血浆中ET-1的水平。结果：低氧组大鼠mPAP明显高于对照组。右心室肥厚显著,血浆中ET-1含量明显高于对照组;治疗组mPAP明显低于低氧组,右心室肥厚轻于低氧组,血浆中ET-1含量明显低于低氧组。结论：pinacidil能有效降低HPH中肺动脉压力、阻抑右心室肥厚,并影响血浆中ET-1的水平。     

Effects of Nigella sativa on oxidative stress and beta-cell damage in streptozotocin-induced diabetic rats

The aim of the present study was to evaluate the possible protective effects of Nigella sativa L. (NS) against beta-cell damage from streptozotocin (STZ)-induced diabetes in rats. STZ was injected intraperitoneally at a single dose of 50 mg/kg to induce diabetes. NS (0.2 ml/kg/day, i.p.) was injected for 3 days prior to STZ administration, and these injections were continued throughout the 4-week study. Oxidative stress is believed to play a role in the pathogenesis of diabetes mellitus (DM). To assess changes in the cellular antioxidant defense system, we measured the activities of antioxidant enzymes (such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase (CAT)) in pancreatic homogenates. We also measured serum nitric oxide (NO) and erythrocyte and pancreatic tissue malondialdehyde (MDA) levels, a marker of lipid peroxidation, to determine whether there is an imbalance between oxidant and antioxidant status. Pancreatic beta-cells were examined by immunohistochemical methods. STZ induced a significant increase in lipid peroxidation and serum NO concentrations, and decreased antioxidant enzyme activity. NS treatment has been shown to provide a protective effect by decreasing lipid peroxidation and serum NO, and increasing antioxidant enzyme activity. Islet cell degeneration and weak insulin immunohistochemical staining was observed in rats with STZ-induced diabetes. Increased intensity of staining for insulin, and preservation of beta-cell numbers were apparent in the NS-treated diabetic rats. These findings suggest that NS treatment exerts a therapeutic protective effect in diabetes by decreasing oxidative stress and preserving pancreatic beta-cell integrity. Consequently, NS may be clinically useful for protecting beta-cells against oxidative stress.     

Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts in streptozotocin-induced diabetic rats

Diabetes induces osteopenia, which is characterized by a deficiency of osteoid and decreased activity of osteoblasts. We recently found that tetracyclines prevent the loss of osteoid and bone matrix and the degeneration of osteoblasts in diabetic rats by a mechanism independent of their antimicrobial efficacy. However, bone remodeling requires the activity of osteoclasts as well as osteoblasts. To determine the in vivo effects of tetracycline on osteoclasts in long bones, either a tetracycline (minocycline, TC) or its chemically modified non-antibiotic analogue (CMT), 4-de-dimethylaminotetracycline, was administrated daily to streptozotocin-induced diabetic rats by oral intubation. After 21 days, the rats were perfusion-fixed with a mixture of formaldehyde and glutaraldehyde, and the humeri were dissected and processed for ultracytochemical demonstration of acid trimetaphosphatase (ACPase) activity. In untreated non-diabetic (control) rats, the osteoclasts at the zone of provisional ossification exhibited abundant mitochondria and cisterns of rough endoplasmic reticulum (RER) throughout the cytoplasm, prominent stacks of Golgi membranes, and lysosomes in the perinuclear cytoplasm, and numerous various pale vacuoles in the cytoplasmic area adjacent to well-developed ruffled border. Intense ACPase activity was observed in the Golgi saccules, lysosomes, pale vacuoles, and the extracellular canals of ruffled border. The reaction products were also noted along the resorbing bone surfaces associated with the osteoclast ruffled border. The osteoclasts in the untreated diabetic rats showed a cytoplasmic organization similar to that of the non-diabetic control rats, but showed little or no ruffled border which was replaced by a broad clear zone in some of these cells. However, most of the osteoclasts on bone matrix in the diabetics were devoid of both a ruffled border and a clear zone. ACPase activity was detected in the osteoclast cytoplasm of diabetic rat, as in the controls, but to a much lesser extent along the broad clear zone facing the resorbing bone surfaces. The osteoclasts in TC-treated diabetic rats possessed both a clear zone and a small ruffled border. However, in some cases, they lacked both structures reminiscent of the untreated diabetic cells. The osteoclasts of CMT-treated diabetic rats exhibited structural and enzymatic features essentially identical to those of the non-diabetic control rats. These results suggest that the diabetes-induced osteopenia results, at least in part, from degeneration of osteoclasts (as well as atrophic osteoblasts) and that tetracyclines may be effective in preventing these abnormalities by a mechanism not dependent on the drugs' antimicrobial properties.     

Effects of chronic oral nickel chloride administration on glycaemia and renal function in normal and diabetic rats

Effects of nickel on glycaemia are conflicting. We have investigated the effects of oral administration of nickel chloride for 5 weeks on glycaemia and renal function in normal and streptozotocin-diabetic rats. The results show increase (P< 0.05) in plasma glucose and sodium and decrease (P< 0.05) in insulin concentrations only in normal experiment by comparison with normal control. Plasma potassium concentration was elevated (P< 0.05) only in diabetic experiment by comparison with diabetic control. Plasma urea levels were raised (P< 0.05) in both groups of experiments by comparison with respective controls and plasma creatinine level was elevated (P< 0.05) only in diabetic experiment. GFR was reduced (P< 0.05) only in normal experiment by comparison with control. Kidney weights in normal and diabetics were not effected by nickel chloride administration. Total food and water intakes in normal and diabetic experiments were lower by comparison with respective controls. These were accompanied by failure to increase body weights. In addition, total urine volume and sodium were reduced in normal and diabetic experiments. Urine potassium was lower only in normal experiment by comparison with normal control. We conclude that chronic nickel chloride administration induces hyperglycemia possibly through reduction in blood insulin levels and could be toxic to renal function.     

The acute effects of insulin on the cardiorespiratory responses to hypoxia in streptozotocin-induced diabetic rats

AIMS: We examined whether or not streptozotocin (STZ)-induced diabetic rats, which have a lower heart rate (HR, beats min(-1)) than control rats, could maintain hypoxic ventilatory response. METHODS: Twenty-six Wistar rats, which had been injected with STZ (60 mg kg(-1), EXP) or vehicle (0.1 m citrate buffer, CONT) intraperitoneally at 9 weeks of age, had their cardiorespiratory responses to normoxia and 12%O(2) examined after 5 weeks. RESULTS: Compared with CONT rats, EXP rats had a higher blood glucose [24 +/- 3 vs. 5 +/- 1 (mean +/- SD) mmol L(-1)], a lower body weight (320 +/- 23 vs. 432 +/- 24 g), lower HR (303 +/- 49 vs. 380 +/- 44 in normoxia, and 343 +/- 56 vs. 443 +/- 60 in hypoxia) and a lower mean arterial blood pressure (MAP) (89 +/- 6 vs. 102 +/- 10 mmHg in hypoxia). In contrast, both groups had similar values in ventilation (V(E)), V(E)-metabolic rate (MR) ratio and arterial blood gases (ABGs). In EXP rats, with an acute insulin supplement (i.v., 0.75 U h(-1) for 1.5-2 h), not only blood glucose, but also HR, and MAP were normalized as those obtained in CONT rats, and in hypoxia further increased without affecting V(E)-MR ratio and ABGs. Such acute cardiorespiratory stimulating effects of insulin could not be obtained in non-diabetic rats (n = 7, 355 +/- 24 g), in which euglycaemia (mean 6.4 mmol L(-1)) was maintained during the measurements. CONCLUSIONS: Our results suggest that, in STZ-induced diabetic rats: (1) ventilation is hardly suppressed by hyperglycaemia, (2) cardiorespiratory responses can be acutely stimulated by short insulin injection, and (3) the effects, including those through acute blood glucose normalization, are possibly specific for the diabetic impairments.     

Effects of treadmill exercise on hypoactivity of the hypothalamo-pituitary-adrenal axis induced by chronic administration of corticosterone in rats

The stress response alters behavior, autonomic function and secretion of multiple hormones, including CRF, ACTH, and glucocorticoid, through the HPA axis. Consecutive stress exposures lead to HPA axis dysregulation such as hyperactivity in Alzheimer's disease and depression, and hypoactivity in post-traumatic stress disorder. In the present study, we established a model of hypoactivated HPA axis in rat through chronic administration of corticosterone (40 mg/kg, s.c.) for 19 consecutive days. In this model, CRF mRNA expression in the hypothalamus and ACTH levels in serum were significantly decreased by chronic administration of corticosterone. In addition, the effect of treadmill exercise was investigated in our hypoactivated HPA axis rat model. Treadmill exercise recovered the dysregulated hypoactivity of the HPA axis induced by corticosterone administration for 19 days. The results of the present study suggest that treadmill exercise may aid recovery of hypoactivated HPA axis dysregulation in psychological diseases such as post-traumatic stress disorder.