Showing papers on "Epinephrine published in 1973"

The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood

Abstract: SUMMARY The origin of hepatotrophic factors in splanchnic venous blood was investigated by modifyingthe portal venous inflow to different parts of the canine liver while leaving the arterial bloodsupply and biliary drainage intactIn one variety of experiment, termed partial transposition, the liver portion perfused with thetotal splanchnic venous blood underwent weight gain and hepatocyte hypertrophy, hyperplasia,and glycogenation compared with the portion perfused with venous blood from thehindquarters, kidneys, and adrenal glands, but the combined weight of the total liver remainedconstant in spite of the rapidly evolving regional disproportions The lobar changes were welldeveloped within one to two months At this time, the hepatic lobes supplied with splanchnicvenous blood had higher concentrations of glucokinase and lower concentrations of cyclic 3 ′,5′-adenosine monophosphate and active phosphorylase than the lobes receiving hindlimb andadrenorenal venous blood, indicating that the biochemical environment of the different liverregions was drastically different by virtue of being under specific hormonal controlThe dissociation was even more dramatically illustrated by dynamic studies in which thedestruction of cyclic 3 ′, 5′-adenosine monophosphate by phosphodiesterase was blocked withaminophylline thereby permitting estimation of the rate of formation of cyclic 3 ′, 5′-adenosinemonophosphate In addition, the modifying effect of tolbutamide-induced endogenous insulinupon exogenously administered glucagon was evaluated by serial determinations of cyclic 3 ′,5′-adenosine monophosphate These investigations with the aminophylline and tolbutamide-glucagon tests demonstrated the anabolic role of insulin and the opposing roles of bothglucagon and epinephrine in contributing to liver homeostasis Epinephrine and glucagoncaused striking increases in cyclic 3′, 5′-adenosine monophosphate, and insulin had theconverse effectAnother type of preparation involving partition of the splanchnic venous blood between theliver portions was termed splanchnic flow division The substances responsible for the hepatichypertrophy, hyperplasia, glycogenation, and weight gain were shown to emanate mainly, ifnot virtually exclusively, from the pancreatic-gastroduodenal-splenic venous drainage Incontrast, intestinal nutritional substrate and hormones from the intestine or adrenal gland werenot profoundly influential in either promoting or preventing the morphologic or glycogenconcentration changes The concentrations of cyclic 3′, 5′-adenosine monophosphate,phosphorylase, and glucokinase in the two sides of the liver did not follow as distinctive apattern as in the partial transposition experiments However, the aminophylline andtolbutamide-glucagon tests revealed the same type of major dissociation of cyclic 3′, 5′-adenosine monophosphate as with the partial transpositions Particularly impressive was theway in which trace doses of tolbutamide-induced endogenous insulin on the side nourished bypancreatic venous blood restrained the cyclic 3′, 5′-adenosine monophosphate response toexogenous glucagon, whereas the other liver fragment which was not so covered by insulinhad completely uninhibited rises in cyclic 3′, 5′-adenosine monophosphateThe conclusion from these experiments is that the hepatotrophic factors previously reportedfrom our laboratories and by other investigators to be in splanchnic venous blood are pancreatichormones and specifically insulin and glucagon Of these, insulin is anabolic and glucagon ismainly catabolic but not exclusively so, since glucagon also has the anabolic effect ofstimulating gluconeogenesis The insulin-glucagon relationship and the interrelationship ofthese hormones to others, such as epinephrine, in the moment to moment regulation of nutrient

Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I. Leukocyte responsiveness to -adrenergic agents.

Abstract: In an effort to better define the role of betaadrenergic blockade in human bronchial asthma, peripheral blood leukocytes and lymphocytes from individuals with this condition were studied for possible alterations in cyclic AMP metabolism. Using a previously described radioimmunoassay to measure cyclic AMP, cells from asthmatic subjects were shown to have a highly significant decrease in their cyclic AMP response to beta-adrenergic agents (isoproterenol, norepinephrine, and epinephrine) by comparison with normal control cells. The alteration in responsiveness was most marked at the time of severe active asthma and returned toward normal during periods of clinical remission. Evidence was presented to indicate that the reduced response in cells from asthmatic individuals was not due to marked alterations in the proportion of T and B lymphocytes. Five normal volunteers were treated with an oral bronchodilator preparation containing theophylline and ephedrine over a 2 wk period without a significant change in the lymphocyte cyclic AMP response. These results provide unambiguous evidence for altered adrenergic responsiveness in bronchial asthma and indicate that purified peripheral blood lymphocytes should be a suitable in vitro system for further elucidation of the abnormality. Despite the reduction in catecholamine responsiveness in the asthmatic population as a whole, major alterations were largely restricted to individuals with severe, chronic asthma. Conclusive evidence for beta-adrenergic blockade in individuals who have not had recent asthmatic symptoms was not obtained, casting some doubt on the theory that bronchial asthma is due to a congenital derangement of cyclic AMP metabolism. Moreover, transient episodes of bronchospasm were often accompanied by a normal cyclic AMP response indicating that episodes of asthma frequently occur in the absence of easily demonstrable adrenergic blockade.

Adrenergic Receptors and the Secretion of Glucagon and Insulin from the Isolated, Perfused Canine Pancreas

Abstract: During perfusion with a glucose concentration of 150 mg/100 ml, infusions of l-epinephrine, l-norepinephrine, and d-l-isoproterenol at physiological concentrations of 2 ng/ml for 9 min stimulated secretion of glucagon in a monophasic response pattern, in contrast to the biphasic response normally encountered after glucagon releasing stimuli as previously reported from our laboratory (1971. J. Clin. Invest.50: 2123). Glucagon was stimulated in spite of a glucose concentration which in itself effectively inhibits glucagon release. Release of insulin was strongly inhibited after epinephrine and norepinephrine, and strongly stimulated after isoproterenol. During perfusion with a glucose concentration of 25 mg/100 ml, secretion of glucagon was greatly accentuated by the catechols investigated. Secretion of insulin remained unchanged after epinephrine and norepinephrine, but was stimulated by isoproterenol. The catechol induced glucagon release was suppressed or abolished when the beta-blocking agent propanolol was simultaneously infused at a concentration of 1 muM, while the inhibition of insulin became further accentuated. The catechol induced glucagon release remained unchanged when alpha blockade was performed using either phentolamine (1 muM) or dibenzyline (10 mug/ml), while the inhibition of insulin was converted to a stimulation. Evidence is thus presented that both the alpha cells and the bet cells are under the influence of adrenergic substances, the stimulation of glucagon release being mediated through a beta receptor and the inhibition of insulin release being mediated through an alpha receptor.

Stimulation of Glucagon Secretion by Epinephrine in Man

Abstract: To determine the influence of the adrenergic system on pancreatic alpha-cell function in man, effects of epinephrine on plasma glucagon levels were studied in 8 normal subjects. During infusion of epinephrine (6 μg/min for 1 hr) plasma glucagon rose progressively from a mean (± sem) level of 125 ± 9.1 pg/ml to a mean maximum of 180 ± 18.7 pg/ml, p < 0.01. Despite coexistent hyperglycemia, plasma insulin did not increase appreciably. Thus epinephrine stimulates glucagon secretion in man while inhibiting insulin release. The adrenergic system therefore appears to influence both pancreatic alphaand beta-cell function in man.

ACCUMULATION OF CYCLIC ADENOSINE 3′, 5′‐MONOPHOSPHATE IN CEREBRAL CORTICAL SLICES FROM RAT AND MOUSE: STIMULATORY EFFECT OF α‐ AND β‐ADRENERGIC AGENTS AND ADENOSINE

Abstract: — Norepinephrine, epinephrine, isoproterenol, and adenosine elicit enhanced accumulations of cyclic AMP in incubated slices of rat cerebral cortex. Combinations of norepinephrine, epinephrine, isoproterenol, or histamine with adenosine have a greater than additive effect on cyclic AMP levels. The effects of isoproterenol appear to be mediated via a classical β-adrenergic receptor whereas the effects of norepinephrine appear due to interactions with both α- and β-adrenergic receptors. The presence of the phosphodiesterase inhibitor, isobutylmethylxanthine, potentiates the effects of the catecholamines and reveals a histamine-mediated increase in cyclic AMP levels. After an initial stimulation of cyclic AMP formation with norepinephrine, followed by washing of the slices, the cyclic AMP-generating system is unresponsive to norepinephrine but does respond to an adenosine-norepinephrine combination. In mouse cerebral cortical slices, catecholamines appear to elicit an accumulation of cyclic AMP primarily via interaction with a β-adrenergic receptor.

Acute Parathyroid Hormone Response to Epinephrine In Vivo

Abstract: The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 mumol/min iPTH increased from 0.48+/-0.12 (mean+/-SE, ng/ml) to 1.09+/-0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 mumol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change. The responses were more pronounced at 0.8 mumol/min epinephrine with a mean iPTH increase from 0.49+/-0.16 ng/ml to 1.74+/-0.35 ng/ml (P < 0.01). Small decreases in plasma calcium occurred at 0.8 mumol/min epinephrine, but the plasma magnesium remained unchanged. However, when the plasma calcium was lowered with ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid (EGTA), a much more pronounced lowering of the plasma calcium was required to produce comparable increases of the plasma iPTH concentrations than when epinephrine was infused. It appears that epinephrine has a direct effect on the release of iPTH from the parathyroid glands. Simultaneous infusions of calcium and epinephrine suppressed the stimulation by epinephrine. This points towards a common mechanism of the regulation of parathyroid hormone secretion caused by decreases in the extracellular calcium concentration and/or alterations in the distribution of calcium within parathyroid cells following the administration of epinephrine. The iPTH response to epinephrine was suppressed in the presence of propranolol. Isoproterenol was less active in raising iPTH than epinephrine, and norepinephrine was the least active. The stimulation by isoproterenol and the suppression by propranolol suggest beta adrenergic receptor sites within the parathyroid glands.

Plasma catecholamines in patients with serious postoperative infection.

Abstract: PREVIOUS REPORTS indicate that urinary catecholamine excretion is not significantly increased in patients after major operation, but is elevated following severe trauma or during a complicated postoperative course. Measuring unnary catecholamines after major surgical procedures, Franksson, Gemzell and Euler'0 found that epinephrine was not elevated in patients who made an uneventful recovery. Although urinary excretion of norepinephrine was increased occasionally, it was normal in the majority of these patients. Patients with major trauma or postoperative complications had consistently increased urinary norepinephrine. In patients with burns Goodall, Stone and Haynes12 found increased urinary excretion of catecholamines. The rise of norepinephrine was usually greater than epinephrine and was approximately proportional to the severity of the burns. Goodall"3 also observed histological depletion of catecholamine granules in the adrenal medulla of patients who died following severe bums. Urinary catecholamines do not reflect the intermittent circulating plasma concentrations, and in septic patients with or without hypotension, oliguria or anuria may preclude measurement of urinary catecholamines. Using the ethylenediamine method, Hammond, Aronow and Moore"' measured plasma catecholamines in a group of surgical patients. They found that plasma norepinephrine and epinephrine were normal in most patients following major surgical procedures, but were increased in patients with postoperative complications. The ethylenediamine method for the determination of

ADENOSINE 3′,5′-MONOPHOSPHATE IN GUINEA PIG CEREBRAL CORTICAL SLICES: EFFECTS OF α- AND β-ADRENERGIC AGENTS, HISTAMINE, SEROTONIN AND ADENOSINE

Abstract: —Norepinephrine and epinephrine, in combination with either adenosine or histamine, enhanced the accumulation of cyclic AMP in guinea pig cerebral cortical slices. Isoproterenol had only marginal effects under the same conditions. Studies with d- and l-norepinephrine and with the α- and β-adrenergic blocking agents, phenoxybenzamine, phentolamine, dihydroergokryptamine, propranolol and sotalol, indicated that the effect of catecholamines on cyclic AMP levels in this tissue was stereo-specific and was mediated primarily via interaction with a classical α-adrenergic receptor. Studies with the antihistaminics, diphenhydramine and pheniramine, and the antiserotonin agent, methysergide, indicated that guinea pig cerebral cortical slices contain receptors for histamine and serotonin, whose activation also stimulates an enhanced accumulation of cyclic AMP in the presence of adenosine.

Adenylate-Cyclase Activity of Rat-Liver Plasma Membranes

Abstract: The adenylate-cyclase activity from a rat-liver plasma-membrane preparation purified according to the Neville's procedure was increased 10 to 12-fold by glucagon, but the addition of epinephrine, at any concentration, failed to activate the enzyme. When the membranes were isolated from adrenalectomized animals, the responses of the enzyme to glucagon and NaF were enhanced and mainly the adenylate-cyclase activity became sensitive to epinephrine with an optimal effect at 0.05 mM epinephrine. Intraperitoneal administration of cortisol for 2 days to the adrenalectomized animals reversed the effect of the hormonal deprivation. But addition of cortisol in vitro was without effect. The use of liver plasma membranes from adrenalectomized rats is therefore proposed as a tool to study the adenylate-cyclase activation by both glucagon and epinephrine. The epinephrine-sensitive adenylate-cyclase activity was completely inhibited by propranolol but not by phentolamine, thus confirming that the metabolic effect of epinephrine is linked to a β-like receptor. Epinephrine and glucagon effects upon adenylate-cyclase activity were both inhibited by concentration of calcium above 0.01 mM but differed with respect to the Mg-ATP concentration. The two hormonally stimulated adenylate-cyclase activities were found to be additive. The effect of epinephrine upon adenylate-cyclase activity was more sensitive to stimulation by low concentration of GTP and other nucleotides than the effect of glucagon. Addition of insulin in vitro at any concentration failed to alter the adenylate-cyclase activity regardless of the concentration of magnesium, the presence of glucose or GTP.

Rapid recovery of vascular adrenergic nerves in the rat after chemical sympathectomy with 6‐hydroxydopamine

Abstract: 1. Twenty-four hours after the last of 4 intravenous doses of 6-hydroxydopamine (2x50 mg/kg on day 1 and 2x100 mg/kg on day 7) a complete impairment of adrenergic nerve function was observed in various organs of the rat.2. A complete recovery of adrenergic nerve function in vascular smooth muscle was observed 7 days after the last dose of 6-hydroxydopamine whilst in non-vascular smooth muscle recovery took between 14 and 21 days.3. On day 8, noradrenaline depletion produced by 6-hydroxydopamine was not as great in vascular tissues, such as the mesentery and renal artery, as in other tissues, such as the heart and salivary glands. Noradrenaline concentrations recovered much more rapidly in vascular than in other tissues.4. Electron microscope studies of small mesenteric arteries showed a complete destruction of adrenergic nerve terminals 24 h after 6-hydroxydopamine (2x100 mg/kg). However, there was a reappearance of growing terminals within 7 days and after 28 days the regrowth of adrenergic nerve terminals seemed complete.5. From the morphological and functional data it is concluded that 6-hydroxydopamine does produce complete destruction of vascular adrenergic nerve terminals. However, these terminals regenerate more rapidly than those in other tissues. This could explain the failure of intravenously administered 6-hydroxydopamine to prevent the development of experimental hypertension in the rat.

Characteristics of the catecholamine and histamine receptor sites mediating accumulation of cyclic adenosine 3',5'-monophosphate in guinea pig brain.

Abstract: —Five areas of guinea pig brain were examined to determine the properties of the receptor sites mediating increases in [3H]adenosine 3′,5′-monophosphate (cyclic AMP). Both epinephrine and histamine were effective in causing increases in cyclic AMP in slices derived from cerebral cortex, hippocampus or amygdala, but not in diencephalon or brainstem. Stimulation of slices of cerebral cortex by either epinephrine or histamine resulted in a small, but reproducible, decrease in specific radioactivity of the [3H]-cyclic AMP produced, as did stimulation of the hippocampus by epinephrine. The catecholamine receptor was an α-adrenergic receptor in all three areas where epinephrine was effective; α-adrenergic stimulation, but not β-adrenergic stimulation, increased levels of [3H]-cyclic AMP. Furthermore, α-, but not β-adrenergic blocking agents, prevented the epinephrine- induced increase of both [3H]- and total cyclic AMP in cerebral cortex and hippocampus. Only antihistaminic agents were capable of antagonizing the histamine-induced increase of both [3H]- and total cyclic AMP in these two brain areas. The catecholamine receptor in the amygdala also appeared to be an α-adrenergic receptor. The effects of histamine and epinephrine together were far greater than the sum of effects of either hormone alone in both cerebral cortex and hippocampus.

Tetrahydroisoquinoline alkaloids: stimulated secretion from the adrenal medulla

Abstract: Isolated cow adrenal glands were perfused for one hour with 23 mM acetaldehyde (1 mg/ml) in Tyrode9s solution. This procedure resulted in synthesis within the glands of tetrahydroisoquinoline alkaloids, which are condensation products of acetaldehyde with endogenous epinephrine and norepinephrine. Subsequent stimulation of the glands by perfusion with carbachol or acetylcholine caused secretion of catecholamines and tetrahydroisoquinoline alkaloids. Depletion of calcium ions prevented these responses; secretory responses were restored by repletion of calcium ions. Pretreatment with tetracaine similarly blocked the secretion of catecholamines and tetrahydroisoquinoline alkaloids. The data indicate that tetrahydroisoquinoline alkaloids are secreted by a process similar to that controlling catecholamine release. The results of these model experiments support the concept that tetrahydroisoquinoline alkaloids may play a role as false transmitters after ingestion of alcoholic beverages.

Adrenergic receptors: a personal and practical view*

Abstract: One of the greatest biologic advances was the discovery of the chemical transmission of information in living organisms. Endocrine glands communicate with each other and with other tissues by means of hormones. For example, the anterior pituitary makes, stores, and releases as necessary the hormone ACTH into the blood stream. Cortical cells of the adrenal gland detect the circulating ACTH and respond by releasing the hormone hydrocortisone into the blood stream. Motor nerve ends communicate in a similar manner with the effector cells that they innervate and control. In these chemical information transmission systems, there are three essential parts: (1) the biosynthesis, storage, and release of the transmitter or hormone, (2) the environment into which the transmitter is released in order to get to the effector cells, and (3) the receiving portion of the effector, the receptor that detects the transmitter and initiates some characteristic response. For the autonomic nervous system this process was foreseen by Elliott and Dale at the turn of the century. In the 1920s the chemical substance acetylcholine was shown by the Nobel laureate Otto Loewe to be one of the motor nervous system transmitters. At first, epinephrine was thought to be the adrenergic transmitter; yet it did not quite fit. Euler proposed norepinephrine as the transmitter. Although he also won the Nobel Prize, some of his ideas required modification. The present essay is concerned in general with the adrenergic transmission system, and in particular with the adrenergic receptive mechanism. When I first started teaching pharmacology, the following terms were regarded as almost synonymous: sympathetic, adrenergic, vasoconstriction, pressor, and decongestant. Chemists made new compounds structurally related to epinephrine, and pharmacologists tested them for blood vessel constricting effects. If the drug raised the blood pressure

Evidence for the Direct Effect of Adrenergic Drugs on the Cerebral Vascular Bed of the Unanesthetized Goat

Abstract: Despite considerable research, the question of whether adrenergic drugs exert direct effects on the cerebral circulation has remained unresolved With the development of a method for monitoring continuously the entire blood flow to one hemisphere in the unanesthetized goat, we have been able to study this problem directly The effects of epinephrine, norepinephrine, and isoproterenol administered by close intra-arterial injection were investigated in 15 goats in which an electromagnetic flowmeter had been implanted previously on the internal maxillary artery, which, in this animal, provides the sole blood supply to a hemisphere Both epinephrine and norepinephrine (01 to 50 µg) produced dose-dependent reductions in cerebral blood flow, a decrease of 55 ± 3% (SEM) occurring with the highest dose Alpha receptor blockade of the ipsilateral hemisphere with phenoxybenzamine totally or partially abolished this cerebral vasoconstriction Isoproterenol (001 to 10 µg) produced dose-dependent increases in cerebral blood flow, an increment of 75 ± 6% occurring with the highest dose Beta blockade with propranolol totally or partially abolished the cerebral vasodilation induced by isoproterenol Thus, epinephrine, norepinephrine, and isoproterenol exert powerful direct effects on the cerebral circulation of the unanesthetized goat, and these effects appear to be mediated by alpha and beta receptors

Effects of L-dopa administration of the concentrations of dopa, dopamine and norepinephrine in various rat tissues.

Abstract: We have studied the effects of i.p. l-dopa on the concentrations of catechols in various rat tissues. Rats were killed at intervals after the last of 10 daily doses of l-dopa or its vehicle (0.05 N HCl); concentrations of dopa, dopamine and norepinephrine were measured in heart, lung, spleen, liver, kidney, striated muscle, stomach and adrenal glands. One hour after l-dopa administration, dopa was detectable in all tissues examined except liver; highest concentrations were found in muscle and spleen. Dopamine levels were also elevated in all tissues examined except lung. l-Dopa treatment caused small increases in norepinephrine concentrations of kidney, lung, muscle and liver; no change in spleen and stomach; and decreased levels in heart. Adrenal epinephrine levels were also depressed at 1, 3, 6 and 24 hours after the last l-dopa dose. Except for the adrenals, the changes in catecholamine levels in these tissues usually coincided with the presence of large amounts of dopa. Our data suggest that the major reservoir for free dopa after each dose of l-dopa is within skeletal muscle; in this sense, l-dopa behaves like any other aromatic l-amino acid. The capacity of a tissue to accumulate dopamine after l-dopa administration bears no obvious relationship to its normal catecholamine content and probably cannot be correlated with its density of sympathetic nerve endings or other cells that normally synthesize endogenous catecholamines.