Epinephrine Secretion Research Articles

Predictive neural networks for learning the time course of blood glucose levels from the complex interaction of counterregulatory hormones.

Diabetes mellitus is a widespread disease associated with an impaired hormonal regulation of normal blood glucose levels. Patients with insulin-dependent diabetes mellitus (IDDM) who practice conventional insulin therapy are at risk of developing hypoglycemia (low levels of blood glucose), which can lead to severe dysfunction of the central nervous system. In large retrospective studies, up to approximately 4% of deaths of patients with IDDM have been attributed to hypoglycemia (Cryer, Fisher, & Shamoon, 1994; Tunbridge, 1981; Deckert, Poulson, & Larsen, 1978). Thus, a better understanding of the complex hormonal interaction preventing hypoglycemia is crucial for treatment. Experimental data from a study on insulin-induced hypoglycemia in healthy subjects are used to demonstrate that feedforward neural networks are capable of predicting the time course of blood glucose levels from the complex interaction of glucose counterregulatory (glucose-raising) hormones and insulin. By simulating the deficiency of single hormonal factors in this regulatory network, we found that the predictive impact of glucagon, epinephrine, and growth hormone secretion, but not of cortisol and norepinephrine, were dominant in restoring normal levels of blood glucose following hypoglycemia.

Insulin stimulates epinephrine release under euglycemic conditions in humans

In healthy subjects, acute physiological hyperinsulinemia induces activation of the sympathetic nervous system, but in the absence of hypoglycemia, plasma epinephrine levels have not been found to increase during insulin administration. However, the venous level of epinephrine reflects the net result of release, clearance, and uptake and therefore is not a good measure of adrenomedullary epinephrine secretion. The influence of 90 minutes of euglycemic physiological hyperinsulinemia (60 mU · m −2 · min −1; plasma insulin concentration, ⋍700 pmol · L −1) on epinephrine kinetics using the 3H-epinephrine tracer method was studied in 12 healthy normotensive, non-obese subjects. After bolus injection, [ 3H]-epinephrine was continuously infused with arterial and venous blood sampling at regular intervals, enabling calculation of total body (systemic) and forearm epinephrine release and clearance. Studies were performed in the basal state and during sympathetic stimulation by lower-body negative pressure (LBNP) of − 15 mm Hg for 15 minutes. Control experiments (“sham” clamps, but with LBNP) were performed in four of the 12 individuals. Euglycemic hyperinsulinemia (all arterial glucose samples ≥ 4.2 mmol · L −1) induced an increase of the arterial epinephrine concentration ( P = .03), and tended to increase total body epinephrine release ( P = .08). Total body epinephrine clearance did not change during hyperinsulinemia. The insulin-induced increase in forearm blood flow ([FBF] by plethysmography, from 3.0 ± 0.4 to 3.8 ± 0.6 mL · dL −1 · min −1, P = .01) was strongly correlated with the increase in arterial epinephrine ( r = .78, P < .01). Plasma epinephrine concentrations did not change during control experiments (sham clamp). Sympathetic stimulation alone as induced by LBNP did not stimulate epinephrine release. However, the combination of insulin and LBNP significantly increased epinephrine release (from 0.37 ± 0.06 to 0.56 ± 0.12 nmol · m −1 · min −1, P = .03). We conclude that acute physiological hyperinsulinemia under euglycemic conditions induces epinephrine release. This effect is enhanced when hyperinsulinemia is combined with sympathetic stimulation by LBNP. Due to increased forearm removal, venous epinephrine concentrations hardly change. Epinephrine release was strongly correlated with the hemodynamic effects of insulin.

Adrenal medulla and exercise training.

The adrenaline release from the adrenal medulla increases during exercise, but at a given absolute work intensity the magnitude of this response is less pronounced in endurance trained vs sedentary individuals most likely due to a lower sympathetic stimulation of the adrenal medulla. However, when trained and untrained subjects are compared at identical relative work loads as well as in response to numerous non-exercise stimuli. endurance trained athletes have a higher epinephrine secretion capacity compared to sedentary individuals. This indicates a development of a so-called "sports adrenal medulla" as a result of a long term adaptation of an endocrine gland to physical training. Such an adaptation is parallel to adaptations taking place in other tissues like skeletal muscle and the heart. and can be advantageous in relation to both exercise performance in the competing athlete and cause a biological rejuvenation in relation to aging.

Conditioned reflex responses of the sympathetico-adrenal system to an aversive taste stimulus.

Studies were carried out on male and female rats in which the effects of isolated presentation of a conditioned stimulus (a saccharine solution) to which the animals had previously developed conditioned reflex taste aversion (RTA) on the level of urinary catecholamine secretion were determined. The studies showed that presentation of an aversive taste stimulus without reinforcement by a negative stimulus increased the levels of urinary adrenaline, noradrenaline, and dopamine secretion; this repeated, albeit more weakly, the effects of the negative reinforcement (angular acceleration) used for development of RTA. After presentation of the isolated aversive taste stimulus, the greatest increase in catecholamine excretion affected adrenaline, which indicates an anxiety state (fear). There was also a significant increase in noradrenaline excretion in these conditions. The accompanying increase in dopamine excretion in experimental and control animals showed this change to be largely nonspecific in nature, and to result from the experimental procedures. Isolated presentation of the conditioned taste stimulus elicited significantly greater increases in urinary catecholamine excretion in males than in females. It is suggested that the time for which the RTA is retained could be increased by activation of the sympathetico-adrenal system resulting from presentation of the nonreinforced taste stimulus which had acquired aversive properties.

Inhibition by a capsaicin antagonist (capsazepine) of capsaicin-induced swimming capacity increase in mice.

We investigated the endurance swimming capacity of mice injected with CAP antagonist (capsazepine). The increase of endurance swimming capacity by the administration of CAP was significantly suppressed by the injection of capsazepine. At the same time, serum adrenaline secretion, which was induced by CAP, was depressed by capsazepine. These findings suggested that the increase in endurance swimming capacity by CAP was mediated by the CAP receptor.

Diversity of Glycemic Thresholds for Epinephrine Secretion and Autonomic Symptoms in Variously Controlled Diabetic Patients

Diversity of Glycemic Thresholds for Epinephrine Secretion and Autonomic Symptoms in Variously Controlled Diabetic Patients

Neuropeptide Y Inhibits Chromaffin Cell Nicotinic Receptor-Stimulated Tyrosine Hydroxylase Activity through a Receptor-Linked G Protein-Mediated Process

Acetylcholine stimulation of bovine chromaffin cells results in increased norepinephrine and epinephrine secretion accompanied by a corresponding increase in synthesis. The addition of neuropeptide Y (NPY) to the culture medium prevents the increase in catecholamine synthesis but not secretion. Treatment of chromaffin cells with nicotine produces a concentration-dependent increase in tyrosine hydroxylase activity (IC50 = 1.2 microM) that is reduced if NPY is present during stimulation. Tyrosine hydroxylase activity decreases in a concentration-dependent fashion if increasing amounts of NPY are included in the culture medium, IC50 = 0.2 nM. Treatment with pertussis toxin completely prevents the effect of NPY. The rank order of potency for inhibition of tyrosine hydroxylase activity is NPY > or = [Leu31,Pro34]NPY > or = peptide YY > NPY2-36 > NPY13-36 > NPY18-36 > or = NPY26-36 >> NPY1-30, suggesting a NPY-Y1 receptor subtype. Examination of the effect of NPY on nicotine stimulation of chromaffin cell protein phosphorylation showed that NPY produces a concentration-dependent decrease in a 60-kDa protein, IC50 = 6.4 nM. The effect of NPY is pertussis toxin-sensitive. The rank order of potency is [Leu31,Pro34]NPY > or = NPY >> NPY18-36. Immunoprecipitation confirmed the identity of the 60-kDa protein as tyrosine hydroxylase.

Effect of exercise and exogenous glucocorticoid on serum level of intact parathyroid hormone.

Most previous studies suggest that physical exercise, or physiological response to exercise such as cortisol and adrenaline secretion regulate parathyroid hormone (PTH) secretion in humans. To investigate the effects and possible interaction of exercise and excessive glucocorticoid on PTH secretion, we examined the serum of levels of intact-PTH, cortisol, adrenocorticotrophic hormone (ACTH), calcium, magnesium and phosphorus before and during one-hour of bicycle-ergometric exercise at 60% of maximal oxygen uptake. These exercise tests were performed on eight Chinese male volunteers aged between 20 and 25 years, once with and once without pretreatment with 0.5 mg of dexamethasone taken orally 9.5 hours in advance. The results showed that dexamethasone pretreatment significantly lowered basal levels of cortisol and ACTH, but intact PTH did not change. After 60 minutes of bicycling, intact PTH level increases by 50% of baseline both with and without dexamethasone pretreatment. Serum levels of calcium, corrected for changes in serum albumin concentration, phosphorus and magnesium also increased in both cases. This study demonstrated an increase of intact-PTH with exercise which was not associated with hypocalcemia or hypomagnesemia, and was not altered in the presence of mild exogenous glucocorticoid excess and suppressed endogenous cortisol secretion.

Effect of cortisol on mammary tight junction (TJ) permeability in lactating dairy cows

Intact mammary epithelial TJ are important for milk synthesis. Recent in vitro studies indicate that glucocorticoids are important for maintenance of mammary TJ. In the present study, we examined the effects of cortisol on mammary TJ integrity in vivo. In two experiments, endogenous levels of cortisol in plasma were manipulated by challenging cows with (0.05 mg, 40 IU; i.v.) adrenocorticotropic hormone (ACTH 1–24 ) or by inducing transport-related stress. In experiment 1, 20 cows were subjected to an ACTH challenge 4, 2, or 1 h before milking, or no challenge (control). In experiment 2, 2 h before milking, 15 cows were challenged with ACTH, transported for 2 h, or used as controls. Blood samples were collected at −5, 60, and 120 min following the start of treatments. Decreased plasma lactose and increased milk K content were used as indicators of TJ permeability. Both ACTH and transport caused a 6-fold increase (P < 0.01) in plasma cortisol at 60 min. Time of ACTH challenge (exp. 1) did not affect plasma lactose, allowing the data to be pooled. ACTH decreased plasma lactose in experiment 1 (−5 vs 60 vs 120 min: 28.0 a vs 26.9 a vs 24.9 b ± 0.8 M, a,b P < 0.05) and experiment 2 (26.1 a vs 24.6 a vs 23.6 b ± 0.8 M, a,b P < 0.01), whereas K content in milk increased (exp. 1, control vs 4 vs 2 vs 1 h: 31.8 a vs 32.1 a vs 32.0 a vs 33.5 b ±0.2 mmol l , a,b P < 0.01; exp. 2, control vs ACTH: 41.1 vs 42.1 ±0.4 mmol l , P < 0.01). These changes are consistent with decreased TJ permeability. Moreover, these changes occurred rapidly (≤ 1 h). Despite elevated cortisol levels with transport, no changes in plasma lactose were observed, but K in milk increased (control vs transport: 40.9 vs 42.1 ± 0.4 mmol l , P < 0.05). This variable response with stress may be due to increased secretion of epinephrine, overiding the beneficial effects of cortisol on TJ. In conclusion, our data, obtained in vivo, support the findings of recent in vitro studies that glucocorticoids play a role in maintaining the integrity of TJ in the epithelium of the mammary gland.

Long-term beta 1-adrenergic blockade restores adrenomedullary activity in primary hypertension.

In this study we examined the effects of long-term treatment of 19 patients with primary hypertension with the beta 1-adrenoceptor antagonist atenolol on norepinephrine and epinephrine kinetics, at rest and during sympathoadrenal stimulation by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotope-dilution technique by steady-state infusion of tritiated norepinephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was studied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infusion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 +/- 0.02 to 0.17 +/- 0.01 nM (p < 0.05), and this was accompanied by a decrease in total body epinephrine spillover from 0.50 +/- 0.05 to 0.35 +/- 0.04 nmol/min (p < 0.05). In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at -40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance rates of epinephrine and norepinephrine were not significantly affected by atenolol. These results suggest that treatment of patients with primary hypertension with the beta 1-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epinephrine, but it does not affect the biochemical indices of sympathoneural activity. It remains speculative whether this selective effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term.

Stimulus-secretion coupling in porcine adrenal chromaffin cells: Effect of dexamethasone

Recent studies from this laboratory established that dexamethasone (DEX) potentiates Ca2+ current via voltage-gated Ca2+ channels (VGCC), and as a consequence potentiates agonist-induced cytosolic Ca2+ transients in rat adrenal chromaffin cells. The present study examined whether DEX can also modulate VGCC activity and agonist-induced cytosolic Ca2+ transients in porcine adrenal medullary chromaffin (PAMC) cells, and if so whether this results in alterations in catecholamine secretion. Forty-eight-hr exposure to 1 microM DEX significantly increased peak Ca2+ current (delta + 138%; n = 6; P < 0.05) in PAMC cells. DEX treatment also significantly potentiated the increase in cytosolic Ca2+ in response to membrane depolarization with KCl (delta + 20%; n = 29; P < 0.05), but did not affect the amplitude of Ca2+ transients elicited by nicotine or acetylcholine. Despite the potentiation of intracellular Ca2+, DEX treatment had no effect on KCl-induced secretion of either norepinephrine or epinephrine. These data demonstrate that as in the rat chromaffin cell, DEX can also increase VGCC activity in PAMC cells. However, the subsequent potentiation of selected agonist-induced increases in intracellular Ca2+ does not appear to be sufficient to alter catecholamine secretion.

Tumor Recurrence and Hypertension Persistence After Successful Pheochromocytoma Operation

Pheochromocytoma is a catecholamine-secreting tumor and a rare cause of hypertension that is usually curable. However, pheochromocytoma may recur as a benign or malignant tumor, and hypertension may persist after successful surgical intervention. The frequency of and risk indicators for tumor recurrence and hypertension persistence after successful surgical intervention have not been adequately studied. We determined tumoral and blood pressure outcome in 129 patients followed-up from initial pheochromocytoma resection to death or to 1994 (796 patient-years). We assessed several candidate indicators for their predictive value for the risk of tumor recurrence or hypertension persistence. Recurrence was defined as the reappearance of disease after normalization of biochemical tests. Pheochromocytoma caused death or persistent or recurrent disease in 28 patients. Of the 114 with benign tumors at initial operation, pheochromocytoma recurred as a benign or malignant tumor 17 to 194 months after initial operation in 16 cases. Kaplan-Meier estimates of pheochromocytoma-free survival were 92% and 80% at 5 and 10 years, respectively. In the 98 living patients without recurrence, Kaplan-Meier estimates of hypertension-free survival were 74% and 45% at 5 and 10 years. In the Cox model, familial pheochromocytoma and a low ratio of plasma epinephrine to total catecholamines were independently associated with recurrence. Familial hypertension and age were similarly associated with hypertension persistence. After surgery for pheochromocytoma, patients should be followed-up indefinitely, especially those with familial tumors or a low epinephrine secretion. Pheochromocytoma should not unreservedly be considered a surgically remediable cause of hypertension.

Endocrine and thermoregulatory responses to acute thermal exposures in 6-month-old pigs reared in different neonatal environments

1. 1. Endocrine and thermoregulatory responses to acute heat (34°C) and cold (10°C) exposures were determined in eight pigs at 6 months of age. Half of the pigs had been reared in a cycling upper thermal environment (27–32°C) for the first 28 days of life, while the others had been reared in a lower thermal environment (21°C). 2. 2. Concentrations of cortisol increased significantly during both acute heat and cold thermal exposures ( P = 0.0001) although the response was greater in the heat than in the cold ( P = 0.003). A prolactin response occurred during acute heat exposure ( P = 0.004). Growth hormone secretion increased during acute cold exposure ( P = 0.001). There was a strong tendency for increased epinephrine secretion during both acute heat and cold exposures ( P = 0.06). No significant effects of either exposure were found on plasma norepinephrine ( P = 0.9), or triiodothyronine ( P = 0.11). 3. 3. Neonatal environment did not affect daily core body temperature ( T c) before acute heat or cold exposures, but did alter amplitude of the 24-h T c cycle. The amplitude was significantly greater in animals reared in the lower thermal environment ( P < 0.001). 4. 4. Acute heat exposure resulted in significant increases in T c ( P < 0.001) and heat production ( P < 0.01). Neonatal thermal environment had no significant effect on T c and heat production responses to acute heat and cold thermal exposures.

Chromaffin cell epinephrine secretion mediated by a macrophage peptide: the role of endotoxin.

Recent studies show that mononuclear cells release a small peptide (molecular weight < 3,000) that stimulates chromaffin cell epinephrine secretion (1). The present study demonstrates that endotoxin (ETX) enhances this mononuclear cell-mediated epinephrine secretion and examines the potential mechanism for regulation of this peptide. Mononuclear cells from bovine spleen were cultured 24 h in serum-free media after which the supernatant (conditioned media, CM) was harvested and filtered to remove molecules with a molecular weight greater than 3,000. In vitro epinephrine secretion from bovine chromaffin cells was used as a test system and CM-secretion expressed as a percentage of total cell content. ETX challenge (1 microgram/mL) of mononuclear cell cultures significantly enhanced bioactivity of CM (control-CM = 11.8 +/- .7, ETX-CM = 17.7 +/- 2.8). Separation of cell populations by adherence to plastic revealed that T cell and/or B cell populations were the main source of the bioactive peptide(s) in unstimulated cell cultures (T/B cell = 12.9 +/- .7, M phi = 6.2 +/- .8). In contrast, ETX induced significant bioactive peptide release from the macrophage population (M phi = 6.2 +/- .8, ETX-M phi = 15.9 +/- 2.8). Polyacrylamide gel analysis revealed a small peptide in nonadherent cell CM that was present only in ETX-challenged macrophage cultures. Additionally, data are presented that demonstrate a correlation between CM bioactivity and protease activity in CM. Proteases secreted from mononuclear cells in response to ETX is hypothesized to cleave the bioactive peptide from a larger "parent" protein. This peptide may play a role in the elevation of plasma catecholamines observed in the setting of critical injury and illness and contribute to development of the systemic inflammatory response syndrome (SIRS) and subsequent shock states.

Hierarchy of Physiological Responses to Hypoglycemia: Relevance to Clinical Hypoglycemia in Type I (Insulin Dependent) Diabetes Mellitus*

Hypoglycemia elicits a characteristic sequence of responses in healthy humans. These responses (and their arterialized venous glycemic thresholds) include: 1) Decreased insulin secretion (approximately 4.5 mmol/L). 2) Increased glucose counterregulatory hormone (glucagon, epinephrine, growth hormone and cortisol) secretion (approximately 3.6-3.8 mmol/L). 3) Symptoms of hypoglycemia (approximately 3.0 mmol/L). 4) Cognitive dysfunction (approximately 2.6 mmol/L). Thus, insulin secretion decreases as plasma glucose levels fall within the physiological range, and counterregulatory hormone secretion increases as plasma glucose levels fall just below the physiological range at substantially higher glucose levels than those required to produce symptoms and impair cognitive function. These data are entirely consistent with the body of evidence that insulin, glucagon and epinephrine stand high in the hierarchy of redundant glucoregulatory factors that prevent, as well as correct, hypoglycemia. When the same methods are used, these thresholds are remarkably reproducible from laboratory to laboratory. Nonetheless, the glycemic thresholds are dynamic rather than static. They vary in relation to recent antecedent glycemia. For example, lower plasma glucose concentrations are required to elicit autonomic, including epinephrine, and symptomatic responses in patients with well controlled IDDM, a phenomenon best attributed to recent antecedent iatrogenic hypoglycemia. This is the basis of the clinical syndrome of hypoglycemia unawareness, which is now known to be reversible with scrupulous avoidance of iatrogenic hypoglycemia. The latter also at least partially reverses reduced epinephrine responses to hypoglycemia, a key component (in the setting of absent glucagon responses) of the syndrome of defective glucose counterregulation. While perhaps seemingly adaptive, these threshold shifts appear to be maladaptive since both defective glucose counterregulation and hypoglycemia unawareness are associated with substantially increased rates of severe iatrogenic hypoglycemia in people with IDDM.

Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy.

Impaired epinephrine secretion and symptom unawareness are characteristic of severe hypoglycemia in individuals with long-standing type I diabetes. Recently, the avoidance of clinical hypoglycemia has been reported to improve epinephrine and symptom responses to hypoglycemia in type I patients. However, the extent to which these defects can be restored in individuals with long-standing type I diabetes and autonomic neuropathy has not been assessed, nor has it been determined whether pancreas transplantation, which not only obviates hypoglycemia but also prevents hyperglycemia, results in the complete recovery of either epinephrine response or symptom awareness during insulin-induced hypoglycemia. We performed stepped hypoglycemic clamp studies in successful pancreas transplantation recipients to assess epinephrine and other counterregulatory hormone responses during hypoglycemia and to determine the degree to which hypoglycemic symptom recognition could be restored. Thirteen pancreas transplant recipients and matched control subjects were studied utilizing stepped hypoglycemic clamp protocol to achieve target glucose levels of 3.9, 3.3, 2.8, and 2.2 mmol/l (70, 60, 50, and 40 mg/dl, respectively). Plasma epinephrine response was significantly greater in healthy control subjects and pancreas transplant patients compared with type I subjects at the glucose plateaus of 3.9, 3.3, and 2.8 mmol/l. However, epinephrine response in pancreas transplant recipients was significantly less than that seen in either healthy control subjects or nondiabetic kidney transplant recipients at each of these glucose plateaus. The magnitude of the epinephrine response in pancreas transplant type I patients did not correlate with either the duration of diabetes, the duration of transplantation, or the measures of autonomic nerve function. Hypoglycemic symptom recognition was significantly greater in pancreas transplant subjects than type I patients and did not differ between pancreas transplant and control groups. No improvement in norepinephrine response was observed after pancreas transplantation, while glucagon responses to hypoglycemia were normalized in pancreas transplant patients. In conclusion, these studies uniquely demonstrate that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long-standing diabetes and established autonomic neuropathy. No correlation was observed between the severity of autonomic neuropathy or the duration of diabetes and the recovery of either the epinephrine or symptom responses to hypoglycemia.

Role of central neural mechanisms in the regulation of hepatic glucose metabolism.

Central monoamine neurotransmitters affect blood glucose homeostasis. Activation of central cholinergic, noradrenergic histaminergic, and serotonergic neurons rapidly increase hepatic glucose output via the sympathetic nervous system. Acute hyperglycemia is mediated by three distinct pathways: the action of epinephrine on the liver, the action of glucagon on the liver, and the direct innervation of the liver. The relative contribution of these factors to hyperglycemia can be altered by diet and the kinds of neurotransmitters evoked in the central nervous system, but the magnitude of epinephrine secretion is closely related to the magnitude of hyperglycemia. On the other hand, neuropharmacological stimulation of central cholinergic muscarinic receptors, histaminergic H1 receptors, and serotonergic 5-HT2 receptors increases hypothalamic noradrenergic neuronal activity, which is associated with hyperglycemia. In contrast, central GABAA receptors play an inhibitory role in the regulation of hepatic glucose metabolism. Thus, central monoaminergic neurons could be linked together, and play a homeostatic role in the regulation of hepatic glucose metabolism.

Pineal effects on adrenal medulla, area postrema and brain water content in relation to intracranial surgery.

We aimed to explore whether and how the pineal influences the adrenal medulla, the area postrema and the brain water content; and is influenced by sham pinealectomy (SPX) in its structures and melatonin secretion. Quantitative morphological methods were mainly used in rats and golden hamsters. Experimental results showed: (1) Pineal effects on the A cell system of the adrenal medulla were inhibitory to the synthesis and secretion of epinephrine into the perivascular space and stimulatory to the opioid synthesis, and augmented by SPX. Time-of-day changes were also influenced by SPX and PX. (2) The sizes of a part of the nuclei of nerve and glia cells in the area postrema and the brain water content increased by SPX depending on the presence of the pineal, suggesting the pineal's stimulatory effects on these following SPX. (3) SPX caused morphological changes suggesting an increased activity of pinealocytes. However, corresponding consistent increases in plasma melatonin levels were not seen following SPX. Possible interpretations of these observations were discussed.

Importance of Catecholamines in Defense against Insulin Hypoglycemia in Humans

Publisher Summary The several differences in the counterregulatory mechanisms observed between the acute and the clinical model of hypoglycemia suggest that, in the clinical model, the secretion of epinephrine may play a much important counterregulatory role as compared with that envisaged on the basis of the acute hypoglycemia model. In this chapter, the contribution of the adrenergic mechanisms to counterregulation in an experimental model of prolonged hypoglycemia closely mimicking the clinical situation is reviewed. For this purpose, the pancreatic-adrenocortical-pituitary clamp, a technique that allows examining the role of a single counterregulatory hormone without confounding changes in the plasma concentrations of other hormones, is used. Catecholamines are found to contribute to human glucose counterregulation because an early phase of hypoglycemia throughout; they exert effects both at the liver and at the muscle level; their counterregulatory effects are not compensated by other hormones, in particular glucagon; thus, the failure of catecholamines to exert their effects in hypoglycemia, such as during α , β pharmacological blockade, results in severe hypoglycemia, despite increase in other counterregulatory hormones. Finally, catecholamines largely work during counterregulation via indirect mechanisms such as stimulation of lipolysis, which enhances gluconeogenesis and hepatic glucose production, and suppress oxidation and utilization of glucose.

NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, affects the central nervous system to produce peripheral hyperglycemia in conscious rats.

To determine whether the nitric oxide (NO) system in the central nervous system (CNS) is involved in the peripheral metabolism of carbohydrate we injected NG-methyl-L-arginine (L-NMA), an inhibitor of NO synthase, into the third cerebral ventricle of unanesthetized, unrestrained rats and determined the plasma level of glucose. This intracerebroventricular (i.c.v.) injection of the drug increased the plasma level of glucose dose-dependently, whereas an intravenous (i.v.) injection had no effect. The hyperglycemia thus induced was suppressed by concomitant i.c.v. or prior i.v. administration of L-arginine. Concomitant administration of D-arginine did not affect hyperglycemia by L-NMA. The i.c.v. injection of 5 x 10(-6) mol L-NMA increased plasma levels of glucose, epinephrine and norepinephrine, and serum levels of glucagon. However, plasma levels of insulin were unchanged, despite the presence of hyperglycemia. The hyperglycemia produced by L-NMA was completely inhibited by bilateral adrenalectomy. It was also inhibited by prior intraperitoneal injection of phentolamine, but not of propranolol or naloxone. Results suggest that L-NMA acts on the CNS to stimulate adrenal secretion of epinephrine and, subsequently, to elevate glucose levels in the peripheral blood. The NO system thus seems to be involved in the neural regulation of the adrenal by the GNS, which in turn regulates peripheral blood glucose levels.