Effects of olfactory bulbectomy and domicile on stress-induced corticosterone release in the rat.

Following bilateral olfactory bulbectomy or sham surgery, rats were housed either in groups of 5 or individually. After 10 days the animals were sacrificed and plasma corticosterone levels were measured. Half the animals in each group received predictable stress in the form of footshock immediately prior to exsanguination. Two levels of corticosterone elevation were noted, an intermediate level (circa 40 μg/100 ml plasma), in bulbectomised animals without stress and in sham operated animals with stress. Extreme corticosterone elevation (circa 80 μg/100 ml plasma) occurred in bulbectomised rats with stress. The type of housing had no effect on corticosterone elevation. The results are discussed in terms of a non olfactory function for the olfactory bulb, and the role of corticosterone and ACTH in acquisition learning.     

Influence of uremia on the proliferation kinetics of a solid transplantable carcinoma (author's transl)]

Previous autoradiographic investigations revealed an impaired regeneration of epithelial tissues in acute experimental uremia. It was the aim of the present study to get information about the effect of uremia on the growth and the proliferation kinetics of a solid tumor (mammary carcinoma HB). Material and Methods: The partly differentiated mammary carcinoma HB (Dr. C. W. Friis/Ry/Denmark) was examined in adult female mice (C3H/Tif). Acute renal failure was induced by ligation of the right ureter and by infarction of two thirds of the left kidney. A group of animals served for urea estimation during the first 7 postoperative days. A sham operation was performed in a control group. A starvation effect was avoided by additional tube feeding. Hemoglobin levels and reticulocytes were estimated in tumour bearing uremic mice and in a control group to get information about anemia in acute uremia. Calculating the tumour volume as a sphere with the geometrical mean of two diameters the tumour doubling time was derived from the growth curve. The autoradiographic experiments started on the 21th day after transplantation of the tumour (= 7th day after experimental uremia and sham operation respectively). The cell cycle was determined by the method of percentage of labeled mitoses. The growth fraction was estimated by continuous labeling method. For details of autoradiographic techniques see Fíaux de Lacroix et al. (1973. Results and Discussion: During the first 48 hours the blood urea increased to more than 230 mg% and then decreased to a level of about 133 mg% at the 7th postoperative day. The blood urea of control animals was in the range of 50 mg%. Tumor bearing mice revealed an anemia (Hb: 8.1 +/- 1.2 g%, reticulocytes 60.1 +/- 36.5%) but no significant differences in hemoglobin levels and reticulocytes counts could be detected in uremic animals (Hb 9.7 +/- 1.7 g%; reticulocytes 31.4 +/- 11.6%). The growth of the tumour was impaired by uremia. The tumour doubling time was prolonged from 7.5 days in untreated and sham operated animals to 15 days in uremic mice. This was mainly due to a lowered growth fraction (from about 50% to 20%), and on the other hand to a prolongation of the generation time (from 15.5 to 19 hours) mainly caused by a prolonged Tg1-phase. The cell loss factor remained constant (about 81% in every group). Our findings in the transplantable solid tumour of uremic mice were similar to the results observed in the epithelium of the stomach, the intestine and of the skin as well as in erythroblasts especially in regard of the changes of the cell cycle. These observations in various tissues suggest a generally impaired cell proliferation in uremia.     

尿毒症及透析患者血浆IL-1β、TNFα、IL-6水平及其意义

目的　研究尿毒症状态和血液透析对血浆细胞因子的影响。方法　应用酶联免疫吸附分析(ELISA)方法检测正常人、尿毒症未透析患者、腹膜透析患者和应用铜仿膜、聚砜膜、聚甲基丙烯酸甲酯膜(PMMA)血液透析患者血浆IL-1β、TNFα、IL-6水平。结果　尿毒症未透析患者血浆TNFα、IL-6水平显著高于正常对照(P<0.05)。在应用不同透析膜15分钟时,血浆细胞因子水平较透析前有不同程度的降低,聚砜膜透析时IL-1β、TNFα降低明显,统计学差异显著(P<0.05)。应用三种透析膜透析时细胞因子无显著性差异。结论　尿毒症未透析状态可导致激活外周血单核细胞(PBMC)产生细胞因子,不同透析膜透析时激活PBMC及吸附、清除细胞因子的程度不同,单纯用细胞因子的血浆水平变化来评价透析膜的生物相容性存在一定局限性。     

Apolipoprotein C-III, hypertriglyceridemia and triglyceride-rich lipoproteins in uremia

Apolipoprotein C-III (ApoC-III) plays an important role in the metabolism of triglyceride-rich lipoproteins and is known to be elevated in patients with uremia. To investigate the role of apoC-III in uremic dyslipidemia, we examined apoC-III, triglyceride levels and lipoprotein particles containing both apoB and apoC-III (LP-Bc) in 27 uremic patients prior to dialysis (predialysis), 30 patients on hemodialysis (HD) and 31 patients on peritoneal dialysis (PD). All three groups of patients had elevated levels of plasma apoC-III (20+/-7 mg/dl for predialysis, 18+/-5 for HD and 22+/-8 for PD, compared to 11+/-3 mg/dl for control subjects [p<0/01 for all comparisons]). ApoC-III was positively correlated with plasma triglycerides in PD patients (r = 0.86, p<0.0001), HD patients (r = 0.67, p<0.0001) and predialysis patients (r = 0.60, p<0.001) as well as in all patients combined (r = 0.75, p<0.0001). ApoC-III was also positively correlated with levels of LP-Bc in all three groups of patients, although this correlation was less strong (r = 0.46, p<0.0001 for all patients combined). In predialysis and PD patients, the majority of apoC-III was found in heparin precipitable lipoproteins, whereas the majority of apoC-III in HD patients was found in HDL, indicating less efficient lipolysis in predialysis and PD patients in comparison with HD. These data support the hypothesis that the elevation of apoC-III in uremia can alter the metabolism of triglyceride-rich lipoproteins, leading to an elevation in triglycerides and LP-Bc. Understanding the mechanism(s) of elevated apoC-III in uremia may help to clarify the causes of uremic dyslipidemia.     

Control of plasma aldosterone in diabetic patients with hyporeninemic hypoaldosteronism

Summary In three patients with diabetes and hyporeninemic hypoaldosteronism changes in renin activity, plasma aldosterone and cortisol were examined under various conditions: orthostasis and intravenous furosemide, infusion of synthetic 1–24 ACTH on two consecutive days and diurnal variations in basal hormone fluctuations.Each patient showed unmeasurably low renin activity unresponsive to orthostasis and intravenous furosemide while plasma aldosterone was below normal range.Under ACTH-infusion only marked increases in aldosterone were observed in one patient whereas cortisol responded normally in all diabetics tested.Analysis of diurnal night day fluctuations (20.00–8.00) in plasma aldosterone and cortisol revealed a close and statistically significant relationship between both hormones in each of the three patients (p<0.05–<0.001). Variations in plasma aldosterone thus were mediated through changes in endogenous pituitary ACTH. Compared with normal controls however, diurnal aldosterone curves were set at a lower level.Our results demonstrate that a reduced sensitivity of the adrenal gland to ACTH is not responsible for the observed subnormal plasma aldosterone levels in these patients. Therefore, the lack of circulating angiotensin II seems to be the causative reason of hypoaldosteronism.The exact mechanism of undetectable renin activity in these patients remains unknown.     

Increased cardiac contractility in acute uremia: interrelationships with hypertension.

To study the effects of acute uremia on the inotropic state of the rat heart, we subjected rats to bilateral nephrectomy and studied their hearts in the open chest 24 h later. Uremic rats had significantly higher systolic blood pressure than sham-operated animals. Left ventricular systolic pressure and maximum dP/dt, both during ejection and isovolumic contrations, were higher for any given end-diastolic pressure in hearts of uremic rats than in sham-operated animals. This difference in performance charcteristics was not abolished by doses of propranolol that blocked the heart rate response to isoproterenol. The administration of phenoxybenzamine during the 24 h of uremia abolished the blood pressure rise in uremic rats, but the increased contractile state persisted. Treatment of sham-operated animals with methoxamine to produce the same course of blood pressure as observed in uremic rats was also associated with an increased inotropic state. These results indicate that in the rat, acute uremia is associated with an increased inotropic state that is not mediated by beta-adrenergic mechanisms. The systolic hypertension of acute uremia is not the major cause of the increased contractility, although systolic hypertension without uremia can mimic the performance characteristics found in hearts of uremic rats.     

Aldosterone reverses potassium-induced food aversions in adrenalectomized rats

Young adult male rats were individually housed and given a standard ration (66 ml) of a liquid diet (Nutrament) each day. The animals were divided into 7 groups: five groups were bilaterally adrenalectomized (ADX) and given one of 5 doses of aldosterone and/or dexamethasone by continuous, osmotic minipump infusions. The remaining two groups served as intact and sham operated controls. Each of the seven groups were subdivided into 3 dietary groups: a basal potassium dietary group, a moderately potassium-supplemented dietary group, and a highly potassium-supplemented dietary group. All rats with intact adrenals as well as those ADX rats given basal or 10 X basal aldosterone treatment consumed all of their allotted 66 ml of diet each day, independent of the level of potassium supplementation. ADX rats given little or no aldosterone treatment that were given access to the moderately or highly supplemented diets became anorexic, eating little or none of the diet. These data are discussed with reference to the factors controlling the intake of ADX rats.     

Effect of protein intake on weight gain and plasma amino acid levels in uremic rats.

Chronically uremic rats weighing approximately 180-200 g and sham-operated controls of similar weight were pair fed diets containing 5, 15 or 23% protein for 10-12 wk. At each level of protein intake, uremic animals gained less weight and had lower protein efficiency ratios than controls. In addition, certain plasma amino acid levels were altered in the uremic animals. These included tyrosine and the tyrosine/phenylalanine ratio, which were decreased, and citrulline, glycine, and the methylhistidines, which were increased. In both uremic and control rats, plasma concentrations of certain amino acids, primarily nonessential ones, varied inversely with protein intake; with the 5% protein diet, the ratio of essential to nonessential amino acids was significantly reduced. These observations indicate that both uremia and reduced protein intake may affect growth and amino acid metabolism in rats with chronic renal failure. The finding that uremic rats utilize protein less efficiently may indicate that marked reductions in protein intake may be particularly hazardous to the nutritional status of the uremic patient.     

Altered monocyte function in uremia

Uremia appears to suppress immune function predisposing patients to infections. When the defect in cellular immunity was studied by exposing mononuclear cells (MNC) from uremic patients and controls to tetanus toxoid, diptheria toxoid, or Candida albicans antigen in vitro, the uremic cells were far less responsive. Monocytes and T cells, which are both involved in the proliferative response to soluble antigens, were isolated from MNC of uremic patients and HLA class II matched controls and incubated with tetanus toxoid. Tetanus toxoid-pulsed uremic monocytes were unable to stimulate the proliferation of HLA identical control T lymphocytes. Lymphocytes from uremic patients, however, were stimulated by tetanus toxoid-pulsed control monocytes. Therefore, the ability of monocytes to function as accessory cells is severely affected by uremia. The uremic monocytes were FcR+, produced IL-1 beta, and expressed levels of HLA class II antigens comparable to controls. Although the biochemical defect in uremic monocytes remains unknown, the abnormality could explain many of the immunological changes of uremia.     

Renin, cortisol, and aldosterone during transcendental meditation.

The effects of transcendental meditation (TM) on plasma renin activity (PRA) and plasma concentrations of aldosterone, cortisol, and lactate were studied by measuring these variables before, during, and after 20--30 min of meditation. Subjects, who rested quietly rather than meditating, served as controls. There were no differences in the basal values for these variables between meditators and controls, but controls, in contrast to meditators, showed a significant increase in cortisol between the first (A) and second (B) samples of the control period. PRA increased slightly (14%) but significantly (p less than 0.03) during TM, but not during quiet rest in controls. Cortisol decreased progressively (after sample B) throughout the experiment to the same degree in both groups. Aldosterone and lactate did not change. The data do not support the hypothesis that TM induces a unique state characterized by decreased sympathetic activity or release from stress, but do suggest that meditators may be less responsive to an acute stress.     

Search for the uremic toxin. Decreased motor-nerve conduction velocity and elevated parathyroid hormone in uremia.

In a retrospective analysis to determine whether secondary hyperparathyroidism in uremia has a role in uremic peripheral neuropathy, we simultaneously measured motor-nerve conduction velocity and serum parathormone level in 42 uremic patients. We compared age-matched groups of nondiabetic uremic patients, divided into three groups according to serum parathyroid hormone, for degree of impairment of motor-nerve conduction velocity, and 12 diabetic patients with uremia. The group with highest levels had a significantly (P less than 0.01) lower conduction velocity (25.3 +/- 4.9 m per second) than the group with normal or slightly elevated parathyroid hormone, who had only mild depression of nerve conduction (45.1 +/- 1.3 m per second). Mean serum calcium and creatinine were not significantly different between groups. Nerve conduction velocity was similarly depressed in 17 patients on additional dialysis studied prospectively and divided into groups according to parathyroid hormone levels. These results suggest a relation between high parathormone levels and uremic neuropathy and implicate parathyroid hormone as a uremic toxin.     

Effects of maternal bilateral ureteral ligation on the differentiation of glomerular anionic sites in fetal rat kidney

Effects of maternal bilateral ureteral ligation on the differentiation of glomerular anionic sites in fetal kidney were studied with the colloidal iron method. The ligation was performed on days 17, 19, and 21 of pregnancy, and the animal were euthanized 1 day after each ligation. On fetal day 20, in the fetuses from ligated mothers, colloidal iron was concentrated in laminae rarae interna and externa of the glomerular basement membrane. In the fetuses from sham-ligated mothers, however, a different pattern of iron distribution was noted. In most areas of the glomerular basement membrane, colloidal iron was randomly distributed as in both fetuses of fetal day 18. In the remaining areas, the same pattern of colloidal iron distribution as was noted in the fetuses from ligated mothers of fetal day 20 was observed. On fetal day 22, colloidal iron was densely accumulated in laminae rarae interna and externa of the glomerular basement membrane in both groups. However, the iron-free zone was slightly thicker in the fetuses from the ligated mothers. These findings suggest that maternal bilateral ureteral ligation accelerates the differentiation of glomerular anionic sites in the kidney of fetal rats.     

Adrenocortical response to one-leg and two-leg exercise on a bicycle ergometer

Summary Twelve healthy male subjects exercised for 30 min on a bicycle ergometer, using only one leg, at a work load that was nearly exhausting. Nine subjects (group A) showed a marked rise in plasma cortisol concentration (240±50 nmol·l^–1), but in three subjects no such rise occurred (group B). All group B subjects had elevated cortisol levels prior to the period of exercise, which may have inhibited the adrenocortical response. Seven subjects of group A also performed the same work load using both legs. Under this regime, increases in plasma cortisol and aldosterone levels, blood lactate level and heart rate, but not plasma potassium, were significantly smaller than for one-leg exercise. These findings are consistent with the hypothesis that activation of the hypothalamic-pituitary-adrenal (HPA) system during exercise could be mediated through the stimulation of chemoreceptors in the exercising muscles. This effect could be reinforced by HPA stimulation in response to the greater acceleration of heart rate in one-leg exercise. The marked rises in plasma potassium levels might be responsible for the elevation of plasma aldosterone concentration particularly in those experiments when this occurs earlier than, or in the absence of, rises in cortisol concentration.     

Opiates and the anorexia of uremia

Uremia results in a decrease in food intake. In the present study we investigated whether opiates known to stimulate feeding would alter food intake in rats made uremic by 1 and 5/6 nephrectomy. Morphine increased food intake in sham nephrectomized rats, but failed to alter food intake in uremic animals and depressed the ingestion of rat chow in a group of weight restricted rats. Butorphanol tartrate increased feeding in sham and uremic animals but did not alter intake in the weight restricted group. Higher doses of butorphanol were needed to stimulate feeding in the uremic rats compared to the sham group, suggesting a relative resistance to opioid-induced feeding in the uremic rats. The opiate antagonist, naloxone, suppressed food intake in the uremic and sham groups more effectively than in the weight restricted rats. These data suggest that the opioid feeding system functions in a reduced fashion in uremic rats, but probably is not the sole factor involved in producing the anorexia associated with uremia.     

Plasma adenosine 3′:5′ — cyclic monophosphate response to glucagon in uremia

Summary The effect of a single, intravenously administered dose of glucagon on plasma cyclic adenoside monophosphate (cAMP) was studied in seven normal subjects, ten patients with chronic renal failure (CRF), and ten patients with terminal renal insufficiency (TRI) receiving long-term haemodialysis treatment (HD). Ten minutes following glucagon administration, uremic patients displayed a significantly (P < 0.0001) greater increase in cAMP than control subjects. Glucose levels after glucagon administration did not differ significantly between the normal and uremic groups, and lipolysis was less pronounced in the uremic patients than in the controls (P < 0.003). These results could not be attributed to differences in serum insulin response. The findings demonstrate differences in the hepatic adenylate cyclase and cAMP response between normal and uremic subjects. These alterations in cAMP responsiveness may play a role in the pathophysiology of the metabolic disturbances associated with uremia.     

Effects of stress on exacerbation of diabetes mellitus, serum glucose and cortisol levels and body weight in rats.

OBJECTIVE: The effects of stress on the serum glucose, serum cortisol levels and body weight were investigated to clarify the possible link between the stress and diabetes. METHODS: The experiments were performed on nondiabetic and streptozotocin diabetic rats divided to control, sham and stressed groups. Water immersion was used as stressor. After the experiment, blood samples were collected. The serum glucose level (SGL) was measured by the glucose oxidase method and serum cortisol level (SCL) was determined by radioimmunoassay. RESULTS: Stress caused a significant increase in glucose level in both nondiabetic and diabetic rats. In diabetes rats, a significant increase in SCL was observed. Stress did not cause, however, significant increases in SCL. A significant weight loss took place in rats exposed to stress and that was much greater in diabetic animals. CONCLUSION: The stress with mainly psychic component exacerbated the diabetes in streptozotocin treated rats and the glucose levels increased significantly also in nondiabetic controls, but no glucose was detected in their urine.     

The influence of nephrectomy,ureteral ligation,and of estradiol on plasma renin substrate in unilaterally nephrectomized rats

Summary The effects of three experimental conditions on the concentration of plasma renin substrate were studied with special reference to plasma renin concentration in unilaterally nephrectomized rats.After simultaneous bilateral nephrectomy the maximum increase in plasma renin substrate was 17 times higher than normal within 24 h, while in rats which were unilaterally nephrectomized 10 days previously, followed by the removal of the remaining kidney (two-step bilateral nephrectomy), the maximum increase in plasma renin substrate was markedly suppressed (6-fold of normal). The maximum increases in plasma renin substrate by estradiol treatment in normal and unilaterally nephrectomized rats were about the same, associated with similarly decreased plasma renin concentrations. The similar increase in plasma renin substrate was found after ureteral ligation in unilaterally nephrectomized rats and bilateral ligation of the ureters in normal rats. This was the case where the plasma renin concentrations changed differently after ureteral ligation. After two-step bilateral nephrectomy plus estradiol treatment the maximum increase in plasma renin substrate was found to be higher than that found after two-step bilateral nephrectomy, but was lower than that after simultaneous bilateral nephrectomy.It is suggested that under the pathological conditions that stimulate renin substrate production, the plasma rein substrate concentration is less affected by circulating renin.This work was supported in part by a grant No. 048212 from the Japanese Ministry of Education     

Studies on acute glucose-induced aldosterone suppression: Role of renin-angiotensin system

Summary Glucose loading is known to cause acute suppression of plasma aldosterone and stimulation of plasma renin activity. The relative contribution of variations in circulating angiotensin II to the regulation of aldosterone secretion following glucose loading was assessed in ten normal subjects. The effects of a standard oral glucose loading test (100 g) on plasma concentrations of glucose, insulin, potassium, aldosterone, renin activity and cortisol were studied (a) under basal conditions, and (b) after inhibition of angiotensin II with the converting enzyme inhibitor captopril (50 mg t.i.d. during 3 days). Under basal conditions the acute increase in plasma glucose and insulin after glucose loading was accompanied by a significant decrease (P<0.01) in plasma cortisol and aldosterone and by a significant increase in plasma renin activity (P<0.01); plasma potassium was decreased slightly but not significantly. Following captopril treatment preloading plasma renin activity was increased significantly, most probably reflecting an effective reduction of angiotensin II. Glucose loading caused a similar suppression of plasma aldosterone, as observed under basal conditions. This observation suggests that renin activation does not substantially contribute to the acute regulation of plasma aldosterone after an oral glucose load.     

Plasma Renin Aktivität und Aldosteronverhalten bei kritisch kranken Patienten

Summary To investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 µg i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18–84 years). Of the patients 19 received dopamine treatment (3–13 µg/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P<0.05) of lethality with plasma renin activity and cortisol levels and correlations (P<0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients.Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.

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Abkürzungen ACTH Adrenocorticotropes Hormon - TRH Thyreotropin-Releasing Hormon - ZNS Zentrales Nervensystem     

Neonatal exposure to short days and low temperatures blunts stress response and yields low fluctuating asymmetry in Siberian hamsters

Fluctuating asymmetry (FA) refers to small, non-directional deviations from perfect bilateral symmetry in morphological characters. Individuals with low FA presumably either developed in a relatively stable environment and/or were better able to buffer against developmental stressors. The present study investigated the effects of seasonal factors measured by day length and ambient temperature manipulations on the development of bilateral characters and concomitant changes in stress responses. Siberian hamsters were exposed to either long days (16 h of light per day) or short days (8 h of light per day) combined with either standard temperatures (21+/-2 degrees C) or low temperatures (8+/-2 degrees C) on the day of birth until weaning. Cortisol concentrations at baseline and following acute restraint stress, and FA values were measured in adulthood. Females reared in winter-like conditions with short day lengths and low temperatures had low FA and low cortisol concentrations following restraint stress compared to other females. Females reared in long day lengths and standard temperatures had the highest rate of increase in cortisol concentrations after restraint among other female groups. No group effects were observed in males regarding day length and temperature manipulations. Baseline and post-restraint cortisol concentrations were higher in females than males for all groups except in animals reared in short day lengths and low temperatures. Our results suggest that winter-like conditions during neonatal period evoke hyposensitivity to stress in adult females and this blunted response to stress is a key factor in achieving ideal growth patterns.