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At least 19 recordsLinked to original sources
PubMed1979

Clinical comparison of dipivalyl epinephrine and epinephrine in the treatment of glaucoma.

Dipivalyl epinephrine, 0.1%, though slightly less effective in decreasing intraocular pressure, showed significantly fewer side effects than epinephrine hydrochloride, 2%. Seventeen patients with symmetrically increased intraocular pressures who completed a six-month double-masked crossover study showed a significant decrease in intraocular pressure averaging 23.7% for dipivalyl epinephrine over the entire study and 27.4% for epinephrine. In the first treatment period, dipivalyl epinephrine was slightly less effective than epinephrine. In the second treatment period, dipivalyl epinephrine was statistically less effective than epinephrine. Two of the original 25 patients were dropped from the study because of epinephrine allergy or intolerance, one had uncontrolled pressures with either drug, and five failed to maintain adequate follow-up. Complaints of side effects such as burning and irritation occurred much more frequently in eyes receiving epinephrine (24%) than dipivalyl epinephrine (3%). Mild mydriasis occurred with each drug, averaging +0.65 mm with dipivalyl epinephrine and +0.55 mm Hg with epinephrine. No effect on blood pressure or pulse rate was found for the two drugs.

Adult↗
PubMed1976

The glycolytic effect of 1-epinephrine and nor-epinephrine on the liver of the chick embryo.

The glycolytic effect of 1-epinephrine and nor-epinephrine administered in-ovo for two hours on the liver of the chick embryo is reported. 1-epinephrine was more glycolytic than nor-epinephrine throughout the study. The glycolytic effect of 1-epinephrine was dosage-dependent throughout the study while nor-epinephrine brought about dosage-dependent liver-glycogen-depletion only in the nine day embryo.

Animals↗
PubMed1975

Subsensitivity to epinephrine following the administration of epinephrine and ephedrine to normal individuals.

Cardiovascular and metabolic responses to exercise and consecutive epinephrine infusions 24 hours apart were measured in 7 normal individuals before and following a week's administration of ephedrine sulfate. There was evidence of less beta adrenergic response to the second control epinephrine infusion compared to the first control infusion, and the depression of the rise in blood lactate was significantly different. A week of ephedrine produced more profound depression of the beta adrenergic responses to epinephrine with significant differences in the rise in blood glucose and lactate, and the pulse and blood pressure responses. Furthermore, these same responses remained significantly altered when a second epinephrine infusion was performed 36 hours following the last dose of ephedrine. The alterations in the response to epinephrine induced by ephedrine are consistent with the concept of effector cell "subsensitivity," an adaptive response to prolonged excessive stimulation.

Analysis of Variance↗
PubMed1978

[Clinical studies conducted with a new epinephrine derivative for the treatment of glaucoma (Dipivalyl epinephrine)].

Dipivalyl epinephrine, an epinephrine derivative, has been developed to improve the pharmacokinetic properties of the compound. Our open-label investigation included the administration of dipivalyl epinephrine ophthalmic solution to the eyes of 33 patients with an open-angle glaucoma. Former topical medication of parasympathomimetic agents was continued. The 0.1% dipivalyl epinephrine treatment approximated the results obtained with 1% epinephrine borate or phenylephrine 5% in reducing the intraocular pressure.

Clinical Trials as Topic↗
PubMed1977

Correlation between increased bronchial responsiveness to histamine and diminished plasma cyclic adenosine monophosphate response after epinephrine in asthmatic children. Diminished plasma cyclic adenosine monophosphate response after epinephrine in moderate childhood asthma.

The respiratory threshold to histamine and the plasma cyclic adenosine monophosphate (AMP) every 5 min for 40 min after subcutaneous epinephrine were determined in 21 children with moderate bronchial asthma who were without symptoms at the time of study. There was a statistically significant correlation between a high respiratory sensitivity to histamine and a low plasma cyclic AMP response to epinephrine. The plasma cyclic AMP response was compared with that in 16 control subjects. The asthmatic patients had significantly diminished responses; the difference was greatest for the values 25 min after stimulation. This study supports the hypotheses that the bronchial hyperresponsiveness in asthma is due partly to a defective beta adrenergic system and that the defect is permanent, existing also during periods without symptoms or medication and in patients with moderate asthma.

Adolescent↗
PubMed1978

Effects of topical 1-epinephrine and dipivalyl epinephrine on intraocular pressure and pupil size in the normotensive and glaucomatous Beagle.

Dipivalyl epinephrine and l-epinephrine were evaluated in various concentrations in normotensive and glaucomatous Beagles. In higher concentrations, both drugs produced significant lowering of intraocular pressure. Mydriasis and some local irritation occurred. The hypotony after drug administration tended to be greater in glaucomatous than in normotensive Beagles. The glaucomatous Beagle may be a valuable biomedical model in the investigation of various pharmacologic substances.

Animals↗
PubMed1978

Ocular absorption and metabolism of topically applied epinephrine and a dipivalyl ester of epinephrine.

An analogue of epinephrine (EPI), dipivalyl epinephrine (DPE), has been found to reduce intraocular pressure (IOP) significantly at lower concentrations than EPI itself. In order to understand the reason for this increased activity, the ocular penetration, distribution, and metabolism of these two compounds were compared. About 10 times as much DPE as EPI was absorbed by rabbit eyes, with the cornea as the major repository for the increased amount of drug absorbed. Comparison of the partition coefficients of the two compounds showed DPE to be from 100 to 600 times as lipophilic as EPI. The radioactive materials found in the aqueous humor after treatment with either compound had the same mobility in a thin-layer chromatographic system. The data indicate that following the increased penetration of the lipophilic prodrug, DPE is hydrolyzed to EPI in the eye.

Absorption↗
PubMed1975

Hormone action at the membrane level. IV. Epinephrine binding to rat liver plasma membranes and rat epididymal fat cells.

[3-H]Epinephrine binding to isolated purified rat liver plasma membranes is a reversible process. An initial peak in binding occurs at about 15 min and a plateau occurs by 50 min. Optimal binding occurred at a membrane protein concentration of 125mug. Rat liver plasma membranes stored at-70 degrees C up to 4 weeks showed no difference in epinephrine binding capacity as compared to control fresh membranes. Epinephrine binding to liver plasma membranes was decreased by 79% by phospholipase A2 (phosphatide acylhydrolase EC 3.1.1.4), 81% by phospholipase C (phosphatidylcholine choline phosphohydrolase EC 3.1.4.3) and 59% by phospholipase D (phosphatidylcholine phosphatidohydrolase EC 3.1.4.4). Trypsin and pronase digestion of the membrane decreased epinephrine binding by 97 and 47% respectively. In the presence of 10-3M Mg-2+ ions, increasing concentrations of QTP decreased epinephrine binding to liver plasma membranes. A maximal effect was demonstrated with 10-5M GTP, representing an inhibition of 52% of the control. In a Mg-2+ -free system, epinephrine binding was unaffected by GTP. However, in a Mg-2+ -free system, increasing concentrations of ATP cause increasing inhibition of hormone binding. ATP at 10-3 M reduced epinephrine binding to 28% of the control. GRP (10-5 M) was shown to inhibit epinephrine uptake rather than epinephrine release from the membrane. [3-H]Epinephrine binding to isolated rat epididymal fat cells shows an initial peak within 5 min followed by a gradual rise which plateaus after 60 min. Epinephrine binding increased nearly linearly with increasing fat cell protein concentration (40-200 mug protein). GTP (10-5 M) and ATP (10-4 M) decreased epinephrine binding to rat epididymal fat cells by 41%. Nearly complete inhibition of binding was demonstrated with 10-2-10-3M ATP. Epinephrine analogs that contain two hydroxyl groups in the 3 and 4 position on the benzene ring act as inhibitors of [3-H]epinephrine binding to rat adipocytes. Alteration of the epinephrine side chain has relatively little influence on binding. Analogs in which one of the ring hydroxyl groups is missing or methylated are poor inhibitors of [3-H]epinephrine binding. Alpha-(phentolamine and phenoxybenzamine) and beta-(propranolol and dichorisoproterenol) adrenergic blocking agents were tested with respect to their ability to influence [3-H]epinephrine binding and their influence on epinephrine-stimulated lipolysis. Only dichloroisoproterenol significantly inhibited epinephrine binding (by 25%). The two beta-adrenergic blocking agents caused an inhibition of epinephrine-stimulated glycerol release, with propranolol being most effective. Phentolamine and phenoxybenzamine had no significant effect on the epinephrine stimulation of glycerol release by fat cells.

Adipose Tissue↗
PubMed1978

Change of coupling system of receptor-adenylate cyclase induced by epinephrine and GTP in plasma membranes of rat liver.

1. The binding of [3H]epinephrine to plasma membranes was affected (temporary release of bound epinephrine and characteristic retardation of epinephrine binding) not only by GTP but also by dGTP and guanylylimidodiphosphate, whereas the binding of [3H]dihydroalprenolol was not affected by GTP. GTP affected the binding of [3H]epinephrine in the presence of alpha-antagonists, but not in the presence of beta-antagonists, suggesting that the GTP effects are specific to beta-agonists and beta-receptors. 2. The half-maximal release of bound [3H]epinephrine was found at 8.8 . 10(-6) M GTP in the absence of ATP, whereas it was found at 1.6 . 10(-6) M GTP in the presence of 0.3 mM ATP in coincidence with the half-maximal activation of adenylate cyclase by GTP in the presence of 0.3 mM ATP (as measured at 30 s of incubation). 3. In the presence of 4 . 10(-5) M GTP, adenylate cyclase activity as measured at 30 s of incubation (State I) tended to increase with epinephrine concentration, showing no saturation tendency even at 1 . 10(-4) M epinephrine. The activity of State II, which is established at 4 min of incubation, was much lower than that of State I but was found to reach a plateau as the epinephrine concentration increased, showing half-maximal activation at an epinephrine concentration between 2 . 10(-6) and 2 . 10(-7) M. 4. Apparent kinetic parameters (Km and V) for State I as assayed at 30 s of incubation suggested that GTP alone may increase V slightly, whereas epinephrine plus GTP may increase the V to a further extent and simultaneously decrease the Km. 5. Adenylate cyclase of plasma membranes pretreated with epinephrine plus GTP was stimulated by GTP alone similarly to untreated membranes, but it was no longer responsive to the synergistic activation by epinephrine plus GTP. Accordingly, the binding of [3H]epinephrine to the pretreated plasma membranes was no longer affected by GTP. 6. The results of the present study seem to support the idea that the most active and coherently coupling state (State I) of the beta-receptor-adenylate cyclase system generated in the presence of epinephrine plus GTP is very labile and degenerates before reaching equilibrium. In turn, State II, in which the coherently coupling mechanism is largely impaired, seems to be established in due time. The characteristic biphasic kinetics of [3H]epinephrine binding in the presence of GTP seem to be related to the above change occurring in the beta-receptor-adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1979

Synergistic interactions of physiologic increments of glucagon, epinephrine, and cortisol in the dog: a model for stress-induced hyperglycemia.

To evaluate the role of anti-insulin hormone actions and interactions in the pathogenesis of stress-induced hyperglycemia, the counterregulatory hormones, glucagon, epinephrine, and cortisol were infused alone as well as in double and triple combinations into normal conscious dogs in doses that were designed to simulate changes observed in severe stress. Infusion of glucagon, epinephrine, or cortisol alone produced only mild or insignificant elevations in plasma glucose concentration. In contrast, the rise in plasma glucose produced by combined infusion of any two counterregulatory hormones was 50-215% greater (P < 0.005-0.001) than the sum of the respective individual infusions. Furthermore, when all three hormones were infused simultaneously, the increment in plasma glucose concentration (144+/-2 mg/dl) was two- to fourfold greater than the sum of the responses to the individual hormone infusions or the sum of any combination of double plus single hormone infusion (P < 0.001). Infusion of glucagon or epinephrine alone resulted in a transient rise in glucose production (as measured by [3-(3)H]glucose). While glucagon infusion was accompanied by a rise in glucose clearance, with epinephrine there was a sustained, 20% fall in glucose clearance. When epinephrine was infused together with glucagon, the rise in glucose production was additive, albeit transient. However, the inhibitory effect of epinephrine on glucose clearance predominated, thereby accounting for the exaggerated glycemic response to combined infusion of glucagon and epinephrine. Although infusion of cortisol alone had no effect on glucose production, the addition of cortisol markedly accentuated hyperglycemia produced by glucagon and(or) epinephrine primarily by sustaining the increases in glucose production produced by these hormones. The combined hormonal infusions had no effect on beta-hydroxybutyrate concentration. It is concluded that (a) physiologic increments in glucagon, epinephrine, and cortisol interact synergistically in the normal dog so as to rapidly produce marked fasting hyperglycemia; (b) in this interaction, epinephrine enhances glucagon-stimulated glucose output and interferes with glucose uptake while cortisol sustains elevations in glucose production produced by epinephrine and glucagon; and (c) these data indicate that changes in glucose metabolism in circumstances in which several counterregulatory hormones are elevated (e.g., "stress hyperglycemia") are a consequence of synergistic interactions among these hormones.

Animals↗
PubMed1978

Epinephrine-induced elevation of guanosine 3':5'-cyclic monophosphate in isolated fat cells of rat.

The effects of epinephrine (as low as 0.1 muM) on guanosine 3':5'-cyclic monophosphate (cGMP) and adenosine 3':5'-cyclic monophosphate (cAMP) in isolated fat cells were examined. Epinephrine increased both cGMP and cAMP levels, with the elevation of cAMP preceding the rise of cGMP. Maximal elevation was obtained with 1 muM epinephrine for each nucleotide. The increase in content of cGMP and cAMP due to epinephrine was completely blocked by a beta-adrenergic antagonist (5 muM propranolol). Phentolamine (10-100 muM), an alpha-adrenergic antagonist, enhanced the response to epinephrine resulting in elevation of cAMP levels, whereas a high concentration (100 muM) of phentolamine suppressed the elevation of cGMP. The ability of epinephrine to increase cGMP and cAMP levels was markedly diminished by "feedback regulator" partially purified from the incubation mixtures of isolated fat cells exposed to epinephrine [Ho, R.J. & Sutherland, E. W. (1971) J. Biol. Chem. 246, 6822-6827], whereas an increase in cGMP, but not cAMP, levels was observed in isolated fat cells incubated with "feedback regulator" alone (without epinephrine). These observations suggest the possibility that the epinephrine-induced elevation of cGMP levels in isolated fat cells might be mediated by an increase in formation of intracellular "feedback regulator" due to an elevation of cAMP by epinephrine.

Adipose Tissue↗
PubMed1979

Differential effects of epinephrine on glucose production and disposal in man.

Normal subjects were infused 1) with epinephrine (50 ng/(kg.min)) for 180 min followed by epinephrine plus glucagon (3 ng/(kg.min)) for 60 min after which the epinephrine infusion rate was increased (125 ng/(kg.min)) or 2) with epinephrine plus somatostatin (500 microgram/h) for 180 min. Epinephrine increased glucose production and plasma glucagon transiently but caused persistent suppression of glucose clearance and sustained hyperglycemia (despite increased plasma insulin and gluconeogenic substrates); glucose production increased again on addition of glucagon and on increasing the epinephrine infusion rate. During epinephrine plus somatostatin, glucose production still increased transiently, but further suppression of glucose clearance caused more marked hyperglycemia. In conclusion, 1) in man hyperepinephrinemia within the physiological range caused sustained suppression of glucose clearance but only a transient increase in glucose production; 2) this transient hepatic response a) was not due to glycogen or substrate depletion, b) occurred without changes in plasma glucagon or insulin, c) was specific for epinephrine but permitted subsequent responses to changes in plasma epinephrine; 3) epinephrine can serve as a physiological regulator of glucose homeostasis in man both by increasing glucose production and by decreasing glucose clearance.

Adult↗
PubMed1978

L-tryptophan inhibition of epinephrine-stimulated phosphorylase activity in vivo and in vitro.

The administration of L-tryptophan prevented the normal rise in blood sugar concentration that usually follows the injection of epinephrine into rats. Of the several possible mechanisms by which tryptophan could inhibit epinephrine-induced hyperglycemia, one might be that tryptophan prevented the activation of the enzyme, phosphorylase, which is an indirect result of epinephrine action on the liver. This report presents evidence supporting this hypothesis: (1) The injection of tryptophan (2.5 mM/kg) prevented epinephrine-induced glycogenolysis in the liver of rats by 100%. (2) The time courses of epinephrine-induced hyperglycemia and activation of phosphorylase in liver were nearly identical. (3) The injection of tryptophan completely inhibited (100%) the epinephrine-induced phosphorylase activation. (4) The addition of tryptophan in vitro completely inhibited (100%) the epinephrine-induced activation of phosphorylase. (5) Tryptophan inhibition of epinephrine-induced hyperglycemia occurs immediately after tryptophan administration. (6) The addition of cyclic AMP blocked the tryptophan inhibition of epinephrine-induced phosphorylase activation. This evidence suggests that tryptophan may inhibit epinephrine-induced hyperglycemia in rats by preventing the activation of liver phosphorylase.

Animals↗
PubMed1978

The regulation of skeletal muscle alanine and glutamine formation and release in experimental chronic uremia in the rat: subsensitivity of adenylate cyclase and amino acid release to epinephrine and serotonin.

The mechanism of the increased alanine and glutamine formation and release from skeletal muscle in experimental uremia was investigated using epitrochlearis preparations from control and chronically uremic rats. In uremic muscle, insensitivity to epinephrine or serotonin suppression of alanine and glutamine release was observed. With control muscles, 1 nm or greater, epinephrine inhibited alanine and glutamine release, whereas with uremic muscles, epinephrine concentrations <1 muM did not alter amino acid release. Decreased alanine and glutamine release with 1 nM serotonin was observed in control muscles, but no inhibition was observed with concentrations <1 muM in uremic muscle. Muscle amino acid levels were the same in control and uremic muscles in the presence or absence of epinephrine or serotonin. The reutilization of released alanine by protein synthesis or oxidation to CO(2) was not differentially affected by epinephrine in uremic muscles as compared with control muscle. Dibutyryl-cAMP inhibited amino acid release equally in uremic and control muscles. Epinephrine or serotonin increased cAMP levels two- to four-fold or more in control than in uremic muscle. Basal- and fluoride-stimulated adenylate cyclase activities were equal in uremic and control muscle homogenates and in membrane fractions, but 10 muM epinephrine-stimulated adenylate cyclase was reduced 30-60% with uremia. At any concentration of epinephrine (0.001-100 muM), the stimulation of membrane adenylate cyclase activity was one- to twofold greater with control membranes than with uremic muscle membranes. With either control or uremic muscle, peak adenylate cyclase activity was observed at 1 muM epinephrine. These data indicate that skeletal muscle in chronic uremia acquires an insensitivity to the metabolic action of epinephrine or serotonin. This insensitivity may be attributable in part to the diminished increments in muscle cAMP levels produced by adrenergic and serotonergic agonists. The decreased cAMP levels may derive in turn from a decreased activity or subsensitization of the agonist-stimulated adenylate cyclase in uremic muscle.

Adenylyl Cyclases↗
PubMed1978

(+/-)-[3H]Epinephrine and (-)[3H]dihydroalprenolol binding to beta1- and beta2-noradrenergic receptors in brain, heart, and lung membranes.

(+/-)-[3H]Epinephrine binds to beta-receptors in calf cerebellar and rat lung membranes in the presence of 1.0 mM pyrocatechol and 1.0 microM phentolamine, with dissociation constants at 4 degrees C of 11 nM and 24 nM, respectively. (+/-)-[3H]Epinephrine associates to equilibrium within 20 min in both tissues, and over 50% of the binding is rapidly dissociable. Inhibition of binding by agonists and antagonists is highly stereoselective, and the structure-activity relationships of adrenergic agents in inhibiting (+/-)-[3H]epinephrine binding suggest an interaction with beta2 type noradrenergic receptors. (-)-Isoproterenol has an apparent Ki of 2 nM, (-)-epinephrine is 1.5 to 3 times weaker, and (-)-norepinephrine is 30 to 60 times weaker. Salbutamol and terbutaline, selective beta2-agonists, are potent inhibitors of binding, as are several nonspecific antagonists. Properties of the sites labeled by (+/-)-[3H]epinephrine in calf cerebellum and rat lung are closely similar. (-)-[3H]Dihydroalprenolol binding in calf cerebellum and rat lung also shows beta2 characteristics. Antagonists have similar potencies in inhibiting (-)-[3H]dihydroalprenolol and (+/-)-[3H]epinephrine binding in both tissues, but agonists are in general more potent inhibitors of (+/-)-[3H]epinephrine. Sodium and lithium selectively lower the affinity of (+/-)-[3H]epinephrine at its binding sites and the affinities of agonists, but not antagonists, at the (-)-[3H]dihydroalprenolol site. Specific (+/-)-[3H]epinephrine binding was not detectable in calf cortex and rat heart, where (-)-[3H]dihydroalprenolol binding suggests a beta1-receptor. A physiological significance of (+/-)-[3H]epinephrine binding is suggested by the strong correlation for agonists and antagonists between affinities in inhibiting binding, and in stimulating or inhibiting a beta-receptor-coupled adenylate cyclase in frog erythrocytes.

Alprenolol↗
PubMed1978

Ocular hypotensive efficacy of topical epinephrine in normotensive and hypertensive rabbits: continuous drug delivery vs eyedrops.

The ocular hypotensive efficacy of continuously delivered epinephrine is compared to that of pulsed doses provided by eyedrops in both normotensive and hypertensive rabbit eyes. In normotensive eyes, 2 microgram/hr and 4 microgram/hr epinephrine delivered into the tear film continuously for 12 hours reduces intraocular pressure as well as eyedrop pulses of 0.5% epinephrine hydrochloride or 2% epinephrine bitartrate (doses of 500 and 1100 microgram, respectively). Ocular hypertension induced by an intragastric water load in rabbits is significantly inhibited by continuous delivery of epinephrine at the rates of 3 or 6 microgram/hr, or by 2% epinephrine bitartrate (1% free base) eyedrops. Epinephrine delivered continuously at rates of 2-6 microgram/hr for 6 to 12 hours (12-72 microgram total) has hypotensive efficacy equivalent to 15 to 40 times as much epinephrine applied once in eyedrops. Epinephrine bitartrate eyedrops reduce tear film pH well below normal. Continuous delivery of epinephrine bitartrate does not reduce tear film pH below normal levels.

Administration, Topical↗