Pharmacodynamic model for joint exogenous and endogenous corticosteroid suppression of lymphocyte trafficking

The circadian pattern of the immune system correlates with that of circulating T-helper cells and inversely with cortisol concentrations. Corticosteroids, both endogenous and exogenous, cause lymphocyte dimunition in blood by retention of cells in the lymphatic circulation. A physiologic pharmacodynamic model was developed to describe changes in circulating lymphocytes as a function of both endogenous cortisol and methylprednisolone concentrations. The model was applied to T-helper and T-suppressor cell data collected from six asthmatic men during baseline, after single-dose, and after 6 days of 20 mg daily methylprednisolone. The model described all phases of the study well. Baseline circadian rhythm of lymphocytes was related to cortisol concentrations. Multiple-dosing of methylprednisolone caused apparent tolerance and decreased the sensitivity of lymphocytes to corticosteroids by 116% and markedly reduced endogenous cortisol concentrations. A 60% increase in circulating T-helper cells was observed which could be accounted for by dual changes in receptor sensitivity and endogenous cortisol. Supported by National Institutes of Health Grant 24211 from the National Institute of General Medical Sciences and by the Sandoz Pharmaceutical Research Fellowship in Immunology Therapeutics from the American College of Clinical Pharmacy for Dr. Milad.     

PREGNANCY ATTENUATES ACTIVITY OF THE BARORECEPTOR REFLEX

1. Pregnancy-induced changes in acute blood pressure regulation are reviewed. 2. Pregnant animals are less able to maintain arterial pressure during haemorrhage than non-pregnant animals. 3. Baroreceptor reflex-mediated increases in heart rate, renal sympathetic activity, vasopressin, ACTH and cortisol are reduced during pregnancy. Therefore, one explanation for the subnormal ability of pregnant animals to regulate arterial pressure during haemorrhage is that the baroreceptor reflex is not as effective. 4. Chronic increases in oestrogen levels in non-pregnant rabbits do not reduce the gain of baroreflex control of renal sympathetic activity. This and other findings suggest that oestrogen alone does not mediate the blunted baroreflex activity observed during pregnancy.     

The impact of radioimmunoassay on our understanding of human adrenal physiology

Radioimmunoassay has only been used for a relatively short time to study the human hypothalamic-pituitary-adrenal system, but the findings have already contributed immeasurably toward a better understanding of the physiology of this system. In some instances classical concepts have been confirmed and extended. Other findings have led to revisions of old concepts and the formulation of new ones. These physiologic studies have produced new and better laboratory tests for the pituitary-adrenal function that are simple and reliable enough to be used not only in clinical research but in the routine practice of medicine. Even greater contributions from radioimmunoassay can be expected in the future.     

Disturbance of circadian rhythms in severely brain-damaged patients correlated with CT findings

Summary Twelve patients aged 3–14 years with severe brain damage of prenatal, perinatal or postnatal origin were studied for 2–4 days regarding the circadian rhythms of sleep and wakefulness, body temperature and blood cortisol levels. Six patients had developed a disorder in the circadian rhythm of sleep and wakefulness. The circadian rhythm of body temperature was maintained in 11 of the patients and was little disturbed compared to those of sleep and wakefulness and cortisol levels. The three overt rhythms of circadian activity were not necessarily disturbed simultaneously, which does not contradict the multiple oscillatory theory of the human timekeeping system. CT findings suggested that the brain-stem plays a more important role than the cerebral hemispheres in the regulation of human circadian rhythms.     

应激对大鼠海马金属硫蛋白亚型表达的影响

目的 :　观察应激对大鼠海马脑区金属硫蛋白亚型表达的影响。方法 :　以束缚为应激原建立心理应激动物模型。将动物随机分为四组 :正常对照组 (Ctr)、束缚 1 w组 (R1 )、束缚 2w组 (R2 )和束缚 4w组 (R4)。取动物脑和肝脏以镉饱和法测定金属硫蛋白含量 ,取海马组织提取总 RNA,以 RT- PCR检测金属硫蛋白亚型 MT- 1 m RNA和 MT- 3m RNA,并取血测定血浆皮质醇和 IL- 6水平。结果 :　束缚应激后 ,大鼠体重增长明显减慢 ,血浆皮质醇、IL- 6水平显著高于Ctr组 ;海马脑区两种亚型金属硫蛋白 m RNA的表达水平升高 ,脑和肝脏金属硫蛋白含量也明显增加。结论 :　束缚应激可影响海马金属硫蛋白的表达 ,使其在蛋白质水平和 m RNA水平均出现明显升高 ,其可能机制是 ,在应激条件下皮质醇和 IL- 6等因子的上调对这种应激蛋白的表达发挥了诱导作用     

EFFECT OF ARTERIAL CHEMORECEPTOR STIMULATION WITH ALMITRINE BISMESYLATE ON PLASMA RENIN ACTIVITY, ALDOSTERONE, ACTH AND CORTISOL IN ANAESTHETIZED, ARTIFICIALLY VENTILATED CATS

1. Changes in plasma renin activity (PRA) and in the plasma concentration of aldosterone, adrenocorticotrophic hormone (ACTH) and cortisol in response to an intravenous infusion of the chemoreceptor stimulant almitrine bismesylate (0.2 mg/kg) were studied in two groups of anaesthetized, paralysed and constantly ventilated cats. In one group, the peripheral arterial chemoreceptors remained innervated, whereas in the other they were denervated by bilateral cervical vagotomy and section of the carotid sinus nerves. 2. Animals with innervated chemoreceptors (n= 16) reacted to almitrine bismesylate with a significant (P < 0.05) increase in both ACTH and cortisol. These responses were not present in cats in which the peripheral arterial chemoreceptors had been surgically denervated (n= 16). 3. Plasma renin activity and plasma aldosterone increased with time during experiments on both the chemoreceptor-intact and chemoreceptor-denervated cats. Almitrine did not affect the time course of the rise in PRA and plasma aldosterone in either group of animals. 4. These data indicate that, under the conditions of our experiments, almitrine induced arterial chemoreceptor reflex mechanisms stimulate ACTH and cortisol release, but has no chemoreceptor-dependent influence on PRA or plasma aldosterone.     

A longitudinal evaluation of dexamethasone and cortisol plasma concentrations in the dexamethasone suppression test before and during treatment with antidepressant drugs

Thirty depressed in- and outpatients received serial dexamethasone suppression tests (DSTs). Plasma dexamethasone and cortisol concentrations were drawn at 1600 on the day following a 1-mg oral dose of dexamethasone. The first DST was performed after patients were drug-free for a period of 1 week; the second, third, and fourth DSTs while patients received antidepressant medication. Dexamethasone and cortisol concentrations drawn in the drug-free period correlated significantly. The cortisol to dexamethasone ratio changed significantly with time in DST nonsuppressors, suggesting that nonsuppression is associated with an altered pharmacodynamic response of the hypothalamopituitary-adrenal axis to dexamethasone during depression. When dexamethasone concentrations from the drug-free period were compared with those drawn during antidepressant treatment, no significant differences were noted.     

A 5-Day Estradiol Therapy, in Amounts Reproducing Concentrations of the Early-Mid Follicular Phase, Prevents the Activation of the Hypothalamo-Pituitary-Adrenal Axis by Interleukin-1α in the Ovariectomized Rhesus Monkey

In a previous report, we have shown that intracerebroventricular (icv) administration of the cytokine interleukin-1a (IL-1α) in the ovariectomized (OVX) rhesus monkey results in the acute activation of the hypothalamo-pituitary-adrenal (HPA) axis and the inhibition of LH and FSH secretion. Here, we compare the cortisol response to IL-1α administration in OVX monkeys and in OVX animals replaced with estradiol (E) to reproduce E concentrations typical of the early-mid follicular phase. Cortisol, LH and FSH were measured after an icv infusion of physiological saline or IL-1α (2.1 or 4.2 μg/30 min) in both groups. E-containing capsules were implanted sc 5 days prior to the experiment. In OVX, E concentrations were <5 pg/ml. Cortisol concentrations decreased throughout the afternoon after saline infusion (to 49.7 ± 5.1% of baseline at 5 h; n = 7), but increased significantly after IL-1α to 158.3 ± 13.8% (n = 7). In OVXE, cortisol also declined after saline (to 76.4 ± 16.2%; n = 5). There were 2 types of response to IL-1α: in grp 1 (mean E 18.0 ± 0.7 pg/ml), the cortisol response was similar to that in OVX (160.8 ± 17.0%; n = 5), while in grp 2 (E: 30.7 ± 3.1 pg/ml), the cortisol response was absent (66.6 ± 7.2% of baseline at 5 h; NS vs saline in OVXE; n = 7). The cortisol response to IL-1α was restored in 2 monkeys when E was increased to >100 pg/ml, confirming our previous observations. While saline infusion did not affect LH (102.3 ± 10.2% of baseline at 5 h) or FSH (102.5 ± 4.4%) secretion in OVX monkeys, there was a significant decrease in both hormones after IL-1α (LH: 33.3±3.7%, FSH: 66.2 ± 6.5%; P<0.05 vs saline). This effect was lessened in OVXE animals: By 5 h, areas under the LH curve were 62.8 ± 10.9% of baseline in grp 1 and 85.3 ± 7.9% in grp 2 (NS vs saline), while those under the FSH curve were 84.0 ± 6.5% in grp 1 and 77.7 ± 4.3% in grp 2 (NS vs saline). The data demonstrate a striking effect of a 5-day estradiol treatment in preventing the HPA axis response to the cytokine IL-1α in the OVX monkey. This action, however, occurs only within restricted estradiol concentrations that reproduce E levels typical of the early-mid follicular phase of the menstrual cycle. While the precise mechanism through which estradiol exerts this action remains to be investigated, the results may have clinical relevance to the issue of estrogen replacement therapy in physiology and pathology.     

Morning and Evening Adrenocortical Responses to ACTH Stimulation in Endogenously Depressed Patients: A Preliminary Report

Abstract: Adrenocortical stimulation with ACTH both in the morning (M-test) and in the evening (Etest) and the dexamethasone suppression test were carried out in patients suffering from endogenous depression (DEP) and normal controls (NOR). A greater cortisol release in DEP was recognized than in NOR in the M-test, an earlier peak response of DEP was shown in the M-test than in the Etest, and a lack of association between hypersecretion of cortisol during depression and cortisol output after ACTH administration was noted. These findings, together with the results of DST, suggest that excessive activity of the hypothalamic-pituitary-adrenal (HPA) axis in depression may result, partly, from adrenocortical hyperresponsiveness.