Glucocorticoid receptor density correlates with health risk factors and insulin resistance in Caucasian and African American subjects.

Activation of the hypothalamic-pituitary-adrenal axis leads to secretion of cortisol, which binds to peripheral glucocorticoid receptor and mediates a complex series of metabolic and immune effects. Cortisol also binds to receptors in the hypothalamus and pituitary, and inhibits further secretion of adrenocorticotropic hormone thus preventing an excessive response. Excess glucocorticoid effect is seen in Cushings disease, adrenal adenomas/carcinomas and in glucocorticoid resistance. Within such pathology there are health consequences of excessive glucocorticoid action, including obesity, hypertension, and glucose intolerance or diabetes. We hypothesized that increased glucocorticoid receptor in peripheral tissue might mediate an excess glucocorticoid effect in the absence of increased cortisol secretion. The objective of the study was to investigate the relationship between glucocorticoid receptor density in leukocytes and health risk indices relevant to obesity and diabetes in a sample of Caucasian and African American subjects. Comparison of glucocorticoid receptor concentration with subject body mass index, percentage body fat, waist circumference, insulin resistance, plasma cortisol levels, gender, and lipid profiles were conducted. Increased glucocorticoid receptor density significantly correlated with body mass index, percentage body fat, waist circumference, and insulin resistance. No significant correlation was observed for glucocorticoid receptor density with lipid profiles. Furthermore, no significant differences were observed in glucocorticoid receptor density between Caucasian and African American subjects or male and female participants. Our results show that high risk health conditions, such as obesity and type-2 diabetes, may be associated with a form of hypothalamic-pituitary-adrenal axis dysfunction, characterized by localized leukocyte glucocorticoid receptor over-expression.

African Americans and Caucasian Americans: differences in glucocorticoid-induced insulin resistance.

African Americans are more insulin resistant than Caucasian Americans and this discrepancy cannot be explained by measures of body weight or body composition. The aim of the study was to compare the sensitivity of African Americans and Caucasian Americans to glucocorticoids by measuring glucose and insulin responses to a meal challenge under conditions of placebo and glucocorticoid. A total of 160 healthy or overweight/obese African American and Caucasian American participants completed exercise testing and a liquid meal challenge during separate laboratory visits. Participants were evaluated following treatments with placebo and dexamethasone (4 mg). Main outcome measures were correlation between body composition measures (body mass index, percent body fat, waist circumference) and insulin responses; insulin and glucose responses after a liquid meal challenge; and calculated HOMA. After dexamethasone treatment African Americans were significantly more hyperinsulinemic after a meal as indicated by higher peak insulin (p=0.02) and postprandial insulin areas under the curve (p=0.006) than Caucasians. Additionally, African Americans were more insulin resistant than Caucasian Americans under both placebo and dexamethasone as determined by fasting insulin and HOMA (p=0.05). Waist circumference correlated with post-dexamethasone insulin AUC and HOMA in Caucasian Americans (p<0.05), but none of the body composition measures were predictive of IR for African Americans. African Americans are more sensitive to glucocorticoids (dexamethasone) than Caucasian Americans, as indicated by significantly greater peak insulin and postprandial insulin areas under the curve. The glucocorticoid receptor and its potential interactions with stress may contribute to this ethnic disparity.

A case study of nitrogen saturation in western U.S. forests.

Virtually complete nitrification of the available ammonium in soil and nitrification activity in the forest floor are important factors predisposing forests in the San Bernardino Mountains of southern California to nitrogen (N) saturation. As a result, inorganic N in the soil solution is dominated by nitrate. High nitrification rates also generate elevated nitric oxide (NO) emissions from soil. High-base cation saturation of these soils means that soil calcium depletion or effects associated with soil acidification are not an immediate risk for forest health as has been postulated for mesic forests in the eastern U.S. Physiological disturbance (e.g., altered carbon [C] cycling, reduced fine root biomass, premature needle abscission) of ozone-sensitive ponderosa pine trees exposed to high N deposition and high ozone levels appear to be the greater threat to forest sustainability. However, N deposition appears to offset the aboveground growth depression effects of ozone exposure. High nitrification activity reported for many western ecosystems suggests that with chronic N inputs these systems are prone to N saturation and hydrologic and gaseous losses of N. High runoff during the winter wet season in California forests under a Mediterranean climate may further predispose these watersheds to high nitrate leachate losses. After 4 years of N fertilization at a severely N saturated site in the San Bernardino Mountains, bole growth unexpectedly increased. Reduced C allocation below- ground at this site, presumably in response to ozone or N or both pollutants, may enhance the bole growth response to added N.

Nitrate in polluted mountainous catchments with Mediterranean climates.

The mountains of southern California receive some of the highest rates of nitrogen (N) deposition in the world (approximately 40 kg ha(-1) year(-1)). These high rates of deposition have translated into consistently high levels of nitrate (NO3-) in some streams of the San Bernardino Mountains. However, not all streams are exhibiting these high levels of NO3-. Perennial streams have high NO3- concentrations (approximately 200 micromoles l(-1)) while ephemeral streams do not (approximately 20 micromoles l(-1)). This difference points to groundwater as the source of the NO3- observed in streams. Furthermore, the evidence indicates a differential impact of N deposition on terrestrial and aquatic systems in Mediterranean climates, with aquatic systems being impacted more quickly. The primary reason for this difference involves the asynchrony between the time that atmospheric deposition occurs (summer), the time period of maximum soil NO3- availability and leaching (winter), and the time of maximum plant N demand (spring). Our results indicate that semiarid Mediterranean climate systems behave differently from more humid systems in that, because of this asynchrony, aquatic systems may not be indicative of changes in terrestrial ecosystem response. These differences lead us to the conclusion that the extrapolation of impacts from humid to Mediterranean climates is problematic and the concept of N saturation may need to be revisited for semiarid and seasonally dry systems.

Endocrine response to high-intensity exercise: dose-dependent effects of dexamethasone.

We recently reported that in 30-50% of healthy men and women the release of ACTH and cortisol stimulated by exercise is not suppressed by prior administration of a 4-mg dose of dexamethasone (DEX). We now explore other potential differences between these subjects and those whose exercise response was suppressed by examining the effect of a smaller, 1-mg, dose of DEX on exercise-stimulated ACTH and cortisol. Men (n = 15) and women (n = 9) were studied during three high intensity exercise tests: one after taking placebo, one after taking 1 mg DEX, and one after taking 4 mg DEX. Before participation, subjects underwent a test for classification as either a high (HR; n = 10) or low (LR; n = 14) reactor and a maximal exercise test to assess maximal aerobic capacity. Distinct dose-related reductions in plasma concentrations of ACTH, cortisol, and dehydroepiandrosterone (DHEA) were noted for HR under the treatment conditions, whereas both doses of DEX blocked ACTH, cortisol, and DHEA release in LR. Furthermore, basal plasma cortisol, DHEA, and DHEA sulfate were significantly higher in HR compared to LR. Thus, there are inherent basal and stress-reactive differences in HR and LR, and these differences may be useful in constructing a model for the mechanisms and physiological regulation of hypothalamic-pituitary-adrenal axis activation. The question of whether these differences in reactivity of the ACTH-cortisol axis between the HR and LR groups have implications for individual short term function or long term health remains to be answered.

Hormone-containing cosmetics may cause signs of early sexual development.

Exogenous hormone exposure can cause early sexual development, but only one report suggests that this may occur secondary to the use of hair-care products. This study evaluated the usage frequency and biological effects of hormone-containing hair-care products. We reviewed the records of 102 consecutive dependent children referred for evaluation of sexual precocity. Eight children (7.8%) were using these products. All eight were black (100%), compared to 57 (61%) of the 94 patients not using such products (p < 0.05). There was no significant difference between these two groups in mean age, sex distribution, height, height standard deviation score, bone age:chronologic age ratio, or serum estradiol level. We conclude that exposure to hormones in hair-care products may be more frequent than expected and should be considered in the differential diagnosis of early sexual development in children.

Evidence to suggest nitric oxide is an interstitial regulator of Leydig cell steroidogenesis.

Recent studies have suggested that nitric oxide (NO) may function as both an intracellular and intercellular signal that affects neural and immunological activity, vascular tone, platelet adhesion, and production of some hormones. Arginine analogs such as NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine methyl ester (L-NAME) act to inhibit the intracellular formation of NO and have been used to study the effects of decreased NO formation on physiological systems. A single in vivo study has suggested that a similar analog, NG-nitro-L-arginine, increases serum testosterone (T), but the organ site and mechanism of action were not investigated. The present study was performed to investigate the effects of NO synthase inhibitors on Leydig cell function. L-NMMA and L-NAME, but not the inactive enantiomer (D-NMMA), increased both basal and human chorionic gonadotropin (hCG)-stimulated T production while decreasing guanosine 3':5'-cyclic monophosphate (cGMP). There was no effect on either adenosine 3':5'-cyclic monophosphate (cAMP) accumulation or specific hCG binding. These results suggest that NO formation, which is inhibited by L-NMMA and L-NAME, is important in the regulation of Leydig cell T production by interstitial cells of the testis, and that changes in cGMP levels might be involved in this process.

Growth response of bigcone Douglas fir (Pseudotsuga macrocarpa) to long-term ozone exposure in southern California.

Long-term radial growth of bigcone Douglas fir (Pseudotsuga macrocarpa) was studied throughout its range in the San Bernardino Mountains of southern California, where ambient ozone has been high for approximately the past 40 years. A gradient of both ozone concentration and precipitation exists from west (high) to east (low). Growth rates of bigcone Douglas fir are considerably lower since 1950 throughout the San Bernardino Mountains, with the largest growth reductions in the western part of the range where ozone exposure is highest. Needle retention is also somewhat lower at high ozone sites. Lower annual precipitation since 1950 may have some impact on long-term growth reductions, and short-term growth reductions induced by drought are an important component of long-term growth reductions at sites with high ozone exposure. An ozone-climate stress complex may be responsible for recent reductions in the growth of bigcone Douglas fir.

Effect of chronic growth hormone administration on diabetic nephropathy in the rat.

Indirect data exist which implicate elevated growth hormone (GH) as a factor in the development of diabetic nephropathy. The administration of somatostatin (SRIH) has been shown to reverse many of the changes found in early diabetic nephropathy; however, it is unknown whether SRIH causes these effects by the suppression of GH or by other unspecified factors. To study directly the possible effect of excess GH in the development of diabetic nephropathy, either ovine growth hormone (0.2 mg oGH) or diluent buffer was administered IM daily for 19 weeks to diabetic rats and to controls. Severity of nephropathy was assessed by 24 hour urine albumin excretion (UAE), relative kidney weight, and kidney histology. Results showed that diabetic rats overall had elevated UAE and kidney weight vs non-diabetic rats (46.2 +/- 8.6 vs 5.4 +/- 1.3 mg per day and 5.7 +/- 0.2 vs 2.7 +/- 0.1 mg per g of body weight, respectively, p < 0.001). However, no differences were detected between diabetic rats treated with GH compared to control diabetic rats. Additionally, diabetic rats had histopathologic changes consistent with early diabetic nephropathy, but no difference in severity scores was found between diabetic groups. These data provide evidence against GH as an etiologic factor in the development of diabetic nephropathy and it is speculated by the authors that SRIH exerts its protective renal effects in diabetes by mechanisms other than GH suppression.

A comparison of NO and N2O production by the autotrophic nitrifier Nitrosomonas europaea and the heterotrophic nitrifier Alcaligenes faecalis.

Soil microorganisms are important sources of the nitrogen trace gases NO and N2O for the atmosphere. Present evidence suggests that autotrophic nitrifiers such as Nitrosomonas europaea are the primary producers of NO and N2O in aerobic soils, whereas denitrifiers such as Pseudomonas spp. or Alcaligenes spp. are responsible for most of the NO and N2O emissions from anaerobic soils. It has been shown that Alcaligenes faecalis, a bacterium common in both soil and water, is capable of concomitant heterotrophic nitrification and denitrification. This study was undertaken to determine whether heterotrophic nitrification might be as important a source of NO and N2O as autotrophic nitrification. We compared the responses of N. europaea and A. faecalis to changes in partial O2 pressure (pO2) and to the presence of typical nitrification inhibitors. Maximal production of NO and N2O occurred at low pO2 values in cultures of both N. europaea (pO2, 0.3 kPa) and A. faecalis (pO2, 2 to 4 kPa). With N. europaea most of the NH4+ oxidized was converted to NO2-, with NO and N2O accounting for 2.6 and 1% of the end product, respectively. With A. faecalis maximal production of NO occurred at a pO2 of 2 kPa, and maximal production of N2O occurred at a pO2 of 4 kPa. At these low pO2 values there was net nitrite consumption. Aerobically, A. faecalis produced approximately the same amount of NO but 10-fold more N2O per cell than N. europaea did. Typical nitrification inhibitors were far less effective for reducing emissions of NO and N2O by A. faecalis than for reducing emissions of NO and N2O by N. europaea.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of somatostatin and captopril on glomerular prostaglandin E2 production in normal and diabetic rats.

Somatostatin (SRIH) has recently been shown to be effective in reversing many of the early changes of diabetic nephropathy. It is unknown whether SRIH exerts its protective effects via its ability to suppress growth hormone (GH) or via other direct renal effects. Since changes in glomerular prostaglandin (PG) E2 production are thought to be an important part of the underlying pathophysiology of diabetic nephropathy, we sought to determine if SRIH altered glomerular PG E2 production in the rat. Whole glomeruli isolated from streptozotocin-diabetic rats and from controls were incubated with either saline, captopril, or varying concentrations of SRIH, and PG E2 production was determined by direct radioimmunoassay of media. Incubation with captopril (10(-4) M) resulted in equivalent increases in PG E2 production in glomeruli from both control and diabetic rats (140.8 +/- 12.8% and 150.2 +/- 18.9% respectively). Incubation with high concentrations of SRIH (10(-6) M) also resulted in significant increases in glomerular PG E2 production in both diabetic and control rats. However, at low SRIH concentrations (10(-10) M), glomerular PG E2 production was increased only in the diabetic rats (167.0 +/- 11.4% vs 95.3 +/- 9.2% in normals). We conclude that SRIH increases glomerular PG E2 production, and that glomeruli from diabetic rats appear to be more sensitive to lower concentrations of SRIH when compared to normal rats. It is possible that this effect on PG E2 production may underlie the favorable effects of SRIH on the glomerulus in diabetes.

The effects of dorsal raphe administration of eltoprazine, TFMPP and 8-OH-DPAT on resident intruder aggression in the rat.

To evaluate the role of somatodendritic 5-HT1A receptors in the mediation of aggressive behaviour, eltoprazine, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride) and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) were administered locally into the dorsal raphe nucleus of rats. 8-OH-DPAT (1 and 10 micrograms) and eltoprazine (10 and 30 micrograms) reduced aggression, but concomitantly reduced social interest and increased inactivity. TFMPP (1 and 10 micrograms) did not reduce aggression. As 8-OH-DPAT and to a lesser extent eltoprazine affect 5-HT1A receptors, it is proposed that a general reduction of serotonergic neurotransmission by activation of somatodendritic serotonergic autoreceptor leads to a non-specific reduction of aggression. As TFMPP has a significantly lower affinity for 5-HT1A receptors than 8-OH-DPAT or eltoprazine, the lack of effect of TFMPP supports this view.

The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino)tetralin on resident intruder aggression in the rat.

Various serotonergic agents may reduce aggression in rats, but how they act in different parts of the brain is unknown. This study attempted to unravel part of this question by application of different serotonergic ligands into the lateral ventricle (i.c.v.) of male rats (resident-intruder aggression). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin; 1 and 10 micrograms), a specific 5-HT1A agonist, affected neither aggression nor any other behaviour. The mixed 5-HT1A,B,C agonist, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride), and the 5-HT1A/1B agonist, eltoprazine ((1-(2,3)-dihydro-1,4-benzodioxin-5-yl)piperazine hydrochloride), suppressed aggression at i.c.v. doses of 10 and 30 micrograms. This reduction was not caused by sedation. These data suggest a role of postsynaptic 5-HT1B receptors in mediating the anti-aggressive effects of mixed 5-HT1 agonists.