Peripheral Catecholamine Research Articles

A role for nitric oxide in endotoxin-induced depletion of the peripheral catecholamine stores.

Endotoxemia is associated with increased sympathetic nerve activity and depletion of norepinephrine (NE) and epinephrine (EPI) contents in the adrenal gland and in sympathetically innervated tissues. Endotoxin (bacterial lipopolysacchride [LPS]) causes an increased production of nitric oxide (NO) by inducing nitric oxide synthase (iNOS) expression in various tissues. This increased production of NO contributes significantly to the hypotension associated with endotoxemia. At high concentrations, NO also can act as a neurotoxin. In this study we tested the hypothesis that increased production of NO is involved in depletion of catecholamine content in various tissues from rats treated with a nonlethal dose of LPS. Catecholamine content was measured by high-performance liquid chromatography with electrochemical detection (HPLC-EC) and NOS activity was measured by the 3H-I-arginine to 3H-I-citrulline conversion method. The NE content was decreased in rat adrenal gland, lung, spleen, tail artery, and aorta after LPS. The maximal decrease was at 24 h and returned to control levels at 6 days (144 h). There was no depletion of the NE content in the heart. The EPI content in the adrenal gland was greatly depleted (91%) from 12 to 72 h after LPS. LPS increased the NOS activity in all tissues examined. The time course for NOS activity showed an increase at 3 h, a further increase at 6 h, and a return to control level at 48 h after LPS. The increase in NOS activity occurred before maximal catecholamine depletion. Aminoguanidine, a relatively selective iNOS inhibitor, completely prevented NE depletion in all tissues and partially prevented adrenal EPI depletion induced by LPS. These results are consistent with the hypothesis that LPS-induced production of NO plays a role in depletion of tissue NE and EPI.

Plasma Corticosterone and Immune Reactivity in Restrained Female C3H Mice

Psychological stressors are known to stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system resulting in the release of corticosterone and catecholamines respectively. They have also been reported to induce cytokine production. All these molecules affect various immune parameters and can alter overall immune competence of the individual. The' purpose of this investigation was to study the regulation of the production of corticosterone during stress and its possible effects on immune reactivity.In a first series of experiments, the possible regulation of corticosterone production by interleukin (IL)-1β and peripheral catecholamines during restraint was assessed using a pharmacological approach in mice. Plasma IL-1β concentrations remained at basal after 1-h restraint and the stress-induced increase of plasma corticosterone was not modified by a peripheral injection of an EL-1 receptor antagonist (IL-1ra). By contrast, chemical sympathectomy potentiated the restraint-induced increase in plasma corticosterone concentration, this potentiation being reversed by IL-1ra.In a second series of experiments, the role of corticosterone in stress-immune relationships was studied in adrenalectomized mice subjected to restraint and immunized with sheep erythrocytes. Non-specific immunity, i.e. proliferation of splenocytes and thymocytes and plasma levels of IL-1β, as well as specific immunity, i.e. antibody production and delayed hypersensitivity, were not altered after 2-h restraint. Adrenalectomy failed to induce immune effects in stressed animals, except that delayed hypersensitivity was stronger in adrenalectomized animals, revealing that the high levels of corticosterone produced during stress have an anti-inflammatory activity.The present data show that the stress-induced production of corticosterone was modulated by both peripheral catecholamines and IL-1β. However, this production of corticosterone was unable to modulate immune reactivity except delayed hypersensitivity.

Differences in habituation to psychosocial stress between the HPA-axis, the cardiovascular system and peripheral catecholamines

Differences in habituation to psychosocial stress between the HPA-axis, the cardiovascular system and peripheral catecholamines

Effect of intracerebral norepinephrine depletion on outcome from severe forebrain ischemia in the rat

Manipulations of plasma catecholamine concentrations influence outcome from ischemic brain insults. It has been suggested that these effects are mediated by influences on brain catecholamine concentrations. This study examined whether major changes in brain norepinephrine concentrations can alter outcome from severe forebrain ischemia. Sprague–Dawley rats were administered 50 mg/kg i.p. N-(chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4) or were left untreated (control). One week later, these rats were subjected to either 7 or 8 min of normothermic forebrain ischemia (bilateral carotid occlusion and MABP=30 mmHg) and allowed to recover for 4 days. Histologic damage was then evaluated. In other control and DSP-4-treated animals, hippocampal microdialysate norepinephrine concentrations were measured before, during and after 8 min of forebrain ischemia. Norepinephrine concentrations were also determined in brain homogenates from non-ischemic DSP-treated and control rats. A 95% depletion of norepinephrine was observed in brain homogenates from non-ischemic DSP-4-treated rats compared with control. During ischemia, microdialysate norepinephrine concentrations increased in control but not in DSP-4-treated rats ( P=0.002). For plasma, intra-ischemic epinephrine concentrations increased 8–10-fold and returned to baseline values post-ischemia with no differences between groups. Plasma norepinephrine values remained unchanged in both groups. Histologic damage resulting from either 7 or 8 min of ischemia in hippocampal structures, caudoputamen, and neocortex was similar between DSP-4-treated and control groups. This study could not identify any effect of major changes in brain norepinephrine concentrations on ischemic brain damage. These data indicate that peripheral catecholamine effects on near-complete forebrain ischemic outcome are unlikely to be mediated by effects on central catecholamine concentrations.

High expression of monoamine oxidases in human white adipose tissue: evidence for their involvement in noradrenaline clearance.

The clearance of plasma adrenaline and noradrenaline by human adipose tissue suggests the expression of the catecholamine-degrading enzyme monoamine oxidases and of catecholamine transport systems in adipocytes. In the present study, we identified and characterized the monoamine oxidases and an extraneuronal noradrenaline transporter expressed in human adipocytes. Enzyme assays using the monoamine oxidase A/B substrate [14C]tyramine showed that abdominal and mammary human adipocytes contain one of the highest monoamine oxidase activities in the body. Characterization of the enzyme isoforms by inhibition profiles of [14C]tyramine oxidation and Western and Northern blot analyses showed that mRNAs and proteins related to both monoamine oxidases A and B were expressed in adipocytes. Quantification of each enzyme isoform performed by enzyme assay and Western blot showed that monoamine oxidase A was predominant, representing 70-80% of the total enzyme activity. In uptake experiments, the monoamine oxidase substrate [3H]noradrenaline was transported into white adipocytes (Vmax 0.81+/-0.3 nmol/30 min/100 mg of lipid, Km 235+/-104 microM). The inhibition of [3H]noradrenaline uptake by specific inhibitors indicated that white human adipocytes contain an extraneuronal-type noradrenaline transporter. Competition studies of [14C]tyramine oxidation showed that noradrenaline is metabolized by monoamine oxidases in intact cells. In conclusion, the concomitant expression of monoamine oxidases and of a noradrenaline transporter in human white adipocytes supports the role of the adipose tissue in the clearance of peripheral catecholamines. These results suggest that adipocytes should be considered as a previously unknown potential target of drugs acting on monoamine oxidases and noradrenaline transporters.

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Human brain metabolic response to caffeine and the effects of tolerance.

Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.

Effects of acupuncture on peripheral T lymphocyte subpopulation and amounts of cerebral catecholamines in mice.

The aim of this study was to investigate the effects of acupuncture on peripheral lymphocyte subpopulations and cerebral catecholamines. In order to examine the effects of acupuncture, two experiments were performed. Experiment 1: Eighteen female mice (strain; C57BL/6) at the age of 7 weeks were divided three groups, (a) sham operated (control; n=6), (b) ovariectomized (OVX; n=6), and (c) ovariectomized and stimulated by subcutaneous needles on acupuncture point, Shenshu (BL23) at the both sides of the back for 20 days (OVX+Acu; n=6). These animals were sacrificed at 20 days after needle insertion, and the splenic lymphoid cells were examined by two-color flow cytometry, using monoclonal antibodies (mAb) to the cell surface antigens, CD3, CD4, CD8a and NK1.1 (CD56). In the ovariectomized (OVX) group, the peripheral CD4/CD8 ratio was significantly increased and the ratio of natural killer (NK) cells (CD3-NK1.1+; CD3 negative, NK1.1 positive) to T lymphocytes was decreased compared to the sham control group. In the ovariectomized with needle insertion (OVX+Acu) group, the CD4/CD8 ratio was reduced, but the NK cells ratio was not changed compared to the OVX group. Experiment 2: To investigate the acute effects of subcutaneous needle insertion, male C57BL/6 mice (7 weeks old) were used (n=6, each group). The acupuncture points Shen-shu (BL23) on the backs of the male mice were also stimulated by subcutaneous needles for 3 and 7 days. As a result, the CD4/CD8 ratio was significantly decreased at day 3 and day 7, compared to the control group. On the other hand the NK cells ratio and activated T-cells were increased at day 7. The mitogenic activities in the splenic lymphocytes were also increased by acupuncture stimulation at day 3. Catecholamine contents in the hippocampus were measured by high performance liquid chromatography with the electro-chemical detector (ECD-HPLC) method. No significant change was observed in either dopamine contents or norepinephrine; however, dopamine metabolite, homovanillic acid (HVA) and DOPAC (3,4-dihydroxyphenylacetic acid) were increased at day 3. The study suggests that acupuncture has effects on peripheral lymphocyte subpopulations and may modulate mitogenic activity. In addition, acupuncture may stimulate dopamine turnover.

Peripheral catecholamine alterations in adolescents with polycystic ovary syndrome.

Polycystic ovary syndrome (PCO) is one of the most common endocrine disorders affecting women. Several lines of evidence have suggested the involvement of the sympathetic nervous system (SNS) in this condition. The present work was designed to assess neurochemically SNS activity in patients during the early stages of PCO. Fourteen patients with PCO (aged 14 to 21 years) were studied on a random day and 9 normal regularly cycling adolescents (aged 14 to 20 years) were studied during the early follicular phase (days 2 to 5). Hormonal profile was determined in basal conditions. LH and FSH were also measured after i.v. administration of 100 micrograms GnRH. Plasma concentrations of dihydroxyphenylalanine (Dopa), noradrenaline (NA), adrenaline (A), total dopamine (DA) and dihydroxyphenylglycol (DHPG) were determined in basal conditions and in response to GnRH by HPLC with electrochemical detection or a radioenzymatic method. Basal urinary Dopa, catecholamines and catechol metabolites (DHPG, vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), metanephrine (MN) and normetanephrine (NMN)) were determined by HPLC with electrochemical detection. Basal plasma LH, testosterone, androstenedione, oestrone and LH/FSH ratio were higher (P < 0.01) and serum sex hormone-binding globulin (SHBG) were lower (P < 0.01) in PCO patients than in control subjects. Basal and GnRH-stimulated plasma free Dopa, A, NA and total DA were similar in patients and controls. Plasma DHPG was lower (P < 0.01) in PCO patients (4.20 +/- 0.30 nmol/l) than in controls (8.0 +/- 1.0 nmol/l) throughout the study. Urinary A, NA, DA, Dopa, MN, MHPG, HVA, and VMA were similar in patients and controls. Urinary DHPG was lower (P < 0.01) in PCO patients (0.50 +/- 0.02 mumol/d) than in controls (0.73 +/- 0.09 mumol/d). On the other hand PCO patients had a higher urinary excretion of NMN than controls (PCO: 1.20 +/- 0.10; C: 0.78 +/- 0.10 mumol/d, P < 0.05). Our results show the same endocrinological features in adolescent PCO patients as those reported in adults. The results also demonstrate a peripheral catecholaminergic alteration which suggests an alteration in noradrenaline deamination and/or uptake in adolescent patients. This study however does not permit us to conclude that PCO is primarily caused by this sympathetic alteration.

Sympathetic Activity in Patients With Panic Disorder at Rest, Under Laboratory Mental Stress, and During Panic Attacks

The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.

Menek Goldstein (1926–1997)

Professor Goldstein was born in 1926 in Kolomea, Poland. As a 15-year-old boy he escaped from a line-up in the Ghetto by running away under gun fire. He was then hidden by a Catholic family for a long period. He studied at the University in Berne, Switzerland, and from 1953 to 1956 worked as Research Assistant in their Department of Chemistry and received his PhD in Biochemistry in 1955. In 1956 he moved to the United States, initially the Worcester Foundation for Experimental Biology in Shrewsbury, Massachusetts and the following year the New York University Medical Center, where he played an active role for the rest of his life. He became Assistant Professor in Biochemistry in 1960, Associate Pro- fessor in 1963 and was appointed to Professor in Neurochemistry in 1969. In fact, this was one of the first Professorships in neurochemistry in the United States. Menek Goldstein received several honours, including the Robert and Adele Blank Lectureship Award (1986) and the Sarah L. Poiley Memorial Award (1989) at the New York Academy of Sciences; he was also elected Honorary Doctor of the Karolinska Institute in 1982, where he also held the additional title of Foreign Adjunct Professor from 1992. He was a member of several Editorial and Advisory Boards including the American Parkinson Disease Foundation and National Parkinson Foundation.Menek Goldstein's first publications, together with I. Abelin, were entitled `Specific dynamic action of proteins' (1954) and `Determination of catecholamines and brenzcat- echines in urine' (1956). In fact, these were to be the main themes of his research throughout his life, his work being focused on catecholamines and their enzymes. During his career he published more than 350 original articles, numerous abstracts and co-authored more than 70 articles for books. One of his most important scientific contributions was to purify all four enzymes in the catecholamine synthetic pathway, that is tyrosine hydroxylase, aromatic l-amino acid decarboxylase, dopamine β-hydroxylase and phenylethanolamine N-methyl transferase, three of which he achieved as the first. This pioneering work was rapidly followed by the production of powerful antisera which allowed central and peripheral catecholamine systems to be mapped. This work was the foundation of our collaboration with Menek, which resulted in the first mapping of the central adrenaline systems. His antisera also made possible the description of co-existence between classical transmitters and neuropeptides. Other important contributions include discoveries relating to the activation and regulation of the catecholamine biosynthesis and the role of cyclic nucleotides in dopamine synthesis control, which led to an extensive analysis of central dopamine receptors and their role in Parkinson's disease. He and his collaborators developed a monkey model with experimentally induced lesions mimicking the symptoms seen in Parkinson's disease, i.e. tremor and hypokinesia. In this way it was possible to test and develop new drugs for treatment of this disease. In the dopamine receptor field he is, among other things, well known for his analysis of the so- called receptor reserve for dopamine agonists, which are important for our understanding of how autoreceptors regulate dopamine synthesis and release. Finally, he also made important contributions in the Lesch–Nyhan syndrome, a biochemical abnormality involving dopamine D1 receptor dysfunction.We met Menek, together, for the first time in Basel in 1969, at the International Pharmacology Congress. This meeting turned out to have considerable consequences, not only for our professional, but also our personal, lives, and would result in a warm and life-long friendship and, eventually, in more than 200 publications together and inspiring encounters at many scientific and more personal meetings. Menek often visited Sweden where he was a dear guest and had many friends. Although he never married and had no children, Menek was surrounded by people who loved him, especially Mirra who was his loving companion for many years. We enjoyed spending time with him at the NYU Medical Center where he worked, or in the apartment house where he lived. It was a pleasure to see how he called a friendly `how are you?' to everyone and how their faces lit up when they returned Menek's greetings. The same happened at conferences – Menek knew so many, and so many knew and liked Menek. Visits to New York will not be the same without him: no planning of experiments, no steaks and Delicatessen, and no strolling around on the east side of Manhattan. Science without Menek will be much less fun but the warm memories of a wonderful friend will comfort us for years to come.

Long-term exposure to ozone alters peripheral and central catecholamine activity in rats.

In addition to its noxious influence on lung airways, ozone inhalation can induce extrapulmonary neural dysfunctions the mechanisms of which are poorly understood. This study was intended to characterize the effects of long-term exposure to ozone (0.5 ppm, 5 days) on catecholamine activity in rat sympathetic efferents and brain areas of prime importance to adaptation to environmental stressors. Catecholamine activity was assessed by estimating the turnover rate of catecholamines and in vivo tyrosine hydroxylase activity in peripheral and central structures, i.e., heart, lungs, superior cervical ganglia, cerebral cortex, hypothalamus and striatum, A2 cell group within the nucleus tractus solitarius (NTS), and locus ceruleus (A6). Ozone inhibited norepinephrine turnover in heart (-48% of the control level) but not in lungs. Ozone failed to modify the tyrosine hydroxylase activity in superior cervical ganglia, and the catecholamine content in the adrenal glands. In the central nervous system, ozone inhibited tyrosine hydroxylase activity in noradrenergic brainstem cell groups, including the locus ceruleus (-62%) and the caudal A2 subset (-57%). Catecholamine turnover was decreased by ozone in the cortex (-49%) and striatum (-18%) but not in the hypothalamus. The data show that ozone can produce marked neural disturbances in structures involved in the integration of chemosensory inputs, arousal, and motor control.

Catecholamines in the Periphery

Recent research related to catecholamines in the periphery has dealt with assessment of peripheral catecholaminergic function, catecholamines and stress, catecholamines and pain, catecholamines and neuroimmunology, adrenomedullary secretion and cosecretion, neurocardiology, catecholamines and metabolism, and roles of catecholamines in the brain in regulation of the cardiovascular system. All of these are discussed in this chapter. Peripheral catecholaminergic systems probably play a role in many neurocardiologic disorders, either secondarily as homeostatic effectors or primarily as etiologic factors. The hemodynamic hallmark of neurocardiogenic syncope is systemic vasodilation, with or without bradycardia. The vasodilation results from sudden, marked decreases in sympathoneural outflows. In contrast, plasma epinephrine (Epi) levels generally increase in this setting. Studies show a close association between lymphocyte concentrations of catecholamines and of cyclic adenosine monophosphate (cAMP). The usefulness of lymphocyte norepinephrine (NE) concentrations in evaluating sympathoneural function remains unknown. Studies using microdialysis, specific activity of [ 3 H]normetanephrine, and NE concentrations in lymph is likely to enable estimates of NE concentrations in interstitial fluid and, thereby, estimates of release of NE from sympathetic nerves. More convincing, consistent evidence is required to understand the role of catecholaminergic systems in components of immune responses. Increased use of microdialysis in adipose tissue and skeletal muscle is likely to enhance understanding of catecholaminergic systems in patients with a variety of metabolic disorders, including insulin-dependent diabetes mellitus (IDDM) and obesity.

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.

2410 An animal model for autonomic neuropathy in transgenic mice

This chapter discusses clonidine and methyldopa that could, in addition to modifying brain stem or hypothalamic cardiovascular centers, influence sympathetic activity and blood pressure by an effect on alpha receptors in the spinal cord on pre-ganglionic neurons in the intermediolateral horn. Clonidine, unlike methyldopa, is active in its own right and does not require metabolic transformation. Clonidine has served as a most useful clinical pharmacological probe in the assessment of central mechanisms of blood pressure control. It lowers blood pressure, heart rate, and plasma noradrenaline in hypertensives and normotensives, but it does not lower blood pressure, heart rate, plasma, or urinary catecholamines in adrenalin patients with peripheral catecholamine secretory tumours, phaeochromocytoma. It does not lower blood pressure in subjects that have traumatic tetraplegia, but it attenuates pressor responses to bladder stimulation. Patients with autonomic neuropathy respond to clonidine with a fall in blood pressure if efferent sympathetic pathways are intact. The chapter explains that baroreceptor deafferation does not prevent the effects of clonidine. However, it is likely that in man, as in animals, central mechanisms and a central site of action are quantitatively important in the hypotensive action of clonidine and methyldopa.

An animal model for autonomic neuropathy in transgenic mice

This chapter discusses clonidine and methyldopa that could, in addition to modifying brain stem or hypothalamic cardiovascular centers, influence sympathetic activity and blood pressure by an effect on alpha receptors in the spinal cord on pre-ganglionic neurons in the intermediolateral horn. Clonidine, unlike methyldopa, is active in its own right and does not require metabolic transformation. Clonidine has served as a most useful clinical pharmacological probe in the assessment of central mechanisms of blood pressure control. It lowers blood pressure, heart rate, and plasma noradrenaline in hypertensives and normotensives, but it does not lower blood pressure, heart rate, plasma, or urinary catecholamines in adrenalin patients with peripheral catecholamine secretory tumours, phaeochromocytoma. It does not lower blood pressure in subjects that have traumatic tetraplegia, but it attenuates pressor responses to bladder stimulation. Patients with autonomic neuropathy respond to clonidine with a fall in blood pressure if efferent sympathetic pathways are intact. The chapter explains that baroreceptor deafferation does not prevent the effects of clonidine. However, it is likely that in man, as in animals, central mechanisms and a central site of action are quantitatively important in the hypotensive action of clonidine and methyldopa.

Neural Control of Phenylethanolamine-N-methyltransferase via Cholinergic Activation of Egr-I

Phenylethanolamine-N-methyltransferase (PNMT) is both neurally and hormonally regulated like other enzymes involved in catecholamine biosynthesis. In the adrenal medulla, the major source of peripheral catecholamines, PNMT expression is neurally controlled via the splanchnic nerve, which provides cholinergic innervation to the medulla. Administration of the catecholamine reuptake inhibitor—reserpine—leads to reflex stimulation of the splanchnic nerve and a rise in PNMT enzymatic activity and mRNA. The molecular mechanism for the neural activation of PNMT gene expression, beginning with cholinergic receptor activation through PNMT gene activation, remains to be elucidated. If RS1 cells, derived from the PC12 cell line, are transiently transfected with a PNMT promoter-reporter gene construct, pRP863LUC, consisting of the proximal 863 bp of PNMT promoter-regulatory sequences linked to the firefly luciferase gene, and a functional Egr-1 expression construct, pCMVEgr-1, Egr-1 activates the PNMT promoter to stimulate luciferase expression as much as four- to fivefold. Gel mobility shift assays in the presence of an anti-Egr-1 antibody confirm that Egr-1 protein will complex with 21 bp oligonucleotides, encoding these Egr-1 binding sites. To examine whether Egr-1 might mediate the neural activation of the PNMT gene, the effects of the cholinergic agonist, carbachol (CCh), on luciferase reporter gene expression and Egr-1 mRNA were examined. Carbachol induced a time-dependent rise in luciferase, with a peak 1.5-fold induction at 6 hr, after which luciferase activity declined and returned to basal levels by 36 hr. To provide further evidence for the role of Egr-1 in the neural control of PNMT gene expression, the effects of CCh on PNMT promoter activity was examined when the Egr-1 binding site was mutated. Only in the case of neural activation by metrazole are quantitative and temporal changes in Egr-I and PNMT mRNA consistent with Egr-1 acting as a transcriptional activator of PNMT gene expression.

Plasma catechols and monoamine oxidase metabolites in untreated Parkinson's and Alzheimer's diseases

Prior studies have documented functional and pathological compromise of the peripheral sympathetic nervous system in patients with Parkinson's disease, suggesting the possibility of reduced catecholamine release into the circulation. We measured free plasma catechols in early and untreated patients with Parkinson's disease, but found no evidence of reduced concentrations, compared to control subjects or a group of patients with probable Alzheimer's disease. Rather, there was a significant elevation of plasma norepinephrine within the Parkinson's disease group. Furthermore, 6 of 15 untreated Parkinson's disease patients (40%) displayed markedly elevated plasma concentrations of the catecholamine MAO metabolites, DOPAC or DOPEG. Despite this finding, platelet MAO-B activity measured in these and all other Parkinson's disease patients fell well within the range of the control subjects, and was also statistically similar to the group with Alzheimer's type dementia. Plasma dopa levels were similar in all groups, whereas the majority of patients in the three groups had plasma free dopamine and epinephrine concentrations below the limits of detection. These trends toward increased, rather than decreased, circulating catechol concentrations suggest that peripheral sympathetic nervous system catecholamine production and release is not severely compromised in patients with early Parkinson's disease. In addition, we were unable to confirm certain previous reports of elevated MAO-B activity in patients with Parkinson's or Alzheimer's diseases.

Peripheral Catecholamines Are Involved in the Neuroendocrine and Immune Effects of LPS

There is evidence for bidirectional communication between the brain and the immune system. The immune system is subjected to neuroendocrine influences and reciprocally the hypothalamo-pituitary-adrenal axis is modulated by immune signals. Lipopolysaccharides (LPS), used to mimic infectious/inflammatory diseases, induce a series of stress markers, including modifications of monoaminergic transmission, enhancement of HPA axis activity, and decreased immune activity. In the present work we investigated the participation of peripheral catecholamines in the immune and endocrine responses to LPS in vivo. We studied the effects of LPS after chemical sympathectomy using 6-hydroxydopamine (6-OHDA), which does not cross the brain-blood barrier (BBB) in adults when peripherally injected. 6-OHDA administration was able to interfere with the effects of LPS on immune cells; however, the effects depended on the lymphoid tissue tested. In fact, the depression of mitogenesis induced by LPS was reversed by 6-OHDA in the spleen but not in the thymus. Moreover, 6-OHDA also interfered with the endocrine modifications induced by LPS. This neurotoxin completely or partially inhibited the effect of LPS on ACTH and corticosterone secretion, respectively. Taken together, these results clearly demonstrate that in vivo, the peripheral sympathetic nervous system participates in the immune and endocrine effects of LPS.

Norepinephrine release in the rat frontal cortex under treadmill exercise: a study with microdialysis

Cortical norepinephrine (NE) release and metabolism were studied by using chronic microdialysis in rats performing a treadmill exercise at 25 m/min with a 3% slope. Cortical microdialysates and peripheral blood were collected at rest, during 1- or 2-h treadmill running, and for 1 h after exercise. Microdialysate NE and its main metabolites, 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol, and plasma epinephrine (Epi) and NE were determined by high-performance liquid chromatography with electrochemical detection. The results show that treadmill running is able to stimulate concomitantly peripheral catecholamine secretion and central noradrenergic activity, i.e., NE turnover and release. The duration of the central activation and its prolongation over recovery period increases as the duration of the running increases. A positive correlation was found between the central noradrenergic activation and peripheral Epi secretion but not peripheral NE. These findings confirm and extend our previous observations in exercising men and give support to the hypothesis that the elevation of circulating Epi can be a relevant factor mediating, directly or indirectly, the exercise-induced central neurochemical, psychological, and cognitive changes.