Showing papers on "Epinephrine published in 1990"

Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium.

Abstract: beta-Adrenergic pathways in the human ventricular myocardium mediate the powerful positive inotropic effects of released neurotransmitters (norepinephrine) and circulating hormones (epinephrine) and the response to therapeutically administered beta-agonists. Two genetically and pharmacologically distinct receptors, beta 1 and beta 2, mediate the contractile effects of catecholamines in a similar manner. The biologic signal produced by the occupancy of beta-adrenergic receptors by catecholamine agonists is transduced, amplified, and regulated by a family of guanine nucleotide-binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Although the major biochemical effector of beta-adrenergic receptors is the enzyme protein--coupled directly to ion channels that regulate inotropic and electrophysiological effects. In human ventricular myocardium, heart failure produces changes in the beta-adrenergic receptor pathways that have the collective effect of reducing the degree of inotropic stimulation that may be produced by a given amount of beta-agonist. These changes include downregulation of beta 1-adrenergic receptors, uncoupling of beta 2-adrenergic receptors, and an increase in the functional activity of the inhibitory G protein. These effects in turn are probably caused by exposure to increased amounts of neurotransmitter resulting from a complex series of changes in the cardiac sympathetic nervous system. Finally, the components of the beta-receptor-G protein system may be both acutely and chronically modulated by certain kinds of pharmacological therapy. These observations underscore the importance of the adrenergic nervous system in heart failure, and they create the potential for the development of new interventional strategies designed to alter the natural history of heart muscle disease and heart failure.

Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium.

Abstract: We determined the relative contribution of beta 1- and beta 2-adrenoceptor stimulation to the positive inotropic responses of human atrial myocardium to catecholamines. (-)Norepinephrine produced stimulation predominantly through beta 1-receptors and (-)epinephrine through both beta 1- and beta 2-receptors. However, there were marked differences in the responses of tissues from patients treated with the beta 1-selective antagonist atenolol compared with non-beta-blocker-treated patients; surprisingly, beta 2-mediated responses were enhanced, and beta 1-mediated responses were unaltered. There was an enhanced responsiveness to (-)epinephrine (atenolol treated: -log M EC50, 7.57 +/- 0.07; non-beta-blocker treated: -log M EC50, 6.77 +/- 0.17; p less than 0.001), and the relative importance of beta 2-adrenoceptor stimulation was increased for both (-)norepinephrine and (-)epinephrine. In tissues from atenolol-treated patients, salbutamol, a beta 2-selective partial agonist, had an enhanced potency and a greater intrinsic activity (atenolol treated: -log M EC50, 7.13 +/- 0.09; intrinsic activity, 0.86 +/- 0.04; non-beta-blocker treated: -log M EC50, 5.76 +/- 0.44; intrinsic activity, 0.39 +/- 0.13). We investigated possible mechanisms underlying the enhanced responsiveness to beta 2 stimulation. Determination of beta 2-adrenoceptor affinity for salbutamol showed no change of affinity in atenolol-treated patients. Responses of the tissues to the cyclic AMP analogue dibutyryl cyclic AMP were not different between atenolol-treated and non-beta-blocker-treated patients. The results suggest that chronic blockade of beta 1-adrenoceptors causes enhanced coupling of beta 2-adrenoceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.

Beta-adrenergic receptors in lymphocyte subsets after exercise. Alterations in normal individuals and patients with congestive heart failure.

Abstract: Dynamic exercise increases the number of beta-adrenergic receptors in mixed lymphocytes by a mechanism that is incompletely understood. In a set of in vivo studies, we have investigated the effects of dynamic exercise on the subset distribution of circulating lymphocytes and on the number of beta-adrenergic receptors in each of these subsets in two groups of patients. In healthy subjects, exercise increased plasma norepinephrine and epinephrine and caused lymphocytosis. Whereas the number of Thelper cells increased only modestly, the number of Tsuppressor/cytotoxic and natural killer cells more than tripled. The number of beta-adrenergic receptors varied among subsets but was not significantly altered by dynamic exercise in any subset except natural killer cells (35% increase, p = 0.0302). In a group of patients with congestive heart failure, dynamic exercise increased plasma norepinephrine but did not alter plasma epinephrine and did not cause significant lymphocytosis. We did not detect any significant alterations of circulating leukocyte subsets or beta-adrenergic receptors in any of these subsets after exercise. A combined analysis of healthy patients and heart failure patients revealed a significant correlation between increases in plasma epinephrine and increases in circulating lymphocytes. We conclude that the exercise-induced increase in beta-adrenergic receptors of mixed lymphocytes is predominantly caused by a redistribution of circulating cell subsets that differ in their beta-adrenergic receptor number. This appears to be mediated by epinephrine rather than norepinephrine.

Effects of splanchnic nerve stimulation on the adrenal cortex may be mediated by chromaffin cells in a paracrine manner

Abstract: The effects of nerve activation and of the catecholamines epinephrine and norepinephrine on adrenal corticosteroid release were investigated in intact isolated perfused pig adrenals with preserved nerve supply. To study the contact zones of medullary and cortical tissues, porcine adrenals were examined on the histological and ultrastructural levels. Splanchnic nerve activation stimulated in parallel the release of epinephrine (from a basal value of 0.31 +/- 0.11 to 8.13 +/- 0.60 microgram/min) and norepinephrine (from 0.76 +/- 0.68 to 12.94 +/- 3.58 micrograms/min) and the release of the corticosteroids cortisol (from 0.62 +/- 0.19 to 2.00 +/- 0.35 micrograms/min) and aldosterone (from 3.34 +/- 0.59 to 7.53 +/- 1.63 ng sigma in). Also, perfusion of the isolated adrenals with catecholamines provoked a significant release of the corticosteroids. Epinephrine (10(-6) M) stimulated the release of cortisol (from 0.59 +/- 0.31 to 2.66 +/- 0.34 micrograms/min) and aldosterone (from 2.12 +/- 0.42 to 4.68 +/- 0.92 ng/min). Norepinephrine (10(-6) M) stimulated the release of cortisol (from 0.26 +/- 0.07 to 1.28 +/- 0.10 micrograms/min) and aldosterone (from 1.28 +/- 0.37 to 3.57 +/- 0.80 ng/min). Using an immunostaining for synaptophysin, which is specific for neuroendocrine cells, chromaffin cells could be detected within all three zones of the adrenal cortex. The two endocrine tissues appear to be closely interwoven. On the ultrastructural level, medullary cells are in apposition to cortical cells, with close cellular contacts. These results show that the release of corticosteroids cortisol and aldosterone can be stimulated through the sympatho-adrenal system. Taking into consideration the close colocalization of cortical and medullary tissues, this stimulation may be mediated by chromaffin cells in a paracrine manner.

Somatotropin in lactating cows: effect on response to epinephrine and insulin.

Abstract: The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephrine was determined in lactating cows treated with bovine somatotropin (bST). Also, the effects of insulin on lipolysis and glucose clearance were examined. Lactating cows (190 +/- 24 days postpartum) received daily subcutaneous injections of methionyl bST (40 mg) or excipient during two 12-day treatment periods. Epinephrine challenges (0.1, 0.2, 0.4, 0.8, 1.2, and 1.6 micrograms/kg body wt) were administered intravenously on days 6-11 and an insulin challenge (1 microgram/kg) on day 12. Milk energy secretion increased 55% without any change in voluntary feed intake during bST treatment. Circulating concentrations of NEFA were chronically elevated and reciprocally paralleled changes in net energy balance. Maximal response of plasma NEFA and glycerol to epinephrine was markedly increased during bST treatment, whereas the dose of signal-producing half-maximal response (ED50) was unchanged. Antilipolytic effects of insulin were also enhanced, whereas the effect of insulin on the fractional rate of glucose change was reduced. Thus bST alters tissue response to homeostatic signals to allow more nutrients to be partitioned for milk synthesis. Furthermore, the alterations in response to epinephrine and insulin appear to predominantly occur at a postreceptor level.

Chronic hyperinsulinemia and blood pressure. Interaction with catecholamines

Abstract: Although hyperinsulinemia and increased adrenergic activity have been postulated to be important factors in obesity-associated hypertension, a cause and effect relation between insulin, catecholamines, and hypertension has not been established. The aim of this study was to determine whether chronic hyperinsulinemia, comparable with that found in obese hypertensive patients, causes hypertension in normal dogs, increases plasma catecholamines, or potentiates the blood pressure effects of norepinephrine. In six normal dogs, insulin infusion (1.0 milliunits/kg/min) for 7 days, with euglycemia maintained, increased fasting insulin fourfold to sixfold. However, mean arterial pressure did not increase, averaging 99 +/- 2 mm Hg during the control period and 91 +/- 3 mm Hg during the 7 days of insulin infusion. Insulin did not alter plasma norepinephrine or epinephrine, which averaged 171 +/- 27 and 71 +/- 14 pg/ml, respectively, during the control period and 188 +/- 29 and 45 +/- 12 pg/ml during the 7 days of insulin infusion. In six dogs, norepinephrine was infused (0.2 microgram/kg/min) for 7 days to raise plasma norepinephrine to 2,940 +/- 103 pg/ml. Insulin infusion (1.0 milliunits/kg/min) for 7 days during simultaneous infusion of norepinephrine did not further increase mean arterial pressure, which averaged 101 +/- 3 during norepinephrine and 98 +/- 2 mm Hg during insulin plus norepinephrine infusion. Thus, chronic hyperinsulinemia did not increase mean arterial pressure or plasma catecholamines and did not potentiate the blood pressure actions of norepinephrine. These observations provide no evidence that chronic hyperinsulinemia or interactions between insulin and plasma catecholamines cause hypertension in normal dogs.

Simultaneous determination of plasma noradrenaline and adrenaline kinetics. Responses to nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia in the rabbit.

Abstract: Liquid chromatographic fractionation and detection of exogenous radiolabelled and endogenous catechols was used to examine simultaneously the plasma kinetics of noradrenaline and adrenaline in the conscious rabbit. Plasma clearances and release of noradrenaline and adrenaline into plasma were compared before and during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia, stimuli purported to differentially affect catecholamine release from sympathetic neurons and the adrenal medulla. Plasma concentrations of dihydroxyphenylglycol (DHPG) were also measured to assess presynaptic sympathetic function.

Effect of epinephrine and lidocaine therapy on outcome after cardiac arrest due to ventricular fibrillation.

Abstract: One hundred ninety-nine patients with out-of-hospital cardiac arrest persisted in ventricular fibrillation after the first defibrillation attempt and were then randomly assigned to receive either epinephrine or lidocaine before the next two shocks. The resulting electrocardiographic rhythms and outcomes for each group of patients were compared for each group and also compared with results during the prior 2 years, a period when similar patients primarily received sodium bicarbonate as initial adjunctive therapy. Asystole occurred after defibrillation with threefold frequency after repeated injection of lidocaine (15 of 59, 25%) compared with patients treated with epinephrine (four of 55, 7%) (p less than 0.02). There was no difference in the proportion of patients resuscitated after treatment with either lidocaine or epinephrine (51 of 106, 48% vs. 50 of 93, 54%) and in the proportion surviving (18, 19% vs. 21, 20%), respectively. Resuscitation (64% vs. 50%, p less than 0.005) but not survival rates (24% vs. 20%) were higher during the prior 2-year period in which initial adjunctive drug treatment for persistent ventricular fibrillation primarily consisted of a continuous infusion of sodium bicarbonate. The negative effect of lidocaine or epinephrine treatment was explained in part by their influence on delaying subsequent defibrillation attempts. Survival rates were highest (30%) in a subset of patients who received no drug therapy between shocks. We conclude that currently recommended doses of epinephrine and lidocaine are not useful for improving outcome in patients who persist in ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral blood flow and energy metabolism during stress

Abstract: Many, but not all, stressful events are accompanied by increases in cerebral blood flow and/or energy metabolism. The stressful events include pharmacological paralysis, footshock, conditioned fear, hypotension, hypoglycemia, hypoxia, noise, and ethanol withdrawal. These increases are significant because 1) all brain regions are often affected, i.e., certain stressful events have global effects on cerebral blood flow and energy metabolism; and 2) various stressful events appear to have a common adrenergic mechanism for increasing cerebral blood flow and energy metabolism. The adrenergic mechanism involves beta-adrenergic receptor stimulation by either epinephrine secreted from the adrenal medulla or possibly norepinephrine endogenous to the brain. While adrenergic mechanisms are not the only mechanism controlling flow and metabolism for a given stressful condition, they do appear to be common to many situations. At least part of the increase in cerebral blood flow and energy metabolism during many conditions appears to be the result of the stress response and not directly a result of the condition itself.

Catecholamines increase lymphocyte beta 2-adrenergic receptors via a beta 2-adrenergic, spleen-dependent process

Abstract: We investigated the mechanisms underlying the increase in mononuclear leukocyte (MNL) beta 2-adrenergic receptor (AR) number and responsiveness after acute infusion of catecholamines. Infusion of isoproterenol and epinephrine, but not of norepinephrine, acutely increased MNL beta-AR density, and this was blocked by the beta 2-selective antagonist ICI 118,551 but not by the beta 1-selective antagonist bisoprolol, suggesting a beta 2-AR-mediated effect. Infusion of isoproterenol but not of norepinephrine also induced a lymphocytosis, with an increase in the number of circulating suppressor/cytolytic T (Ts/c)- and natural killer (NK)-cells but a decrease in helper T (Th)-cells, leading to a decreased Th-Ts/c-cell ratio. beta-AR density was higher in Ts/c-cells than in Th-cells. After isoproterenol infusion, beta-AR density was elevated in all lymphocyte subsets but not in monocytes or platelets, suggesting a lymphocyte-specific phenomenon. Infusion of isoproterenol in splenectomized patients did not alter lymphocyte subset composition and only slightly increased beta 2-AR density. In healthy subjects lymphocyte proliferation in response to various mitogens was attenuated after infusion of isoproterenol but not of norepinephrine; this effect was abolished in splenectomized patients. We conclude that the elevated MNL beta-AR density after acute exposure to beta-adrenergic agonists is caused by a release of lymphocyte subsets from the spleen into the circulation and/or by an exchange of lymphocyte subsets between the spleen and the circulation, whereby freshly released splenic lymphocytes appear to carry more beta-AR than those found in the circulation. This appears to impair immune responsiveness in a dual manner, by decreasing the Th-/Ts/c-cell ratio and by rendering lymphocytes more sensitive to the antiproliferative effects of catecholamines via a higher beta-AR density.

Is physiologic sympathoadrenal catecholamine release exocytotic in humans

Abstract: In cultured cells and isolated perfused organs, catecholamines are coreleased with chromogranin A (CgA) from adrenal chromaffin cells and sympathetic neurons. The corelease suggests that exocytosis is the mechanism of catecholamine secretion. To investigate whether physiologic catecholamine secretion is exocytotic in humans, we measured plasma norepinephrine, epinephrine, and CgA responses to differentiated stimuli of sympathoadrenal discharge. The CgA radioimmunoassay antibody recognized authentic CgA in normal human adrenal chromaffin vesicles. Insulin-induced hypoglycemia and caffeine ingestion, in decreasing order of potency, selectively stimulated epinephrine release from the adrenal medulla. During hypoglycemia, plasma levels of epinephrine and CgA rose, and peak plasma levels of epinephrine and CgA correlated, suggesting that gradations in epinephrine release represented gradations in exocytosis. However, significant increments in plasma CgA were not observed after caffeine ingestion. Furthermore, the rise of CgA levels during hypoglycemia lagged 60 minutes behind those of epinephrine. A less-pronounced temporal dissociation between CgA and epinephrine release was also shown in isolated chromaffin cells in vitro. Selective adrenal vein catheterization suggested a barrier to CgA transport across the adrenal capillary wall. Short-term, high-intensity dynamic exercise, assumption of the upright posture, prolonged low-intensity dynamic exercise, and smoking, in decreasing order of potency, stimulated norepinephrine release from sympathetic nerve endings. Only the first sympathetic neuronal stimulus resulted in significant increments in plasma CgA, increments considerably less than those attained during adrenal medullary activation by insulin hypoglycemia. During high-intensity exercise, peak plasma norepinephrine and CgA levels correlated, suggesting that gradations in norepinephrine release represented gradations in exocytosis. The human adrenal medulla was a far more prominent tissue source of CgA than human sympathetic nerves--adrenal medullary homogenates contained 97-fold more CgA (micrograms/g) than sympathetic nerve homogenates. In conclusion, catecholamine secretion during selective stimulation of either sympathetic nerves or the adrenal medulla is, at least in part, exocytotic. Furthermore, stimulation of the former results in comparatively modest changes in plasma CgA compared with changes attained during stimulation of the latter. CgA appears to be transported by a route different from that of catecholamines from adrenal medullary chromaffin cells to the circulation in vivo.

Test doses: optimal epinephrine content with and without acute beta-adrenergic blockade.

Abstract: The authors studied the optimal epinephrine content of an epidural test dose, and determined criteria to identify intravascular injections in subjects with or without beta-adrenergic blockade. Nine healthy nonpregnant subjects 25-36 years of age were given intravenous infusions of saline or esmolol in random order. During each infusion, they received a series of five injections (3 ml each) of either saline, 1% lidocaine or 1% lidocaine containing 5, 10, or 15 micrograms of epinephrine. Thirty minutes after completing these two infusions, propranolol was administered as a bolus injection, and the series of five injections repeated. All injections were double blind and randomized. During saline infusion, all injections containing epinephrine significantly increased heart rate (HR) by an average of 31-38 beats/min when compared with that following plain lidocaine (P less than 0.05), and increased systolic blood pressure by an average of 17-26 mmHg (P less than 0.05 for the 15-micrograms dose only). During esmolol infusion, epinephrine injections increased HR by an average of 23-31 beats/min (P less than 0.05), and increased systolic blood pressure by an average of 18-30 mmHg (P less than 0.05 for 10 and 15 micrograms). After propranolol injection, epinephrine injections caused a decrease in HR by an average of 21-28 beats/min (P less than 0.05), whereas systolic blood pressure increased by an average of 22-35 mmHg (P less than 0.05 for 10 and 15 micrograms only). Without beta-adrenergic blockade, an increase in HR greater than or equal to 20 beats/min was 100% sensitive and specific for intravascular injection of 10 or 15 micrograms of epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of epinephrine on amino acid and energy metabolism in humans.

Abstract: Epinephrine was infused for 8.5 h into five normal, healthy, young adult men on four different occasions at 0, 0.5, 1, and 2 micrograms/min to elevate circulating levels of epinephrine into the high physiological range as seen in stress and trauma. Energy expenditure, heart rate, and blood pressure were measured at hourly intervals. [1-13C]leucine, [ring-2H5]phenylalanine, and [2-15N]glutamine were infused during the last 3.5 h to follow essential amino acid and glutamine kinetics. This design was adapted to study the effects of epinephrine on energy and protein metabolism after acute and temporary metabolic responses to epinephrine had occurred. Plasma glucose was significantly increased by approximately 20 mg/dl from 83 mg/dl (saline infusion) at all levels of epinephrine infusion. Amino acid levels were depressed with epinephrine infusion, with the largest drop occurring for the essential amino acids (-27% at the 2.0-micrograms/min dose). Energy expenditure was increased with epinephrine infusion in a dose-dependent fashion (+17% increase at 2.0 micrograms/min infusion). These effects were sustained for the duration of 8.5 h epinephrine infusion. There was no significant change in leucine or phenylalanine flux, indicative of protein breakdown, or in leucine oxidation. Glutamine flux was significantly (but modestly, +7%) increased at only the 2.0-micrograms/min infusion rate. Changes in kinetics that altered amino acid levels were not apparent by 7 h of epinephrine infusion (the beginning of the plateau period for the tracer infusion study). Although epinephrine can produce long-term elevations of metabolic rate, its effects on protein metabolism are minimal beyond acute changes affecting amino acid levels.

Synergistic Action of Triiodothyronine and Hydrocortisone on Epinephrine-Induced Reabsorption of Fetal Lung Liquid

Abstract: The influence of triiodothyronine and hydrocortisone on maturation of the response to epinephrine that leads to reabsorption of lung liquid was investigated in nine chronically catheterized fetal sheep. Experiments were performed on thyroidectomized fetal sheep at 116-120 d gestation, well before the reabsorptive response to epinephrine is normally seen. After i.v. administration of either triiodothyronine (60 /ig/d) or hydrocortisone (10 mg/ d) for 3 d (three fetuses in each case), all fetuses continued to secrete lung liquid during exposure to epinephrine (secretion rate=5.9 ± 3.2 mL/h in triiodothyronine-treated and 4.4 ± 1. 9 mL/h in hydrocortisone-treated fetuses). However, when the two hormones were administered together in the same doses to three fetuses, a striking reabsorptive response to epinephrine was seen (absorption rate=-12.3 ± 3.6 mL/h), similar to that observed in the mature fetus. Induction of this capacity to reabsorb lung liquid may be of importance in the management of respiratory problems of the newborn infant.

Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects

Abstract: Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.

Fetal adrenal medulla catecholamine response to hypoxia-direct and neural components.

Abstract: In the fetus, the adrenal medullary catecholamine responses to hypoxia are mediated by direct and neural mechanisms. The present study determined the maturation of these responses in unanesthetized ovine fetuses from 109 to 136 days gestation. In intact fetuses at 109-119 days gestation, hypoxia lowered arterial PO2 from 23.4 +/- 0.9 to 9.5 +/- 0.4 mmHg and induced acute increases in plasma norepinephrine (P less than 10(-5)) and epinephrine (P less than 10(-5)) concentrations. Fetuses at 130-136 days gestation showed similar changes in PO2 and plasma catecholamines as in younger fetuses. Blockade of neural input to the adrenal by hexamethonium (25 mg/kg) reduced but did not eliminate the increases in plasma norepinephrine and epinephrine concentrations in fetuses at 109-119 days gestation, while it completely abolished these responses in fetuses at 130-136 days gestation. These results suggest that in unanesthetized ovine fetuses a direct response of the adrenal medulla to hypoxia is present at 110 days gestation. In contrast, at 130 days gestation the response to hypoxia is entirely neurally mediated. Thus neural innervation to the ovine fetal adrenal medulla matures before 110 days gestation, much earlier than previously reported.

Increased cerebral blood flow and plasma epinephrine in hypoglycemic, preterm neonates.

Abstract: Cerebral blood flow, plasma epinephrine, and plasma norepinephrine were measured in 25 spontaneously breathing, preterm neonates (mean gestational age 304 weeks) 2 hours after birth, during a routine screening for low blood glucose levels Increased cerebral blood flow and plasma epinephrine values were observed when blood glucose levels were low, whereas plasma norepinephrine was constant throughout the blood glucose range Hypoglycemia (defined as blood glucose concentration less than 30 mg/dL) was found in 13 neonates who were treated with intravenous glucose and milk enterally Blood glucose levels were normal in the remaining 12 control neonates who received milk by a gastric line Approximately 30 minutes after treatment with intravenous glucose and/or milk, cerebral blood flow had decreased by a mean of 113% in the 13 hypoglycemic neonates but was still 375% higher than cerebral blood flow in the control neonates despite normalization of plasma epinephrine concentration Mean arterial blood pressure and blood gas values were identical between groups throughout the investigation It is suggested that a normal coupling between cerebral metabolic demands and flow is present in very preterm neonates and that epinephrine may play a role in the cerebral hyperperfusion Although none of the neonates had clinical signs of hypoglycemia, the data suggest that counterregulatory mechanisms are invoked when blood glucose values are less than 30 to 45 mg/dL

Galanin and Epinephrine Act on Distinct Receptors to Inhibit Insulin Release by the Same Mechanisms Including an Increase in K+ Permeability of the B-Cell Membrane*

Abstract: The mechanisms by which galanin and epinephrine affect pancreatic B-cell function were studied in normal mouse islets In the presence of 15 mM glucose and 25 mM Ca2+, galanin (50 nM) and epinephrine (100 nM) hyperpolarized the B-cell membrane and suppressed electrical activity only transiently These changes were accompanied by a decrease in 86Rb+ efflux from islet cells and nearly complete inhibition of insulin release Both agents also decreased 86Rb+ efflux in the absence of Ca2+ Low concentrations (10-15 microM) of diazoxide, an activator of ATP-sensitive K+ channels, mimicked some effects of galanin and epinephrine However, insulin release was more markedly inhibited by galanin or epinephrine than by diazoxide when electrical activity was similarly decreased, and diazoxide had no effect on 86Rb+ efflux in the absence of Ca2+ When the permeability to K+ was increased by 100 microM diazoxide and the hyperpolarization reversed by high extracellular K+, galanin and epinephrine still inhibited insulin release, but did not affect the membrane potential or 86Rb+ efflux Galanin and epinephrine decreased glucose utilization and oxidation in islet cells by about 10%, whereas diazoxide had no effect Blockade of alpha 2-adrenoceptors by yohimbine suppressed the effects of epinephrine, but not those of galanin It is concluded that activation of galanin and alpha2-adrenergic receptors inhibits insulin release by the same mechanisms These may involve an increase in K+ permeability of the B-cell membrane by opening ATP-sensitive K+ channels and an additional effect independent of the membrane potential

Myocardial catecholamine content after heart transplantation.

Abstract: Myocardial catecholamine levels have not yet been determined in the transplanted human heart. We measured norepinephrine, epinephrine, and dopamine in endomyocardial biopsies from 19 short-term (organ age, 6.6 +/- 6 months) and five long-term (organ age, 62 +/- 2 months) heart transplant patients. Results were compared with those from 10 normal control subjects. In 17 of 19 short-term heart transplant patients, myocardial catecholamines were undetectable, indicating values below 0.1 pg/micrograms noncollagen protein, which was the detection threshold of our assay. In the remaining two patients, myocardial catecholamines (pg/microgram noncollagen protein) were norepinephrine (1.4 and 3.2), epinephrine (0.8 and 1.9), and dopamine (0.9 and 2.3), respectively. In the five long-term heart transplant patients, myocardial catecholamines were not detected. Catecholamine concentrations in 10 healthy control subjects were norepinephrine (10.3 +/- 2.9), epinephrine (0.36 +/- 0.51), and dopamine (0.52 +/- 0.40). Low myocardial norepinephrine levels (less than 20% of control values) with unexplained high levels of epinephrine and dopamine were found in single transplant patients. In most heart transplant patients, however, myocardial catecholamines were undetectable up to five years after transplantation, indicating that the adrenergic response of these hearts probably depends on variations in plasma catecholamines or cardiac beta-receptor density.

Adrenal Medullary Transplantation Into the Brain for Treatment of Parkinson's Disease: Clinical Outcome and Neurochemical Studies

Abstract: Transplantation of adrenal medulla into the caudate nucleus as treatment for Parkinson's disease was performed in eight patients. Although our previous 6-month follow-up revealed early modest improvement, an extension of that follow-up to 1 year disclosed no additional gains in any patient. At the end of 1 year, only one patient could be categorized as moderately improved; three patients were mildly improved, and four patients were unimproved. The rationale for transplanting adrenal medulla was to reestablish a physiologic source of dopamine to the striatum. We measured cerebrospinal fluid (CSF) and plasma catecholamines and metabolites before and after transplantation. Conjugated dopamine (the predominant form of dopamine found in the CSF) and homovanillic acid (the major dopamine metabolite) were modestly and inconsistently increased in the CSF. Conjugated and free epinephrine and norepinephrine, as well as 3-methoxy-4-hydroxyphenylglycol concentrations were not increased in CSF after graft placement, an indication that the adrenal chromaffin cells were no longer producing high levels of these nondopamine catecholamines and metabolites. CSF cortisol concentrations were not increased after transplantation, compared with values from controls, consistent with low numbers of functioning adrenal cortical cells contaminating the graft (or poor survival). Posttransplantation CSF did not induce a neurotrophic effect in cell cultures of 15-day embryonic rat dorsal root ganglion or PC12 (rat pheochromocytoma) cell lines. Survival of samples of patients' adrenal medullary tissue for 2 weeks in tissue culture attested to the viability of the graft at the time of transplantation. The relative concentrations of dopamine to epinephrine or norepinephrine increased in these cultured adrenal medullary cells, presumably because of loss of the glucocorticoid influence on catecholamine synthesis. A wide variety of factors could have contributed to our failure to replicate the earlier impressive results of adrenal-to-brain transplantation reported by others. Continued transplantation studies in animal models of parkinsonism are necessary for better elucidation of these factors.

In situ studies of catecholamine-induced lipolysis in human adipose tissue using microdialysis.

Abstract: The effects of catecholamines on lipolysis in situ were investigated in humans. Subcutaneous adipose tissue was microdialyzed with solvents containing adrenergic agents. Norepinephrine caused a rapid increase in the glycerol level in adipose tissue (lipolysis index) that was further increased by the alpha adrenoreceptor blocker phentolamine. At 10(-11) mol/l of norepinephrine caused a 100% stimulation of lipolysis (P less than .025). In the presence of phentolamine the lipolytic effects of catecholamines at 10(-12) mol/l was isoproterenol greater than epinephrine greater than norepinephrine. All these three lipolytic catecholamines caused a transient increase in the adipose tissue dialysate glycerol level, which peaked after 20 to 30 min of catecholamine exposure and then declined. The apparent tachyphylaxia could not be overcome by a gradual increase of the catecholamine concentration from 10(-12) to 10(-8) mol/l. However, the selective alpha-2 adrenoreceptor agonist clonidine caused a continuous and dose-dependent decrease in the dialysate glycerol level; the minimum effective concentration was 10(-9) mol/l. In conclusion, catecholamines have a lipolytic effect in situ at much lower concentrations than those in the circulation. This effect is transient and is related to beta adrenoreceptors. In additio, catecholamines have alpha adrenoreceptor-mediated effects on lipolysis in situ.

Beta-adrenergic receptors on human tracheal epithelial cells in primary culture.

Abstract: Human tracheal epithelial cells in suspension, whether obtained by brushing at bronchoscopy or from necropsy specimens by proteolytic digestion and EDTA treatment, increase adenosine 3',5'-cyclic monophosphate (cAMP) production in response to isoproterenol. These cells in primary culture also respond to beta-adrenergic agonists in order of potency isoproterenol greater than epinephrine greater than norepinephrine. The response is inhibited by propranolol or ICI 118551 (a beta 2-adrenergic selective blocker) but not by atenolol (a beta 1-adrenergic blocker). Binding of [125I]iodocyanopindolol (ICYP) to membranes was rapid, stereoselective, and saturable and displayed receptor density 8.0 +/- 4.6 fmol/mg protein (mean 228 receptors/cell) and a dissociation constant (KD) for ICYP of 35 +/- 14 pM for freshly isolated cells and a KD of 25 +/- 13 pM and receptor density of 17 +/- 17 fmol/mg protein for cells in culture. The 50% inhibitory concentration (IC50) for atenolol was 470 microM and for ICI 118551 was 0.012 microM. Analysis of the ICI 118551 displacement curve indicates that greater than 90% of the receptors are of the beta 2-adrenergic class. Prostaglandins E1 or E2, vasoactive intestinal peptide, carbachol, phenylephrine, or platelet-activating factor did not affect either the maximal cAMP response or the isoproterenol dose-response relationship. Neither clonidine nor epinephrine plus propranolol altered cellular cAMP content, and cyclooxygenase inhibition did not change the cAMP response to epinephrine. We conclude that in human tracheal epithelial cells in primary culture, adrenergic stimulation affects cAMP levels only through beta 2-adrenergic receptors and that modulation of this system by platelet-activating factor or muscarinic, alpha 1-, or alpha 2-adrenergic agents does not occur.