Human immune cells mediate catecholamine secretion from adrenal chromaffin cells

OBJECTIVES: To determine the ability of human mononuclear cells to produce factors that cause catecholamine secretion from adrenomedullary chromaffin cells; to determine conditions that stimulate mononuclear cells to produce such factors; and to compare these results with catecholamine secretion in response to the cytokines interleukin (IL)-1 and IL-2. DESIGN: Randomized, controlled, prospective study using in vitro conditions. SETTING: University research laboratory. SUBJECTS: Human mononuclear cells and porcine chromaffin cells. INTERVENTIONS: Circulating human mononuclear cells were isolated and cultured overnight in RPMI media. Cell-free media from these cultures (conditioned media) were then tested for the ability to cause epinephrine secretion from porcine chromaffin cells. Mononuclear cells were stimulated with phytohemagglutinin or by mixing cells from two different individuals while suppression was tested with dexamethasone. Catecholamine secretion in response to IL-1 and IL-2 (50 and 500 units/well, respectively), or nicotinic agonist dimethylphenylpiperazinium (10 microM, which mimics the action of acetylcholine), was tested for comparison. MEASUREMENTS AND MAIN RESULTS: Isolated porcine chromaffin cells had stable catecholamine content at the time of secretion measurements, and catecholamine release from cells into the media was measured using electrochemical detection after high-performance liquid chromatography separation. Catecholamine secretion was expressed as a percentage of the total cellular content. Epinephrine secretion due to human conditioned media was 6.9 +/- 1.0% compared with 1.4 +/- 0.6% for control media (p < .05) and 14.6 +/- 3.3% for dimethylphenylpiperazinium (p < .05). Epinephrine secretion with conditioned media from mixed cells (mixed leukocyte reaction) was 16.6 +/- 1.2%, which was higher than the epinephrine secretion caused by media from a single donor (6.9% +/- 1.0, p < .001). Pretreatment with dexamethasone inhibited the formation of bioactive products from mixed mononuclear cell preparations. Cytokines IL-1 and IL-2 did not stimulate chromaffin cell epinephrine secretion above background release with control media incubation. In all cases, norepinephrine secretion was similar to that of epinephrine, and results are included in all figures. CONCLUSIONS: Factors released from human immune cells can mediate epinephrine and norepinephrine release from adrenomedullary cells through a nonneural mechanism. Such immune cell factor release can be modulated by immunostimulation and steroid suppression. Release of such factors in vivo may contribute to increased circulating epinephrine in response to infectious challenge and may be an important factor in the critically ill patient.     

The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids

In the present study we examined the coupling of NADPH oxidation to substrate hydroxylation and the effects of steroids on this process in reconstituted P450scc and P450c11 systems. To determine the relative rates of substrate hydroxylation vs electron leakage we assayed both the steroid product and H2O2 in the same sample. For both P450 systems the rates of steroid product and superoxide formation increased as NADPH concentration was increased. However, P450c11 was found to be more leaky. The leakage from the P450scc system was not affected by pregnenolone, the product of cholesterol side chain cleavage. In contrast, corticosterone, the product of P450c11, increased the rate of futile NADPH oxidation by the P450c11 system. We also tested a series of steroids to analyze the stereospecificity of their effects. Relative to the control without steroid, both C-19 and C-21 steroids with 11 alpha-hydroxy groups (11 alpha-OH-testosterone and 11 alpha-OH-cortisol) decreased leakage, and those with 11 beta-OH groups (11 beta-OH-testosterone and cortisol) stimulated both NADPH oxidation and electron leakage as measured by H2O2 formation. The results revealed a correlation between the effects previously observed in living cells and in our reconstituted systems. These findings provide further evidence that mitochondrial P450 systems indeed function as a significant source of oxygen radicals in steroidogenic cells.     

Cortisol and catecholamine kinetics during continuous hemodiafiltration in patients with multiple organ dysfunction syndrome

OBJECTIVE: To assess the influence of continuous hemodiafiltration (CHDF) on cortisol and catecholamine kinetics in multiple organ dysfunction syndrome. DESIGN: Consecutive clinical study. SETTING: General intensive care unit of a university hospital. PATIENTS: Ten adult patients with multiple organ dysfunction syndrome requiring CHDF. MEASUREMENTS AND RESULTS: A total of 40 samples were collected during CHDF for cortisol and catecholamine assays. The clearances for cortisol, epinephrine, norepinephrine and dopamine were 2.5 +/- 1.7 ml/min, 26.3 +/- 2.7 ml/min, 16.7 +/- 4.2 ml/min and 26.3 +/- 2.6 ml/min (Mean +/_ SE), and their daily extractions were 1.8 +/- 0.2 mg/day, 11.4 +/- 4.8 micrograms/day, 1.0 +/- 0.1 micrograms and 2.3 +/- 0.3 micrograms/day, respectively. There were no significant changes in blood cortisol and catecholamine levels during CHDF conducted for 48 h. CONCLUSIONS: The cortisol and catecholamine losses during CHDF were small and unlikely to lead to hemodynamic disturbances.     

Apoptosis in the chick wing bud and the permanence of FGF-2 rescue

The concentrations of plasma epinephrine (E) and norepinephrin (N) measured at rest in bullfrogs (Rana catesbeiana) were 12.0 and 8.2 nmol liter-1 respectively: the ratio of [E]/[N] was 1.33 (+/- SE 0.35). Adrenal glands contained high concentrations of epinephrine (2,923 nmole g wet weight-1) and norepinephrine (6,194), at a ratio of 0.46 (+/- SE 0.04) [E]/[N]. This differs from the measured plasma ratio and endogenous release ratios of about 2 for [E]/[N] reported for other Rana species, although the 95% confidence interval of our plasma ratio (0.97) spans the range of values from 0.36 to 2.3, including the observed plasma ratio of 0.46. Therefore, resting plasma catecholamine levels generally reflect the proportional adrenal content of catecholamines. Plasma epinephrine and norepinephrine concentrations significantly increased after activity to 50.4 and 18.1 nmol liter-1, respectively. The ratio of epinephrine to norepinephrine ([E]/[N]) also increased (but not significantly) to 8.53 (+/- SE 4.23), suggesting a shift away from some adrenal tone at rest to sympathetic nerve dominance with activity. Graded hemorrhage led to further increases in plasma epinephrine concentration and [E]/[N] but not norepinephrine, indicating sympathetic but not adrenal involvement. The in vitro epinephrine sensitivity of vascular beds indicates recruitment of the dorsal aorta vascular beds before the pulmocutaneous vascular bed. The minimum sensitivity of vascular beds to perfused epinephrine (10(4) nmol liter-1) was at higher concentrations than maximal plasma concentrations measured during hemorrhage. The bullfrog is less tolerant of hemorrhage than the cane toad Bufo marinus. The major difference in the catecholamine response of these two species was the massive contribution of adrenal catecholamines with severe hemorrhage in toads, which is absent in bullfrogs. This suggests that the enhanced hemorrhage and dehydration tolerance of toads may in part be the result of their greater adrenal gland development and activity.     

Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events

We studied the effects of cigarette smoking, sham smoking and smoking during adrenergic blockade in 10 subjects to determine whether smoking released the sympathetic neurotransmitter norepinephrine, as well as the adrenomedullary hormone epinephrine, and whether smoking-associated hemodynamic and metabolic changes were mediated through adrenergic mechanisms. Smoking-associated increments in mean (+/- S.E.M.) plasma norepinephrine (227 +/- 23 to 324 +/- 39 pg per milliliter, P less than 0.01) and epinephrine (44 +/- to 113 +/- 27 pg per milliliter, P less than 0.05) were demonstrated. Smoking-associated increments in pulse rate, blood pressure, blood glycerol and blood lactate/pyruvate ratio were prevented by adrenergic blockade; increments in plasma growth hormone and cortisol were not. Since significant smoking-associated increments, in pulse rate, blood pressure and blood lactate/pyruvate ratio, preceded measurable increments in plasma catecholamine concentrations, but were adrenergically mediated, these changes should be attributed to norepinephrine released locally from adrenergic axon terminals within the tissues rather than to increments in circulating catecholamines.     

Anaphylactic reactions to bee-sting challenges in allergic children are not modified by endogenous catecholamines

To investigate the role of basal catecholamine levels and the response of the adrenergic system to expected bee stings, plasma catecholamines were measured before and 1 and 2 min after bee-sting challenges. Twenty-one children (aged 4-15 y) with bee-sting allergies were selected for sequential challenges to establish the need for venom immunotherapy. The time interval between the challenges varied from 2 to 6 wk. Epinephrine, norepinephrine, and dopamine plasma levels were measured using a simultaneous single-isotope radioenzymatic assay. On the first challenge, 33% of the children experienced a normal local reaction, 29% a large local reaction, and 38% a systemic reaction. On the second challenge in 18 out of 21 subjects, 67% experienced a normal normal local reaction, 22% a large local reaction, and 11% a systemic reaction. Epinephrine and norepinephrine plasma levels increased significantly on the first and second challenges. Dopamine plasma levels showed a significant increase on the first challenge only. Plasma catecholamine levels after the second challenge revealed a significant positive correlation between epinephrine increases measured 1 and 2 min after the challenge and the concomitant sting reaction. Basal epinephrine, norepinephrine, and dopamine plasma levels did not differ significantly between patients who experienced different types of sting reactions. Based on our data, we conclude that clinical reactions to in-hospital insect-sting challenges are not affected by early increases in plasma catecholamine levels produced by the expected stress situation.     

Increased urine catecholamines and cortisol in women with irritable bowel syndrome

OBJECTIVES: There are few data on the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in individuals with chronic GI symptoms. The current study was designed to describe and compare urine catecholamine (norepinephrine, epinephrine) and cortisol levels in women diagnosed with irritable bowel syndrome (IBS-patients), women who report similar symptom levels but had not sought health care services (IBS-nonpatients; IBS-NP), and asymptomatic (control) women. METHODS: Seventy-three women (24 IBS; 24 IBS-NP; 25 controls) were interviewed for demographic, GI, gynecological, and psychological data and then followed for two menstrual cycles with a daily health diary. Urine samples were obtained in the evening and morning at specific phases across two menstrual cycles. RESULTS: Women in the IBS group had significantly higher PM and AM urine norepinephrine levels. Urine epinephrine and cortisol levels were also generally higher in women with IBS. Differences in neuroendocrine indicators of arousal were not accounted for by differences in demographic variables, lifestyle characteristics, menstrual distress, or average daily measures of anxiety or depression. CONCLUSIONS: Increases in indicators of sympathetic nervous system activation in women seeking health care for IBS may reflect greater symptom distress or may contribute to increased symptom distress.     

Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids

The effects of progesterone and estradiol on cholesteryl ester (CE) formation by monocyte-derived human macrophages were examined. Formation was assessed from incorporation of 14C-cholesterol during a 20-h incubation with hormone and from that of 3H-oleate (3 h) after hormone removal. Progesterone inhibited cholesterol into CE and decreased CE cellular levels. Inhibition: 1) was reversed by progesterone removal; 2) was independent of the progesterone receptor (not blocked by the receptor antagonist RU40555); and 3) exhibited specific structural requirements; 11alpha-OH-progesterone was inhibitory, whereas its stereoisomer 11beta-OH-progesterone was not. In contrast to progesterone, estradiol was ineffective. We had reported that dexamethasone enhanced CE accumulation by human macrophages (1). In this study, we describe similar effects of the endogenous steroid, cortisol, and of the most widely prescribed glucocorticoid, prednisolone. Both steroids increased CE formation from two folds, in the presence of cholesterol-liposomes, to five folds, in the presence of modified low-density lipoprotein. Progesterone (0.1-1 micromol/L), added during glucocorticoid treatment, blocked this increase. The progesterone block: 1) was duplicated by the steroid receptor inhibitor RU40555; 2) was not reversed by hormone removal; and 3) reflected inhibition of glucocorticoid-induced increases in messenger RNA for acyl-CoA-cholesterol:acyl transferase. Thus, progesterone exerted two effects on macrophages: it acutely inhibited CE formation, and it prevented glucocorticoid-induced increases in acyl-CoA-cholesterol-acyl transferase gene expression and CE synthesis.     

Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo

Catestatin (bovine chromogranin A(344-364); RSMRLSFRARGYGFRGPGLQL), reduces catecholamine secretion from chromaffin cells in vitro. We investigated the effects of this peptide on catecholamine release and blood pressure in vivo. Intravenous catestatin reduced pressor responses to activation of sympathetic outflow by electrical stimulation in rats, and the catestatin effect persisted even after adrenergic (alpha plus beta) blockade. Catestatin did not alter plasma norepinephrine levels, but increased plasma epinephrine 11-fold. Catestatin also blunted pressor responses to exogenous neuropeptide Y agonists. A control peptide (chromogranin A(141-160)) did not alter pressor or catecholamine responses to electrical stimulation. Pretreatment with a histamine H1 receptor antagonist blocked both the vasodepressor response to catestatin and the elevation in plasma epinephrine. Catestatin elevated endogenous circulating histamine 21-fold, and exogenous histamine mimicked both the epinephrine elevation and the vasodepressor actions of catestatin. We conclude that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.     

N-syndecan and HB-GAM (heparin-binding growth-associated molecule) associate with early axonal tracts in the rat brain

Heparin-Binding Growth-Associated Molecule (HB-GAM)/pleiotrophin is an 18 kDa extracellular matrix- and cell-surface-associated protein shown to enhance neurite outgrowth of perinatal forebrain neurones in vitro. The heparan sulphate proteoglycan N-syndecan (Raulo et al., 1994) has been isolated as a receptor/coreceptor for the HB-GAM. We have investigated, whether HB-GAM and N-syndecan could have a similar role in neurite outgrowth and axon guidance in early axonal tracts of brain. In the present study N-syndecan was found to be spatiotemporally associated with the developing axonal tracts already on embryonic day 9 in rat, as revealed by coexpression with class III beta-tubulin, which is one of the earliest neuronal markers (Easter et al., 1993; Brittis et al., 1995). Later, N-syndecan and HB-GAM were detected in the first afferent serotonergic projections arising from the pontine raphe nuclei. The expression pattern of HB-GAM peaked in the developing rhombencephalon at embryonic stage (E) 13-14. At the same time, N-syndecan was expressed in the developing raphe neurones growing neurites towards the diencephalon along HB-GAM immunoreactive pathways. When rhombencephalic neurones were cultured on decreasing concentrations of substrate-bound HB-GAM, E13 neurones showed a significantly better neurite outgrowth response than E11, E16 or E18 neurones. The neurite outgrowth of raphe neurones in vitro was inhibited by adding soluble heparin or N-syndecan into the culture medium, whereas addition of chondroitin sulphate had no effect. In a simple pathway assay, E13 raphe neurones selectively preferred attaching and growing neurites on pathways containing HB-GAM as compared with regions containing either laminin or fibronectin alone. Our results suggest that HB-GAM may function as a developmentally regulated cue for rhombencephalic neurones that possess N-syndecan on their cell membrane.     

Soluble factors from rat basophilic leukemia (RBL-2H3) cells stimulated cooperatively the neurite outgrowth of PC12 cells

Culture media from rat basophilic leukemia cells (RBL-2H3) induced the neurite outgrowth of rat pheochromocytoma PC12 cells, a model system for neuronal differentiation. The extension of the neurite outgrowth was dependent on the culture time of RBL-2H3 cells in the DMEM medium. The DMEM medium conditioned by RBL-2H3 cells for 48 h induced neurite outgrowth of PC12 cells significantly. The neurite extension was much higher than that by medium containing 1 ng/ml nerve growth factor (NGF) but was rather lower than that by medium containing 10 or 50 ng/ml NGF. The neurite extension by 50 ng/ml NGF was completely suppressed by excess anti-NGF antibody (1-1.5 microg/ml), while the extension by culture medium conditioned by RBL-2H3 cells for 48 h was not completely suppressed in the presence of the same amount of anti-NGF antibody. The neurite extension by the culture medium of RBL-2H3 cells was also suppressed by anti-interleukin (IL)-6 antibody (1 microg/ml), although IL-6 itself (20 units) could scarcely induce the neurite outgrowth of PC12 cells. This suggests that IL-6 in the culture medium of RBL-2H3 cells could be effective in inducing the neurite extension in cooperation with NGF. In the presence of an excess of both anti-NGF and anti-IL-6 antibodies, the culture medium of RBL-2H3 cells induced the neurite extension of PC12 cells. This suggests that the action of the various factors from RBL-2H3 cells may be synergistic as far as the neurite outgrowth of PC12 cells is concerned.     

Release and clearance rates of epinephrine in man: importance of arterial measurements

Previous estimates of catecholamine kinetics in human subjects have been based on the measurement of the catecholamine levels in forearm venous plasma. However, the use of forearm venous measurements may introduce considerable error, since venous catecholamine levels may primarily reflect metabolism in the organ drained rather than in the total body. In this study, arterial levels of epinephrine were found to significantly exceed forearm venous levels, both basally (mean +/- SEM, 71 +/- 13 vs. 50 +/- 7 pg/ml; n = 6; P less than 0.05) and during infusions of epinephrine [0.1 microgram/min (112 +/- 9 vs. 77 +/- 11 pg/ml; P less than 0.005) or 2 micrograms/min (862 +/- 71 vs. 437 +/- 66 pg/ml; P less than 0.001)]. During the 2 micrograms/min epinephrine infusion, arterial plasma norepinephrine rose from 191 +/- 37 to 386 +/- 78 pg/ml (P less than 0.001), while venous norepinephrine levels did not change significantly. Fractional extraction (arterial - venous + arterial X 100) of epinephrine across the forearm was 26 +/- 8% in the basal state and increased to 33 +/- 6% and further to 51 +/- 4% during the epinephrine infusions. The addition of propranolol (5 mg, iv, plus an 80 micrograms/min infusion) reduced fractional extraction from 51 +/- 4% to 35 +/- 5%. Whole body clearance of epinephrine, calculated from arterial measurements, was 33 +/- 3 ml/kg . min during the 0.1 microgram/min infusion and 35 +/- 3 ml/kg . min during the 2 micrograms/min epinephrine infusion, values 50% lower than the clearance rates calculated from venous measurements. Propranolol infusion resulted in a fall in whole body clearance to 20 +/- 2 ml/kg . min (P less than 0.001), suggesting that epinephrine clearance is partly dependent on a beta-adrenergic mechanism. Basal endogenous release rate (clearance X basal epinephrine level) was estimated to be approximately 0.18 microgram/min, a value much less than that reported in studies using venous measurements. We conclude that arterial rather than venous measurements should be used to estimate catecholamine kinetics in vivo.     

Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment

Evidence from animal as well as human studies has suggested that significant sex differences exist in hypothalamus-pituitary-adrenal axis (HPA) activity. As gonadal steroids could be important modulators of HPA sex differences, stress responses were investigated in subjects of advanced age after dehydroepiandrosterone (DHEA) or placebo treatment. After a 2-week treatment with 50 mg DHEA daily or placebo, 75 men and women (mean age, 67.6 yr) were exposed to the Trier Social Stress Test (TSST). The TSST is a brief psychosocial stress that consists of a free speech and mental arithmetic task in front of an audience. The results show that the TSST induced significant increases in ACTH, salivary free cortisol, total plasma cortisol, norepinephrine, and heart rates (all P < 0.0001) as well as decreased positive affect in the elderly (P = 0.0009). Men showed larger stress responses in ACTH (P = 0.004), salivary free cortisol (P = 0.044), and plasma total cortisol (P = 0.076) compared to women. No sex differences were observed in norepinephrine, epinephrine, or heart rate responses. In contrast to ACTH and cortisol response differences, women reported that they were significantly more stressed by the TSST than men (P = 0.0051). Women treated with DHEA showed ACTH stress responses similar to those of men, but significantly enhanced compared to those of women taking placebos (P < 0.009). No other stress response differences emerged between DHEA and placebo groups. Finally, DHEA treatment did not result in an improvement of subjective well-being. We conclude that elderly men show larger HPA responses than women to psychosocial stress, as studied in the TSST. Estrogen effects on hypothalamic CRF-producing neurons might be responsible for these sex differences.     

Differential regulation of phenylethanolamine N-methyltransferase expression in two distinct subpopulations of bovine chromaffin cells

Chromaffin cells were isolated from bovine adrenal glands and fractionated into two distinct subpopulations by density gradient centrifugation on Percoll. Cells in the more dense fraction stored epinephrine (E) as their predominant catecholamine (81% of total catecholamines), contained high levels of phenylethanolamine N-methyltransferase (PNMT) activity, and exhibited intense PNMT immunoreactivity. This population of chromaffin cells was termed the E-rich cell population. Cells in the less dense fraction, the norepinephrine (NE)-rich cell population, stored predominantly NE (75% of total catecholamines). Although the NE-rich cells had only 3% as much PNMT activity as did the E-rich cells, 20% of the NE-rich cells were PNMT immunoreactive. This suggested that the PNMT-positive cells in the NE-rich cell cultures contained less PNMT per cell than did E-rich cells and may not be typical adrenergic cells. The regulation of PNMT mRNA levels and PNMT activity in primary cultures of E-rich and NE-rich cells was compared. At the time the cells were isolated, PNMT mRNA levels in NE-rich cells were approximately 20% of those in E-rich cells; within 48 h in culture, PNMT mRNA in both populations declined to almost undetectable levels. Treatment with dexamethasone increased PNMT mRNA levels and PNMT activity in both populations. In E-rich cells, dexamethasone restored PNMT mRNA to the level seen in freshly isolated cells and increased PNMT activity twofold. In NE-rich cells, dexamethasone increased PNMT mRNA to levels twice those found in freshly isolated cells and increased PNMT activity sixfold. Cycloheximide blocked the effects of dexamethasone on PNMT mRNA expression in NE-rich cells but had little effect in E-rich cells. Angiotensin II, forskolin, and phorbol 12,13-dibutyrate elicited large increases in PNMT mRNA levels in E-rich cells but had no effect in NE-rich cells. Our data suggest that PNMT expression is regulated differently in the two chromaffin cell subpopulations.     

Lipid oxidation. Part 3. Oxidation of egg phosphatidylethanolamine

The norepinephrine content of the whole brainstem and of its different parts and the epinephrine and norepinephrine (NE) content in the blood and adrenals in dogs and rats during ontogenesis were studied. The catecholamine (CA) level in the blood and different parts of the dog brainstem increased to the age of 20-30 days and then decreased. The NE value of the whole dog brainstem increased to the age of 9-30 days, and then decreased. The content of NE of the rat brainstem increased to the age of 120 days and then decreased. The amount of CA of the dog and rat adrenals increased progressively from birth to adulthood. The CA brain and adrenal level of dogs during postnatal ontogenesis was lower than in rats.     

Adrenal responses of Angus x Hereford cattle to the stress of weaning

To test adrenal responsiveness of beef cattle to stress, plasma norepinephrine, epinephrine, and cortisol responses of Angus x Hereford cattle to weaning were measured in blood samples taken from 1) eight cows and their 4- to 6-mo-old calves before and after separation and, the following day, before and after being reunited and 2) an equal number of control animals. After separation and before they were reunited, dams were returned to their original pen and calves to an adjacent pen. Experimental trials were conducted every 2 wk and included two cow/calf pairs per trial. Norepinephrine concentrations tended to increase in calves after separation, were increased (+82 pg/mL, P < .01) on the 2nd d before animals were reunited, and decreased (-88 pg/mL, P < .01) after animals were reunited. Epinephrine concentrations tended to increase in calves after separation, were increased in calves (+128 pg/mL, P < .001) and dams (+104 pg/mL, P < .001) on the 2nd d before animals were reunited, and decreased after calves (-162 pg/mL, P < .001) and dams (-101 pg/ml, P < .001) were reunited. There were no significant effects of time on catecholamine concentrations for control animals. Cortisol concentrations for treated and control animals tended to increase in sequential samples each day; however, the increases were small (approximately 1 ng/mL) and concentrations remained low (> 5 ng/mL). In conclusion, peripheral catecholamine concentrations in beef calves and epinephrine concentrations in dams increased in response to stress associated with weaning and separation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.     

Catecholamine secretion as a function of perceived coping self-efficacy.

Hypothesized that perceived coping self-efficacy mediates the effects of environmental events on catecholamine secretion. Differential levels of perceived self-efficacy were induced in 12 female phobic Ss, aged 19–40 yrs, through modeling. Their level of catecholamine secretion was then measured as they were presented with coping tasks in their high, medium, and low ranges of perceived self-efficacy. High perceived self-efficacy was accompanied by low levels of plasma epinephrine and norepinephrine during interaction with a phobic object, whereas moderate perceived self-inefficacy gave rise to substantial increases in plasma catecholamines. Both catecholamines dropped sharply when Ss declined tasks for which they judged themselves completely inefficacious. In contrast, dihydroxyphenyl-acetic acid was released maximally by mere apperception of task demands that Ss regarded as overwhelming their coping capabilities. After perceived self-efficacy was strengthened to the maximal level by S modeling, all of the tasks were performed without any differential catecholamine responses. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex hormone modulation of neural development in vitro

The sex hormonal milieu during human and primate development is thought to influence adult cognition, perception, and behavior. Similarly in the rat, the neonatal sex hormonal milieu dictates adult behavior, as well as patterns of neural organization within the CNS. Specifically, estrogen and androgen alter neurite outgrowth, neuritic spine development, and synaptogenesis in the limbic system and spinal cord. To examine specific molecular/cellular effects of sex hormones on neurons, in vitro models were developed, using the PC12 cell line. Wild-type cells (PC12-WT) were stably transfected either with an expression vector coding for the human estrogen receptor (ER), androgen receptor (AR), or with a control vector. Resultant clones were isolated, screened for incorporation of vector and expression of ER or AR mRNA and protein, and analyzed for morphologic responses to estrogen and androgen, respectively. PC12-WT, NEO9 (ER-negative, AR-negative), SER8 (ER-positive, AR-negative), and AR8 (ER-negative, AR-positive) cells were exposed to nerve growth factor and graded doses of estradiol or dihydrotestosterone (DHT) for 2 days. In SER8 cells, estradiol led to dose-dependent increases in the frequency of neurite outgrowth, spine development, and interneuritic connectivity. Estradiol increased the frequency of gap junction frequency and length, and functional dye-coupling in SER8 cells. Conversely, in AR8 cells, DHT induced a dose-dependent increase in mean neurite length, branch order, and neuritic field area, while neurite branch segment length and soma area were unaffected. These results suggest that SER8 and AR8 cells in vitro recapitulate various sex hormonal effects on neurons in vivo. Estrogen and androgen appear to induce inherent neural morphologic programs in which androgen increases neurite arborization and the receptive field of individual cells, increasing the likelihood for intercellular communication, while estrogen actually induces this communication, in the form of spines, synapses, and gap junctions. Thus estrogen and androgen act in different but complementary ways to modulate neural development and organization.     

The El Ni?o Southern Oscillation and the historic malaria epidemics on the Indian subcontinent and Sri Lanka: an early warning system for future epidemics?

A new class of angiogenesis inhibitors consist of a non-anticoagulating derivative of heparin, which binds to vascular endothelial cells, coupled to a steriod (e.g., cortisol) which suppresses endothelial cell division. We linked heparin to a further 10 steroids in an effort to identify ones which would yield more effective or safer angiogenesis inhibitors. Steroids having a C3 ketone group were linked by reaction with a hydrazide derivative of heparin. Steroids having a C20 ketone group and lacking a C3 ketone could not be prepared by this method, necessitating the development of alternative methods. The most efficient was to convert the steroid into a derivative having a hydrazone group at C20 and then link the steroid hydrazone to heparin. Conjugates prepared from steroids having C3 ketones were at most 6-fold more inhibitory than the free steroids to endothelial cells in tissue culture. In contrast, steroids having a C20 ketone but lacking a C3 ketone (tetrahydrocortisone, tetrahydrocortisol and tetrahydro S) became highly inhibitory to endothelial cells only after conjugation to heparin. They inhibited [3H]thymidine incorporation by 50% at a steroid concentration of 18-30 microM and by 95% at 300 microM. Since tetrahydrocortisone, tetrahydrocortisol and tetrahydro S lack glucocorticoid and mineralocorticoid activity, they may prove safer alternatives to cortisol for prolonged administration, as is likely to be necessary with anti-angiogenic therapies.