Differences in thyroid function tests after administration of a single supraphysiological dose of ACTH or a high dose of a synthetic steroid.

OBJECTIVE: Although the suppressive action of synthetic steroids on the hypothalamus-pituitary-thyroid (HPT) axis is established, little is known regarding the effect of the administration of synthetic adrenocorticotropic hormone (ACTH). DESIGN: In the context of a randomized, open label, comparative study assessing the efficacy and safety of ACTH and betamethasone in the treatment of hospitalized patients with acute gout, we compared the effects of these agents on thyroid function tests. METHODS: Serum TSH, total T4 and T3 and cortisol were measured before and at 24 and 48 h after a single intramuscular dose of synthetic ACTH (1 mg) or betamethasone (6 mg), in 38 hospitalized patients with acute gout and normal thyroid function. RESULTS: The final analysis included 32 patients, due to missing data. The ACTH and betamethasone groups did not differ regarding the mean age, gender, severity of gout attack, and baseline thyroid parameters. In the ACTH group TSH and T4 were significantly decreased at 24 and at 48 h compared to baseline, while T3 was decreased at 24 but not at 48 h. In the betamethasone group T3 remained stable; TSH and T4 decreased significantly from baseline levels at 24 h; at 48 h, TSH had returned to and T4 showed a partial rebound towards pre-treatment values. CONCLUSIONS: A single IM administration of 1 mg of synthetic ACTH has more profound and prolonged effects on the HPT axis, lasting for at least 48 h, compared to a single IM dose of 6 mg betamethasone.

Peptide ACTH4-7-PGP: Effects on Various Types of Pain and Pain-Induced Behavior in Rats after Systemic and Central Administration.

The effects of peptide ACTH4-7-PGP (Semax) were studied in 12 min after its intraperitoneal (in doses of 5, 15, 50, 150, and 450 µg/kg) or intracerebroventricular (in doses of 16, 40, and 400 pg) administration to rats with different types of pain and pain-induced behavior. It was found that the peptide increased pain sensitivity and induced avoidance behavior during thermal stimulation ("hot plate" test), but had an analgesic effect (more pronounced after central administration) and weakened emotional-affective behavior in electrocutaneous stimulation of the paws (foot-shock model) and tail in rats. It was shown that changes in activity of supraspinal brain structures were of primary importance in the mechanism of action on the nociceptive process and the formation of behavior.

Role of adrenocorticotropic hormone in the modulation of pollinosis induced by pollen antigens.

BACKGROUND: A mild restraint stressor suppressed an increase in the levels of Th2-dependent cytokines and IgE, thereby reducing the symptoms of pollinosis. In the present study, to clarify the mechanism of action of adrenocorticotropic hormone (ACTH) in improving the symptoms of pollinosis, we studied the effects of ACTH on the plasma level of histamine, mast cell number in nasal-associated lymphoid tissue (NALT) and the T cell differentiation in splenocytes. METHODS: The role of ACTH in the development of pollen antigen-induced pollinosis was studied in mice. Allergic symptoms and parameters were measured on day 17 after sensitization. To investigate the effects of ACTH on T cell differentiation, we stimulated splenocytes obtained from control mice with ACTH and CD3/CD28 in vitro, and measured the cytokine production in the culture supernatant. RESULTS: The plasma levels of IL-10, IgE and histamine and mast cell number in NALT were increased in the sensitized animals in association with a concomitant increase in the incidence of sneezing and nasal rubbing. The intraperitoneal administration of ACTH decreased the IL-10, IgE and histamine levels in the plasma and mast cell number in NALT, while increasing the IFN-γ level and suppressing the incidence of nasal rubbing. Furthermore, the production of IFN-γ increased, while the IL-4 level was suppressed after 2 days in culture. CONCLUSIONS: The present findings showed that ACTH directly affects T cell differentiation and promotes Th1-type reactions. The regulation of the Th1/Th2 balance by ACTH may result in a decrease in the pathological features of pollinosis.

Aldosterone secretion in patients with septic shock: a prospective study.

OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.

Aldosterone secretion in patients with septic shock: a prospective study / Secreção de aldosterona em pacientes com choque séptico: estudo prospectivo

OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.

OBJETIVO: Avaliar os níveis séricos dos principais fatores que regulam a ativação da zona glomerulosa e a produção de aldosterona em pacientes com choque séptico, assim como sua resposta ao teste de cortrosina em alta dose (250 µg). SUJEITOS E MÉTODOS: Em 27 portadores de choque séptico, foram aferidos níveis basais de aldosterona, cortisol, ACTH, renina, sódio, potássio e lactato, bem como realizado teste de cortrosina. RESULTADOS: Renina se correlacionou com níveis basais de aldosterona e sua variação após teste de cortrosina. Cortisol basal e sua variação não se correlacionaram com ACTH. Apenas três pacientes apresentaram disfunção concomitante da secreção de aldosterona e cortisol. CONCLUSÕES: Ativação das zonas fasciculada e glomerulosa são independentes. Secreção de aldosterona é dependente da integridade do sistema renina-angiotensina-aldosterona, enquanto secreção de cortisol não parece predominantemente dependente do eixo hipotálamo-hipófise-adrenal. Esses resultados sugerem que a ativação da adrenal em pacientes críticos ocorre por múltiplos mecanismos.

[The results of the application of the pre-formed physical factors and neuroprotective therapy for the rehabilitative treatment of the patients with diabetic retinopathy].

To evaluate the effectiveness of the neuroprotective agent used to treat the patients presenting with non-proliferative diabetic retinopathy. The study included 114 patients (228 eyes) at the age varying from 42 to 70 who presented with diabetes mellitus and non-proliferative diabetic retinopathy. Three groups were formed depending on the mode of treatment. The patients in main group underwent endonasal electrophoresis of 0.1% semax preparation. Patients of the comparison group were treated with intranasal instillations of semax and those of the control group received only standard hypoglycemic therapy and treatment with Doxy-Hem. The patients of the first two groups showed positive dynamics of the studied functional characteristics (visual, perimetric, and electrophysiological ones). The most pronounced and long-standing (up to 12 months) positive effect on the visual function was documented in the main group. The results of the present study give reason to recommend the inclusion of endonasal electrophoresis in the combined rehabilitation treatment of the patients presenting with diabetes mellitus and non-proliferative diabetic retinopathy.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite.

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.

Role of the hypothalamo-pituitary-adrenal axis in the modulation of pollinosis induced by pollen antigens.

BACKGROUND: To clarify the mechanism of stress-induced modification of allergic diseases, we studied the effect of restraint stress on plasma levels of cytokines and the symptoms of pollinosis in mice. METHODS: The effects of restraint stress and the role of the hypothalamo-pituitary-adrenal axis (HPA-axis) in the development of pollen antigen-induced pollinosis were studied in control, hypophysectomized, adrenalectomized or ACTH-administered mice. Twenty days after sensitization, animals were subjected to mild restraint stress for 3 hours, and plasma levels of IFN-gamma, IL-10, and IgE were measured. We analyzed the incidence of sneezing and nasal rubbing in the sensitized animals. RESULTS: Plasma levels of IL-10 and IgE increased in the sensitized animals with a concomitant increase in the incidence of sneezing and nasal rubbing. The increases in plasma IgE, IL-10 and the incidence of sneezing and nasal rubbing were suppressed by restraint stress. Adrenalectomy increased IFN-gamma, inhibited the increase in plasma IL-10 and IgE, and suppressed the incidence of sneezing. In contrast, hypophysectomy increased plasma levels of IL-10, IFN-gamma, and IgE and the incidence of sneezing. Intraperitoneal administration of ACTH decreased IL-10 in plasma but increased IFN-gamma and suppressed the incidence of nasal rubbing. CONCLUSIONS: The present findings show that the HPA-axis and ACTH play important roles in the regulation of plasma cytokines and IgE thereby modulating symptoms of pollinosis. The results also suggest that a mild restraint stress suppresses the increase in Th2-dependent cytokines and IgE to reduce the symptoms of pollinosis.

Endogenous ACTH, not only alpha-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms.

ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH) are both consecutively processed from proopiomelanocortin (POMC), which is synthesized in hypothalamic arcuate neurons innervating the paraventricular nuclei (PVN). POMC secretion/synthesis is regulated by energy availability. ACTH and alpha-MSH bind with equal affinity to melanocortin-4 receptors and elicit similar effects on signal transduction in-vitro. Endogenous alpha-MSH thus far is believed to be the major physiological agonist and to act in an anorexigenic manner. Until now, it was fully unknown whether endogenous ACTH is also involved in the regulation of appetite and food intake. In this study in rats, we now show that icv ACTH as well as alpha-MSH possess anorexigenic effects in the PVN or areas in close proximity in vivo and that the effect of ACTH is direct and not mediated via alpha-MSH. We investigated the roles of endogenous ACTH and alpha-MSH by PVN application of the respective antibodies under different physiological conditions. In satiated rats with high levels of ACTH and alpha-MSH in the PVN, antibody administration increased food intake and body weight gain; hungry animals were unaffected. Finally, repeated injections of ACTH antibodies into PVN resulted in persistently increased food intake during the light period. These data now provide robust evidence that endogenous ACTH without further processing acts in the PVN or areas in close proximity to reduce food intake under conditions of feeding-induced satiety.

Eye temperature and heart rate variability of calves disbudded with or without local anaesthetic.

The possibility that pain can be detected from changes in eye temperature and heart rate variability (HRV) during disbudding was examined in thirty calves, randomly assigned to four treatments: 1) sham handling (control), 2) local anaesthetic (LA, cornual nerve injection) and sham disbudded, 3) sham LA and disbudded, 4) LA and disbudded. During a 40 min sampling period, maximum eye temperature, behavior and HRV parameters were recorded continuously. One week later, twelve disbudded calves were injected with adrenocorticotrophic hormone (ACTH) or saline and maximum eye temperature was recorded. There was a rapid drop in eye temperature during the 5 min following disbudding without LA (P<0.05). Eye temperature then increased and was higher than baseline over the remaining sampling period following both disbudding procedures (P<0.001), a response which could not be explained by increased physical activity LA increased eye temperature prior to disbudding (P<0.001). Heart rate increased (P<0.001) during the 5 min following disbudding with and without LA, however, LF/HF ratio only increased during this time (P<0.01) following disbudding without LA. Eye temperature did not change following ACTH, suggesting that hypothalamus-pituitary-adrenal axis (HPA) activity is not responsible for the changes in eye temperature following disbudding. The increase in LF/HF ratio following disbudding without LA suggests an acute sympathetic response to pain, which could be responsible for the drop in eye temperature via vasoconstriction. HRV and eye temperature together may be a useful non-invasive and more immediate index of pain than HPA activity alone.

ACTH reduces the rise in ApoB-48 levels after fat intake.

It has been repeatedly demonstrated that ACTH administration lowers plasma lipid concentrations in man. The present study was designed to test the hypothesis, based on observations of decreased apolipoprotein B (ApoB) synthesis and secretion in vitro, that ACTH administration inhibits the postprandial output of ApoB in man. Therefore, we studied the response to a fat-rich meal supplemented with Vitamin A in eight healthy volunteers, who underwent this test without premedication, after 4 days administration of ACTH, and after 4 days administration of a glucocorticoid (betamethasone). As expected, fasting plasma levels of low-density lipoproteins (LDL)-cholesterol (-25%) and ApoB (-17%) decreased after ACTH, but not after betamethasone administration. Also, the elevation of plasma ApoB-48 in response to fat intake (to twice the basal levels) was markedly reduced after ACTH administration. However, the postprandial rise in plasma triglycerides and retinyl palmitate was unimpaired, suggesting that ACTH administration induced the secretion of fewer but larger chylomicrons. The effect of betamethasone on the postprandial response was similar but less pronounced. This study confirms earlier reports on the lipid-lowering effects of ACTH and supports our theory, based on in vitro studies, that the lipid-lowering effects of ACTH administration in man involves an inhibition of ApoB production.

[Clinical efficacy of shortened ACTH therapy --an individualized method for minimization of adverse effects--Part 1. The short-term outcome].

To minimize adverse effects and to get good efficacy of ACTH therapy against West syndrome, we tried a new 2-steps therapeutic protocol consisting of the shortened ACTH therapy and the additional ACTH therapy. In a prospective multi-institutional study, 20 patients with newly diagnosed West syndrome who had failed to respond to high-dose vitamin B6 and zonisamide were treated by this shortened ACTH therapy. Synthetic corticotropin (ACTH-Z 0.025 mg/kg/dose, max 0.25 mg) was administrated intramuscularly seven times on every other day for 14 days. At 1 month after discontinuing corticotropin, spasms and hypsarrhythmia disappeared in 10/20 (50%) and 13/17 (59%) patients respectively. Subsequently, 9 out of the 10 patients with persistent spasms received additional therapy for 1 or 2 weeks with daily intramuscular ACTH-Z, which was tapered off over a few weeks. Including the additional ACTH therapy, the disappearance of spasms and hypsarrhythmia were found in 13 patients (65%) and 13 patients (76%). Adverse effects during the shortened ACTH therapy were fewer than additional ACTH therapy but not statistically significant. Severe adverse effects were not observed in both ACTH therapy. In the 2-steps therapeutic protocol according to the response to ACTH, favorable results were obtained in seizure control, EEG findings and the degree of adverse effects.

Effects of milk production capacity and metabolic status on HPA function in early postpartum dairy cows.

Increasing milk yields in modern dairy cows cause concern that high yield may impair the cows' health and welfare, for example, via negative effects on metabolic status and hypothalamo-pituitary-adrenocortical (HPA) function. This study aims to investigate whether a high level of milk production, and the associated metabolic status, affects HPA function in dairy cows and changes their adaptive capacity. Additionally, it aims to establish whether possible effects of milk production level only show under challenging conditions. Holstein-Friesian cows, which produced on average 11,443 and 7727 kg of fat and protein-corrected milk (FPCM)/305 d in their previous lactation, were compared. During the dry period, the cows were fed to requirements or overfed. High milk yield and the concomitant large energy deficit were associated with 1) increased pituitary (re)activity, i.e., increased ACTH baseline concentrations and higher ACTH concentrations after corticotropin-releasing hormone (CRH) administration, and 2) decreased adrenocortical reactivity, i.e., lower cortisol responses after ACTH administration. Although significant, the effects of milk production level on HPA function were relatively small. Animals showed seemingly normal hormonal responses to CRH and ACTH administration. Also, cortisol baseline concentrations were unaffected. It seems, therefore, unlikely that the adaptive capacity of the high-producing cows was significantly impaired compared with their low-producing herdmates.

[Seizure and developmental prognosis of West syndrome--combination therapy with high-dose vitamin B6, valproate and low-dose ACTH].

Twenty patients with West syndrome were initially treated with high-dose vitamin B6 (40 to 50 mg/kg/day) and valproate (40 to 50 mg/kg/day). Three became seizure free. For the remaining 17 patients, low-dose synthetic ACTH (0.01 mg [0.4 IU]/kg/day) was added to the regimen. One month after the end of ACTH therapy, 13 patients were seizure free. Thus 16 patients in total(80%) were free of seizures(group A). The treatment was ineffective for the remaining 4 patients (20%; group B). During the following for a mean period of 64 months (range, 48 to 83 months), 9 in group A had a relapse of epileptic seizures. However, only 4 in this group had epileptic seizures at the end of the study (5-7 years of age), all of which were partial and infrequent. In group B, two had frequent intractable seizures, and one was seizure free at the end of the study. One died at the age of 1 year. In group A, 2 patients showed normal or subnormal mental development. Mild, moderate and severe mental retardation were seen in 3, 4 and 7 patients respectively. In group B, all patients showed severe mental retardation. In this study, the rate of evolution into intractable epilepsy was low, but long-term mental development was poor. Seizure control by itself seemed to be insufficient to improve long developmental prognosis of West syndrome.

Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women.

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 +/- 5.4 years) received single-dose oral prednisone (20 mg) before and after 200 mg/day of oral prasterone for one menstrual cycle (approximately 28 days). Identical assessments, timed to onset of menses, were conducted pretreatment (baseline) and at days 28 and 29 of prasterone treatment and included serum total and free prednisolone, prednisone, DHEA, DHEA-S (dehydroepiandrosterone sulfate), ACTH-stimulated cortisol, and sex hormones and 24-hour urine free cortisol. Pharmacokinetic parameters of prednisolone as assessed by Cmax, t 1/2, AUC, or serum protein binding were not affected by prasterone. The ACTH-stimulated plasma cortisol concentrations were mildly reduced, but 24-hour urinefree cortisol excretion was unchanged during prasterone administration. Serum androstenedione and testosterone increased, while no changes in serum estradiol or estrone occurred. The administration of 200 mg oral prasterone produced serum concentrations of DHEA and DHEA-S significantly greater than endogenous levels. Chronic dosing with 200 mg/day of prasterone did not alter either prednisolone pharmacokinetics or inhibition of cortisol secretion by prednisolone.

A high dose of vitamin E inhibits adrenal corticosterone synthesis in chickens treated with ACTH.

The present experiment was conducted to study the effects of dietary vitamin E on plasma corticosterone (CTC) concentration and adrenal steroid syntheses in chickens treated with adrenocorticotropic hormone (ACTH). Chickens were divided into ACTH(-) and ACTH(+) groups, and each group was further divided into three subgroups administered with vitamin E (500 or 5,000 mg/kg diet) and without the vitamin. Vitamin E (DL-alpha-tocopheryl acetate) was mixed with the basal diet at levels of 500 and 5,000 mg/kg and fed for 6 d. ACTH (20 IU/kg body weight) was given daily by intraperitoneal injection for 5 d. alpha-Tocopherol levels in the plasma and adrenal gland were markedly elevated by vitamin E feeding, and the level of adrenal free cholesterol (CHOL), which is used for steroid synthesis, was significantly decreased by vitamin E feeding in a dose-dependent manner. However, the level of adrenal CHOL ester was unchanged by any treatment. The elevations of pregnenolone, progesterone and CTC levels in the adrenal gland of chickens with ACTH treatment were decreased by vitamin E administration. The elevation of plasma CTC concentration in the ACTH(+) group was dramatically decreased by vitamin E administration, while that concentration was not influenced by the vitamin administration in the ACTH(-) group. These findings indicate that vitamin E suppresses the elevation of the plasma CTC concentration due to ACTH in chickens, possibly by inhibiting the conversion of CHOL ester to free CHOL in the adrenal gland.

Low dose (1 microg) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis.

Adrenocortical function in patients with active pulmonary tuberculosis is a debate of matter. Previous studies related to adrenocortical function in patients with active pulmonary tuberculosis demonstrated a high rate of suboptimal cortisol response to standard dose ACTH (250 microg) stimulation test. The aim of this study was to assess the hypothalamo-pituitary-adrenal (HPA) axis in low dose (1 microg) and standard dose ACTH (250 microg) stimulation tests in the patients with active pulmonary tuberculosis. Twenty-seven patients and 21 healthy subjects were included in the study. Cortisol levels were measured before, 30 and 60 min after ACTH (1 microg or 250 microg iv) injection. Cortisol responses to 1 microg ACTH at 30 and 60 min were significantly higher in the patient group than in the control group (p<0.05). Peak cortisol levels were significantly higher in the patient group than in the control group after both 1 microg and 250 microg ACTH administration (p<0.05). Cortisol responses to 250 microg ACTH at 30 and (at 30 and 60) 60 min were significantly higher in the patient group than in the control group (p<0.05). Peak cortisol levels obtained after 250 microg ACTH and after 1 microg ACTH were similar in the patient group (p>0.05). This study shows that 1 microg ACTH iv gives an equivalent peak cortisol value to 250 microg ACTH in patients with activated HPA axis. The cortisol levels obtained at 08:00, 11:00, 17:00 and 24:00 h were significantly higher in the patients than in the controls. This study clearly shows that HPA axis is activated in active pulmonary tuberculosis rather than underactivated.

Adrenocorticotrophin dose-response relationships in the rat: haemodynamic, metabolic and hormonal effects.

OBJECTIVE: To determine adrenocorticotrophin dose-response relationships for increase of blood pressure and metabolic parameters of the Sprague-Dawley rat. METHODS: We injected 120 male Sprague-Dawley rats twice daily subcutaneously for 10 days with 0.5, 1, 5, 50, 100, 200 or 500 microg/kg synthetic adrenocorticotrophin per day (all n = 10) or subjected them to sham injection (0.9% NaCl; n = 50). Systolic blood pressure, 24 h food intake, water intake, urine volume and body weight were measured. Data from a further 45 rats treated with 500 microg/kg per day adrenocorticotrophin in previous studies were included in the blood pressure analyses. After we had killed these rats, their organ weights (kidney, heart, adrenal) and plasma electrolyte, adrenocorticotrophin and serum corticosterone concentrations were measured. RESULTS: On the final day of treatment systolic blood pressure of sham-injection control rats was 123 +/- 1 mmHg (n = 50). Compared with sham treatment, a low dose of adrenocorticotrophin (1 microg/kg per day) increased systolic blood pressure from 122 +/- 1 to 130 +/- 2 mmHg (P < 0.001) without any metabolic effects, whereas a high dose of adrenocorticotrophin (500 microg/kg per day) increased systolic blood pressure from 121 +/- 1 to 150 +/- 2 mmHg (P < 0.001, n = 55) with increases in intake of water and urine volume (P < 0.001, n = 10) and a decrease in body weight (P < 0.001, n = 10). Plasma adrenocorticotrophin and serum corticosterone concentrations for the sham-injection control group were 162 +/- 12 pg/ml (36 +/- 3 pmol/l) and 376 +/- 18 ng/ml (1038 +/- 50 nmol/l), respectively. Plasma adrenocorticotrophin concentration was elevated by injections of 100 (P < 0.05), 200 (P < 0.01) and 500 microg/kg adrenocorticotrophin per day (P = 0.001). Serum corticosterone concentration was not significantly different from that of sham-injection rats with 0.5-5 microg/kg adrenocorticotrophin per day but was increased by injection of 50-500 microg/kg adrenocorticotrophin per day (P < 0.001). CONCLUSIONS: These results define 1 microg/kg adrenocorticotrophin per day, administered subcutaneously, as the threshold dose for causing a rise in blood pressure in the rat Thus administration of adrenocorticotrophin increases systolic blood pressure at doses that induce minimal adrenocorticotrophin metabolic effects. Administration of a low dose of adrenocorticotrophin to the rat is a suitable model for stress-induced hypertension.