Adrenaline Excretion Research Articles

Relationship between waking–sleep blood pressure and catecholamine changes in African–American and European–American women

A blunted decline in waking to sleep blood pressure (BP) is more common in African-American (AA) than European-American (EA) women. The causes of reduced BP 'dipping' in AA women are not known, although several factors including ethnic differences in catecholamine sensitivity have been suggested. The purpose of this study was to investigate the possible contribution of catecholamine influences on BP to ethnic differences in BP dipping in a sample of working women. Healthy female participants wore ambulatory BP monitors over the course of 1 work day and night. Urine samples for assay of epinephrine and norepinephrine were collected at work (approximately 11.00-15.00 h), home (approximately 06.00-22.00 h) and during sleep (approximately 22.00-06.00 h). Analysis of covariance was used to assess the relationships between changes in BP and the catecholamines by ethnicity. AA women (n=51; age=38.9+/-8.5 years) had smaller proportional BP changes from work to sleep and home to sleep than EA women (n=110; age=37.1+/-9.2 years). Overall, the work to sleep change in epinephrine excretion was positively associated with changes in both SBP (P<0.003) and DBP (P<0.001); however, there was an ethnic difference in the epinephrine-BP relationship. For AA women, these associations were highly positive and significant, but for EA women, there was little correlation. Nonetheless, the analysis also revealed that overall, the work to sleep BP changes were not directly related to ethnic differences in catecholamine variation. The AA-EA difference in waking-sleep BP changes (dipping) is not directly related to ethnic differences in catecholamine variation; however, AA seem to have a greater BP sensitivity to epinephrine.

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Human sympathoadrenal system and adrenal cortex in prepubertal and pubertal periods

A complex study of the functional state of the sympathoadrenal system and adrenal cortex in 10-15-year-old children of both sexes was carried out using the indices of daily excretion of adrenaline, noradrenaline, 17-ketosteroids, and 17-hydroxycorticosteroids. A synchronism in the functional activity of the mediator component of the sympathoadrenal system as well as of the androgenic and glucocorticoid functions of the adrenal cortex was observed with age and during pubertal development of children. At the same time, heterochronic maturation was observed in the sex groups: in girls at the age of 10 and 12 years and in boys at the age of 14-15 years. The changes of different direction and intensity in the excretion of the studied hormones and hormonal metabolites were observed in the sex and age groups. A sharp increase in the daily excretion of glucocorticoid metabolites accompanied by a considerable decrease in the age index of noradrenaline secretion was observed in 14- and 15-year-old boys from beginning to end of school year; in addition, an increase in the daily excretion of sex hormones was observed at the age of 15 years. In girls, these indices varied within the age range, which points to a more sophisticated neuroendocrine control of physiological functions in girls during puberty.

Oleuropein, a Phenolic Compound in Extra Virgin Olive Oil, Increases Uncoupling Protein 1 Content in Brown Adipose Tissue and Enhances Noradrenaline and Adrenaline Secretions in Rats

The effects of oleuropein, a phenolic compound in extra virgin olive oil (EV-olive oil), on triglyceride metabolism were investigated by measuring the degree of thermogenesis in interscapular brown adipose tissue (IBAT), and noradrenaline and adrenaline secretions in rats. In Experiment 1, rats were given a high-fat diet (control diet) with the oleuropein supplementation of 1, 2 or 4 mg/kg of diet (0.1, 0.2 or 0.4% oleuropein diet, respectively). After 28 d of feeding, body weight, perirenal adipose tissue, epididymal fat pad, and plasma triglyceride, free fatty acid and total cholesterol concentrations were reduced by the 0.1, 0.2 or 0.4% oleuropein diet and were significantly lowest in rats fed the 0.4% oleuropein diet, as compared with those of rats fed with the control diet. The content of uncoupling protein 1 (UCP1) in IBAT and urinary noradrenaline and adrenaline excretions were significantly higher in rats fed the 0.1 or 0.2% oleuropein diet, as compared with those of rats fed with the control diet, although there were no significant differences in rats fed the 0.4% oleuropein diet. In Experiment 2, the effects of oleuropein on noradrenaline and adrenaline secretion were evaluated. The intravenous administration of oleuropein and oleuropein aglycone significantly increased plasma noradrenaline and adrenaline concentrations. Furthermore, oleuropein aglycone induced the secretions of noradrenaline and adrenaline about ten fold more potently than oleuropein. These results suggest that the phenolic compound oleuropein in EV-olive oil enhances thermogenesis by increasing the UCP1 content in IBAT and noradrenaline and adrenaline secretions in rats.

Depression and Coronary Heart Disease: More Pieces of the Puzzle

Depression and Coronary Heart Disease: More Pieces of the Puzzle

The Effects of Arginine and Selective Inducible Nitric Oxide Synthase Inhibitor on Pathophysiology of Sepsis in a CLP Model

Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models. Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined. A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival. It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis.

Heterozygous α2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction

Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that alpha(2C)-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human alpha(2C)-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of alpha(2C)-gene copy number for feedback control of epinephrine release in gene-targeted mice. Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/-) or no functional alpha(2C)-adrenoceptor gene (alpha(2C)-/-). Heterozygous alpha(2C)-receptor deletion (alpha(2C)+/-) resulted in a 43% reduction of adrenal alpha(2C) mRNA copy number and in a similar decrease in alpha(2)-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74+/-15% in alpha(2C)+/- and by 142+/-23% in alpha(2C)-/- mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in alpha(2C)-adrenoceptor-deficient mice. alpha(2C)+/- mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than alpha(2C)+/+ mice. Adrenal alpha(2)-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, alpha(2C), operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of alpha(2C)-adrenoceptor dysfunction in humans.

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A 352–372 )

Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by approximately 47%) and downward deflections (by approximately 44%), increased cardiac parasympathetic index (by approximately 2.4-fold), and decreased cardiac sympathetic index (by approximately 26%). Renal norepinephrine excretion was diminished by approximately 26% and epinephrine excretion by approximately 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to approximately 70,000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by approximately 5 to 6 mm Hg, and the polymorphism accounted for approximately 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Extra virgin olive oil increases uncoupling protein 1 content in brown adipose tissue and enhances noradrenaline and adrenaline secretions in rats

The effects of extra virgin olive oil (EV-olive oil) on triglyceride metabolism were investigated by measuring the degree of thermogenesis in interscapular brown adipose tissue (IBAT) and the rates of noradrenaline and adrenaline secretions in rats, both in vivo and in situ. In Experiment 1 (in vivo), rats were given an isoenergetic high-fat diet (30% fat diet) containing corn oil, refined olive oil, or EV-olive oil. After 28 days of feeding, the final body weight, weight gain, energy efficiency, perirenal adipose tissue and epididymal fat pad and plasma triglyceride concentrations were the lowest in the rats fed the EV-olive oil diet. The content of uncoupling protein 1 (UCP1) in IBAT and the rates of urinary noradrenaline and adrenaline excretions were the highest in the rats fed the EV-olive oil diet. In Experiment 2 (in situ), the effects of the extract of the phenolic fraction from EV-olive oil and a compound having excellent characteristics as components of EV-olive oil, hydroxytyrosol, on noradrenaline and adrenaline secretions were evaluated. The intravenous administration of the extract of the phenolic fraction from EV-olive oil significantly increased plasma noradrenaline and adrenaline concentrations, whereas that of hydroxytyrosol had no effect. These results suggest that phenols except hydroxytyrosol in EV-olive oil enhance thermogenesis by increasing the UCP1 content in IBAT and enhancing noradrenaline and adrenaline secretions in rats.

Renal Albumin Excretion

Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning catecholamine biosynthesis, storage, catabolism, receptor action, and postreceptor signal transduction. We studied 134 single nucleotide polymorphisms at 46 loci for a total of >51,000 genotypes. Albumin excretion heritability was 45.2+/-7.4% (P=2x10(-7)), and the phenotype aggregated significantly with adrenergic, renal, metabolic, and hemodynamic traits. In the adrenergic system, excretions of both norepinephrine and epinephrine correlated with albumin. In the kidney, albumin excretion correlated with glomerular and tubular traits (Na(+) and K(+) excretion; fractional excretion of Na(+) and Li(+)). Albumin excretion shared genetic determination (genetic covariance) with epinephrine excretion, and environmental determination with glomerular filtration rate and electrolyte intake/excretion. Albumin excretion associated with polymorphisms at multiple points in the adrenergic pathway: catecholamine biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention, diagnosis, and treatment.

A Case of Cured Diabetes Mellitus after Occult Malignant Pheochromocytoma Removal

Pheochromocytoma is characterized by a combination of various clinical manifestations that include the classic triad of severe headache, palpitations and diaphoresis. In addition, hyperglycemia can be caused by overproduction of catecholamines, which are secreted by a catecholamine-secreting neoplasm of adrenal or extra-adrenal chromaffin tissue. We encountered a case of diabetes with an occult malignant adrenal pheochromocytoma, who did not have any classic manifestations. A 37-year-old male was admitted because of polydipsia, polyuria, and weight loss. Fasting blood glucose level was 497 mg/dL, hemoglobin A1c level was 15%, and diabetic retinopathy and peripheral polyneuropathy were also accompanied. Incidentally, right adrenal mass was detected by ultrasonography of abdomen. Urinary excretion of total metanephrine and epinephrine were elevated. Adrenal CT showed a 7.1 cm sized right adrenal cystic mass with enhancing solid portion and hemorrhagic content. The scan with 123I-MIBG revealed the cystic mass with increased rim uptake in the region of right adrenal gland. After removal of the tumor, the increased levels of catecholamine were normalized. Moreover, blood glucose level was normalized without administration of insulin or oral hypoglycemic agents. The pathologic examination showed that the neoplasm was a malignant adrenal pheochromocytoma. We report this case that diabetes was cured after removal of malignant tumor with literature review at first in Korea. (J Kor Diabetes Assoc 31:520~524, 2007)

Catechol-O-Methyltransferase Gene Polymorphism Modifies the Effect of Coffee Intake on Incidence of Acute Coronary Events

BackgroundThe role of coffee intake as a risk factor for coronary heart disease (CHD) has been debated for decades. We examined whether the relationship between coffee intake and incidence of CHD events is dependent on the metabolism of circulating catecholamines, as determined by functional polymorphism of the catechol-O-methyltransferase (COMT) gene.Methodology/Principal FindingsIn a cohort of 773 men who were 42 to 60 years old and free of symptomatic CHD at baseline in 1984–89, 78 participants experienced an acute coronary event during an average follow-up of 13 years. In logistic regression adjusting for age, smoking, family history of CHD, vitamin C deficiency, blood pressure, plasma cholesterol concentration, and diabetes, the odds ratio (90% confidence interval) comparing heavy coffee drinkers with the low activity COMT genotype with those with the high activity or heterozygotic genotypes was 3.2 (1.2–8.4). Urinary adrenaline excretion increased with increasing coffee intake, being over two-fold in heavy drinkers compared with nondrinkers (p = 0.008 for trend).Conclusions/SignificanceHeavy coffee consumption increases the incidence of acute coronary events in men with low but not high COMT activity. Further studies are required to determine to which extent circulating catecholamines mediate the relationship between coffee intake and CHD.

Influence of Sympathetic Activity on Blood Pressure and Vascular Damage Evaluated by Means of Urinary Albumin Excretion

To analyze the influence of sympathetic activity on blood pressure (BP) and its effects on urinary albumin excretion (UAE), the authors carried out a cross-sectional study in their local health coverage area. The following variables were monitored in a representative sample of the general population made up of 495 individuals: anthropometric parameters; blood glucose, creatinine, and lipid levels; 24-hour urinary albumin, norepinephrine, and epinephrine excretion; and BP of patients with known hypertension and newly discovered BP > or =140/90 mm Hg, evaluated by ambulatory monitoring. In the multivariate analysis, only gender, systolic BP, and UAE were associated with norepinephrine levels; only gender, systolic BP, and body mass index were associated with epinephrine. After excluding those patients with chronic kidney disease, the multivariate analysis showed a strong association between UAE > or =30 mg/d and elevated norepinephrine and epinephrine levels. The authors concluded that in the subject population there is an association between elevated adrenergic activity and higher UAE, independent of factors such as age and BP.

Effects of Chronic Osteoarthritis Pain on Neuroendocrine Function in Men

Chronic pain has been associated with elevated cortisol, reduced LH and testosterone (T), and/or augmented circulating or excreted catecholamines. Most endocrine studies have been conducted in patients in whom the potentially confounding effects of depression, inflammatory disease, or coexistent medication use have not been controlled. The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T. This was a case control study conducted at a clinical research center. Participants included 16 opioid-naive men with chronic osteoarthritis pain, aged 35-65 yr with body mass index 20-30 kg/m2, and 12 healthy, opioid- and pain-free men of similar ages and body mass indexes. We compared circulating concentrations of ACTH, cortisol, LH, and T derived from every 20-min blood sampling (2000-0800 h), and 24-h urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine. There were no significant differences in mean or integrated concentrations of ACTH, cortisol, LH, or T, or in the corresponding approximate entropy scores in osteoarthritis patients, compared with control subjects. The 0800-h serum LH concentrations were elevated in patients vs. controls (6.42 +/- 1.65 vs. 3.99 +/- 1.54 IU/liter, mean +/- sd, P = 0.02), whereas there were no significant group differences in total or free T, SHBG, cortisol binding globulin, dehydroepiandrosterone sulfate, or urinary cortisol and catecholamines. These data suggest that neuroendocrine function is not significantly altered in otherwise healthy men with chronic musculoskeletal pain and that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.

β-Endorphin involvement in the regulatory response to body sodium overload

The present study was performed to examine the role of the endogenous β-endorphinergic system on blood pressure regulation, sympathetic and brain activity during body sodium overload. β-Endorphin knockout (βend −/−), heterozygous (βend +/−) and wild-type (βend +/+) mice were submitted for two weeks to either a normal- or a high-sodium diet (NSD and HSD, respectively), and systolic blood pressure (SBP), urinary catecholamines (as an index of sympathetic nervous system activity), and the brain pattern of Fos-like immunoreactivity (as a marker of neuronal activation) were evaluated in each group. HSD caused a significant increase in SBP in βend −/− mutant mice compared with βend +/+ mice kept in the same experimental conditions ( P<0.01), but no statistical differences were observed between βend +/− and βend +/+ on a HSD. Moreover, when animals from the three genetic lines were fed with a NSD no changes in SBP were evidenced. With regard to brain activity, βend −/− mice maintained on a HSD showed a significant increase in Fos-like immunoreactive neurons in the median preoptic nucleus ( P<0.01) compared with βend +/− and βend +/+ animals. Additionally, βend −/− mice had higher levels of urinary epinephrine excretion ( P<0.05) on a HSD in comparison to βend +/+ and βend +/− animals in the same experimental conditions. No differences, however, were registered in norepinephrine and dopamine urinary excretion in animals from the three genetic lines after two weeks on either a HSD or a NSD. In summary, our results indicate that the β-endorphinergic system may play a part in the compensatory response to sodium overload, since the absence of β-endorphin causes an increase in systolic blood pressure, and increases median preoptic nucleus neural activity and urinary epinephrine excretion.

Catecholamine Excretion and Circadian Blood Pressure Profile in Patients with Pheochromocytoma

Circadian blood pressure (BP) rhythm is often disturbed in patients with secondary forms of hypertension. The aim of the present article was to investigate changes in circadian BP profile parameters using two-step statistical approach by Fourier analysis in relation to day and night urinary catecholamine excretion in 35 patients with pheochromocytoma (mean age 42+/-19 years). Twenty-four-hour ambulatory BP measurements (ABPM) were obtained using the SpaceLabs 90,207 monitor. Daytime and night-time urine collection was obtained in all patients to determine circadian catecholamine excretion. Fourier analysis was applied to estimate measures of BP circadian rhythm in ABPM, including the highest (Max) and lowest (Min) systolic (SBP) and diastolic (DBP) BP values, norad (ampSBP, ampDBP), and early acrophase (APSBP, APDBP). The Fourier indices of circadian BP rhythm were: MaxSBP 153+/-28 mm Hg, MaxDBP 99+/-16 mm Hg, MinSBP 117+/-17 mm Hg, MinDBP 69+/-11 mm Hg, ampSBP 18+/-8 mm Hg, ampDBP 14+/-5 mm Hg, APSBP 10+/-5 (h), and APDBP 11+/-3 (h). Urine noradrenaline (NA), adrenaline (A), and dopamine (DA) excretion during the day (d) and night (n) were: dNA 103.5+/-89.8 microg/14 h, nNA 52+/-70.8 microg/10 h, dA 13.2+/-17.9 microg/14 h; nA 6.13+/-9.6 microg/10 h, dD 181.8+/-87.3 microg/14 h, and nD 89.3+/-59.8 microg/10 h. A positive correlation was observed between urine dNa excretion and MaxDBP (r=0.37, P<0.05), and urine nNA and urine dA excretion were correlated with APDBP (r=0.47, r=0.35, respectively, both P<0.05). Thus, in addition to the effect on mean 24-h BP values, catecholamines released by tumor may also disturb circadian BP rhythm in patients with pheochromocytoma.

Occupational Differences in Job Strain and Physiological Stress: Female Nurses and School Teachers in Hawaii

The two objectives are to test the hypothesis that women in a profession with low decision latitude will have greater catecholamine excretion and higher blood pressure than women in a profession with greater decision latitude, and to assess the influence of ethnicity on the occupational comparison. Premenopausal women who were either full-time teachers in public schools (teachers; N = 92) or nurses or nurse's aides (nurses; N = 55) in East Hawaii who were not currently taking antihypertensive medication had ambulatory blood pressure (BP) and urinary catecholamine excretion measured over an approximate 4-hour period at work and home and over an approximate 8-hour period overnight. The women also filled out the Job Content Questionnaire (JCQ). The nurses had significantly lower scores on the "decision latitude" subscale of the JCQ. After controlling for the effects of ethnicity, age, body mass index, JCQ subscale scores, smoking habits, and menopausal status in regression analyses, the nurses also had significantly higher mean systolic and diastolic BP both in work and home settings and higher mean rates of both norepinephrine and epinephrine excretion in all daily settings (p < .05). There were no significant ethnic differences in scores on the JCQ subscales, but Asian-Americans had significantly higher systolic BP in all daily settings and higher diastolic BP overnight (p < .05) than Euro-Americans. These results suggest that among professional women, physiological stress responses are significantly greater when occupation-related decision latitude is low (nurses) than when it is high (teachers). The physiological response to stress is carried over into the home and overnight settings when occupation-related decision latitude is low (nurses). Individual scores on the JCQ were not significantly related to physiological measures in this study, however. Inclusion of contrasting occupations may be necessary to properly evaluate the relationships between individually reported job strain and heightened physiological stress responses in studies of working women.

Targeted Ablation of the Chromogranin A (Chga) Gene: Normal Neuroendocrine Dense-Core Secretory Granules and Increased Expression of Other Granins

Chromogranin A (CgA), originally identified in adrenal chromaffin cells, is a member of the granin family of acidic secretory glycoproteins that are expressed in endocrine cells and neurons. CgA has been proposed to play multiple roles in the secretory process. Intracellularly, CgA may control secretory granule biogenesis and target neurotransmitters and peptide hormones to granules of the regulated pathway. Extracellularly, peptides formed as a result of proteolytic processing of CgA may regulate hormone secretion. To investigate the role of CgA in the whole animal, we created a mouse mutant null for the Chga gene. These mice are viable and fertile and have no obvious developmental abnormalities, and their neural and endocrine functions are not grossly impaired. Their adrenal glands were structurally unremarkable, and morphometric analyses of chromaffin cells showed vesicle size and number to be normal. However, the excretion of epinephrine, norepinephrine, and dopamine was significantly elevated in the Chga null mutants. Adrenal medullary mRNA and protein levels of other dense-core secretory granule proteins including chromogranin B, and secretogranins II to VI were up-regulated 2- to 3-fold in the Chga null mutant mice. Hence, the increased expression of the other granin family members is likely to compensate for the Chga deficiency.

Urinary catecholamine excretion in tetanus

Imperfect understanding of the pathophysiology of tetanus has limited therapeutic advances. Autonomic disturbance is a major cause of mortality and is believed to be associated with catecholamine release, predominantly norepinephrine. We measured epinephrine and norepinephrine concentrations in 24-h urine collections from tetanus and critically ill patients suffering from other severe diseases. In patients with severe tetanus, mean (SD) epinephrine was 164.18 (129.37) nmol x day(-1) compared with 45.18 (37.74) nmol x day(-1) in mild-moderate disease (p = 0.008). In the severe group, mean (SD) norepinephrine was 411.64 (208.5), and 121.00 (81.81) nmol x day(-1) in moderately ill patients (p < 0.001). Compared with critically ill control patients, median epinephrine was 331.77 in tetanus patients and 89.70 nmol x day(-1) in controls (p < 0.001). Median norepinephrine concentration was 788.02 nmol x day(-1) in tetanus and 300.05 nmol x day(-1) in control patients, p = 0.006. The study finds a novel result of increased epinephrine excretion in tetanus and confirms that catecholamine excretion in tetanus exceeds that in other critically ill patients. These results should be considered in designing more effective therapeutic strategies.

Increased urinary dopamine excretion in association with bilateral carotid body tumours - clinical, biochemical and genetic findings

This report describes a rare case of a patient with increased urinary dopamine excretion in association with bilateral carotid body tumours. Excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and 4-hydroxy-3-methoxymandelic acid (HMMA) were within the reference ranges, and an (123)I-meta-iodobenzylguanidine (MIBG) scan showed uptake in the neck masses, with no other abnormal uptake anywhere else in the body. The patient is being managed conservatively as the tumours are not amenable to resection on account of their size and vascularity. There are only four previous case reports of dopamine-secreting tumours of the carotid body described in the literature, all of whom were women. The tumours were unilateral in three cases and bilateral in the fourth case. Familial cases of carotid body tumours have a higher prevalence of bilateral tumours than non-familial cases. Recent reports in the literature have suggested that a significant number of patients with extra-adrenal catecholamine-secreting paragangliomas have a genetic mutation in one of the identified susceptibility genes for catecholamine-secreting tumours, despite having no other affected family members, and a mutation has been found in the succinate dehydrogenase gene for this patient.