Adrenal Medullary Hormones Research Articles

Direct identification of amino acid-derived hormones with single-atom resolution using an engineered aerolysin nanopore.

The amino acid-derived hormones (AAHs), which are relatively small hydrophobic molecules derived from the amino acid tyrosine and tryptophan, play critical roles in the regulation of organism development and metabolism process. Direct identification of AAHs and their metabolites is highly desirable but very challenging because they simultaneously possess the features of small volume, hydrophobicity and highly structural similarity. Nanopore, capable of sensing the analytes in a single-molecule manner, may be engineered to identity AAHs. The key aporia is the ion current instability caused by the introduction of hydrophobic amino acids inside the nanopore confinement that is essential to improve the spatial and temporal resolution for small hydrophobic molecules sensing. Herein, we design a mutant aerolysin that precisely introduces a hydrophobic chemical environment in the critical sensing region with a highly controlled hydrogen bonds network to balance the ion follow stability and hydrophobic interactions. With this hydrophobic enhanced aerolysin nanopore, direct identification of AAHs was achieved, including thyroid hormone, pineal hormone and adrenal medullary hormone. Furthermore, three thyroid hormones with single iodine atom difference (T4, T3, and T2), were observed to be clearly discriminated in their mixture. Our engineered nanopore can even distinguish isomers of T3 and rT3 that vary only slightly in structure. Assisted with a custom clustering machine learning algorithm, the thyroid hormones T4, T3, and T2 in their mixture could be quantified, which suggests a simple and rare approach to measure the AAHs in clinical samples.

Adrenal obliteration by balloon-occluded retrograde venous ethanol injection in a swine model

Purpose: To evaluate the effects of adrenal obliteration by balloon-occluded retrograde venous ethanol injection.Material and methods: We inserted a micro-balloon catheter into the left adrenal vein of six pigs and retrogradely injected absolute ethanol (0.06 ml/kg) under balloon occlusion. Two pigs were sacrificed on day 3, 7, and 14 after the procedure, respectively. We evaluated adrenal cortical and medullary hormones of the left renal vein, venograms, magnetic resonance imaging scans obtained before and after the procedure, autopsy and microscopic findings, and the weight of the bilateral adrenal glands.Results: The hormone levels were extremely high on day 3 after the procedure. Post-procedure, partially-enhanced parenchyma and shaggy veins were observed. On the post-mortem examination, the left adrenal glands showed hemorrhage and adhesion on the third and seventh day and fatty proliferation 14 days after the procedure. Microscopic examination revealed hemorrhagic necrosis on day 3, inflammatory cell infiltration on day 7, and partial fibrosis 14 days after the procedure. The weight of the left adrenal gland on day 14 was lower than that of the right gland.Conclusions: This procedure elicited partial adrenal infarction with a high catecholamine concentration in the left renal vein.

A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla

Here we review the tight neural control of the differential secretion into the circulation, of the adrenal medullary hormones adrenaline and noradrenaline. One or the other catecholamines are differentially released on various stress conditions. This is specifically controlled by central nervous system nuclei at the cortex, hypothalamus and spinal cord. Different firing patterns of splanchnic nerves and nicotinic or muscarinic receptors cause the selective release of noradrenaline or adrenaline, to adapt the body to the 'fight or flight' reaction, or during severe hypoglycaemia, haemorrhage, cold, acute myocardial infarction or other severe stressful conflicts. Endogenously acetylcholine (ACh) released at the splanchnic nerve-chromaffin cell synapse, acting on muscarinic and nicotinic receptors, causes membrane depolarization and action potentials (AP) in chromaffin cells. These changes vary with the animal species, the cell preparation (intact bisected adrenal, adrenal slices, or isolated fresh or cultured cells) or the recording technique (intracellular microelectrodes, patch-clamp, perforated-patch, cell-attached). Conflicting results leave many open questions concerning the actions of ACh on chromaffin cell excitability. The use of adrenal slices and field electrical stimulation will surely provide new insights into these mechanisms. Chromaffin cells have been thoroughly used as models to study the relationship between Ca2+ entry, cytosolic Ca2+ signals, exocytosis and endocytosis, using patch-clamp and amperometric techniques. Cells have been stimulated with single depolarizing pulses (DPs), DP trains and with simulated AP waveforms. These approaches have provided useful information but we have no data on APs generated by pulsatile secretory quanta of ACh, trying to mimic the intermittent and repetitive splanchnic nerve discharge of the neurotransmitter. We present some recent experiments using ultrashort ACh pulses (25 ms), that cause non-desensitizing repetitive APs with each ACh pulse, at low ACh concentrations (30 microM). Ultrashort pulses of a high ACh concentration (1000 microM) causes a single AP followed by a prolonged depolarization. It could be interesting trying to correlate these 'patterns of splanchnic nerve discharge' with Ca2+ signals and exocytosis. This, together with the use of adrenal slices and transmural electrical stimulation of splanchnic nerves will provide new physiologically sound data on the regulation of adrenal medullary secretion.

Dysfunction of releasing adrenaline in asthma by nerve growth factor

In early embryo period, adrenal medulla development is parallel with adrenergic nerves. For this reason, adrenal medullary cells may be provided with potential ability of transdifferentiation toward nerve cells. In vitro, it was well testified that if adrenal medullary cells are treated with nerve growth factor, then the cells will be transdifferentiated toward sympathetic neurons characterized by morphous, biochemistry and physiological functions. As a result, adrenal medullary cells after being transdifferentiated may be impaired in the functions of endocrine secretion, and the composition and level of adrenal medullary hormone are changed. The above mentioned may be regarded as the reflection of cellular redundancy, besides the transdifferentiation, multiple organelle copies, cellular plasticity and so on are all reflections of cellular redundancy. According to cellular redundancy, in addition to their regular and specific functions, some cells(types) are of other additional functions which will be activated in special state such as diseases, external interference and so on. The theory of cellular redundancy is seemed to unpuzzle the dysfunction of releasing adrenaline in asthma. Compared with the normal control group, the study showed that the levels of adrenaline in the asthmatic patients were not increased when patients encountered the strong stimuli. Subsequently, overexpression of nerve growth factor was also detected in asthmatic patients and animals. However, accompanied with alleviation of airway inflammation, these phenomena were changed when asthmatic models were treated with antibody of nerve growth factor. What makes these phenomena linked? The existence of functional redundancy of medullary cells may be the most important factor. This hypothesis suggests that overexpression of nerve growth factor activate functional redundancy of adrenal medullary cells, which makes these cells transdifferentiated toward sympathetic neurons. The transdifferentiation (tendency) may impair the functions of endocrine secretion of adrenal medullary cells. As a result, adrenal medulla cannot release enough adrenaline to relieve bronchoconstriction in asthmatic attack.

Responses of hepatic glucose output to electro-acupuncture stimulation of the hindlimb in anaesthetized rats

Responses of hepatic glucose output (HGO) to electro-acupuncture (EA) stimulation of the hindlimb were investigated in anaesthetized rats, focusing on involvement of the somatic afferent and autonomic efferent nerves. HGO was measured with a microdialysis probe implanted into the left lateral lobe of the liver. Stainless steel needles with a diameter of 0.25 mm were inserted into the right tibialis anterior muscle and connected to an electrical stimulator. The EA stimulation was delivered for 10 min at 10 mA, 20 Hz. Atropine was injected in order to block the action of the parasympathetic nerves, whereas phentolamine and propranolol were injected in order to block the action of the sympathetic nerves. Furthermore, adrenal sympathetic nerves were crushed bilaterally to block the reflex secretion of adrenal medullary hormones. The EA stimulation significantly increased HGO for 20 min after the onset of stimulation. The increases of HGO were abolished by severing the femoral and sciatic nerves, demonstrating that the responses are elicited via activation of somatic afferent nerves. Furthermore, the increases were diminished after severance of the adrenal sympathetic nerves, which regulate catecholamine secretion from the adrenal medulla. The increases were totally abolished after pretreatment with phentolamine, an α-adrenergic blocker, and propranolol, a β-adrenergic blocker. On the other hand, the increases of HGO in response to the EA stimulation were augmented after pretreatment with atropine, a muscarinic cholinergic blocker. The present results demonstrate that EA stimulation to a hindlimb can reflexly increase HGO via activation of somatic afferents and, thereby, sympathetic efferents, including sympathetic efferents to the adrenal medulla. The present results further show that the increases of HGO in responses to EA stimulation are simultaneously reflexly inhibited via the parasympathetic nerves.

Sympathetic nervous system and experimental diabetes: role of adrenal medullary hormones.

The sympathetic nervous system is of major importance in the regulation of various physiological functions. The present review discusses the mechanisms which control glucose homeostasis and the role of the sympathetic nervous system in experimental diabetes with special emphasis on the role of adrenal medullary hormones, over-activity of the sympathetic nervous system and its relationship to hypertension in the diabetic state and the effect of stress. The chapter also reviews the ability of various drugs and pharmacological agents to produce hyperglycemia in experimental animals and how this information can be used in screening new chemical entities and in differentiating the mode of action of these agents.

Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action.

The beta-adrenergic receptors (beta-AR) are present on the surface of almost every type of mammalian cell. These receptors are stimulated physiologically by the neurotransmitter, norepinephrine and the adrenal medullary hormone, epinephrine. There are three subtypes of beta-AR, namely, beta1-AR, beta2-AR, and beta3-AR; the pharmacological and physiological responses of an individual cell result from the particular mixture of the three beta-AR subtypes present on that cell. Species-specific structure (amino acid sequence) also causes modification of the function of a given beta-AR subtype. Knowledge of the beta-AR subtypes present in various cell types, coupled with knowledge of receptor structure (sequence), will allow an understanding of the complexity of physiological function regulated by beta-AR. Oral administration of some beta-AR agonists increases muscle and decreases fat accretion in cattle, pigs, poultry, and sheep. The large number of physiological functions controlled by beta-AR suggests that the mechanism(s) for the observed changes in carcass composition may be extremely complex. Any proposed mechanism must begin with the possibility of direct effects of the agonist on skeletal muscle and adipocyte beta-AR. However, many other mechanisms, such as modification of blood flow, release of hormones, or central nervous system control of feed intake may contribute to the overall effects observed with a given beta-AR agonist in a given species. Furthermore, the pharmacodynamic properties of a particular agonist are complex and expected to vary among species as well as within the same species at different ages or when fed different diets.

Reflex modulation of catecholamine secretion and adrenal sympathetic nerve activity by acupuncture-like stimulation in anesthetized rat.

The effects of acupuncture-like stimulation of the abdomen and a hindlimb on the secretion rates of adrenal medullary catecholamine hormones (adrenaline and noradrenaline) and adrenal sympathetic efferent nerve activity were studied using urethane-anesthetized rats. Acupuncture needles (diameter of 340 microns) were inserted into the skin and underlying muscles of either the abdomen or a hindlimb to a depth of 10 mm and then twisted at a frequency of about 1 Hz for 90 s. The stimuli induced three types of response in both catecholamine secretion and adrenal sympathetic nerve activity (i.e., decrease, increase, and no change). These different responses corresponded with three similar types of response in mean arterial pressure. In spinalized animals, the stimuli produced only increases in both catecholamine secretion and nerve activity, and abdominal stimulation elicited a larger response than hindlimb stimulation. The responses of adrenal nerve activity were eliminated after surgically severing the afferent nerves innervating the abdomen and hindlimb. These findings indicate that the secretion of adrenal medullary hormones is controlled reflexively by acupuncture-like stimulation via excitation of somatic afferent nerves and also via the reflex responses of adrenal sympathetic efferent nerves. Both the spinal cord and supraspinal structures act as reflex centers. The excitatory reflex properties at the propriospinal and segmental levels are modified into a generalized, either excitatory or inhibitory, response by supraspinal structures.

Definitions of stress and sympathetic neuronal responses.

1. The precise physical definitions of stress as a force per unit area and of strain as the deformation of a solid subjected to that force are conceptually similar to the demands placed upon living organisms and the responses of organisms to those demands. 2. Cannon recognized that a "breaking strain" at a "critical stress" level can overwhelm homeostatic mechanisms and suggested that such a state is signaled by appearance of "secondary, irrelevant effects." The primary mechanisms of maintaining homeostasis are highly specific; and compensatory responses are mediated by the autonomic nervous system, and the less specific responses are mediated by the adrenal medullary hormone, epinephrine. 3. Selye extended this concept to include other hormonal responses, particularly of the hypothalamic-pituitary-adrenal axis, as components of a stereotypic response common to all stresses. He redefined stress as a state in which this stereospecific response has been evoked and popularized the notion that a variety of diseases are produced as a result of excessive or deficient adaptive processes during the stress response. 4. Both Cannon and Selye recognized that the responses to stresses differ among individuals and that such differences are due to genetic differences as modified by experience (Selye called these "conditioning factors"). Both attributed highly specific homeostatic responses to nervous control and both recognized that hormonal responses are necessarily less specific than neuronal responses. 5. Selye's concept of a single stereotypic syndrome that results from any demand upon the body, however, needs to be modified to reflect differences in the pattern of responses to various stresses. Data on responses to several stresses show that when homeostatic mechanisms do not predominate, the pattern of nonspecific, particularly hormonal, responses may differ among stresses. The essential fact, however, that most demands upon the body, when exceeding a critical level, elicit an array of complex neuroendocrine responses, and that these responses may have harmful effects, remains a landmark contribution.

The peptide VIP is a neurotransmitter in rat adrenal medulla: physiological role in controlling catecholamine secretion.

1. The perfused adrenal gland of the rat was used to establish the identity of a non-cholinergic substance involved in splanchnic nerve-mediated secretion of catecholamines. 2. The perfused adrenal medulla was rich in vasoactive intestinal polypeptide (VIP) content (28 pmol g-1 of wet tissue). VIP-immunoreactive nerve fibres were present in the adrenal medulla and the adrenal cortex. 3. Field stimulation (10 Hz for 15 min plus 1 Hz for 15 min) caused a large increase in the output of VIP in the perfusate over the spontaneous release of VIP. Secretion of catecholamines was also greatly elevated by field stimulation. Field stimulation-evoked output of VIP and catecholamines was abolished after chronic denervation of the adrenal glands. 4. Infusion of acetylcholine (ACh) did not increase the output of VIP but caused a robust secretion of catecholamines. 5. The VIP output declined when the stimulation frequency was increased (8.6 x 10(-3) fmol pulse-1 at 1 Hz and 4.0 x 10(-3) fmol pulse-1 at 10 Hz). 6. In contrast, the output of 3H-acetylcholine (3H-ACh, expressed as a fraction of tissue 3H-ACh content) increased from 7.0 x 10(-2) pulse-1 at 1 Hz to 16.3 x 10(-2) pulse-1 at 10 Hz. 7. Secretion of catecholamines evoked by low-frequency stimulation (1 Hz) was reduced by 40% in the presence of cholinergic receptor antagonists (atropine plus hexamethonium). Inclusion of a VIP receptor antagonist ([Ac-Tyr1, D-Phe2]-GRF 1-29 amide) caused about 75% inhibition. 8. The VIP receptor antagonist inhibited VIP-evoked secretion of catecholamines without affecting ACh-evoked secretion. 9. In conclusion, VIP satisfies all the essential criteria to assume the role of a neurotransmitter in the rat adrenal medulla. The contribution of VIP to the secretion of adrenal medullary hormones is more prominent at low rates of neuronal activity whereas ACh is the major contributor at higher activity.

Immune-mediated mechanisms in multiple sclerosis

Sirs: We recently read with interest the report on cerebrospinal fluid (CSF) C D 4 + / C D 8 + T-cell ratio and myelin basic protein in relapsing multiple sclerosis (MS) patients by Salmaggi et al. [8]. Abnormali t ies in lymphocyte phenotypes appear to exist primarily in the CSF rather than in peripheral blood, which is in line with earlier reports by others [7]. Immune response may be responsible for demyelination during progressing disease. Indeed, markers of immune activation such as interleukin-2 [4], interleukin-2 receptor-bearing lymphocytes [1], tumour necrosis factor-ct (TNF-ct) [5] and neopterin [2] have been found with increased incidence in CSF of MS patients. The presence of increased neopterin indicates intrathecal activation of human macrophages by 7-interferon [3]. Other cytokines, for instance TNF-a, can amplify the effect of 7-interferon on macrophages to produce neopterin [11]. The referenced data further support the concept that local immune response contributes to demyelination in MS leading to irreversible damage of the central nervous system (CNS). However , this model alone cannot explain the full spectrum of MS, which is also characterized by reversibility of symptoms. The presence of high neopterin levels during immune activation processes shows that cytokines influence pteridine metabol ism [3,11]. The mono-oxygenases involved in the biosynthetic pathway of the neurotransmit ters serotonin, D O P A , and adrenal medullary hormones strictly depend on tetrahydrobiopter in as cofactor [6]. Thus, altered pteridine metabol ism may influence the supply of these neurotransmitters. In addition, we have shown that neopterin release by human macrophages is paralleled by activation of indoleamine (2,3)-dioxygenase ( IDO) in vitro and in vivo [11]. In a variety of human cells and cell lines I D O is activated in response to 7-interferon and TNF-c~ [10]. As a consequence, t ryptophan is degraded and t ryptophan metabolites such as kynurenine and quinolinic acid accumulate [9]. Subnormal availability of t ryptophan may result in diminished product ion of serotonin by neuroendocrine cells, and neurotoxicity of the t ryptophan metaboli tes formed [9] could precipitate neurological symptoms in patients. Clearly, cytolytic immune mechanisms may cause demyelination and irreversible damage of the CNS. However, 7-interferon and TNF-ct are released f rom immune cells during long-lasting inf lammatory conditions and may initiate metabolic changes which affect the CNS. These interactions between the immune system and the CNS may be of particular relevance in MS because cytokines are released f rom immune cells in close proximity to neuroendocrine cells. In contrast to demyelinat ion in MS patients the metabolic disturbances are reversible when the underlying immune activation process is stopped. This fact may in part explain the disappearance of some neurological symptoms in patients when the underlying immune activation ceases, e.g. during immunosuppressive therapy.

The effect of adrenal denervation on the metabolic effects of hyperammonemia in sheep.

The metabolic effect of intravenous infusion of ammonium chloride (60 mumol/(kg body weight.min] was compared in five sheep before and after adrenal denervation. Adrenal denervation completely abolished the hyperglycemic effect of ammonium chloride, diminished the rise of pyruvate and lactate concentration, and failed to influence the lipolytic effect of NH4Cl. It is suggested that the metabolic effects of ammonia are in a different degree related to the action of ammonia on the central nervous system and (i) the hyperammonemic effect of ammonia completely depends on the neurogenic increase of adrenal medullary hormones; (ii) the rise of blood lactate and pyruvate level observed during hyperammonemia is only partially mediated by adrenaline; and (iii) the lipolytic effect of ammonia ion does not depend on the nerve-controlled secretion of adrenal medullary hormones.

Restoration of catecholamine content of previously depleted adrenal medulla in vitro: importance of synthesis in maintaining the catecholamine stores.

The functional integrity of adrenal chromaffin storage vesicles was studied in the perfused rat adrenal gland subjected to intense exocytosis. Continuous perfusion with 55 mM K+-Krebs solution produced a large and uninterrupted secretion of catecholamines. Total amounts secreted within 45 min were 4.66 micrograms and represented almost 30% of the total tissue catecholamine content. If perfusion with excess K+ was extended to 90 min, the secretion increased further to 5.76 micrograms. Despite such a large secretory response, the catecholamine content of the K+-stimulated adrenal medulla was comparable to that of unstimulated control, suggesting an enhanced resynthesis to maintain the normal levels. Pretreatment of rats with alpha-methyl-p-tyrosine, and including this agent in the perfusion medium during stimulation with K+, caused a marked reduction in catecholamine content. The degree of depletion depended on the extent of stimulation with K+ (45% in 45 min and 60% in 90 min). Although depleted catecholamine stores did not show spontaneous recovery in 2 h, inclusion of tyrosine, L-3,4-dihydroxyphenylalanine or dopamine (but not epinephrine or norepinephrine) completely restored the catecholamine content of previously depleted adrenal medulla. Repletion achieved by tyrosine was time dependent (evident in 30 min and maximum in 2 h) and blocked by alpha-methyl-p-tyrosine but not by calcium deprivation. The ratio of epinephrine to norepinephrine remained constant during various stages of the experiment, suggesting both types of vesicles were equally affected by different treatments. The secretory response (10 Hz for 30 s) was unaffected even though tissue catecholamine stores were significantly depleted (50%). In summary, we have demonstrated that catecholamine content of the isolated perfused adrenal gland can be reduced by stimulation of exocytotic secretion in the presence of tyrosine hydroxylase inhibitor. Since the depleted stores can be fully refilled by synthesis of catecholamines from its precursors, it is suggested that chromaffin vesicles may be reutilized for the purpose of synthesis, storage, and secretion of adrenal medullary hormones.

Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis.

We have recently shown that vasoactive intestinal polypeptide (VIP) is as potent as acetylcholine in inducing the secretion of catecholamines from the rat adrenal medulla. In the present study we have investigated the molecular mechanism involved in the exocytotic secretion of catecholamines by VIP and the effects of VIP on Ca45 uptake and phosphoinositide breakdown and compared them with those of the classical cholinergic agonists. We now show that omission of Ca2+ from the perfusion medium had almost no effect on VIP-induced secretion; however, addition of 1 mM EGTA to calcium-free medium abolished the secretion. Stimulation with VIP did not result in a net increase in Ca45 uptake and it was not modified by a protein kinase C activator, phorbol ester. All these effects of VIP were comparable to those of muscarine. VIP (0.3 to 10 microM) and muscarine (30 to 100 microM) produced time-and concentration-dependent increase (up to 700%) in the production of [3H]inositol phosphates. The production of [3H]inositol phosphates by VIP and muscarine occurred in calcium-free and EGTA medium. The effect of VIP on [3H]IP, [3H]IP2, and [3H]IP3 production was reduced by (1 to 30 microM) VIP antagonist (an analogue of growth hormone-releasing factor, Ac-Tyr1hGRF) and 1 to 20 microM naloxone. Although nicotine produced a brisk secretory response, there was no change in [3H]inositol phosphates. We conclude that inositol 1,4,5-trisphosphate generated upon activation of VIP and muscarine receptors is linked to exocytotic secretion of adrenal medullary hormones through release of internal Ca2+ ions.

Neuropeptide Y in the adrenal gland: Characterisation, distribution and drug effects

The occurrence of neuropeptide Y-like immunoreactivity in the adrenal gland was investigated by means of radioimmunoassay, chromatography and immunohistochemistry. The adrenal levels of neuropeptide Y-like immunoreactivity varied considerably between species with lowest amounts in the rat and highest in the cow where immunoreactivity was observed in chromaffin cells and nerve fibres in the capsule and cortex. The distribution of neuropeptide Y-like immunoreactivity in the cow medulla overlapped that of enkephalin-like immunoreactivity. Chromatographic characterisation of rat and cow adrenal extracts showed that the majority of the neuropeptide Y-like immunoreactivity was similar in molecular weight and solubility properties to porcine neuropeptide Y. Rat adrenal contained additional material some of which may represent oxidised neuropeptide Y. The administration of insulin and reserpine to rats in vivo showed that the turnover of adrenal neuropeptide Y-like immunoreactivity is regulated by the splanchnic nerve. Splanchnic activation following insulin-induced hypoglycaemia elicited a 60% depletion of neuropeptide Y-like immunoreactivity 2 h post insulin injection. A smaller (maximum 40%) depletion of neuropeptide Y-like immunoreactivity was measured 24 h after reserpine injections which may be explained by splanchnic activation. Five days after reserpine injections the levels of adrenal neuropeptide Y-like immunoreactivity were increased to 200% of control levels and remained slightly elevated at 25 days. Adrenal enkephalinlike immunoreactivity showed similar but not identical changes following reserpine. The reserpine-induced elevation in neuropeptide Y-like immunoreactivity at the 5-day time point was abolished in rats with a chronic bilateral splanchnectomy. This evidence indicates that neuropeptide Y may be considered as a new adrenal medullary hormone.

Stress and Immune Responses IV. Adrenal Involvement in the Alteration of Antibody Responses in Restraint-Stressed Mice

We investigated the correlation between restraint stress-induced alteration of antibody responses and adrenal hormones. Adrenalectomy (Adx) blocked both the suppression of antibody response against T cell-dependent (TO) antigen and the enhancement of that against T cell-independent (TI) antigen in stressed mice. Adx also inhibited the atrophy of both thymus and spleen caused by restraint. Pre-treaiment of metyrapone, an inhibitor of adrenocortical steroid biosynthesis, had an effect that was similar to, but far weaker than that of Adx on stressed mice. The pre-administration of phenoxybenzamme, an α-adrenergic blocking agent, to mice prevented both the inhibition of antibody response to TD antigen and the decrease in spleen cell number of restrained mice. A similar effect was observed in mice pre-treated with 6-hydroxydopamine, an adrenergic neuron degenerating agent. However, no effects of these two agents were observed on the enhancement of antibody response to TI antigen The suppressive effect of the antibody response to TD antigen was augmented by the pre-administration of propranolpl, a β-adrenergic blocking agent. These results suggest that the suppression of the function of T cells in restrained mice are attributed to the released adrenocortical and adrenal medullary hormones and activated sympathetic nervous system and that the enhancement of B cell function is due to the adrenocortical hormones.

Epinephrine is unessential for stimulation of liver glycogenolysis during exercise.

To determine the role of adrenal medullary hormones in controlling the rate of liver glycogenolysis during exercise, adrenodemedullated (ADM) and sham-operated (SO) rats were run on a rodent treadmill at 21 m/min up a 15% grade for 0, 30, or 60 min. Rats were anesthetized by intravenous injection of pentobarbital sodium, and liver, muscle, and blood were collected and frozen. Liver glycogen decreased at similar rates in ADM and SO rats. Hepatic adenosine 3',5'-cyclic monophosphate (cAMP), plasma glucagon, and plasma free fatty acids increased to the same extent in both ADM and SO rats. The adrenodemedullation caused a reduction in glycogenolysis in the fast-twitch white region of the quadriceps, soleus, and lateral gastrocnemius during exercise. The normal exercise-induced increase in blood glucose and lactate and the decline in plasma insulin were not observed in the demedullated rats. During submaximal exercise the principal targets for epinephrine released from the adrenal medulla appear to be pancreatic beta-cells and skeletal muscle and not the liver.

Responses of adrenal sympathetic nerve activity and catecholamine secretion to cutaneous stimulation in anesthetized rats

Reflex effects of cutaneous mechanical stimulation on adrenal sympathetic efferent nerve activity and secretion rates of the adrenal medullary hormones (epinephrine and norepinephrine) were studied in anesthetized rats. Noxious pinching stimulation of the lower chest or hindpaw skin for 3 min produced proportional reflex increases in both the nerve activity and secretion rates of epinephrine and norepinephrine from the adrenal medulla in animals with an intact central nervous system. However, lower chest stimulation elicited a longer lasting response than hindpaw stimulation. 7–17 min vs 1 min after cessation of the stimulation, respectively. After spinal transection at the C1–2 level, only lower chest stimulation was capable of producing a reflex response, lasting 1 min after cessation of the stimulation. Contrary to the responses elicited by pinching, non-noxious brushing stimulation of the lower chest of hindlimb skin for 3 min in animals with an intact central nervous system produced proportional reflex decreases in nerve activity and epinephrine and norepinephrine secretion rates during the stimulation period only. Some slight increases in both nerve activity and secretion rates, lasting several minutes, followed cessation of the stimulation. However, in spinalized animals, non-noxious lower chest or hindlimb stimulation produced opposite effects, increasing both the nerve activity and secretion rates of epinephrine and norepinephrine. In spinalized animals lower chest brushing stimulation elicited a much stronger response than hindlimb brushing stimulation. It was concluded that: (1) the secretion of adrenal medullary hormones can he controlled reflexly by mechanical cutaneous stimulation through the central nervous system via adrenal sympathetic efferent nerves; (2) the excitatory effect of the cutaneo-adrenal medullary reflexes was independent of noxious or non-noxious stimulation at the spinal level, whereas in rats with an intact central nervous system the effect was either excitatory or inhibitory in response to noxious or non-noxious stimulation, respectively; (3) there is a marked segmental organization of this reflex at the spinal level which is modified into a generalized response through supraspinal central structures.

The participation of adrenal medullary hormones in the metabolic effects of hyperammonaemia.

SummaryThe metabolic effects of intravenous infusion of ammonium chloride were compared in 8 sheep before and after adrenalectomy. Marked hyperammonaemia in adrenalectomized animals did not produce hyperglycaemia or hyperinsulinaemia as it did in intact sheep. The changes in plasma lactate and pyruvate were less pronounced in the operated sheep. It is suggested that: 1. ammonia causes secretion of catecholamines in the adrenal medulla, 2. the metabolic effects of hyperammonaemia are caused both directly by the ammonium ion and indirectly by catecholamines, 3. medullary hormones maintain the insulin level in the blood and 4. medullary hormones maintain lactate formation in extrahepatic tissues and stimulate glucose and urea production.ZusammensfassungBeteiligung der Hormone des Nebennierenmarks an den metabolischen Auswirkungen einer HyperammonämieDie metabolischen Auswirkungen einer intravenösen Infusion von Ammoniumchlorid wurden bei 8 Schafen vor und nach der Adrenalektomie untersucht. Im Unterschied zu den intakten Schafen verursachte die markante Hyperammonämie bei den adrenalektomierten Tieren weder eine Hyperglykämie noch eine Hyperinsulinämie. Bei den operierten Schafen waren auch die Veränderungen des Laktats und Pyruvats im Plasma weniger ausgeprägt. Es werden folgende Schlüsse gezogen: 1. Ammonium bewirkt im Nebennierenmark eine Ausschüttung von Katecholaminen. 2. Die metabolischen Auswirkungen der Hyperammonämie sind sowohl direkt bedingt durch das Ammonium als auch indirekt durch die Katecholamine. 3. Nebennierenmarkhormone halten den Insulinspiegel im Blut aufrecht. 4. Nebennierenmarkhormone halten die Laktatbildung im extrahepatischen Gewebe aufrecht und stimulieren die Glukose‐ und Harnstoffbildung.RésuméParticipation de l'hormone médullo‐surrénale sur l'effet métabolique d'une hyperammonémieLes effets métaboliques d'une infusion intraveineuse de chlorure d'ammonium ont été examinés chez 8 moutons avant et après l'adrénalectomie. A la différence des moutons indemnes, l'hyperamonnémie marquée n'a causé chez les animaux adrénalectomiés ni hyperglycémie ni hyperinsulinémie. Les modifications du lactate et du pyruvate dans le plasma furent moins prononcées chez les moutons opérés. Les conclusions suivantes ont été tirées: 1. L'ammonium provoque une sécrétion de catécholamine dans la médullosurrénale. 2. Les effets métaboliques de l'hyperammonémie sont aussi bien dus directement au ion ammonium qu'indirectement à la catécholamine. 3. Les hormones médullosurrénales maintiennent le taux d'insuline dans le sang. 4. Les hormones médullosurrénales maintiennent la formation de lactate dans les tissus extrahépatiques et stimulent la formation de glucose et d'urée.ResumenLa participación de hormonas de la medula adrenal en los efectos metabólicos de la hiperamonemiaSe examinaron los efectos metabólicos de una infusión intravenosa de cloruro amónico en 8 ovejas antes y después de la adrenalectomía. A diferencia con las ovejas intactas no ocasionaba la hiperamonemia notable en los animales adrenalectomizados ni hiperglucemia ni hiperinsulinemia. En las ovejas operadas también se hallaban menos pronunciados los cambios del lactato y piruvato en el plasma sanguíneo. Se sacan las conclusiones siguientes: 1. El amonio ocasiona en la medula adrenal la secreción de catecolaminas. 2. Los efectos metabólicos de la hiperamonemia están condicionados tanto directamente por el amonio como indirectamente por la catecolamina. 3. Las hormonas de la medula anterrenal mantienen el nivel de insulina en sangre. 4. Las hormonas de la medula adrenal mantienen en pie la formación de lactato en el tejido extrahepático y estimulan las producciones de glucosa y urea.

Blood pressure responses to prolonged infusions of adrenaline and noradrenaline in conscious dogs.

Adrenaline was infused intravenously into conscious dogs to test whether chronically elevated plasma levels can produce arterial hypertension. Adrenaline infused at 12.5 micrograms/kg/hr from 4 days produced no change in mean arterial pressure (1.1 +/- 2.7 mmHg) despite raising plasma adrenaline concentrations from 49 +/- 20 pg/ml to 1420 +/- 279 pg/ml. Myocardial tissue levels of adrenaline averaged 435 ng/g, compared to 20 ng/g in vehicle infused dogs. Longer infusions of adrenaline (11 days) at doses from 1.25 micrograms/kg/hr to 12.5 micrograms/kg/hr were also without significant effect on arterial blood pressure. In contrast, infusion of noradrenaline at 6.25 micrograms/kg/hr for 11 days produced sustained elevation of mean arterial pressure (11.7 +/- 5.1 mmHg). Although adrenaline infusion alone did not alter arterial pressure, a small rise (5.6 +/- 1.6 mmHg) was measured when the dogs were also given cortisone (50 mg twice daily). These results are therefore not in accord with the hypothesis that increased plasma levels of adrenaline may cause hypertension by activation of pre-junctional beta-adrenoceptors. However simultaneous administration of adrenaline and cortisone did elevate blood pressure, indicating that increases in both adrenal cortical and medullary hormones may be required to produce hypertension.