123I-MIBG scintigraphy of catecholamine systems: impediments to applications in clinical medicine.
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3-Iodobenzylguanidine↗
Biomedical subjects
K Pacak
Publications and source records attributed to K Pacak.
Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.
Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.
Adrenergic beta-Agonists↗
Intracranial arachnoid cysts.
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Arachnoid Cysts↗
How do levels of (endogenous) glucocorticoids, interleukin-10 and interleukin-12 relate to multiple sclerosis relapse before, during and after pregnancy?
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Female↗
The role of ascending neuronal pathways in stress-induced release of noradrenaline in the hypothalamic paraventricular nucleus of rats.
Central catecholaminergic pathways carrying pain-related signals to the hypothalamic paraventricular nucleus (PVN) were investigated in laboratory rats. Four per cent formalin injected subcutaneously was employed as a stressful stimulus. Neuronal activity in brainstem catecholaminergic and paraventricular neurones was assessed by Fos immunohistochemistry. Stress-induced noradrenaline (NE) release from nerve terminals in the PVN was measured in extracellular fluid by in-vivo microdialysis. Within 30 min, formalin elicited a four- to sixfold increase in plasma ACTH and corticosterone concentrations and intense Fos-like activity was seen in the superficial zones of the lumbar spinal cord ipsilateral to the side of the formalin injection. In brainstem catecholaminergic neurones, the PVN, and midline thalamic nuclei, formalin-induced Fos-immunopositivity was equally present in the ipsi- and contralateral sides of the injection. An immediate elevation (4-5 times higher than baseline levels) of NE levels was measured in both the right and left PVN after a formalin injection into the right paw. Unilateral surgical transections at the medulla-spinal cord junction failed to affect formalin-induced elevations in NE levels in the PVN independently of the side of the formalin injection or the knife cut. Thus, this observation clearly shows that fibres carrying pain-evoked signals ascend bilaterally from the spinal cord to the brainstem and forebrain. Hemisections of the medulla oblongata between the level of A1-A2 NE cell groups and the locus coeruleus reduced but did not eliminate formalin-induced NE release from the PVN ipsilateral to the knife cut. This effect was independent of the side of the formalin injection. In the contralateral PVN, high and similar NE levels were measured in response to a formalin injection into the right or the left leg. The present study indicates that formalin-induced pain signals are carried by sensory fibres to the ipsilateral spinal cord. From there, axons of different dorsal horn neurones reach noradrenergic cells on both sides of the medulla oblongata. The majority of noradrenergic fibers ascend on the same side and innervate the ipsilateral PVN. Since formalin administration resulted in a moderate elevation of NE levels in the PVN on the operated side, the role of other ascending noradrenergic (from the locus coeruleus) or noncatecholaminergic fibres that could modulate NE release from the PVN should be considered.
Animals↗
How does metyrapone decrease seizures?
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Animals↗
Solitary cerebellar metastasis from papillary thyroid carcinoma: a case report.
Papillary thyroid carcinoma is a common thyroid malignancy that generally has a good prognosis. However, this type of cancer may give rise to distant metastasis and may behave more aggressively in older patients. Here we report clinical, radiological, and pathological findings of a patient with papillary thyroid carcinoma who had a solitary cerebellar metastasis. The patient was known to have metastatic thyroid cancer to the lungs, but this had been stable and the cerebellar metastasis presented an unanticipated significant problem. The rapid detection of cerebellar metastatic disease is critical because neurosurgical removal of the solitary lesion should be considered as the treatment of choice. This case also serves to remind us of the importance of considering possible metastatic brain lesions and their acute life-threatening complications in contrast to the relatively prolonged course associated with metastases of thyroid carcinoma to other organs.
Aged↗
Heterogeneous neurochemical responses to different stressors: a test of Selye's doctrine of nonspecificity.
Selye defined stress as the nonspecific response of the body to any demand. Stressors elicit both pituitary-adrenocortical and sympathoadrenomedullary responses. One can test Selye's concept by comparing magnitudes of responses at different stress intensities and assuming that the magnitudes vary with stress intensity, with the prediction that, at different stress intensities, ratios of increments neuroendocrine responses should be the same. We measured arterial plasma ACTH, norepinephrine, and epinephrine in conscious rats after hemorrhage, intravenous insulin, subctaneous formaldehyde solution, cold, or immobilization. Relative to ACTH increments, cold evoked large norepinephrine responses, insulin large epinephrine responses, and hemorrhage small norepinephrine and epinephrine responses, whereas immobilization elicited large increases in levels of all three compounds. The ACTH response to 25% hemorrhage exceeded five times that to 10%, and the epinephrine response to 25% hemorrhage was two times that to 10%. The ACTH response to 4% formaldehyde solution was two times that to 1%, and the epinephrine response to 4% formaldehyde solution exceeded four times that to 1%. These results are inconsistent with Selye's doctrine of nonspecificity and the existence of a unitary "stress syndrome," and they are more consistent with the concept that each stressor has its own central neurochemical and peripheral neuroendocrine "signature."
Adrenocorticotropic Hormone↗
Stress-induced Fos-like Immunoreactivity in the Pons and the Medulla Oblongata of Rats.
Immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brainstem neurons in response to acute stressors like immobilization, formalin-induced pain, cold exposure, hemorrhage and insulin-induced hypoglycemia. Different stressors induced Fos-like immunoreactivity in different pontine and medullary neurons. A single, 3 hour immobilization was found to be a very strong stimulus that activated brainstem catecholaminergic (tyrosine hydroxylase-immunopositive) neurons and cells in the raphe and certain pontine tegmental nuclei, as well as in the reticular formation. Pain, induced by a subcutaneous injection of formalin was also effective on catecholamine-synthesizing neurons and on others cells in the nucleus of the solitary tract. Cold exposure activated cells mainly in the sensory spinal trigeminal and parabrachial nuclei and in the so-called "pontine thermoregulatory area". Moderate Fos-like immunoreactivity was induced by a hypotonic (25%) hemorrhage in medullary catecholaminergic neurons, the nucleus of the solitary tract and the Barrington nucleus. Among stressful stimuli used, insulin-induced hypoglycemia elicited the smallest Fos activation in the lower brainstem. The present observations indicate that different stressors may use different neuronal pathways in the central organization of the stress response.
Journal Article↗
Regulation of Peripheral Catecholamine Responses to Acute Stress in Young Adult and Aged F-344 Rats.
Young adult (3-month-old) and aged (24-month-old) Fischer-344 male rats received i.v. infusions of 3H-labeled norepinephrine (NE) and epinephrine (EPI) to examine the effects of aging on the neuronal uptake of NE and sympathoadrenal release of NE and EPI. Spillovers of NE and EPI into plasma and their clearance from the circulation were estimated from plasma concentrations of endogenous and 3H-labeled NE and EPI. The efficiency of neuronal uptake was assessed from changes in plasma clearance of NE and concentrations of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), during immobilization stress or neuronal uptake blockade with desipramine. Stress-induced increases in plasma NE and higher plasma NE concentrations in aged compared to young adult rats were due to both decreases in NE clearance and increases in NE spillover. EPI spillover and clearance were reduced in aged compared to young adult rats, so that plasma EPI levels did not differ between groups. Young adult and aged rats had similar desipramine-induced decreases in NE clearance, whereas desipramine-sensitive decreases and stress-induced increases in plasma DHPG were larger in aged rats. This indicates that neuronal uptake is intact and that increased NE spillover at rest and during stress in aged rats reflects increased NE release from sympathetic nerves. The results show that aging is associated with divergent decreases in EPI release from the adrenal medulla and increases in NE release from sympathetic nerves. Increased plasma concentrations of NE in aged compared to young adult rats also result from decreased circulatory clearance of NE, but this does not reflect any age-related impairment of NE reuptake.
Journal Article↗
Identification of endogenous peroxidase-containing cells as eosinophils in the gastrointestinal system.
Endogenous peroxidase (EPX) activity in certain cells in the gastrointestinal system interferes with immunohistochemical methods based on the horseradish peroxidase-catalyzed substrate deposition. We studied the distribution and characteristics of these cells. We also report an effective and antigen-preserving EPX blocking method, to make possible the evaluation of immunoperoxidase stainings in cryostat sections. The EPX-containing cells (EPX cells) are present in every part of the gastrointestinal tract, predominantly in the tunica propria. We identified them as eosinophil cells in May-Grünwald-Giemsa stained sections. The complete match was confirmed by different fluorescence techniques. Firstly, the EPX cells were labeled by a red fluorochrome-conjugated substrate of peroxidase enzymes, rhodamine-tyramide, whereas the eosinophil cells were labeled by the green fluorochrome, l-hydroxy-3,6,8-pyrenetrisulfonic acid, which is known to label exclusively eosinophilic granules at pH 10. Secondly, all the EPX cells reacted with a monoclonal antibody against the eosinophil peroxidase enzyme. Finally, a set of commercially available leukocyte markers was used to characterize the EPX cells colabeled by fluorochrome-tyramides. Neither macrophages nor mast cells showed EPX activity. Increased numbers and altered distribution were seen in stressed rats and in ulcerated human stomach.
Animals↗
Interrelations between sympathoadrenal system and hypothalamo-pituitary-adrenocortical/thyroid systems in rats exposed to cold stress.
The interrelations between sympathoadrenal (SA) system and hypothalamo-pituitary-adrenocortical (HPA) or hypothalamo-pituitary-thyroid (HPT) system during cold stress were examined by measuring plasma levels of dihydroxyphenylalanine (DOPA), catecholamine and their metabolites in adrenalectomized (ADX) and thyroidectomized (TX) rats exposed to cold stress (-3 degrees C). Plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), thyroid-stimulating hormone (TSH) and thyroid hormones in cold-stressed rats were measured also. Plasma ACTH levels were increased transiently after 1 h of cold exposure, after which the circadian rhythm and plasma levels of ACTH were similar to those of normal rats. Plasma CORT levels were also elevated after 1 h of cold exposure; the increased levels of CORT tended to return to normal levels after 9 h of cold, but remained higher than those of normal rats during at least 24 h of cold exposure. Plasma ACTH levels of 5 day cold-stressed rats were no longer elevated above those of control rats and plasma CORT levels were only slightly higher than in control animals. However, plasma levels of TSH and free thyroid hormones were elevated after 1 day and remained elevated after 5 days of cold exposure. Thus, cold stress appears to activate chronically the HPT system, but only transiently activates the HPA system. ADX rats had higher basal plasma levels of dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), DOPA and homovanillic acid (HVA) than those of sham-operated (SHAM) rats, but norepinephrine (NE) levels were not significantly greater than in SHAM animals. TX rats had higher basal plasma levels of NE, epinephrine (EPI) and dopamine (DA), as well as much higher plasma levels of the metabolites. Exposure to cold increased plasma NE levels in both ADX and TX rats, but the increments in TX rats were much greater than in SHAM and ADX groups. Plasma EPI levels were not significantly elevated during cold exposure in SHAM rats, but were highly elevated in TX rats exposed to cold. TX rats had much larger increments in plasma levels of DHPG, MHPG, DA, dihydroxyphenylacetic acid (DOPAC) and HVA during cold exposure than those of SHAM and ADX rats. These results are consistent with the view that endogenous glucocorticoids restrain responses of catecholamine synthesis, release, reuptake, and metabolism in sympathetic nervous system of cold-stressed animals, but that in the absence of an effective HPT system, there is enhanced sympathoadrenal medullary function and augmentation of their responses to cold as a means for maintaining body temperature when the HPT thermogenesis system is impaired.
Adrenal Glands↗
Brainstem hemisection decreases corticotropin-releasing hormone mRNA in the paraventricular nucleus but not in the central amygdaloid nucleus.
Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus and in the central nucleus of the amygdala (ACE) participate in neurohumoral and behavioral responses to stress. To understand better the central regulation of CRH, the present study assessed the effects of ipsilateral surgical hemisection of the brainstem on expression of CRH mRNA in the PVN and the ACE. In situ hybridization was used to demonstrate PVN CRH mRNA expression in hemisected, sham-operated or intact rats before and after 3 h of immobilization (IMMO). In addition, hypothalamic-pituitary-adrenocortical (HPA) axis activity at baseline and during IMMO was assessed by measurements of plasma concentrations of ACTH and corticosterone. IMMO markedly increased CRH mRNA expression in the PVN in all experimental groups. Rats with brainstem hemisections had lower PVN CRH mRNA expression ipsilateral to the lesion and markedly blunted responses after IMMO, compared to values in sham-operated rats. In contrast, neither hemisection nor IMMO affected CRH mRNA expression in the ACE. Lesioned and SHAM-operated groups did not differ in baseline or IMMO-induced increases in plasma ACTH or corticosterone levels. The present results indicate that baseline levels and IMMO-induced increments in CRH mRNA expression in the PVN, but not in the ACE, depend on ipsilaterally ascending medullary tracts and that IMMO-induced HPA activation does not depend on these pathways.
Adrenocorticotropic Hormone↗
Effects of immobilization on in vivo release of norepinephrine in the bed nucleus of the stria terminalis in conscious rats.
Release of norepinepriine (NE) and its metabolites in the bed nucleus of the stria terminalis (BNST) was examined using in vivo microdialysis in conscious rats before, during and after 2 h of immobilization. Microdialysate levels of NE and of dihydroxyphenylglycol (DHPG) increased by 170-290% above basal levels during the 1st h of immobilization and decreased gradually thereafter. In contrast, levels of dihydroxyphenylacetic acid (DOPAC) increased gradually over the entire period of immobilization, peaking at 110% above baseline levels. These findings indicate that in rats a single immobilization is attended by increased synthesis, release and reuptake of NE within the BNST. The results are consistent with previous findings relating to stress-induced release of NE in the hypothalamic paraventricular nucleus, central nucleus of the amygdala and cerebral cortex and suggest concurrent noradrenergic activation in several brains centers during acute stress.
3,4-Dihydroxyphenylacetic Acid↗
Effects of hypercortisolemia or hyperinsulinemia on neurochemical indices of catecholamine release and synthesis in conscious rats.
Glucocorticoids and insulin (INS) complexly affect sympathoneural and adrenomedullary outflows. This study assessed effects of chronic hypercortisolemia and effects of INS independent of INS-induced hypoglycemia on neurochemical indices of different aspects of catecholaminergic function in conscious rats. Since L-DOPA is the precursor of the endogenous catecholamines and the immediate product of the rate-limiting enzymatic step in catecholamine biosynthesis, alterations in rates of appearance (spillover) of L-DOPA in arterial plasma may reflect alterations in catecholamine synthesis. The study therefore included examination of whether cortisol (CORT) or INS affects L-DOPA spillover or renal excretion of dopamine (DA) derived from plasma L-DOPA. Arterial plasma levels and urinary excretion rates of endogenous catechols and radiolabelled L-DOPA and DA were measured during systemic intravenous infusions of [3H]L-DOPA. CORT was administered via a subcutaneous minipump reservoir for one week prior to [3H]L-DOPA infusion, and INS was infused with glucose to examine effects of hyperinsulinemia independently of hypoglycemia. CORT decreased plasma levels and urinary excretion of norepinephrine (NE). INS did not. Neither CORT nor INS affected levels of other catechols, L-DOPA spillover, or the rate of urinary excretion of [3H]DA for a given plasma level of [3H]L-DOPA. The results suggest that CORT inhibits sympathetically-mediated NE release without altering overall rates of catecholamine turnover or synthesis in sympathetic nerves in vivo and that INS effects on catecholaminergic function depend entirely on INS-induced hypoglycemia.
Animals↗
Functional alpha 3-glycine receptors in rat adrenal.
The adrenal medulla contains high-affinity strychnine binding sites, presumed to be receptors for glycine. In this study, glycine injection (400 pmol) via a cannula attached to a microdialysis probe increased in vivo concentrations of catecholamines in the adrenal microdialysate in anesthetized rats. Strychnine perfusion (20 pmol/20 min) blocked these responses. To identify receptors potentially mediating this effect, we tested for RNA transcripts of the three known alpha subunits of strychnine binding site, using the reverse transcription-polymerase chain reaction. Only mRNA encoding the alpha 3 isoform was found in the rat adrenal. The findings suggest that in the rat adrenal, glycine stimulates catecholamine release by binding to strychnine binding sites and that those sites probably contain the alpha 3 isoform.
Adrenal Medulla↗
Stress-induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary-adrenocortical and sympathoadrenal activity: in vivo microdialysis studies.
The hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system are major effector systems that serve to maintain homeostasis during exposure to stressors. In the past decade, interest in neurochemical regulation and in pathways controlling activation of the HPA axis has focused on catecholamines, which are present in high concentrations in specific brain areas--especially in the hypothalamus. The work described in this review has concentrated on the application of in vivo microdialysis in rat brain regions such as the paraventricular nucleus (PVN) of the hypothalamus, the central nucleus of the amygdala (ACE), the bed nucleus of the stria terminalis (BNST), and the posterolateral hypothalamus in order to examine aspects of catecholaminergic function and relationships between altered catecholaminergic function and the HPA axis and sympathoadrenal system activation in stress. Exposure of animals to immobilization (IMMO) markedly and rapidly increases rates of synthesis, release, and metabolism of norepinephrine (NE) in all the brain areas mentioned above and supports previous suggestions that in the PVN NE stimulates release of corticotropin-releasing hormone (CRH). The role of NE in the ACE and the BNST and most other areas possessing noradrenergic innervation remains unclear. Studies involving lower brainstem hemisections show that noradrenergic terminals in the PVN are derived mainly from medullary catecholaminergic groups rather than from the locus ceruleus, which is the main source of NE in the brain. Moreover, the medullary catecholaminergic groups contribute substantially to IMMO-induced noradrenergic activation in the PVN. Data obtained from adrenalectomized rats, with or without glucocorticoid replacement, and from hypercortisolemic rats suggest that glucocorticoids feedback to inhibit CRH release in the PVN, via attenuation of noradrenergic activation. Results from rats exposed to different stressors have indicated substantial differences among stressors in eliciting PVN noradrenergic responses as well as of responses of the HPA, sympathoneural, and adrenomedullary systems. Finally, involvement of other areas that participate in the regulation of the HPA axis such as the ACE, the BNST, and the hippocampus and the importance of stress-induced changes in expression of immediate early genes such as c-fos are discussed.
Adrenal Cortex↗
Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism?
1. The clinical utility of plasma metadrenalines for examination of sympatho-adrenal function and catecholamine metabolism was assessed from plasma measurements of these metabolites in a number of clinical conditions (hypertension, cardiac failure, bilateral adrenalectomy and X-chromosomal deletions of the gene for monoamine oxidase), and before and during activation of sympathetic outflow or infusions of noradrenaline and adrenaline. 2. Plasma concentrations of normetadrenaline were less than 25% of those of noradrenaline, concentrations of metadrenaline and adrenaline were similar and those of sulphate-conjugated metadrenalines were 20- to 30-fold higher than free metadrenalines. Hypertensive patients had elevated plasma concentrations of adrenaline, noradrenaline and conjugated but not free metadrenalines. Cardiac failure patients had 2- to 4-fold increases in plasma noradrenaline and free and conjugated normetadrenaline. Adrenalectomy resulted in undetectable plasma concentrations of adrenaline, 91-97% decreases in free and conjugated metadrenaline and a 40% decrease in normetadrenaline relative to noradrenaline. Patients with X-chromosomal deletions of the gene for monoamine oxidase had 6- and 16-fold increases in plasma free and conjugated normetadrenaline and 2- and 4-fold increases in free and conjugated metadrenaline. 3. Infusion of catecholamines increased plasma concentrations of free metadrenalines by less than 6% of increases in precursor amines, indicating that most plasma normetadrenaline (84%) and metadrenaline (90%) is derived from metabolism of catecholamines before their entry into the circulation. Considerable O-methylation of catecholamines within the adrenals explains why sympatho-adrenal activation resulted in smaller proportional increases in plasma metadrenalines than catecholamines. 4. Plasma metadrenalines provide supplementary information about sympatho-adrenal activity to that provided by catecholamines, but are more useful for examination of the extraneuronal inactivation of catecholamines, particularly detection of neurochemical phenotypes in genetic disorders of catecholamine metabolism. Significant formation of metadrenalines within chromaffin tissue explains why measurements of plasma metadrenalines provide an extraordinarily sensitive method for diagnosis of phaeochromocytoma.
Adrenal Glands↗