Participation of Antidiuretic Hormone (ADH) in Asthma Exacerbations Induced by Psychological Stress via PKA/PKC Signal Pathway in Airway-Related Vagal Preganglionic Neurons (AVPNs).

AIMS: Present study was performed to examine whether ADH was implicated in psychological stress asthma and to explore the underlying molecular mechanism. METHODS: We not only examined ADH levels in the cerebrospinal fluid (CSF) via radioimmunoassay, but also measured ADH receptor (ADHR) expression in airway-related vagal preganglionic neurons (AVPNs) through real-time PCR in all experimental mice. Western blotting was performed to evaluate the relationship between ADH and PKA/PKC in psychological stress asthma. Finally, the role of PKA/PKC in psychological stress asthma was analyzed. RESULTS: Marked asthma exacerbations were noted owing to significantly elevated levels of ADH and ADHR after psychological stress induction as compared to OVA alone (asthma group). ADHR antagonists (SR-49095 or SR-121463A) dramatically lowered higher protein levels of PKAα and PKCα induced by psychological stress as compared to OVA alone, suggesting the correlation between ADH and PKA/PKC in psychological stress asthma. KT-5720 (PKA inhibitor) and Go-7874 (PKC inhibitor) further directly revealed the involvement of PKA/PKC in psychological stress asthma. Some notable changes were also noted after employing PKA and PKC inhibitors in psychological stress asthma, including reduced asthmatic inflammation (lower eosinophil peroxidase (EPO) activity, myeloperoxidase (MPO) activity, immunoglobulin E (IgE) level, and histamine release), substantial decrements in inflammatory cell counts (eosinophils and lymphocytes), and decreased cytokine secretion (IL-6, IL-10, and IFN-γ), indicating the involvement of PKA/PKC in asthma exacerbations induced by psychological stress. CONCLUSION: Our results strongly suggested that ADH participated in psychological stress-induced asthma exacerbations via PKA/PKC signal pathway in AVPNs.

Fear and power-dominance motivation: proposed contributions of peptide hormones present in cerebrospinal fluid and plasma.

We propose that fear and power-dominance drive motivation are generated by the presence of elevated plasma and cerebrospinal fluid (CSF) levels of certain peptide hormones. For the fear drive, the controlling hormone is corticotropin releasing factor, and we argue that elevated CSF and plasma levels of this peptide which occur as a result of fear-evoking and other stressful experiences in the recent past are detected and transduced into neuronal activities by neurons in the vicinity of the third ventricle, primarily in the periventricular and arcuate hypothalamic nuclei. For the power-dominance drive, we propose that the primary signal is the CSF concentration of vasopressin, which is detected in two circumventricular organs, the subfornical organ and organum vasculosum of the lamina terminalis. We suggest that the peptide-generated signals detected in periventricular structures are transmitted to four areas in which neuronal activities represent fear and power-dominance: one in the medial hypothalamus, one in the dorsolateral quadrant of the periaqueductal gray matter, a third in the midline thalamic nuclei, and the fourth within medial prefrontal cortex. The probable purpose of this system is to maintain a state of fear or anger and consequent vigilant or aggressive behavior after the initial fear- or anger-inducing stimulus is no longer perceptible. We further propose that all the motivational drives, including thirst, hunger and sexual desire are generated in part by non-steroidal hormonal signals, and that the unstimulated motivational status of an individual is determined by the relative CSF and plasma levels of several peptide hormones.

Cerebrospinal fluid corticotropin-releasing factor (CRF) and vasopressin concentrations predict pituitary response in the CRF stimulation test: a multiple regression analysis.

There is considerable evidence that stress-related psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), are associated with hypersecretion of corticotropin-releasing factor (CRF) within the central nervous system (CNS). One line of evidence that is consistent with central CRF hypersecretion in these disorders is the blunted adrenocorticotropin hormone (ACTH) response to intravenous CRF administration, likely a consequence, at least in part, of downregulation of anterior pituitary CRF receptors. The present study tests the hypothesis that elevated cerebrospinal fluid (CSF) concentrations of CRF and a secondary ACTH secretagogue, arginine vasopressin (AVP), are associated with diminished adenohypophyseal responses in a standard CRF stimulation test. CSF concentrations of CRF and AVP, and plasma ACTH responses to the administration of 1 microg/kg ovine CRF (oCRF) were measured in healthy adult women with and without current major depression and/or a history of significant childhood abuse. The primary outcome measure was ACTH area under the curve (AUC) in the CRF stimulation test. Multiple linear regression was performed to identify the impact of CSF CRF and AVP concentrations upon the pituitary response to CRF stimulation. The regression model explained 56.5% of the variation in the ACTH response to CRF stimulation. The relationship of CSF concentrations of CRF to ACTH responses to CRF were best described by a third-order function that was inversely correlated over most of the range of studied values. The association of ACTH response with CSF concentration of AVP and the dose of oCRF followed second-order kinetics. These findings support the hypothesis that central CRF hypersecretion is associated with a blunted ACTH response to exogenously administered CRF, explaining almost 60% of the variation in the ACTH response to CRF.

The plasma and CSF vasopressin levels in brain tumors with brain edema.

Vasopressin (VP) levels were evaluated by radioimmunoassay (RIA) in the arterial (A), peripheral (Vp) and jugular (Vj) vein blood and in CSF in 102 patients with brain tumors. In 60 cases the patients' state was complicated by brain edema (BE) and hemodynamic disturbances (HDD). The obtained data revealed significantly higher VP levels: 1) in A, Vp and CSF in patients with BE (Group A) in comparison with patients without BE (Group B), 2) in Vj in patients with HDD only (Group Bc) and 3) in Vp in patients with HDD and BE (Group Ac) in comparison with Group Bc (p < 0.05). There were marked extremely high VP levels in Vj in patients with severe haemorrhage, tachycardia and high blood pressure (BP) and in CSF in patients with tachycardia, high BP and cardiac arrest (p < 0.05 correspondingly in each of the cases). Our results on a clinical basis confirmed CSF VP influence on BE development. We also confirmed the neurohumoral (through blood) and neurotransmitter (possibly through CSF and/or vasopressinergic pathways) VP influences on cardiovascular regulation mechanisms. We content that this is a pathogenetic basis for application of VP direct or indirect antagonists for preventing and treating brain edema in neurosurgical patients.

The CSF aldosterone in brain tumors with brain edema.

The study of renin-angiotensin-aldosterone (RAA) and vasopressin (VP) systems in neurosurgical patients with brain tumors and brain edema (BE) had revealed an excessive activity of these systems with secondary hyperaldosteronism especially with BE that proves the pathogenetic role of these systems. Measurement of Aldosterone (Ald) in CSF may serve as a diagnostic test to help manage the patient's clinical condition. Mechanisms of Ald penetration in CSF assumed to be the result of blood-brain-barrier (BBB) destruction (especially in astrocytomas) and/or the mediation by neuropeptides (for example increasing activity of VP V1-receptors). Results serve as a basis for application of the neuropeptide and hormone antagonists and inhibitors on all stages of cascade reactions taking part in the water and sodium retention.

Specificity of circadian function in transplants of the fetal suprachiasmatic nucleus.

Fetal tissues obtained from specific regions of the developing hypothalamus were transplanted to determine whether the precursor neurons of the suprachiasmatic nucleus (SCN) can be distinguished from those of the presumptive paraventricular nucleus (PVN) on the basis of the functional capacity to generate circadian rhythms. The presumptive SCN, the PVN, and a portion of the neocortical primordium were dissected from the developing forebrains of normal Long-Evans fetuses, separated, and selectively transplanted into the periventricular-third ventricle region of adult, vasopressin (VP)-deficient Brattleboro rats. In host animals that received grafts containing the precursor population of SCN neurons, the temporal profile of VP levels in the cerebrospinal fluid (CSF) oscillated with a circadian periodicity in a manner similar to that observed in normal Long-Evans rats. CSF collected serially from animals with grafts of the presumptive PVN also contained VP, but no circadian variation was manifested in peptide levels. VP was undetectable in CSF samples obtained from Brattleboro rats with cortical grafts. In association with their circadian functional capacity, grafts of the SCN primordium were characterized by clusters of parvicellular neurons immunopositive for VP or vasoactive intestinal polypeptide (VIP) that resembled the cell groups of the in situ SCN. In contrast, transplants of the presumptive PVN did not contain neurons immunoreactive for VIP, and the VP neurons in these grafts resembled the neurosecretory cells of the PVN.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of enhanced cerebrospinal fluid levels of vasopressin, vasopressin antagonist or vasoactive intestinal polypeptide on circadian sleep-wake rhythm in the rat.

Several endogenous peptides have been implicated in the regulation of sleep and wakefulness. The present study was carried out in order to determine whether the light-dark rhythm of vasopressin (VP) in the cerebrospinal fluid (CSF) had functional significance in relaying information from the circadian pacemaker, i.e. the suprachiasmatic nuclei (which synthesize VP as well as vasoactive intestinal polypeptide (VIP], to the centra regulating sleep. After constant delivery of VP in the CSF via an Accurel/collodion implant in the lateral ventricle, the VP CSF level was raised from 20-35 pg/ml to ca. 265 pg/ml whereby a VP rhythm in the CSF could no longer be detected. Under these conditions VP was found to increase the arousal state of the rat in the dark period, which resulted in a higher amplitude of the circadian sleep-wake rhythm. Application of the VP antagonist d(CH2)5[Tyr(Me)2]VP partly had opposite effects. A similar approach with central application of VIP resulted in an increase in rapid eye movement and quiet sleep but did not affect the amplitude of the circadian rhythm. It was concluded that although peptide levels in the CSF may show clear temporal variations with the light-dark cycle, this rhythmicity is not causally related to the circadian aspect of sleep-wakefulness. However, both VP and VIP contribute to the regulation of the amount of time spent in sleep and wakefulness and the level of VP in the CSF is correlated with the amplitude of the rhythm.

CSF neuropeptides in euthymic bipolar patients and controls.

Levels of vasopressin, somatostatin, neurotensin, vasoactive intestinal peptide, corticotrophin-releasing factor and adrenocorticotrophin in CSF were determined in lithium-treated and unmedicated euthymic bipolar patients and controls, in a search for a trait marker in affective disorder. No group differences in levels of these peptides were found. Highly significant positive correlations were found among these peptides (with the exception of neurotensin), suggesting that their presence in CSF is functionally significant, as opposed to the result of random diffusion from the interstitial space of the brain.

Manipulation of vasopressin level in the cerebrospinal fluid of the rat by means of an easily interchangeable controlled-delivery Accurel mini-device.

The procedure described for the continuous release of vasopressin (VP) in the rat lateral ventricle via implantation of a VP-loaded Accurel/collodion mini-device has now been further developed, allowing the introduction, removal and exchange of the Accurel device through a polyethylene guide cannula. In this way, manipulation of the VP level in the cerebrospinal fluid can easily be accomplished. VP levels were measured by radioimmunoassay in liquor withdrawn from the cisterna magna.

Effect of vasopressin on cold-induced brain edema in cats.

Centrally released arginine vasopressin (AVP) has been implicated in the regulation of intracranial pressure (ICP) and brain water, and is elevated in the cerebrospinal fluid (CSF) of some patients with pseudotumor cerebri or subarachnoid hemorrhage. The authors have examined the relationship of AVP levels in CSF to ICP and brain water content in three experimental groups of cats with and without cold-induced vasogenic edema. With the cats under general anesthesia, a cold lesion was made and cannulas were placed in the cisterna magna, lateral ventricle, and aorta. Subsequent central and systemic measurements were made while the animals were awake and free-roaming. In Experiment 1, endogenous AVP levels in CSF were measured every 12 hours over a 48-hour period by radioimmunoassay in cats with sham craniotomy, mild edema, or moderate edema; no significant difference was found between groups although a diurnal variation was seen (range 2 to 18 pg/ml). In Experiment 2, either carrier solution or AVP, in doses of 1.5 or 30 ng, was administered via a lateral ventricle every 2 hours over 24 hours in unlesioned cats. In Experiment 3, cats received 2 or 35 ng of carrier solution or AVP in a similar manner, but coupled with a cold lesion. The CSF AVP levels ranged from an average of 100 to 681 pg/ml and 1.4 to 11.9 ng/ml in the two dose groups in both experiments. Neither the low nor the high dose had an effect on brain water content in normal white matter (Experiment 2), but both doses increased brain water content in edematous white matter (p less than 0.05 in Experiment 3), as determined by wet and dry weight measurements of standardized pieces of white matter. The ICP was decreased by high-dose AVP in normal cats (p less than 0.01 at 24 hours), but in lesioned cats was unchanged by low-dose and increased by high-dose AVP (p less than 0.05 at 18 hours). The authors conclude that pharmacological doses of central AVP facilitate the production of vasogenic edema.

CSF neurotransmitter markers in Alzheimer's disease.

CSF neurotransmitter markers may reflect neurochemical alterations in Alzheimer's disease (AD). The best studied neurochemical deficit in AD is that of acetylcholine. Both acetylcholinesterase and butyrylcholinesterase activity have been reported to be reduced in some but not all studies of AD CSF. Studies of monoamine metabolites have also been controversial but most authors have found reduced concentrations of CSF HVA, lesser reductions in HIAA and no change in MHPG. CSF GABA concentrations have been found to be reduced in AD. Studies of CSF neuropeptides in AD have shown reduced concentrations of somatostatin and vasopressin, normal concentrations of vasoactive intestinal polypeptide and either normal or decreased concentrations of beta-endorphin and corticotropin releasing factor. Although no individual CSF neurochemical markers are specific for AD it may be possible to develop a profile of several neurochemical markers which will have enhanced specificity.

Cerebrospinal fluid vasopressin as a marker of central nervous system metastases from small-cell bronchogenic carcinoma.

Vasopressin (ADH) was measured in CSF and plasma in 75 evaluable patients with known or suspected CNS metastases from small-cell bronchogenic carcinoma (SCBC), and in 66 control patients having neither malignant disease nor organic CNS disease. The presence of CNS metastases was confirmed or excluded on the basis of computed tomographic scans, neurologic examination, and autopsy. Twenty-four of the 75 patients had no CNS metastases. Ten of the 51 patients with CNS metastases had leptomeningeal carcinomatosis (MC). CSF-ADH was significantly increased in patients with MC (P less than .05), but not in patients having exclusively parenchymatous CNS metastases. Taking 2 pg/mL (95th percentile of control patients) as the upper limit of normal, 15 SCBC patients had elevated CSF-ADH, including 12 patients with CNS metastases and six patients with MC. The CSF-ADH to plasma ADH ratio was significantly increased in patients with CNS metastases (P less than .05). Patients without CNS metastases had a ratio less than or equal to 0.8 whereas the ratio was greater than 0.8, in 21 of the 51 patients with CNS metastases. The positive and negative predictive values with 95% confidence limits were 84% to 100% and 31% to 59%, respectively. Patients with inappropriate secretion of ADH (SIADH) constituted a significantly greater proportion of patients with elevated CSF-ADH than of patients with normal CSF-ADH levels (P less than .05). In addition, patients with SIADH constituted a significantly greater proportion of patients with MC than of patients with parenchymatous metastases (P less than .05). The diagnostic application of these findings is limited because of the large number of false-negative results, but it may prove to be of value in conjunction with the measurement of other tumor markers.

Cerebrospinal fluid vasopressin and increased intracranial pressure.

Cerebrospinal fluid and plasma vasopressin were measured in patients with cerebral disorders associated with varying levels of elevated intracranial pressure. The mean cerebrospinal fluid vasopressin concentration was significantly increased in patients with pseudotumor cerebri (2.0 +/- 0.2 [SEM] pg/ml), intracranial tumor (2.3 +/- 0.4 pg/ml), and intracranial hemorrhage (1.9 +/- 0.3 pg/ml) compared with control patients (1.2 +/- 0.1 pg/ml). A significant relationship was found between intracranial pressure and the cerebrospinal fluid vasopressin concentration within all groups of patients and in the whole sample as well (r = 0.79; p less than 0.001). In the groups of patients with intracranial tumor, hydrocephalus, and intracranial hemorrhage, some individuals showed plasma vasopressin concentrations inappropriate to the corresponding plasma osmolality, but no relationship was found between intracranial pressure and plasma vasopressin concentration. It is suggested that increased intracranial pressure is a stimulus to centrally released vasopressin. The clinical importance of increased cerebrospinal fluid vasopressin concentrations is still not known.

Neuropeptides in cerebrospinal fluid.

Most neuropeptides can now be assayed in human cerebrospinal fluid (CSF). Some, such as beta-endorphin and arginine vasopressin, seem to be secreted directly into CSF. Others may reach CSF from plasma either by passage through the blood-brain barrier or by absorption through the circumventricular organs, which lack a blood-brain barrier. The role of neuropeptides in CSF is still unclear. Thyrotropin-releasing hormone, somatostatin, arginine vasopressin, angiotensin II, substance P, vasoactive intestinal polypeptide, beta-endorphin, gastrin, and cholecystokinin are all present in assayable quantities in human CSF. Their functions in this fluid are liable to be as diverse as their functions elsewhere in the body. The release of hypothalamic releasing factors into the CSF may be part of the pathway of pituitary hormone release. Pituitary hormones may function in CSF as part of a feedback loop from the hypothalamus. Other neuropeptides may affect receptors in the central nervous system far away from their release site. Intraventricular neuropeptide injection, anatomical and physiological ablation experiments, receptor studies, and neurobiological techniques now being developed will allow a more complete understanding of CSF neuropeptide function in the future.

Peptides in the cerebrospinal fluid of neuropsychiatric patients: an approach to central nervous system peptide function.

This review highlights that essentially all of the recently discovered putative central nervous system (CNS) peptides and other peptide substances are measurable in human cerebrospinal fluid (CSF). Preliminary evidence also suggests that peptides in CSF may have an active regulatory role in relation to CNS function and behavior. Even if this is not the case, CSF peptides may prove to be a useful indirect marker of CNS peptide function and metabolism. Alterations in peptides have been reported in neurological and psychiatric illness, pain symptoms and their treatment, symptoms such as anxiety, and following treatment with CNS active drugs such as carbamazepine. CSF methodologies provide a strategy for the study of the interaction of classical neurotransmitters and peptide substances and their relationship to neural function and behavior in man. Assessment of peptides in CSF may supplement post mortem studies of peptide levels and receptor distribution and help lead to new diagnostic and treatment approaches in neuropsychiatric disorders.

Vasopressin in the cerebrospinal fluid of patients with normal pressure hydrocephalus and benign intracranial hypertension.

We have studied plasma and cerebrospinal fluid vasopressin (CSF-AVP) and osmolality in 28 patients with cervical or lumbar pain syndromes (control patients), 11 patients with normal pressure hydrocephalus (NPH) and in 5 patients with benign intracranial hypertension (BIH). Vasopressin concentration in lumbar CSF to a high extent reflected the actual ventricular CSF-AVP concentration. In all groups CSF-AVP was lower than plasma AVP. Mean CSF-AVP in the control group was 1.3 pg/ml +/- 0.1 (SEM). In the NPH patients, who all suffered from severe dementia, CSF-AVP level was not different from that found in the control group (1.4 pg/ml +/- 0.2). In contrast to the findings in the two other groups CSF osmolality in BIH patients was higher than plasma osmolality (P less than 0.0). CSF-AVP in the BIH patients, characterized by an elevated intracranial pressure (ICP), was higher than in the control group (2.7 pg/ml +/- 0.4, P less than 0.001).

Investigation of cerebrospinal fluid neuropeptides in idiopathic senile dementia.

Thyrotrophin-releasing hormone and gonadotrophin-releasing hormone were measured in lumbar CSF from patients with idiopathic senile dementia, cerebral tumours and spinal disc lesions. Somatostatin was also measured in lumbar CSF from patients with dementia and patients with other neurological disorders, but the numbers involved were much smaller. The levels of these neuropeptides were significantly reduced in the patients with senile dementia. These results suggest a possible involvement of hpothalamic neuropeptides in idiopathic senile dementia.