Conservation of free but not total or non-sex-hormone-binding-globulin-bound testosterone in serum from Nagase analbuminemic rats

Nagase analbuminemic rats have normal reproductive capacity, normal apparent libido, and normal serum concentrations of LH and FSH. Therefore, it is reasonable to assume that intracellular sex steroid hormone concentrations are normal or at least adequate to maintain normal reproductive function in these rats. To test whether intracellular testosterone concentrations in these rats are maintained by the circulating concentration of free or free-plus-weakly-bound testosterone, we measured the concentrations of total testosterone, free testosterone, and non-sex-hormone-binding-globulin-bound testosterone in sera from five adult male Nagase analbuminemic rats and from five age- and sex-matched controls. We found that the analbuminemic rats had markedly decreased serum concentrations of total and non-sex-hormone-binding-globulin-bound testosterone, but normal serum concentrations of free testosterone. These results suggest that intracellular concentrations of testosterone in biologically relevant organs of the rat are maintained by the concentration of free rather than free-plus-weakly-bound testosterone in plasma, in accord with the free hormone hypothesis.     

Diminished diurnal secretion of corticosterone in aging female but not male rats

Since very little is known about the impact of aging on adrenocortical function in female rats, it was of interest to compare the age changes in the circulating levels of adrenocorticotropin (ACTH) and corticosterone in male and female Sprague-Dawley rats, and correlate these changes with those in plasma prolactin (Prl), which is known to stimulate adrenal steroid secretion. Hormones were measured in young (3-4 months) and old (24-26 months) male rats as well as in young (3-4 months), old (25 months) and senescent (33-35 months) female rats. Sequential plasma samples were obtained from chronically cannulated animals every 30 min from 11:30 a.m. to 4:30 p.m. ACTH was measured in trunk serum--obtained between 11:30 a.m. and 1:30 p.m.--whereas corticosterone and prolactin were measured in plasma using specific RIAs for the corresponding hormones. No age changes were detected in serum ACTH in either sex. The integrated values of plasma corticosterone did not change with age in males but decreased significantly (p less than 0.05) in old and senescent as compared to young females. Plasma corticosterone was higher in young females than in young males but this sex-related difference disappeared with age. Plasma Prl increased significantly with age in both male (p less than 0.05) and female (p less than 0.001) rats but showed no significant correlation with corticosterone levels. The present results suggest that ACTH secretion does not show major age- or sex-related changes. Our corticosterone data are compatible with the idea that gonadal aging has a significant impact on plasma glucocorticoid regulation in female rats but not in males.     

Food restriction regulates adipose-specific cytokines in pituitary gland but not in hypothalamus

White adipose tissue is now recognized as the source of a growing list of novel adipocyte-specific factors, or adipokines. These factors regulate energy homeostasis, including the response to food deprivation. We hypothesized that the brain and pituitary gland would also express adipokines and their regulatory factors and subsequently demonstrated that the rodent brain-pituitary system expresses mRNA and protein for leptin and resistin. We now report that the adipokines FIAF and adiponutrin, as well as the nuclear hormone receptor PPAR gamma, are expressed in pituitary, brain and adipose tissue. In pituitary gland, 24 h of food restriction reduced PPAR gamma expression by 54% whereas both adiponutrin and FIAF were increased 1.7 and 2.3 fold, respectively. These changes in expression were similar to those observed in fat, except for adiponutrin, which by contrast is dramatically reduced 95% by fasting. Furthermore, whereas PPAR gamma 2 is the main isoform affected by fasting in adipose tissue, our data suggest that only PPAR gamma 1 is present and downregulated by fasting in pituitary tissue. In contrast to the sensitivity of pituitary tissue to the effects of fasting, no significant change in expression was observed in basal hypothalamus for any of the genes studied. Overall, our data suggest that pituitary-derived adipokines may play an unexpected role in the neuroendocrine regulation of energy homeostasis.     

Food restriction enhances melatonin effects on the pituitary-gonadal axis in female rats

The effects of melatonin (25 micrograms s.c. daily in the late afternoon for 10 days) on the ovarian morphometry and the gonadotropin secretion were investigated in food-restricted rats and rats fed ad libitum. In food-restricted rats melatonin produced the significant decrease of the surface area of the ovary and of zona granulosa. Moreover, melatonin treatment of food-restricted rats resulted in significant diminishment of the relative areas of Graafian follicles and zona granulosa estimated in relation to the ovary cross-sectional surface area. On the other hand, melatonin did not produce significant alterations of the morphometric indices of the ovary in rats fed ad libitum. Melatonin administration was found to inhibit the effects of gonadoliberin on gonadotropin release in food-restricted but not in normally-fed rats. These findings suggest that food restriction sensitizes the pituitary-ovarian axis to antigonadotropic melatonin action.     

Physiological elevations of plasma beta-endorphin alter glucose metabolism in obese, but not normal-weight, subjects.

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.     

Estrogen treatment enhances nitric oxide bioavailability in normotensive but not hypertensive rats

BACKGROUND: The effects of estrogen on endothelial function remain controversial. Endothelial function is perturbed in hypertension. We aimed to determine whether pre-existing hypertension can modify endothelial-dependent responses to estrogen. METHODS: We compared the effects of estrogen replacement on endothelial function in healthy female adult Wistar Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). Basal and carbachol-stimulated nitric oxide (NO) bioavailability were studied in carotid artery rings in ovariectomized animals treated with estrogen or placebo for 2 weeks in vivo, or after 1 h of incubation in vitro. Basal NO bioavailability was defined as the increase in pressor responses in phenylephrine in the presence of NO synthase blockade. Superoxide (O(2)(-)) levels in aortas were measured by lucigenin chemiluminescence and endothelial NO synthase (eNOS) protein levels by Western blotting. RESULTS: Basal NO bioavailability was increased in WKY treated with estrogen for 2 weeks compared to placebo. In contrast, no change in NO bioavailability was observed in SHRSP. The O(2)(-) levels were higher in SHRSP than in WKY but unaffected by estrogen treatment in either strain. In WKY, but not in SHRSP, estrogen caused upregulation of eNOS. Similarly in vitro exposure to estrogen increased NO bioavailability in WKY but had no effect in SHRSP. In WKY, co-exposure to estrogen and LY294002, a PI3 kinase inhibitor, abrogated the effect of estrogen. CONCLUSIONS: The inability of estrogen to improve endothelial function in SHRSP may relate to a defect in eNOS activation pathways in this hypertensive rat strain.     

Phase shifts in circadian rhythmicity of total,free corticosterone and transcortine plasma levels in hypothyroid male Japanese quails

Control, radiothyroidectomized, and methimasol-treated short day (6L:18D; beginning of light at 0700) male Japanese quails were studied with regard to their circadian rhythmicity of total, free corticosterone and transcortine plasma level.In the controls, the peak of total and free corticosterone coincided with the maximal corticosterone binding capacity of transcortine; these parameters can be characterized by similar daily rhythm. In hypothyroid birds a synchronous phase shift of these parameters has been observed. In methimasol-treated animals the phase shift of the circadian rhythmicity was 6–8 hr, and in the radiothyrodectomized group 12 hr, respectively. According to the degree of hypothyroidism the metabolic clearance rate (MCR) of corticosterone decreased. This effect leads to the phase shift of total corticosterone rhythm, and the shift includes not only free, but also transcortine concentration.     

Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression,but does not correlate with endogenous corticosterone levels

Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels. At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0.05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0.001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0.05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0.001) but higher plasma corticosterone levels (P<0.05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0.01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0.01) and in pups from ADX control mothers (P<0.01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0.05 and P<0.01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery. We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.     

Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys

Many age-associated pathophysiological changes are retarded by caloric restriction (CR). The present study has investigated the effect of CR on plasma lipoprotein (a) [Lp(a)], an independent risk factor for the age-associated process of atherosclerosis. Rhesus monkeys were fed a control diet (n=19 males, 12 females) or subjected to CR (n=20 males, 11 females fed 30% less calories) for >2 years. All female animals were premenopausal. Plasma Lp(a) levels in control animals were almost two fold higher for males than females (47+/-9 vs 25+/-5mg/dl mean+/-SEM, p=0.05). CR resulted in a reduction in circulating Lp(a) in males to levels similar to those measured in calorie-restricted females, (27+/-5 vs 24+/-4 mg/dl mean+/-SEM). For all animals, plasma Lp(a) was correlated with total cholesterol (r=0.27, p=0.03) and LDL cholesterol (r=0.50, p=0.0001) whether unadjusted or after adjustment for treatment, gender or group. These studies introduce a new mechanism whereby CR may have a beneficial effect on risk factors for the development of atherosclerosis in primates.     

DOCA-salt treatment decreases serum total calcium but not ionized calcium concentrations in rats

We examined whether or not DOCA-salt treatment to rats would decrease serum ionized calcium concentrations in relation to the enhanced hypotensive response to the calcium antagonist nifedipine. DOCA-salt treatment increased blood pressure and enhanced the hypotensive effects of nifedipine. Serum total calcium and albumin levels were clearly reduced, but the ionized fraction of calcium was not altered by treatment with DOCA-salt for 4 weeks. The total serum calcium concentration, but not the ionized calcium, significantly correlated with serum albumin in DOCA-salt rats. A reduction in serum ionized calcium may therefore not be induced by DOCA-salt treatment and may not be related to the enhanced depressor response to nifedipine.     

Recombinant human growth hormone enhances tibial growth in peripubertal female rats but not in males

OBJECTIVE: A novel non-invasive technique termed microknemometry, which allows daily leg length measurement, was used to investigate the growth promoting effect of growth hormone (GH) on peripubertal rats. We compared the effect of different patterns of recombinant human (rh) GH administration to peripubertal male rats with the effect produced by two daily administrations of the same amount of rhGH to peripubertal female rats or adult male rats. Another group of peripubertal male rats was also submitted to a 3-day period of starvation, in order to study catch-up growth during refeeding and to determine whether this process could be stimulated by exogenous GH administration. RESULTS: GH treatment was unable to stimulate tibial growth or weight gain in peripubertal males, whereas a clear growth promoting effect was observed in female rats and also in adult male rats. Starvation caused a dramatic body weight loss, and a reduction in tibial growth rate. Peripubertal male rats gained body weight faster than unstarved animals during refeeding, although recovery was not complete after nine days. Tibial growth, however, was resumed at the same speed as in normally fed males. This means that no catch-up effect was observed after refeeding in animals either with or without GH treatment. CONCLUSIONS: During peripuberty, normal male rats grow at a maximal speed that cannot be further increased by exogenous GH treatment, whereas age-matched female rats or older males grow at a slower rate than peripubertal males. Thus, exogenous rhGH administration is capable of enhancing growth velocity.     

Corynebacterium parvum, but not BCG, induces elevations in plasma proteinase activity similar to those observed in tumor-bearing mice

Intraperitoneal administration of Corynebacterium parvum to BALB/c, C57Bl/6 or C3H/HeJ mice lead to the induction of elevated levels of neutral proteinase activity (125I-caseinolytic activity) similar to those observed previously in animals bearing the BCL1 leukemia or the B16-F10 melanoma. Enhanced activity reached a peak at 7-14 days postinjection of the C. parvum and then gradually returned to normal levels by 20-25 days postinjection. Increased plasma proteinase activity could be induced by C. parvum whole cells or the pyridine extract residue of C. parvum but not by BCG or the pyridine extract of C. parvum. BCG did not interfere with the induction of elevated levels of activity by C. parvum. Splenectomized animals responded the same as normal mice indicating that the splenomegaly accompanying the onset of increased plasma proteinase activity was not responsible for the changes. Administration of C. parvum via a subcutaneous site rather than intraperitoneally failed to induce systemic changes in proteinase activity while still inducing splenomegaly. Treatment of animals with C. parvum before or after transplantation of the BCL1 leukemia or the B16-F10 melanoma failed to alter the course of the disease or enhance the increased proteinase activity of plasma over that observed in plasma from animals bearing tumors alone. These observations support the hypothesis that the induction of disturbances in plasma proteinase activity in tumor-bearing animals is due to alterations in host systems and that C. parvum, in contrast to BCG, contains components which can mimic the effect of some tumors on host systems.     

Propranolol enhances the effect of ACTH on plasma cortisol, but not on aldosterone in man

An accidental observation led to the suspicion that propranolol (P) enhances the effect of exogenous ACTH on plasma cortisol. To examine this matter further, large-dose ACTH tests (25 IU im) were performed in 10 normal young males: i) without treatment (n =10); ii) after 11/2 days of P treatment (n = 10); iii) after 11/2 days of metoprolol treatment (n = 6). Six other subjects received infusions of 0.2 IU of ACTH/hour for 12 h: i) without pretreatment; ii) after 11/2 days of P treatment. P pretreatment (80 mg t.i.d.) led to a small but significant decrease in plasma cortisol (9.4 +/- 0.8 micrograms/100 mg; mean +/- SE, vs. 11.3 +/- 0.7 micrograms/100 ml in controls). The maximum percentage increase of plasma cortisol after ACTH injection was 383% +/- 35% (mean +/- SE) after P and 253% +/- 22% in controls (p less than 0.05). The enhancement of the absolute and relative increase of plasma cortisol after ACTH injection seems to be mainly due to lowering of basal cortisol levels, since the effect of ACTH on plasma cortisol in normal subjects in inversely related to basal cortisol. The effect of metoprolol on basal cortisol and the cortisol response to ACTH was less pronounced than that of P. In the long-term-infusion study the effect of P was less apparent than in the acute study. P had no significant effect on basal plasma aldosterone or on the aldosterone response to ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of corticosterone production by vasopressin during water restriction and after drinking in rats

Plasma vasopressin (VP) and corticosterone have each been shown to be rapidly suppressed after drinking in different models of osmotic stimulation in rats; however, no causal relationship between these responses has been investigated. Studies were performed to determine if plasma VP and corticosterone are reduced in parallel after drinking and if manipulation of plasma VP affects plasma, ACTH corticotropins and corticosterone in a model of water restriction. A strong correlation between changes in plasma VP and corticosterone, but not between plasma ACTH and corticosterone, was observed after drinking induced by 6 days of water restriction. Similarly, ingestion of isotonic saline resulted in a biphasic VP response that was paralleled by adrenal and plasma corticosterone, but not by plasma ACTH. Administration of an immunoneutralizing antibody directed against VP resulted in a rapid decrease in plasma corticosterone, but not ACTH, in water-restricted rats, but not in rats receiving water ad libitum. These data suggest that during dehydration, elevated plasma VP can stimulate the production of corticosterone by the adrenal, independently of ACTH. Moreover, they support the hypothesis that the decline in corticosterone after restriction-induced drinking is due, in part, to a decline in plasma VP.     

Migration is associated with lower total, but not free testosterone levels in South Asian men

OBJECTIVE: Serum testosterone measurement is an integral part of the endocrine assessment of men. Little is known about its variation in relation to migration. We examined within a South Asian group the effect of migration to the UK on androgen levels. DESIGN: Circulating testosterone and SHBG concentrations were measured in 97 Gujarati men resident in India and in 79 men from the same villages of origin living in Birmingham, UK. Free testosterone was calculated by Vermeulen's method. Insulin sensitivity (HOMA-S) was determined from paired fasting plasma intact insulin and glucose values. RESULTS: Circulating testosterone was significantly lower in UK Gujarati men (17.2 nmol/l [15.7-18.7]) vs. Indian Gujarati men (21.7 [20.0-23.5]) (P = 0.0002) (age-adjusted median [95% CI]). There was no difference by migration status in circulating free testosterone. Sex hormone binding globulin (SHBG) levels were lower in UK migrants (16.8 nmol/l [15.5-18.1]) than in nonmigrants (21.9 nmol/l [20.5-23.3]) (P < 0.0001). Testosterone level correlated positively with insulin sensitivity (HOMA-S) (rho 0.16, P = 0.04). In multivariate analysis, total testosterone was independently and positively associated with logSHBG (normalized beta (beta) = 0.29, P = 0.002) and independently and negatively with waist circumference (beta = -0.19, P = 0.04), in a model also including height, age, migration status, leptin and fasting insulin. CONCLUSION: Lower circulating testosterone in UK Gujarati men and its association with markers of insulin sensitivity suggest a profound influence of body composition change with migration on testosterone levels. The lower SHBG in this group restores parity in free testosterone. Account should be taken of SHBG in interpreting testosterone levels in men, as well as in women.     

Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats

Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsulinemia, insulin resistance with respect to glucose metabolism, elevated plasma free fatty acid (FFA) levels, hypertriglyceridemia, and decreased high-density lipoprotein (HDL) cholesterol. An association between hyperinsulinemia and dyslipidemia has been suggested, but the causality of the relationship remains uncertain. Therefore, we infused eight 12-week-old male catheterized conscious normal rats with insulin (1 mU/min) for 7 days while maintaining euglycemia using a modification of the glucose clamp technique. Control rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07+/-0.13 mmol/L, decreased to 0.57+/-0.10 (P < .05) upon initiation of the insulin infusion, and gradually increased to 0.95+/-0.12 by day 7 (P = NS vbaseline). On day 7 after a 6-hour fast, plasma insulin, glucose, and FFA levels in control and chronically hyperinsulinemic rats were 32+/-5 versus 116+/-21 mU/L (P < .005), 122+/-4 versus 129+/-8 mg/dL (P = NS), and 1.13+/-0.18 versus 0.95+/-0.12 mmol/L (P = NS); total plasma triglyceride and cholesterol levels were 78+/-7 versus 66+/-9 mg/dL (P = NS) and 50+/-3 versus 47+/-2 mg/dL (P = NS), respectively. Very-low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and cholesterol were similar in control and hyperinsulinemic rats. Plasma FFA correlated positively with total (r = .61, P < .005) triglycerides. On day 7 after an 8-hour fast, hyperinsulinemic-euglycemic clamps with 3-3H-glucose infusion were performed in all rats. Chronically hyperinsulinemic rats showed peripheral insulin resistance (glucose uptake, 15.8+/-0.8 v 19.3+/-1.4 mg/kg x min, P < .02) but normal suppression of hepatic glucose production (HGP) compared with control rats (4.3+/-1.0 v 5.6+/-1.4 mg/kg x min, P = NS). De novo tissue lipogenesis (3-3H-glucose incorporation into lipids) was increased in chronically hyperinsulinemic versus control rats (0.90+/-0.10 v 0.44+/-0.08 mg/kg x min, P < .005). In conclusion, chronic physiologic hyperinsulinemia (1) causes insulin resistance with regard to the suppression of plasma FFA levels and increases lipogenesis; (2) induces peripheral but not hepatic insulin resistance with respect to glucose metabolism; and (3) does not cause an elevation in VLDL-triglyceride or a reduction in HDL-cholesterol.     

Effect of adenosine analogues on plasma corticosterone concentration in rats.

In this study we examined the effect of the adenosine analogues: N6-cyclohexyladenosine, L-N6-phenylisopropyladenosine and 5'-N-ethylcarboxamidoadenosine on the plasma corticosterone concentration in rats. It was found that N6-cyclohexyladenosine (0.1-3.0 mg/kg), L-N6-phenylisopropyladenosine (0.1-1.0 mg/kg) and 5'-N-ethylcarboxamidoadenosine (0.01-1.0 mg/kg) dose-dependently increased the plasma corticosterone level. The effects of N6-cyclohexyladenosine (0.1 mg/kg) and L-N6-phenylisopropyladenosine (0.1 mg/kg) were completely blocked in animals pretreated with dexamethasone (3 x 1 mg/kg), as well as in animals with a pharmacological blockade of the release of hypothalamic corticotropin-releasing factor induced by chloropromazine (10 mg/kg), morphine (20 mg/kg) and nembutal (25 mg/kg), whereas the corticosterone response to 5'-N-ethylcarboxamidoadenosine (0.01 mg/kg) was blocked in dexamethasone-pretreated rats only. On the other hand, the adenosine receptor antagonists: 8-(p-sulfophenyl)-theophylline (30 mg/kg), 8-phenyltheophylline (10 and 30 mg/kg), 1,3-dipropyl-8-(2-amino-4-chloro)-phenylxanthine (1 and 3 mg/kg) and 1,3-dipropyl-7-methylxanthine (1 mg/kg) did not affect the corticosterone response to N6-cyclohexyladenosine, L-N6-phenylisopropyladenosine or 5'-N-ethylcarboxamidoadenosine. The obtained results indicate that N6-cyclohexyladenosine and L-N6-phenylisopropyladenosine stimulate the corticosterone secretion at the hypothalamic level, whereas 5'-N-ethylcarboxamidoadenosine is likely to act at the pituitary level. Although the effects produced by the adenosine analogues show that both A1 and A2 receptors are involved in the corticosterone response, negative results of the interaction studies with adenosine receptor antagonists indicate that further experiments are necessary to elucidate this problem.