The islet enhancer vildagliptin: mechanisms of improved glucose metabolism

Vildagliptin is a potent, selective and reversible inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). GLP-1 and GIP are important for the maintenance of normal glucose homeostasis as they enhance the sensitivity of insulin (beta-cell) and glucagon (alpha-cell) secretion to glucose. The delicate balance that is achieved by the incretin hormones is disturbed in type 2 diabetes mellitus (T2DM). Mechanistic studies of vildagliptin performed to characterise the effects of DPP-4 inhibition on pancreatic islet function and glucose metabolism have found that vildagliptin produces dose-dependent reductions in DPP-4; these result in persistent levels of active GLP-1 and GIP in the circulation leading to improved beta-cell sensitivity to glucose and glucose-dependent insulin secretion, and improved alpha-cell sensitivity to glucose and reduction in inappropriate glucagon secretion. These islet effects in turn lead to a reduction of the inappropriate endogenous glucose production and glucose utilisation during meals, resulting in improved glucose tolerance, and to a reduction of the inappropriate endogenous glucose production during the postabsorptive period that contributes to a reduced fasting hyperglycaemia. These islet effects are associated with improved insulin sensitivity and reduced meal-related hypertriglyceridaemia. In contrast, the GLP-1 effect of significantly delaying gastric emptying was not evident with vildagliptin treatment. The metabolic benefits of vildagliptin observed in T2DM are also evident in subjects with impaired glucose tolerance. Hence, vildagliptin improves glucose metabolism mainly by improving islet function.     

Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats.

The combination of intravenous flucytosine (FC) in 0.9% saline (NaCl) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 +/- 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mg/kg/12 h) in 0.9% saline (15 ml/kg/12 h); group 3, 0.9% saline (15 ml/kg/12 h); and group 4, FC (150 mg/kg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in serum creatinine concentration (P of < 0.05). Groups 2, 3, and 4 sustained significantly less nephrotoxicity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of < 0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of < or = 0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results of this study suggest that FC has a small but significant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.     

Protective effects of incretin on atherosclerosis

Type 2 diabetes is a major risk factor for atherosclerotic disease. Thus, the one of the therapeutic goal is to prevent the progression of atherosclerosis in these patients. Recently, exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonist has direct beneficial effects on vascular cells such as endothelial cell, monocyte/macrophage and vascular smooth muscle cells independent of their glucose lowering effects. These data highlight the potential protective effects of GLP-1 on the progression of atherosclerosis. However, further experimental study is needed to clarify the mechanism of these effects on vascular cells with GLP-1 and large clinical trial is also required to assess whether GLP-1 could reduce the cardiovascular events in patients with type 2 diabetes.     

Acute and chronic effects of sulindac on renal function in chronic renal disease

The effects of oral sulindac on renal hemodynamics were studied in normal subjects, elderly persons with mild renal failure, and patients with chronic renal disease. Renal function was measured before dosing and 24 hours and 28 days after oral sulindac. Effective renal plasma flow was reduced in all subjects after 24 hours. Effective renal plasma flow and the glomerular filtration rate were not altered after 28 days in control subjects, whereas effective renal plasma flow, but not glomerular filtration rate, was lower after 1 month in subjects with renal disease. None of these changes are likely to be of major clinical significance.     

Acute cardiovascular effects of sibutramine in conscious rats

Sibutramine is a serotonin and norepinephrine reuptake inhibitor, used in the treatment of obesity. In this study, cardiovascular effects of sibutramine (0.9, 3, or 9 mg kg(-1) i.p.) were measured in conscious Sprague-Dawley rats, in the absence and presence of beta- and/or alpha-adrenoceptor antagonism (with propranolol and/or phentolamine, respectively). Sibutramine caused pressor and tachycardic effects, with celiac and mesenteric vasoconstrictions, and hyperemic hindquarters vasodilatation. Pretreatment with propranolol inhibited the tachycardic and hindquarters vasodilator effect of sibutramine, whereas phentolamine inhibited the pressor and vasoconstrictor effects of sibutramine. In the presence of phentolamine, sibutramine caused hyperemic mesenteric vasodilatation. In preconstricted, isolated, mesenteric vessels, sibutramine and its metabolites BTS 54505 (N-desmethylsibutramine) and BTS 54354 (N-didesmethylsibutramine) (10 microM) produced significant vasodilations. Neither sibutramine nor BTS 54505 enhanced vessel sensitivity to norepinephrine, whereas BTS 54 354 produced a significant leftward shift in the concentration-response curve to norepinephrine. Collectively, the results indicate that the overt cardiovascular effects of sibutramine involve alpha-adrenoceptor-mediated celiac and mesenteric vasoconstrictions, and beta-adrenoceptor-mediated hindquarters vasodilatation and tachycardia. The mesenteric vasodilator response to sibutramine, seen in the presence of phentolamine, may be a direct effect of the drug and/or its metabolites, on vessel tone. The cardiovascular effects of sibutramine in vivo may be secondary to inhibition of peripheral and/or central reuptake of monoamines by the metabolites BTS 54354 and/or BTS 54505. It remains to explain why BTS 54354, but not BTS 54505, enhanced norepinephrine sensitivity in vitro, because both metabolites are potent inhibitors of the norepinephrine transporter.     

Acute and chronic effects of synthetic atrial natriuretic factor on blood pressure and sodium excretion in spontaneously hypertensive rats

To assess possible roles of atrial natriuretic factor (ANF) in the regulation of blood pressure in spontaneously hypertensive rats (SHR), we performed two series of experiments. First, we studied acute hypotensive, natriuretic and diuretic effects of ANF in pentobarbital-anesthetized SHR and age-matched Wistar-Kyoto rats (WKY). A synthetic ANF of 25 amino acid residues was intravenously administered as a bolus at doses of 0.1, 1.0, 2.5 and 5.0 micrograms/kg. In SHR group, a significant decrease in mean arterial pressure (MAP) was observed at a dose of 1.0 micrograms/kg, and the decrease was dose-dependent. On the other hand, in WKY group, the hypotensive effect of ANF was not observed until a dose of 5.0 micrograms/kg. The diuretic and natriuretic effects of ANF were observed at a dose of 2.5 micrograms/kg in SHR and 5.0 micrograms/kg in WKY, respectively. Second, we also studied chronic effect of ANF on the development of hypertension in 6-week-old SHR. The SHRs, on regular diet or given 1% NaCl solution for drinking, were continuously infused into the jugular vein by osmotic minipumps with ANF (15, 75 and 150 micrograms/kg/day) or vehicle (physiological saline) as controls for up to 14 days. ANF at a dose of 150 micrograms/kg/day attenuated transiently the development of hypertension in the sodium-loaded SHR. However, the blood pressure returned to control levels by day 5. ANF at doses of 15 and 75 micrograms/kg/day did not affect the development of hypertension. In SHR on regular diet, ANF at a dose of 150 micrograms/kg/day did not affect the development of hypertension. In addition, ANF did not induce any significant changes in urine volume, fluid intake, and urinary excretion of sodium and potassium in SHR, whether they were sodium-loaded or not, when compared to those in vehicle-infused SHR. These results indicate that there may be a significant difference in the sensitivity to diuretic, natriuretic and hypotensive actions of ANF between SHR and WKY. Moreover, it is suggested that ANF may play significant roles by its vascular effect at the early stage of development of hypertension in sodium-loaded SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute renal effects of sulindac and indomethacin in chronic renal failure

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 +/- 7.9 to 30.3 +/- 6.3 ml/min) and increased serum levels of creatinine and beta 2-microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 +/- 18.7 to 85.5 +/- 9.7 mmol/24 hr after indomethacin and from 131.7 +/- 11.6 to 103.4 +/- 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 +/- 0.8 to 1.7 +/- 0.6 nmol/L/hr by sulindac and from 2.8 +/- 0.8 to 1.5 +/- 0.5 nmol/L/hr by indomethacin. Urinary N-acetyl-beta-glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.     

Acute effects of griseofulvin on the pharmacokinetics and pharmacodynamics of warfarin in rats

It has been reported that prothrombin time (PT), which is prolonged by warfarin, is reduced when patients on warfarin also take griseofulvin repeatedly. We investigated the cause of the drug interaction and the initial effects of griseofulvin on warfarin pharmacokinetics. Total cytochrome P-450, and the activities of aminopyrine N-demethylase, aniline p-hydroxylase and 7-ethoxycoumarin O-deethylase, after repeated administration of griseofulvin (100 mg/kg orally daily for 5 days) were examined. Acute effects of single doses of griseofulvin (100 mg/kg) on coagulation activity (prothrombin time) and warfarin pharmacokinetics after administration of warfarin were also studied. Repeated administration of griseofulvin induced warfarin-metabolizing enzymes. In contrast, a single administration of griseofulvin increased prothrombin time and serum warfarin concentrations. The activity of a warfarin-metabolizing enzyme (7-ethoxycoumarin O-deethylase) was reduced when griseofulvin was added to rat liver microsomes. The results suggest that reduced warfarin action after repeated administration of griseofulvin may be due to induction of warfarin-metabolizing enzymes, but that there is also an initial increase in warfarin action.     

Acute haemodynamic effects of losartan in anaesthetized cirrhotic rats

BACKGROUND: Portal hypertension in cirrhosis is the result of increased intrahepatic vascular resistance to portal outflow as well as increased portal tributary blood flow. The angiotensin II type 1 receptor antagonist losartan has been suggested as a portal pressure-lowering drug in patients with cirrhosis. AIM: To investigate the systemic and splanchnic haemodynamic effects of different doses of losartan. METHODS: In 35 anaesthetized rats with secondary biliary cirrhosis, 3, 10 or 30 mg of losartan kg(-1) or solvent were administered intravenously. Ten sham-operated rats served as controls. Mean arterial pressure and portal pressure were measured by catheters in the femoral artery or portal vein. Systemic and splanchnic haemodynamics and mesenterico-systemic shunt rate were determined by the coloured microsphere method. RESULTS: Losartan reduced portal pressure (sham: 9.1 +/- 0.4. cirrhosis: 19.3 +/- 1.1, after 3 mg kg(-1) of losartan 16.4 +/- 0.4, after 10 mg kg(-1) of losartan 15.6 +/- 0.6, after 30 mg kg(-1) of losartan 14.9 +/- 0.6 mmHg) without reducing portal sinusoidal resistance. However, in cirrhotic rats it reduced portal tributary blood flow (sham: 4.3 +/- 0.6. cirrhosis: 8.6 +/- 1.4, after 3 mg kg(-1) of losartan 3.8 +/- 0.7, after 10 mg kg(-1) of losartan 4.7 +/- 0.5, after 30 mg kg(-1) of losartan 5.9 +/- 0.9 mmHg). This was owing either to an increase in splanchnic vascular resistance at the 3 mg kg(-1) dose or to a reduction in the splanchnic perfusion-pressure gradient secondary to a reduction in mean arterial pressure at the 10 and 30 mg kg(-1) doses (mean arterial pressure: sham: 109.7 +/- 4.8. cirrhosis: 109.4 +/- 2.8, after 3 mg kg(-1) of losartan 99.7 +/- 2.9, after 10 mg kg(-1) of losartan 89.9 +/- 3.4, after 30 mg kg(-1) of losartan 81.0 +/- 2.9 mmHg). CONCLUSIONS: Low doses of losartan reduce portal hypertension by an increase in splanchnic vascular resistance without hypotensive side-effects on arterial pressure.     

Acute and chronic effects of xanthine oxidase on lung thorax-compliance in guinea pigs

Xanthine oxidase was given intratracheally in a single dose to guinea pigs. Lung compliance was measured after 4 h and 14 days respectively. Lung-thorax compliance was significantly lower compared with saline-treated controls both 4 h and 14 days after application of fluid. At 14 days there was a dose-related response between lung-thorax compliance and xanthine oxidase administered in the range 0–1.0 U. Superoxide dismutase (SOD) had a protective effect on xanthine oxidase action at 4 h, but not after 14 days. We suggest that the decreased lung-thorax compliance was caused by superoxide radicals, produced by the hypoxanthine-xanthine oxidase system, damaging lung tissue. We speculate that free oxygen radicals produced by the hypoxanthine-xanthine oxidase system could be an important contributory pathogenetic factor in producing both acute and chronic lung damage in, for instance, premature babies or adults, with respiratory distress syndrome.     

Acute and chronic morphine administration: effects of mixed-action opioids in rats and squirrel monkeys responding under a schedule of food presentation.

The effects of several opioid compounds were examined in rats and squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation. In rats, dose-effect curves were determined before and after acute pretreatment with 5.6 mg/kg of morphine 5 to 6 hr before the session, as well as during and after the termination of a chronic regimen in which rats received 30.0 mg/kg/day of morphine. In monkeys, dose-effect curves were determined before, during and after the termination of a chronic regimen in which monkeys received 6.0 mg/kg/day of morphine. In morphine-pretreated rats, dose-effect curves for the opioid antagonists naloxone, naltrexone and diprenorphine shifted to the left of those determined when rats were not morphine-pretreated; whereas those for the mu-opioid agonists morphine and I-methadone and mixed-action opioids nalorphine, nalbuphine, butorphanol, pentazocine and bremazocine were unaltered. During chronic morphine administration in rats, dose-effect curves for morphine and butorphanol shifted to the right; whereas the dose-effect curves for naloxone and nalorphine shifted to the left of those determined when rats were not treated with morphine. The effects of pentazocine, nalbuphine, bremazocine and the kappa-opioid agonist U50,488 were unaltered in morphine-maintained rats. In morphine-maintained monkeys, the dose-effect curves for morphine and I-methadone shifted to the right; whereas those for naloxone, nalorphine and nalbuphine shifted to the left of the prechronic dose-effect curves. Dose-effect curves for butorphanol, pentazocine and U50,488 were unaltered. Overall, these results suggest that the chronic morphine administration procedure can be used to distinguish opioid compounds based upon their relative mu agonist and antagonist activity.     

Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.     

Acute and chronic effects of exercise using an Exercycle in healthy, untrained adults

This study examined three factors related to exercise with an Exercycle, a motordriven upper and lower body exercise machine. We examined the effects of Exercycle training on peak oxygen consumption (VO2), peak heart rate, peak minute ventilation, and peak respiratory exchange ratio. We compared the physiologic responses to graded exercise between the Exercycle and a standard lower extremity (LE) cycle ergometer. We also compared the difference in training responses between male and female subjects. A 6-week cardiorespiratory training program was completed by 20 healthy untrained adults (9 male, 11 female), aged 18 to 53 years. Pretraining and posttraining testing was completed on the Exercycle and on an LE cycle ergometer using a graded protocol. Absolute peak VO2 improved by 14% for men and by 7% for women after training based on Exercycle testing and by 6% for both men and women based on LE cycle ergometer testing. The posttraining submaximal heart rates were lower at any given absolute peak VO2 level for the Exercycle but not for the LE cycle ergometer. Exercycle testing revealed a larger peak VO2 than did LE cycle ergometer testing for both genders. The Exercycle appears to be effective for promoting cardiorespiratory fitness in healthy, untrained adults. The authors found comparable submaximal physiologic responses to graded exercise between the Exercycle and the LE cycle ergometer.     

Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus

Acutely, morphine and D-ala2-D-leu-enkephalin (DADLE) inhibited adenylate cyclase in vitro in locus coeruleus (LC), dorsal raphe, frontal cortex and neostriatum and the inhibition by each agonist was blocked by the opiate-receptor antagonist naloxone. Although morphine was equally efficacious in the four brain regions examined (10-15% inhibition), DADLE inhibited cyclic AMP (cAMP) production to a greater extent in cortex and striatum (20-25% inhibition). Pertussis toxin treatment in vitro significantly reduced DADLE-inhibition of adenylate cyclase in all brain areas, indicating that this opiate response is mediated by a pertussis toxin-sensitive G-protein (i.e., Gi and/or Go). Chronic (in vivo) administration of morphine pellets for 5 days, treatment known to induce opiate tolerance and dependence, increased basal, GTP- and forskolin-stimulated adenylate cyclase in the LC, but not in the other three brain regions studied. DADLE was found to inhibit cAMP production in LC in vitro to the same extent in control and morphine-treated rats, suggesting a lack of opiate receptor tolerance. The morphine-induced increase in adenylate cyclase required chronic exposure to the opiate, as shorter treatment times, namely 2 hr and 1 day, failed to produce this effect. In fact, at 2 hr a small decrease in adenylate cyclase in the LC was observed that did not appear to be due to morphine being retained in the membrane fraction. Taken together, the findings of this study provide support for the view that changes in the cAMP system in the LC play a role in mediating acute opiate action as well as in underlying the development of opiate tolerance, dependence and/or withdrawal.     

4T超导恒定强磁场对大鼠的急性毒性作用

目的:探讨4T(40000Gs)导恒定磁场对大鼠是否具有急性毒性作用。超方法:实验于2004-03/09于中国科学院电工所超导国家重点实验室和深圳大学生命科学学院微生物基因工程深圳市重点实验室完成。选择成年健康SD大鼠130只,随机分为11组,实验大鼠分为连续处理24,48,72h3个剂量组(n=10),同时设立相应的3个对照组(n=10)。另针对磁场处理72h后,设立脱离磁场12h及1个月检测组(n=10),再设立脱离磁场作用1个月后实验大鼠一般生殖毒性实验组(n=20),并相应设立生殖毒性对照组(n=20)。采用中国科学院电工所研制的超导恒定强磁场,强度为4T。通过观察各组大鼠的一般情况、病理解剖、血液检查及生化指标检测、微核检测、染色体核型分析等,分析4T磁场对实验大鼠是否具有急性毒性作用;并且进一步观察磁场是否具有潜在或慢性生殖毒性。结果:130只大鼠全部进入结果分析,无脱失。①各组大鼠的一般情况及大体病理解剖、血常规检查指标:差异无显著性意义(F=3.14,P>0.05)。②各组大鼠微核实验中嗜多染红细胞在红细胞中所占比率:差异无显著意义(F=2.97P>0.05)。③各组大鼠均无染色体丢失、臂缺损,以及染色体带型变化。④大鼠的生殖毒性实验结果:生殖毒性组与生殖毒性对照组大鼠(雄性)精子畸形数量及形态比较,差异无显著性意义(F=2.62,P>0.05);生殖毒性组与生殖毒性对照组大鼠(雌性)受孕率、着床数、活胎数、死胎数、吸收胎数变化及胎仔雌雄比例、体质量、体长、尾长、囱门宽度比较,差异无显著性意义(F=2.15,P>0.05)。结论:4T超导恒定磁场对实验大鼠无急性毒性作用,目前临床所使用的磁疗强度远低于此,对于生物体是安全的。     

4T超导恒定强磁场对大鼠的急性毒性作用

目的：探讨4T（40000Gs）超导恒定磁场对大鼠是否具有急性毒性作用。方法：实验于2004-03／09于中国科学院电工所超导国家重点实验室和深圳大学生命科学学院微生物基因工程深圳市重点实验室完成。选择成年健康SD大鼠130只，随机分为11组，实验大鼠分为连续处理24，48，72h3个剂量组（n=10），同时设立相应的3个对照组（n=10）。另针对磁场处理72h后，设立脱离磁场12h及1个月检测组（n=10），再设立脱离磁场作用1个月后实验大鼠一般生殖毒性实验组（n=20），并相应设立生殖毒性对照组（n=20）。采用中国科学院电工所研制的超导恒定强磁场，强度为4T。通过观察各组大鼠的一般情况、病理解剖、血液检查及生化指标检测、微核检测、染色体核型分析等，分析4T磁场对实验大鼠是否具有急性毒性作用；并且进一步观察磁场是否具有潜在或慢性生殖毒性。结果：130只大鼠全部进入结果分析，无脱失。①各组大鼠的一般情况及大体病理解剖、血常规检查指标：差异无显著性意义（F=3．14，P〉0．05）。②各组大鼠微核实验中嗜多染红细胞在红细胞中所占比率：差异无显著意义（F=2．97，P〉0．05）。③各组大鼠均无染色体丢失、臂缺损以及染色体带型变化。④大鼠的生殖毒性实验结果：生殖毒性组与生殖毒性对照组大鼠（雄性）精子畸形数量及形态比较，差异无显著性意义（F=2．62，P〉0．05）；生殖毒性组与生殖毒性对照组大鼠（雌性）受孕率、着床数、活胎数、死胎数、吸收胎数变化及胎仔雌雄比例、体质量、体长、尾长、囱门宽度比较，差异无显著性意义（F=2．15，P〉0．05）。结论：4T超导恒定磁场对实验大鼠无急性毒性作用，目前临床所使用的磁疗强度远低于此，对于生物体是安全的。     

Acute effects of hyperglycemia and hyperinsulinemia on hepatic oxidative stress and the systemic inflammatory response in rats

OBJECTIVES: Intensive blood glucose control to a target value of 80-110 mg/dL has been shown to reduce morbidity and mortality in surgical intensive care unit patients. This was attributed predominantly to correction of hyperglycemia, based on multivariate regression analysis. However, the effects of glucose and insulin have not been independently evaluated. This study investigated the development of hepatic oxidative processes and systemic inflammatory response in rats with different levels of induced hyperglycemia and hyperinsulinemia. The effects of a modest increase in blood glucose following glucose infusion at a level adequate to meet energy requirements, hyperinsulinemia induced by a hyperinsulinemic euglycemic clamp with administered glucose in similar amounts, and marked hyperglycemia and hyperinsulinemia secondary to glucose infusion on hepatic oxidative stress and systemic inflammatory response in vivo were examined. DESIGN: Controlled laboratory study. SETTING: Medical school laboratory. SUBJECTS: Specific pathogen-free male Sprague-Dawley rats. INTERVENTIONS: Blood glucose was monitored over 3 hrs. At the end of study, the serum concentrations of insulin, tumor necrosis factor-alpha, interleukin-1, and alpha1 acid glycoprotein were determined. Malondialdehyde and total glutathione content were measured in the liver. MEASUREMENTS AND MAIN RESULTS: Glucose infusion adequate to provide energy requirements resulted in a modest increase in blood glucose (143+/-8 mg/dL) and hyperinsulinemia (45 microU/mL) and did not induce measurable hepatic oxidative stress or systemic inflammation. A hyperinsulinemic euglycemic clamp (insulin 112+/-9 microU/mL) resulted in evidence of increased oxidative processes in the liver but no change in hepatic antioxidant capacity or evidence of systemic inflammation. When hyperglycemia (approximately 350 mg/dL) and hyperinsulinemia (167+/-9 microU/mL) were induced by excess glucose infusion, rats manifested hepatic oxidative stress, antioxidant depletion, and a mild systemic inflammatory response. CONCLUSIONS: Hyperglycemia is a major cause of the systemic inflammatory response. Maintaining normal blood glucose, by avoiding overfeeding and providing insulin therapy when necessary, appears key to minimizing oxidative stress and systemic inflammation when intravenous nutrition is provided.