Plasma Met-enkephalin and catecholamine responses to insulin-induced hypoglycaemia in greyhounds

The involvement of endogenous opioid peptides in the stress response was investigated by measuring plasma concentrations of Met-enkephalin-like immunoreactivity (MLI), adrenaline and noradrenaline during insulin-induced hypoglycaemia in conscious greyhounds. Moreover, the molecular forms of circulating MLI were characterized using gel filtration chromatography. In the first group of animals, i.v. administration of insulin (0.3 units/kg) provoked marked hypoglycaemia (blood glucose concentrations fell from 4.4 +/- 0.1 to 1.5 +/- 0.2 mmol/l; mean +/- S.E.M.) which was associated with significant (P less than 0.001) rises in plasma MLI concentrations from a basal concentration of 45 +/- 8 to a peak of 189 +/- 39 ng/l. A within-subject study comparing five different insulin doses ranging from 0.004 to 0.3 units/kg showed dose-related effects on blood glucose with nadir concentrations of 4.1 +/- 0.6 mmol/l (after the smallest dose of insulin) and 0.8 +/- 0.1 mmol/l (after the largest dose of insulin). This was associated with dose-related rises in plasma MLI with peak concentrations of 56 +/- 17 and 558 +/- 35 ng/l, plasma adrenaline with peak concentrations of 0.45 +/- 0.06 and 15.76 +/- 1.33 nmol/l and plasma noradrenaline with peak concentrations of 0.49 +/- 0.07 and 2.27 +/- 0.45 nmol/l following the smallest and largest doses of insulin respectively. These results are the first demonstration of raised plasma MLI concentrations following hypoglycaemia. Moreover, they show that the hormonal responses vary with the degree of hypoglycaemia achieved. Together with reports by other investigators these findings might suggest opioid modulation of the responses of the sympathoadrenal system to hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lowering circulating free fatty acid levels on protein metabolism in adult growth hormone deficient patients.

Our study was conducted to define the roles of lowering circulating free fatty acids (FFA) and of growth hormone (GH) replacement on protein metabolism in GH deficient patients.To isolate the specific effects of FFA and GH we studied seven adult subjects with GH deficiency four times: (A) with administration of GH and Acipimox (an inhibitor of lipolysis), (B) with GH, without Acipimox, (C) without GH, with Acipimox and (D) without either. Each study included a 3 h basal period and a 3 h euglycemic clamp. Amino acid metabolism was assessed by stable isotope dilution technique at the whole body level and across the forearm. Overall, we saw no intervention effect on protein metabolism, but when the two situations in which Acipimox was given were combined, Acipimox decreased basal plasma FFA concentrations by 75% and increased serum urea concentrations by 20%, whole body appearance rates (reflecting protein degradation) of phenylalanine (by 7%) and tyrosine (by 11%) and protein synthesis rates for phenylalanine (by 7%), whereas phenylalanine-to-tyrosine conversion was unaffected. Acipimox more than doubled net forearm phenylalanine release during the clamp and increased basal forearm phenylalanine disappearance (reflecting muscle protein synthesis). During the clamp whole body amino acid fluxes and phenylalanine-to-tyrosine conversion decreased together with a decrease in forearm protein breakdown. GH replacement did not affect any of these metabolic parameters. Although we failed to show any role for GH, the results show that lowering of FFA concentrations with Acipimox has pronounced effects on protein metabolism, including increased whole body and forearm protein breakdown, together with increased protein synthesis systemically and locally in the forearm. The increase in serum urea and a doubling of net forearm phenylalanine release after lowering of FFA strongly indicate that the overall effect is catabolic and supports a pivotal protein conserving role of lipids.     

Effects of anoxia and graded acidosis on the levels of circulating catecholamines in turtles

We measured circulating levels of catecholamines in painted turtles subjected to anoxia with different degrees of concomitant acidosis at 20 degrees C and in turtles subjected to long-term submergence at 3 and 10 degrees C. Blood levels of both epinephrine (E) and norepinephrine (NE) increased during N2-breathing, N2/CO2 breathing and submergence, with NE generally being present in higher concentrations than E. During submergence at 20 degrees C, anoxic turtles experienced an extreme acidosis and NE levels exceeded 18,000 pg/ml. The greater the degree of acidosis in anoxic turtles the higher were the levels of plasma NE (log [NE; pg/ml] = 1.640 x pHa + 15.776, r = -0.826). Elevation of plasma E under anoxic conditions was more modest and the correlation between plasma E and pHa was less pronounced (log [E; pg/ml] = -0.329 x pHa + 6.069, r = -0.285). Submergence at lower temperatures also resulted in increases in plasma levels of NE, but while plasma E generally increased during anoxia, this elevation was less dramatic than that observed for NE. Exposure of turtles to either mild (6.5% CO2) or severe (14.5% CO2) normoxic hypercapnia resulted in no increase in E and only modest increases in NE. Upon resumption of air-breathing in all of the 20 degrees C protocols, turtles rapidly restored E and NE to control levels. The function of elevated plasma catecholamines during anoxia and acidemia in turtles is unknown but may be important in stimulating respiratory and cardiovascular recovery once air-breathing is resumed. Catecholamines may also play a role in mediating the rise in blood glucose we observed in this study, which may be an important factor in maintaining tissue viability during anoxic stress.     

Effects of hyperinsulinemia on plasma levels of circulating adhesion molecules

Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), a potential cardiovascular risk factor, are increased in diabetics. Among other factors, hyperinsulinemia has been proposed to enhance its release into the circulation. Thus, we directly examined the effects of insulin infusion on plasma levels of circulating adhesion molecules, and two other endothelial markers, i.e. von Willebrand factor (vWF) and soluble thrombomodulin (sTM). The study design was balanced, randomized, placebo-controlled, double blind, and cross-over. Twelve healthy male subjects received, on separate study days, a euglycemic hyperinsulinemic clamp (3 mU/kg x min) or placebo over 6 h. Plasma levels of cICAM-1, vascular cell adhesion molecule-1, circulating E-selectin, and sTM were measured by enzyme immunoassay; vWF-Ag was measured using a STA clot analyzer. Plasma levels of these adhesion molecules and endothelial cell activation markers were not affected despite a 30-fold increase in insulin levels. Hyperinsulinemia has no adverse effect on circulating ICAM-1, vascular cell adhesion molecule-1, E-selectin, vWF, or sTM and therefore does not directly induce endothelial activation.     

Effects of different photoperiods on circulating levels of melatonin and N-acetylserotonin in the female rabbit

The influence of different photoperiods on the secretion of melatonin and N-acetylserotonin (NAS) in the female rabbit was investigated. Under all photoperiodic conditions, 12-h light: 12-h dark (12L:12D), 2L:22D and 22L:2D, mean melatonin levels were higher during the scotophase. By contrast, mean NAS levels were 2-6-fold greater in the photophase compared to levels in the scotophase. This dissociation of circulating melatonin and NAS suggests that in the rabbit melatonin secretion is tightly controlled by the scotoperiod and NAS is probably produced by and originates from other organs as well as the pineal.     

Effects of posture and ageing on circulating atrial natriuretic peptide levels in man

Possible influences of posture or age on plasma immunoreactive atrial natriuretic peptide (irANP) levels and potential correlates were assessed in 12 young (age +/- s.e.m. 24 +/- 1 year) and 12 elderly (63 +/- 8 year) healthy subjects on a liberal sodium intake. The groups did not differ significantly in their basal 24-h urinary sodium excretion (210 +/- 23 versus 180 +/- 15 mmol/l). However, plasma irANP was five- to ninefold higher in the elderly (P less than 0.05-0.01). Plasma irANP averaged 167 +/- 31 and 24 +/- 3 pg/ml in the elderly and young, respectively, during recumbency, fell (P less than 0.05) to 101 +/- 21 and 11 +/- 1 pg/ml, respectively, with upright posture, and rose (P less than 0.01) to 250 +/- 51 and 50 +/- 9 pg/ml, respectively, after intravenous (i.v.) loading with 0.9% saline (2.14 l in 3 h). Supine blood pressure (BP) and plasma norepinephrine tended to be higher while renin and aldosterone levels were lower (P less than 0.01) in the elderly; the three latter variables rose (P less than 0.001) with upright posture. These findings demonstrate that in normal humans, circulating irANP levels vary with posture and ageing. These changes may have potential physiological relevance and should be considered when interpreting plasma irANP levels in pathological conditions.     

丝裂原活化蛋白激酶及其抑制剂与哮喘

丝裂原活化蛋白激酶信号转导通路是一类在进化过程中非常保守的信号通路,其通过细胞因子、生长因子、神经递质以及各种环境应激在信号转导中起重要作用。在哮喘中,这些胞外刺激引发出复杂的炎症反应和结构改变,包括T细胞的活化、嗜酸粒细胞和肥大细胞浸润、气道高反应性以及气道重构等等,在哮喘的发病机制中起着至关重要的作用,而研制相应的抑制剂必将在哮喘的治疗中具有重要意义。     

Effects of neutralization of circulating melatonin and N-acetylserotonin on plasma prolactin levels

The effect of pinealectomy or immunization against melatonin (Mel) and N-acetylserotonin (NAS) on plasma prolactin (Prl) levels was studied in rats following pineal stimulation induced by blinding or exposure to short photoperiods (1 h light and 23 h darkness daily). Blinding alone or together with pinealectomy or immunization did not alter resting Prl levels or the response to novelty stimulation. Exposure to short photoperiods flattened the diurnal Rrl rhythm seen in control rats kept in 12 h of light and 12 h of darkness daily. Pinealectomy slightly lowered Prl levels but did not affect the diurnal rhythm. Immunization caused a significant reduction in Prl levels, although the diurnal Prl rhythm persisted. These data suggest that Mel and/or NAS may be involved in the maintenance of basal Prl levels.     

The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women

OBJECTIVE: Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the RANK ligand. Moreover, OPG has been shown to be an important inhibitor of osteoclastogenesis in animal models. However, the relationship between circulating OPG levels and female bone status in human populations is unclear. In this study we undertook to investigate the relationship between circulating OPG levels and bone mineral metabolism in healthy women. PATIENTS AND MEASUREMENTS: Our subjects were 287 women aged 37-73 years (mean age 51.5 years). The serum concentrations of OPG were determined by enzyme-linked immunosorbent assay (ELISA). The biochemical markers of bone turnover and FSH were measured using standard methods. Bone mineral densities at the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry. RESULTS: Postmenopausal women had a significantly higher mean value of serum OPG than premenopausal women (1358.5 +/- 32.5 pg/ml vs. 1228.8 +/- 33.3 pg/ml, P < 0.01). Serum OPG levels were positively correlated with age (r = 0.169, P < 0.01), as were urine deoxypyridinoline levels (r = 0.133, P < 0.05) and serum FSH levels (r = 0.187, P < 0.01) in a bivariate correlation analyses. In a multiple regression analysis, only urine calcium excretion was identified as a significant predictor for serum OPG levels. CONCLUSIONS: Circulating OPG levels were found to be associated with urine calcium excretion and menopause in healthy women. Our observations suggest that circulating OPG levels reflect an antiresorptive activity in bone, and they are related to endogenous oestrogen levels.     

Effects of streptozotocin-induced diabetes on circulating levels of vitamin D metabolites

In order to investigate vitamin D metabolism in insulin-deficient diabetic rats, plasma vitamin D metabolites were measured at various periods after induction of diabetes by iv administration of 60 mg/kg streptozotocin (STZ). After STZ injection, plasma insulin was significantly decreased and plasma urea nitrogen increased with the duration of diabetes, while plasma creatinine remained unchanged. Plasma calcium, 25-dihydroxyvitamin D (25(OH)D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) progressively decreased. On the other hand, plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) did not change at any period, but the ratio of 1,25(OH)2D to 25(OH)D became high in proportion to the severity of hypocalcaemia. Since significantly lower 25(OH)D and 24,25(OH)2D levels were observed at the later stage of diabetes, it is suggested that the altered vitamin D metabolism in diabetes is secondary to the disturbances in metabolic homeostasis derived form the insulin deficiency.     

Effects of glutamate on exercise tolerance and circulating substrate levels in stable angina pectoris

The effects of glutamate on exercise tolerance, ischemic threshold and venous substrate concentrations were studied in 20 patients with stable angina pectoris and positive stress tests. Each patient underwent 4 upright bicycle exercise tests on consecutive days. The first and fourth tests were performed without medication while the second and third tests were preceded by a low and high bolus dose of monosodium glutamate, either 0.8 and 1.5 mg/kg body weight intravenously (10 patients) or 40 and 80 mg/kg orally (10 patients). Comparison of the first and fourth tests revealed good reproducibility of electrocardiographic, hemodynamic and metabolic data. Glutamate increased exercise duration (p less than 0.05) in a dose-related way when given intravenously (59 +/- 14 and 153 +/- 14 seconds) and when given orally (53 +/- 21 and 90 +/- 23 seconds; all data are mean +/- standard error of the mean). It also delayed the onset of ST-segment depression (p less than 0.05) by 73 +/- 19, 120 +/- 23, 62 +/- 27 and 80 +/- 30 seconds, respectively. Hemodynamics were not changed by glutamate at rest or at comparable workloads, but at onset of ST-segment depression the heart rate-blood pressure product was increased (p less than 0.05). Glutamate administration induced dose-related 1.5- to 10-fold elevations in plasma glutamate, 15 to 50% decreases in plasma free fatty acids (p less than 0.05) and 5 to 30% increases in plasma alanine contents. Circulating levels of glucose, lactate, citrate and albumin were not modified by glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)- receptor activator of NF kappa B ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemical markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63+/-7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.     

Effects of calcium and calcitonin on circulating levels of glucagon and glucose in diabetes mellitus

Summary The effects of Ca²⁺ and calcitonin infusions on circulating glucagon, glucose, C-peptide, Ca²⁺, and calcitonin were investigated in hyperglucagonaemic insulin-dependent diabetics. In 14 insulin-deprived diabetics and 12 healthy volunteers 2 h infusions of saline (0.154 mol/l), Ca²⁺ (0.375 mmol/kg body weight), and calcitonin (4.5 IU/kg body weight) were performed. There were no significant changes during saline infusion. In the diabetics, Ca²⁺ infusions induced a rise of plasma Ca²⁺ up to 3.2±0.1 mmol/l and a fall of circulating glucagon (-26.4±5.7%; p<0.001) and glucose (-23.3 ±3.6%; p<0.05). Plasma calcitonin rose to twice basal values (p<0.025). During calcitonin infusions plasma Ca²⁺ decreased slightly to 2.1±0.2 mmol/l; a fall was found in both glucose (— 24.4±4.0%; p<0.05) and circulating glucagon (-22.5±4.3%; p<0.001). Two groups of 6 healthy volunteers were subjected to saline and Ca²⁺, or to Ca²⁺ and calcitonin infusions. Both Ca²⁺ and calcitonin infusions induced a fall of serum insulin (— 30.1±6.6%; p< 0.05). Calcitonin depressed circulating glucagon by-18.6±4.4% (p<0.025), whereas during Ca²⁺ infusions glucagon decreased only by -6.5±1.9% (p>0.1). We conclude from our results that an increase of circulating calcitonin induced by Ca²⁺ infusions or by exogenous calcitonin administration appears to depress elevated circulating glucagon and glucose in insulin-dependent diabetics.     

Effects of vasoactive intestinal peptide on thyroid blood flow and circulating thyroid hormone levels in the rat

The effects of vasoactive intestinal peptide (VIP) on thyroid blood flow and hormone levels were studied in rats. Tissue blood flow was determined from the distribution of radioactive microspheres after injection by cardiac puncture directly into the left ventricle of anesthetized rats. Initial results indicated that the systemic infusion of 6.25 micrograms VIP iv resulted in increased thyroid blood flow, but was also associated with hypotension, as measured by left ventricular pressure. In contrast, topical administration of VIP to the left of the thyroid increased blood flow to that lobe, but not to the right lobe, and produced no systemic cardiovascular effects. In a further set of experiments, graded doses of VIP were administered iv. Infusions of 6.25 and 0.625 micrograms VIP were associated with 2- to 3-fold increases in thyroid and pancreatic blood flows, but lower doses were ineffective. Blood flows to the adrenals, brain, small intestine, kidneys, and spleen were not altered by any dose of VIP. Mean left ventricular pressure was again reduced by the 6.25-micrograms dose of VIP, but was not affected by lower doses. The infusions of VIP had no effect on plasma TSH, T3, or T4 levels either 20 min or 2 h after treatment. These results suggest that thyroid blood flow is, in part, controlled by VIP and indicate that changes in thyroid blood flow can occur at doses of VIP that have no apparent effect on circulating thyroid hormone levels.