Pharmacological responses to acute morphine administration in normotensive Wistar-Kyoto and spontaneously hypertensive rats

The effect of acute administration of morphine on analgesia, hyperthermia, hypothermia and catalepsy was determined in spontaneously hypertensive (SH) rats and normotensive Wistar-Kyoto (WKY) rats. A greater analgesic and hyperthermic response to morphine was observed in SH rats than in WKY rats. A dose of morphine (50 mg/kg ip) which produced hypothermia in WKY rats produced pronounced hyperthermia in SH rats. The cataleptic response to morphine was lower in SH rats. The cataleptic response to morphine was lower in SH rats than in WKY rats. The brain and plasma levels of morphine in SH rats were significantly lower as compared to the WKY rats at any dose of morphine used but the ratio of brain to plasma did not differ. It is concluded that SH rats exhibit altered sensitivity to morphine in comparison with their normotensive counterparts.     

Effects of thyroid state and fasting on the concentrations of CoA and malonyl-CoA in rat liver

Liver CoA is markedly higher in hyperthyroid rats as compared to hypothyroid rats, and in fasted rats as compared to fed rats. In hyperthyroid rats the CoA is increased mainly in the cytosol, while in fasted rats the increase is mainly in the mitochondria. Malonyl-CoA is markedly higher in hypothyroid rats than in euthyroid and hyperthyroid rats. With fasting, malonyl-CoA drops 80-85% in all thyroid states. These findings are discussed in relation to the regulation of fatty acid oxidation in the liver.     

The effect of acetoacetate on plasma insulin concentration

1. Sodium acetoacetate was infused into the inferior vena cava of fed rats, 48h-starved rats, and fed streptozotocin-diabetic rats treated with insulin. Arterial blood was obtained from a femoral artery catheter. 2. Acetoacetate infusion caused a fall in blood glucose concentration in fed rats from 6.16 to 5.11mm in 1h, whereas no change occurred in starved or fed-diabetic rats. 3. Plasma free fatty acids decreased within 10min, from 0.82 to 0.64mequiv./l in fed rats, 1.16 to 0.79mequiv./l in starved rats and 0.83 to 0.65mequiv./l in fed-diabetic rats. 4. At 10min the plasma concentration rose from 20 to 49.9muunits/ml in fed unanaesthetized rats and from 6.4 to 18.5muunits/ml in starved rats. There was no change in insulin concentration in the diabetic rats. 5. Nembutal-anaesthetized fed rats had a more marked increase in plasma insulin concentration, from 30 to 101muunits/ml within 10min. 6. A fall in blood glucose concentration in fed rats and a decrease in free fatty acids in both fed and starved rats is to be expected as a consequence of the increase in plasma insulin. 7. The fall in the concentration of free fatty acids in diabetic rats may be due to a direct effect of ketone bodies on adipose tissue. A similar effect on free fatty acids could also be operative in normal fed or starved rats.     

Molecular basis of renal handling of calcium in response to thyroid hormone status of rat

We investigated the effect of thyroid hormone status on renal handing of Ca2+. Further, like kinetics of Ca2+ transport across brush-border membrane (BBM) and basolateral membrane (BLM) of renal epithelial cells was carried out. FE(Ca) was decreased in hyperthyroid (Hyper-T) rats and increased in hypothyroid (Hypo-T) rats as compared to euthyroid (Eu-T) rats. Ca2+ uptake into renal brush-border membrane vesicles (BBMV) was increased in Hyper-T rats and decreased in Hypo-T rats as compared to Eu-T rats. K(m) was lower in Hyper-T rats and higher in Hypo-T rats as compared to Eu-T rats whereas, V(max) remained unaltered. The transition temperature for calcium uptake varied inversely with the thyroid hormone status. Renal BBM of Hyper-T rats showed decreased anisotropy and polarisation of DPH as compared to EU-T rats whereas these values were increased in Hypo-T rats. Thus, the altered BBM fluidity appears to modulate Ca2+ transport across BBM. Na+/Ca2+ exchange activity of renal cells was increased in Hyper-T and decreased in Hypo-T rats as compared to Eu-T rats. V(max) for Na+/Ca2+ exchange was increased in Hyper-T rats and deceased in Hypo-T rats as compared to Eu-T rats, whereas, [Na+](0.5) was similar in all three groups. The c-AMP levels of renal cortex of Hyper-T rats was increased and that of Hypo-T rats decreased as compared to Eu-T rats. Thus, thyroid hormones increased Ca2+ reabsorption in the kidney of rat. Thyroid hormone-mediated modulation of BBM fluidity appears to stimulate Ca2+ uptake into renal BBMV. Thyroid hormones possibly activated the Na+/Ca2+ exchanger through cAMP-dependent pathway.     

COX-2-Derived Prostanoids and Oxidative Stress Additionally Reduce Endothelium-Mediated Relaxation in Old Type 2 Diabetic Rats

Endothelial dysfunction in resistance arteries alters end organ perfusion in type 2 diabetes. Superoxides and cyclooxygenase-2 (COX-2) derivatives have been shown separately to alter endothelium-mediated relaxation in aging and diabetes but their role in the alteration of vascular tone in old diabetic subjects is not clear, especially in resistance arteries. Consequently, we investigated the role of superoxide and COX-2-derivatives on endothelium-dependent relaxation in 3 and 12 month-old Zucker diabetic fatty (ZDF) and lean (LZ) rats. Mesenteric resistance arteries were isolated and vascular tone was investigated using wire-myography. Endothelium (acetylcholine)-dependent relaxation was lower in ZDF than in LZ rats (60 versus 84% maximal relaxation in young rats and 41 versus 69% in old rats). Blocking NO production with L-NAME was less efficient in old than in young rats. L-NAME had no effect in old ZDF rats although eNOS expression level in old ZDF rats was similar to that in old LZ rats. Superoxide level and NADPH-oxidase subunits (p67phox and gp91phox) expression level were greater in ZDF than in LZ rats and were further increased by aging in ZDF rats. In young ZDF rats reducing superoxide level with tempol restored acetylcholine-dependent relaxation to the level of LZ rats. In old ZDF rats tempol improved acetylcholine-dependent relaxation without increasing it to the level of LZ rats. COX-2 (immunolabelling and Western-blot) was present in arteries of ZDF rats and absent in LZ rats. In old ZDF rats arterial COX-2 level was higher than in young ZDF rats. COX-2 blockade with NS398 restored in part acetylcholine-dependent relaxation in arteries of old ZDF rats and the combination of tempol and NS398 fully restored relaxation in control (LZ rats) level. Accordingly, superoxide production and COX-2 derivatives together reduced endothelium-dependent relaxation in old ZDF rats whereas superoxides alone attenuated relaxation in young ZDF or old LZ rats.     

Atorvastatin reduces the plasma lipids and oxidative stress but did not reverse the inhibition of prostacyclin generation by aortas in streptozotocin diabetic rats

The effect of atorvastatin (Lipitor) on diabetes-induced changes in plasma lipids, oxidative stress and the ability of aortic tissues to generate prostacyclin was studied in streptozotocin diabetic rats. In diabetic rats, plasma total cholesterol, triglycerides and serum glucose significantly increased compared to nondiabetic rats. Atorvastatin administration to diabetic rats did not affect hyperglycemia but significantly reduced plasma total cholesterol and triglycerides compared to diabetic rats. The oxidative stress markers urinary isoprostane, liver thiobarbituric acid reactive substances (TBARS) and plasma protein carbonyl content significantly increased in diabetic rats compared to nondiabetic rats. Atorvastatin admnistration to diabetic rats significantly reduced oxidative stress levels compared to diabetic rats, but urinary isoprostane and liver TBARS remained significantly higher than nondiabetic rats. Prostacyclin (PGI(2)) generation by aortic tissues significantly decreased in diabetic rats compared to nondiabetic rats. Atorvastatin administration to diabetic rats did not reverse that inhibition. These results were discussed in the light of the possible effects of hyperglycemia and statins on NAD(P)H-oxidase and cyclooxygenase-2 activities and the genetic difference between rats and other mammals regarding the level of vascular superoxide dismutase (SOD) activity.     

Vasopressin, corticosterone levels, and gastric ulcers during food-restriction stress.

Corticosterone levels and ulcers were compared in vasopressin-containing (LE) and vasopressin-deficient (DI) rats under ad lib and food-restricted conditions. In the ad lib situation, DI and LE rats had similar corticosterone levels and no ulcers. After 1 day of food restriction, the corticosterone levels were elevated in DI and LE rats, with a significantly higher level in LE rats. No ulcers were present in either strain. After 2 days of food restriction, the corticosterone levels were similar in DI and LE rats. The level in DI rats was comparable to that of the preceding day, but the level in LE animals dropped significantly from the previous day. Significant ulceration was evident in DI rats, but absent in LE rats. Following 3 days of food restriction, the corticosterone level in LE rats had returned to the ad lib level, whereas, for DI rats, an elevated level was maintained. There were no ulcers in LE rats, but they were present in DI rats. Thus LE and DI rats responded differently to the stress of food restriction. The mechanism underlying the response is most likely related to changes in the hypothalamic-pituitary-adrenocortical axis and its reaction to stress.     

Rats habituated to chronic feeding restriction show a smaller increase in olfactory bulb reactivity compared to newly fasted rats

During the 1970s, the multiunit reactivity of the olfactory bulb to food odor was extensively shown to increase before their usual meal in rats habituated to having a single 2 h daily meal compared to the same rats recorded after their usual meal. More recently, we reported dramatic modifications of mitral cell single-unit reactivity in adult rats following a simple a manipulation of the olfactory environment--exposure to an odor. The present study aimed at testing the hypothesis that a simple behavioral change such as habituation to chronic food restriction may induce profound changes in olfactory bulb responsiveness compared to occasional fasting. We compared mitral cell reactivity in non-fasted rats, in rats fasted during 22 h for the very first time, and in rats habituated during 15 days to a chronic 22 h food restriction. Mitral cell single-unit reactivity was found to increase less in rats habituated to fasting than in newly fasted rats. Indeed, the proportion of mitral cell responses to food and non-food odors was significantly higher in rats habituated to fasting than in non-fasted rats, but lower than in newly fasted rats. The proportion of simple unsynchronized and synchronized responses of 1b and 2b types was also lower in habituated rats whereas the proportion of complex synchronized responses of 4b type increased. This decreased responsiveness in habituated rats, similar to that observed in rats repeatedly exposed for 20 min per day to an odor during six consecutive days in our previous studies, is discussed with respect to olfactory bulb plasticity.     

Sympathetic hyperfunction causes increased sensitivity of the autonomic nervous system to whole-body X irradiation

Although the etiology of radiation sickness is still unknown, disturbance of the autonomic nervous system is suggested to be a factor. This study was designed to compare the radiosensitivity of spontaneously hypertensive rats possessing sympathetic hyperfunction and control Wistar-Kyoto rats, and to analyze the effects of radiation on the autonomic nervous system in both strains. After a 7.5-Gy dose of whole-body X irradiation, the blood pressure decreased significantly at 8 h and 2 days in the spontaneously hypertensive rats, but not in the Wistar-Kyoto rats. Epinephrine levels in the adrenal gland of spontaneously hypertensive rats decreased at 4, 8 and 24 h, unlike the Wistar-Kyoto rats. Radiation evoked a stronger increase in norepinephrine in the jejunum and colon of spontaneously hypertensive rats than in Wistar-Kyoto rats. Acetylcholine levels in the jejunum of spontaneously hypertensive rats decreased, in contrast to the increase in Wistar-Kyoto rats within 24 h after irradiation. The survival rate of spontaneously hypertensive rats was lower than that of Wistar-Kyoto rats and weight loss, appetite loss and morphological changes in the jejunum were greater in spontaneously hypertensive rats than in Wistar-Kyoto rats after irradiation. These results indicated that X irradiation caused greater activities in autonomic nervous function and severe radiation injury in spontaneously hypertensive rats. Sympathetic hyperfunction may be associated with a higher sensitivity to radiation, including radiation injury and radiation sickness.     

Effects of water-deprivation on aldosterone production in Brattleboro male rats congenitally lacking vasopressin

Effects of water-deprivation on several metabolic parameters and on plasma aldosterone concentration have been investigated in male Brattleboro rats homozygous for hypothalamic diabetes insipidus (DI) and in male Long-Evans rats (LE) as controls. Two separate experiments were performed over a period of 72 hours: 1) to determine the global effect of water-deprivation, water deprived rats were compared with hydrated animals, 2) to elucidate the specific effect of dehydration alone, water-deprived rats were compared with similar food-restricted, but water-supplied DI and LE rats. In hydrated animals, plasma aldosterone concentration was close to 50% less in DI rats than in LE rats. After 72 hours, plasma aldosterone values increased mainly because of dehydration and this increase was greater in DI rats than in LE rats. At the same time, plasma aldosterone concentration remained lower in DI rats compared to LE rats. The changes in plasma aldosterone concentration after dehydration and possible reasons for the impairment of aldosterone production in DI rats are discussed.     

三种老年痴呆动物模型行为学比较

目的老年大鼠、基底前脑损伤大鼠及注射东莨菪碱大鼠常作为老年性痴呆的动物模型,本研究对这三种模型的行为表现进行比较研究。方法采用水迷宫及旷场分析法对这三种模型及青年对照和假手术对照进行了研究。结果老年大鼠、基底前脑损伤大鼠和注射东莨菪碱大鼠的学习记忆能力显著减弱,老年大鼠对新环境的紧张程度增强;基底前脑损伤大鼠和注射东莨菪碱大鼠的空间认知能力显著下降;注射东莨菪碱大鼠的兴奋性异常增强,（Ｐ＜００５）。结论基底前脑损伤动物的行为表现最符合老年痴呆患者的早期临床症状。     

Effects of food deprivation and high fat diet on immunoreactive dynorphin A(1–8) levels in brain regions of Zucker rats

The levels of immunoreactive dynorphin A(1–8) (ir-DYN8) were measured in discrete brain regions of lean Zucker rats subjected to food deprivation for 72 hr and to a high fat diet, and in fatty Zucker rats after food deprivation for 72 hr. Fatty rats showed higher concentrations of ir-DYN8 in the cortex and midbrain, when compared to lean rats fed a stock diet ad lib. Food deprivation increased ir-DYN8 levels in the cortex of lean rats and fatty rats and in the hippocampus of fatty rats, but decreased its content in the striatum of lean rats and in the midbrain of fatty rats. The high fat diet increased ir-DYN8 levels in the cortex and midbrain of lean rats. These results suggest that ir-DYN8 levels in extrahypothalamic structures of Zucker rats could be differentially modified under conditions of hereditary obesity and dietary manipulations.     

WTC rat has unique characteristics such as resistant to streptozotocin

Because we found that WTC rats might be resistant to streptozotocin (STZ), we have elucidated the mechanisms of resistant to the diabetogenic effects of STZ in the WTC rats. Dose response to STZ was evaluated with glucose levels. No significant changes in glucose level to STZ administration were observed in WTC rats. Insulin secretion by suppling glucose was preserved in WTC rats even after STZ administration. Although there was no significant difference in gene expression of both GLUT2 and Kir6.2, which were involved in STZ resistance, between WTC rats and Wistar rats, the expression of metallothionein 2a in pancreas and liver to STZ administration of WTC rats was significantly higher than that of Wistar rats. Moreover, alloxan did not induce diabetes in WTC rats as same as STZ. These results suggest that WTC rats might have powerful antioxidant property to protect β cells in pancreas. Because the STZ-resistant property is very close characteristics to human beings, WTC rats will become a useful animal model in diabetic researches.     

Influence of an estrone-desulfating intestinal flora on the enterohepatic circulation of estrone-sulfate in rats

The fecal and urinary excretion of orally administered [4-14C]estrone-3-sulfate was studied in germfree (GF) rats, conventional (CV) rats and gnotobiotic rats selectively associated with estrone-desulfating and/or cecal-volume reducing microorganisms. The time required to excrete 50% of the total label recovered (t 1/2) was 22 h in CV rats vs 32 h in GF rats. Gnotobiotic rats selectively associated with a cecal volume-reducing flora (CRF rats) excreted the label even faster (t 1/2 = 13 h) than CV rats. Association of GF rats as well as CRF rats with estrone-desulfating microorganisms (termed S1 + S2 + R9 rats and CRF + S1 + S2 + R9 rats, respectively) led to a slower excretion of labeled products (t 1/2 = 38 h in S1 + S2 + R9 rats and t 1/2 = 27 h in CFR + S1 + S2 + R9 rats). Intestinal microbial desulfation also increased the relative part of the urinary excretion from 4% in GF rats to 8% in S1 + S2 + R9 rats and from 3% in CRF rats to 9% in CFR + S1 + S2 + R9 rats. We conclude that intestinal microbial desulfation enhances the enterohepatic circulation of orally administered estrone-3-sulfate.     

Induction of ovulation, mating, and conception in androgen-treated immature rats

Attempts were made to induce pregnancy in androgen-treated immature rats. Treatment with PMSG alone, which causes ovulation in normal immature rats, failed to cause ovulation in androgenized rats. However, treatment with PMSG plus LHRH was effective in causing ovulation. After ovulation, some of the normal and androgenized rats mated. Normal mated rats became pregnant but androgenized mated rats did not. However, when a pituitary gland was transplanted from a normal rat into the kidney capsule of an androgenized rat to maintain functional corpora lutea, implantation occurred in some of the mated animals. The positive decidual reaction in the uteri of such androgenized rats was similar to that observed in normal rats. These results suggest that the uterine sensitivity to blastocyst implantation of androgenized immature rats may be normal.     

Progression of vascular and neural dysfunction in sciatic nerves of Zucker diabetic fatty and Zucker rats

We have examined the progression of vascular and neural deficits in Zucker rats, Zucker diabetic fatty (ZDF) diabetic rats, and age-matched lean ZDF rats from 8 to 40 wk of age. Both the ZDF diabetic and Zucker rats were glucose intolerant at 8 wk of age. The Zucker rats did not become hyperglycemic but were hyperinsulinemic through 32 wk of age. All ZDF diabetic rats became hyperglycemic by 8 wk of age. Through their life span, serum free fatty acids and triglycerides levels were significantly higher in Zucker and ZDF diabetic rats compared with age-matched lean ZDF rats. After 24 and 28 wk of age, endoneurial blood flow was significantly decreased in ZDF diabetic and Zucker rats. Motor nerve conduction velocity was significantly decreased after 12-14 wk of age in ZDF diabetic rats and at 32 wk of age in Zucker rats. ACh-mediated vascular relaxation of epineurial arterioles of the sciatic nerve was impaired after 8-10 wk of age in ZDF diabetic rats and after approximately 16 wk of age in Zucker rats. In contrast, vascular relaxation mediated by calcitonin gene-related peptide was impaired significantly after 28 wk of age in ZDF diabetic rats but not impaired in Zucker rats up to 40 wk of age. Markers of oxidative stress were differentially elevated in ZDF diabetic rats and Zucker rats. These data indicate that vascular and neural dysfunction develops in both Zucker and ZDF diabetic rats but at different rates, which may be the result of hyperglycemia.     

Alterations of Benzodiazepine Receptor Binding in Tremor Rats with Absence-Like Seizures

Tremor rats begin to exhibit clinical or electrical absence-like seizures after 6 weeks of age, and by 14 weeks of age, all have seizures. Central-type benzodiazepine receptor binding was investigated in tremor rats and control rats, aged 4 weeks and 16 weeks. Significantly lower benzodiazepine receptor density and no differences in affinity were found in the hippocampus of the tremor rats in comparison with that of control rats at both ages. This abnormality is considered to be due to a tremor gene and may be the cause of absence-like seizures in tremor rats. A significantly lower receptor density was found in the cerebellum at 4 weeks of age in the tremor rats than in the control rats. These changes may be related to tremorous movements in the tremor rats. Receptor density was significantly lower in the brainstems of tremor rats and control rats at 16 weeks of age than at 4 weeks of age, and the decrease was more marked in control rats. These facts may reflect a reduced decrease in the response to the dysfunction of gamma-aminobutyric acidergic neurons, or the function of the gamma-aminobutyric acid/benzodiazepine receptor system may be secondarily increased to suppress seizures in 16-week-old tremor rats.     

Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.     

Decreased ketonaemia in the monosodium glutamate-induced obese rats

Plasma concentrations of total ketone bodies, acetoacetate (AcAc) and 3-hydroxybutyrate (3-OHBA) in monosodium glutamate (MSG)-induced obese rats were measured. MSG-treated rats showed higher Lee's indices, shorter naso-anal and tail length, and a more marked intraperitoneal fat deposition than control rats. Plasma concentrations of glucose, free fatty acid, triglyceride and phospholipids were significantly increased in the MSG-treated rats as compared to the control rats (24 weeks-old). Plasma levels of total ketone bodies, AcAc and 3-OHBA were all decreased in the MSG-treated rats as compared to control rats. The ratio, 3-OHBA/AcAc in the MSG-treated rats were not different from those in the control rats.     

Mitochondrial respiration and triiodothyronine concentration in liver from postpubertal and adult rats.

The purpose of this study was to investigate the decline in rat liver mitochondria respiration found in adult rats compared to younger ones, and to find a link between this respiratory impairment and a tissue hypothyroidism state. To this end, hepatic concentration and serum levels of triiodothyronine were measured in postpubertal rats (60 days old) and adult rats (180 days old). In addition, in these rats we measured oxidative phosphorylation in homogenate together with coupled and uncoupled respiration in isolated mitochondria using succinate or durohydroquinone as substrate. We found that mitochondria from adult rats consumed less oxygen compared to younger rats due to lower electron transport chain and phosphorylating system activity. In addition, we found that in state 4 condition, mitochondria from adult rats consumed less oxygen than mitochondria from young rats. Finally, we found a decrease in liver triiodothyronine concentration in adult rats. In conclusion, the results of this study show that hepatic mitochondria in adult rats have a decreased ATP synthesis capacity and proton permeability, both consistent with the tissue hypothyroidism found in the liver of adult rats.