Exogenous Epinephrine Research Articles

Evidence for the existence of distinct biophases for alpha- and beta-adrenoceptors in the vascular tissue.

In dog mesenteric artery and saphenous vein strips, the inhibition of neuronal uptake by cocaine increased the potency of exogenous adrenaline for alpha-effects and did not change its potency for beta-effects, whereas inhibition of catechol-O-methyltransferase (COMT) by U-0521 enhanced the beta-effects more than the alpha-ones. On the other hand, cocaine prolonged the duration of adrenaline-induced contraction more than it prolonged the adrenaline-induced relaxation, while U-0521 prolonged the duration of the relaxation much more than that of the contraction. Cocaine and U-0521 also caused differential influences on alpha- and beta-effects caused by endogenous adrenaline, i.e., on alpha- and beta-effects caused by electrical stimulation of strips previously preloaded with adrenaline. It was also observed that the time elapsing between the beginning of the electrical stimulation and the onset of the response (latency) is longer for beta- than for alpha-responses when both are evoked by electrical stimulation. Furthermore, in these strips, alpha-adrenoceptor blocking agents more easily antagonized the contractions caused by exogenous adrenaline than contractions caused by electrical stimulation, whereas propranolol antagonized beta-responses caused by exogenous adrenaline as easily as beta-responses caused by electrical stimulation. It is concluded that there is a biophase for alpha-adrenoceptors, which is under greater influence of neuronal uptake, and another for beta-adrenoceptors, which is under greater influence of COMT activity.

Two different biophases for adrenaline released by electrical stimulation or tyramine from the sympathetic nerve endings of the dog saphenous vein.

To study the distribution of alpha- and beta-adrenoceptors dog saphenous vein strips were electrically stimulated (2ms, 30 V, 0.25--20 Hz). The strips either had spontaneous tone (contraction experiments) or were contracted by 0.28 microM prostaglandin F2 alpha in the presence of 7 microM phentolamine (relaxation experiments). In strips without preloading or in strips preloaded with (--)-noradrenaline alpha-adrenoceptor-mediated excitatory responses were readily evoked (contraction experiments) but not beta-adrenoceptor-mediated inhibitory responses (relaxation experiments). In strips preloaded with (--)-adrenaline both alpha-(contraction experiments) and beta-effects (relaxation experiments were readily elicited by electrical stimulation and by tyramine. Thus, strips preloaded with (--)-adrenaline were used to compare alpha- with beta-effects. In these strips the latency between the beginning of the electrical stimulation and the onset of the response was longer for beta- than for alpha-responses. The same applies to responses to exogenous (--)-adrenaline. However, the ratio "latency for beta-/latency for alpha-responses" was 3.6 +/- 0.2 (n = 8) for responses to electrical stimulation and 1.8 +/- 0.1 (n = 12) for responses to (--)-adrenaline (P less than 0.001). Cocaine (12 microM) enhanced the alpha-effect elicited by electrical stimulation 2.8 +/- 0.2 (n = 7) times but did not change the beta-effect, whereas U-0521 (50 microM) enhanced the beta-effect 3.4 +/- 0.2 (n = 8) times without changing the alpha-effect. In strips preloaded with (--)-adrenaline also tyramine caused concentration-dependent beta-responses (relaxation experiments). The concentration of phentolamine and prazosin required to inhibit contractions caused by electrical stimulation were about 5--7 times higher than those required to inhibit contractions caused by exogenous adrenaline or noradrenaline, whereas propranolol was equipotent in reducing beta-responses to adrenaline released by electrical stimulation and to exogenous adrenaline. Our results strongly support the view that alpha-adrenoceptors are in close contract with the nerve endings and beta-adrenoceptors are in close proximity of COMT in a vessel with the nerve endings evenly distributed throughout the media.

Chemical sympathectomy and exogenous epinephrine regulate the rat mesenteric artery alpha-adrenergic receptor

Chemical sympathectomy and exogenous epinephrine regulate the rat mesenteric artery alpha-adrenergic receptor

Anaphylaxis and plasma catecholamines

The concentrations of plasma catecholamines, cyclic AMP glucose, lactate and glycerol were measured in a high IgE-producing strain of Hooded-Lister rats. Immobilization caused an increase in the levels of plasma catecholamines, especially adrenalin. In rats immunized against egg albumin the rise was higher than in non-sensitized controls, possibly indicating a relationship between sympatho-adrenal activity and serum IgE levels. Anaphylaxis caused by egg albumin induced a rapid and huge increase of plasma catecholamines especially adrenaline. The increase of plasma catecholamines was more rapid and pronounced in awake than in anesthetized rats. The plasma levels of adrenaline following anaphylaxis were larger than those obtained following administration of 5 μg adrenaline i.v. Plasma cyclic AMP, glucose and lactate levels were markedly enhanced already before the injection of antigen. On the other hand, glycerol levels were initially low but increased in parallel to the rise in plasma catecholamines. Administration of dextran to Sprague-Dawley rats induced an anaphylactoid reaction and high plasma levels of adrenaline and noradrenaline. The results indicate a massive sympatho-adrenal activation in anaphylactic and anaphylactoid shock and the use of exogenous adrenaline may cause little additional activation of adrenoceptors.

Role of?-adrenoreception in realization of glycogenolytic and lipolytic effects of an excess of thyroid hormones

Experiments on rats showed that chronic administration of the β-adrenoblocker propranolol in doses blocking glycogenolytic and lipolytic effects of exogenous adrenalin, does not prevent the fall in the glycogen level in the liver and myocardium and the rise in the serum free fatty acid level and in the lipolytic activity of adipose tissue in vitro arising under the influence of large doses of thyroxine.

Glucagon and Catecholamine Secretion During Hypoglycemia in Normal and Diabetic Man

To examine the role of catecholamines in glucopenia-induced glucagon secretion, urinary epinephrine and norepinephrine and plasma immunoreactive glucagon (IRG) were measured during insulin-induced hypoglycemia in normal and insulin-dependent diabetic-man. Despite equivalent levels of hypoglycemia the mean plasma IRG increment in diabetes was only 15% of normals. The increases in epinephrine and norepinephrine were comparable in diabetics and normals; thus, the blunted response in plasma IRG to the stimulus of low blood sugar in diabetics cannot be explained by a generalized defect in catecholamine secretion. It is suggested that an alpha-cell glucoreceptor defect may account for the abnormal response to glucopenia in diabetics. To evaluate the possibility that impaired sensitivity to circulating catecholamines could explain the alpha cell dysfunction in diabetics, exogenous epinephrine was infused in normals and insulin-dependent diabetics. Elevated plasma IRG during epinephrine infusion was observed in only 50% of normals. The diabetics were hyperresponsive; mean increment in plasma IRG 3 times that of normals. The data demonstrate enhanced rather than impaired sensitivity to catecholamines in diabetes mellitus.

Pharmacologic blockade of the effect of histamine on lung cyclic AMP levels in normal and pertussis-vaccinated mice

The pertussis-mediated increase in the ability of histamine to stimulate murine pulmonary cAMP accumulation was shown to appear as early as 1 day, peak by 4 days, and return to control values by 10 days after vaccination. This effect was inhibited by tripelennamine, propranolol and high doses of atropine, but not by prednisone, indomethacin, metiamide or guanethidine. Pulmonary cAMP accumulation after exogenous epinephrine administration was marked and equivalent between control and vaccinated mice. Histologic examination showed a marked polymorphonuclear leucocyte accumulation in the lungs of pertussis-vaccinated mice that followed a temporal course of development comparable to the cAMP abnormality. These data are interpreted to mean that the increase in cAMP after histamine challenge is not responsible for death and may in fact represent a compensatory effort to prevent death. Further, this phenomenon is likely to be related to the accumulating leucocytes.

Effect of giving insulin and adrenalin alternately on changes in the level of blood glucose in chickens of different breeds

Differences in reaction to exogenous insulin and adrenalin were studied among chickens of 'Leghorn', 'White Rock' and 'Rhode Island Red' breeds, using level of blood glucose as indicator of the reaction to hormones. It was found that: 1.) The physiological quantity of glucose in blood in chickens of the three breeds ranged from 157 to 194 mg %. 2.) The reaction of chickens to insulin and adrenalin given alternately, measured by changes of blood glucose, differed according to the breed. The smallest reaction to hormones was in 'Leghorn', the biggest in 'White Rock'. 3.) The chickens of 'Leghorn' and 'Rhode Island Red' breeds, as well as 'Leghorn' and 'White Rock' breeds, differed significantly in maximal glucose level after adrenalin, 4.) The correlation between the normal quantity of blood glucose and the body weight of birds appeared highly significant in cockerels of all three races combined.

Effect of arousal conditions during reinstatement treatment upon learned fear in young rats.

The role of shock and epinephrine-induced arousal in the reinstatement of learned fear was investigated in young rats. Groups of 21-day-old rats received classical fear conditioning to the black compartment of a black/white avoidance box. One week later each rat received one of a number of reinstatement conditions consisting of exposure to the apparatus cues, non-contingent foot shock, or exogenous epinephrine injections, alone or in combination. Subjects were tested for retention of spatial avoidance behavior 1 week following reinstatement. Reinstatement with epinephrine and exposure to the training contextual cues, non-contingent foot shock followed by cue exposure, and non-contingent foot shock alone were all found to be as effective as shock administered in conjunction with the cues (the same conditions as those prevailing during training). Cue exposure alone and epinephrine injections without the training cues were ineffective reinstating agents.

An evaluation of the cardiac sensitizing potential of a fabric protector in aerosol form, containing 1,1,1-trichloroethane

Experiments were designed to assess the cardiac sensitizing potential of Scotchgard Brand Fabric Protector FC-4101 [which contains 1,1,1-trichloroethane (TCE)] under simulated misuse conditions. Beagle dogs were prepared for telemetric monitoring of their electrocardiogram (ECG) and placed in a 290-liter chamber. They were observed for possible effects of inhalation exposure to FC-4101, alone or in combination with intravenous epinephrine (8 and 16 μg/kg) and/or stress induced by a 2-sec blast from an air horn. The effects of inhaled pure TCE with Freon 12 propellant were also investigated. Changes in heart rate consisted of a bradycardia (presumably of reflex origin) due to epinephrine and stress, and a mild tachycardia following exposure to FC-4101 producing a concentration of 5000 ppm TCE in air. Following exposure to FC-4101 producing a concentration of 10,000 ppm TCE in air and following exposure to concentrations of 5000 ppm TCE in air and 10,000 ppm TCE in air with Freon 12 propellant, no tachycardia occurred. Inhalation of FC-4101 did not act synergistically with exogenous epinephrine (8 μg/kg) or endogenous epinephrine released in response to stress to induce cardiac arrhythmias. The arrhythmias induced by 16 μg/kg of epinephrine and stress were not intensified by the concurrent inhalation of FC-4101, 5000 ppm TCE. It is concluded that the simulated misuse conditions utilized in this study, FC-4101 and pure TCE with Freon 12 propellant did not cause cardiac sensitization.

LOCAL ANESTHESIA IN OTOLARYNGOLOGY A RE-EVALUATION

Almost a half century following attempts to ban its use, cocaine remains at the pinnacle of topical anesthesia in otolaryngology. To understand how nonaddicting synthetic substitutes such as procaine, dibucaine, tetracaine and lidocaine have not totally supplanted cocaine, requires an in-depth analysis of its unique pharmological properties, untoward effects and potential substitutes. Almost all of the reported cocaine deaths occurred after subcutaneous injection; when used topically, cocaine's toxicity has been confined to an occasional reaction. Certain variables under physician control may be manipulated to reduce the chance of reaction to a minimum. For example, intermittent application of a particular dosage results in lower blood levels, and allowing sufficient time between doses reduces the amount necessary to obtain the desired anesthesia. If total dosage is kept below 200 mg there are few reactions. A singular advantage of cocaine over other topical anesthetics is its inherent ability to cause vasoconstriction, thus retarding its own absorption. The addition of a topical vasoconstrictor such as epinephrine is thus redundant, and may actually be harmful as cocaine sensitizes the patient to exogenous epinephrine. Finally, the usual preoperative dosages of barbiturates are entirely inadequate to prevent or treat cocaine reactions. Why, then, have synthetic local anesthetics not replaced cocaine? Inherent differences in topical effectiveness, duration of anesthesia and toxicity provide the answer. Of other local anesthetics possessing topical effectiveness tetracaine is about six times more toxic than cocaine. Dibucaine is as toxic as tetracaine, and lidocaine, while relatively nontoxic, provides only a 15 minute duration of topical anesthesia. A review of cocaine and its potential substitutes thus leads to the conclusion that cocaine is still a vital and necessary instrument in the otolaryngologist's armamentarium, singularly providing excellent topical anesthesia of usable duration, vasoconstriction, and shrinkage of mucous membranes, all with a quite acceptable margin of safety.

Influence of hemorrhage on adrenal secretion, blood glucose and serum insulin in the awake pig.

A study was performed to quantitate the adrenal medullary and cortical response to hemorrhage in awake animals bled at different rates and to relate these responses to simultaneous changes in blood glucose and serum insulin. A series of awake pigs were bled either slowly or rapidly of 30% of their calculated blood volume. Infusions of exogenous epinephrine were performed in an additional series of unbled animals and infusions of epinephrine plus hydrocortisone were similarly performed in an additonal series. Increase in blood glucose and epinephrine secretion rate following hemorrhage were found to be significantly dependent upon the rate of initial hemorrhage. Cortisol secretion was found to rise significantly during and following hemorrhage in both rapidly and slowly bled animals. Serum insulin levels remained at baseline levels during shock, despite the presence of significant hyperglycemia. In unbled animals infused with epinephrine at rates comparable to those measured in shock, elevations in blood glucose were markedly lower, shifting to the right of the dose-response curve during hemorrhage. Simultaneous infusions of cortisol and epinephrine resulted in a dose-response curve which did not differ significantly from that following infusion of epinephrine alone.

The effects of hypoxia on blood sugar levels and on the endocrine pancreas, interrenal, and chromaffin tissues of the lamprey, Lampetra fluviatilis (L.)

Hyperglycaemia has been demonstrated in river lampreys ( Lampetra fluviatilis) subjected to a reduced oxygen tension of 20% air saturation for periods of up to 14 days. Maximum blood sugar values were recorded after 7 days hypoxia (mean 92.1 ± 30.9 mg/100 ml) compared with a mean value of 44.5 ± 2.3 mg/100 ml for controls. Similar tests over 7 days on hypophy-sectomised animals failed to show significant changes in glycaemia. Marked hyperglycaemia was also observed after injections of adrenalin. No significant changes in liver glycogen concentrations occurred after periods of hypoxia. After 7 days hypoxia, slight vacuolisation occurred in the islet tissue of only a few of the experimental animals, but at 14 days all showed extensive hydropic degeneration affecting the light cells. Equally severe lesions were also seen in all the hypophysectomised animals after only 7 days hypoxia, but did not appear in any of the control series that had been hypophysectomised 1–2 months previously and maintained under normal oxygen tensions. Vacuolisation also occurred in only a small proportion of the animals subjected to daily glucose loading over a 8–11 day period, but was not seen after shorter periods of adrenalin administration. Measurements of nuclear diameters of islet cells showed marked increases in nuclear volumes after 24 hr of glucose loading or after adrenalin injections, but not after hypoxia treatment. Aldehyde-fuchsinophil granulation of the dark cords was reduced after glucose loading, but was still retained by the cells of the dark cords after hypoxia treatment. Marked differences have been recorded in the mean nuclear volumes of light and dark cells and, although both respond to glucose loading, the increases in nuclear size tended to be greater in the light cells. Stimulation of mitotic division has been seen in hypoxia, glucose loading, and especially after exogenous adrenalin treatment, but is apparently confined to light cell lobules. The histological observations and nuclear measurements are consistent with the view that both light and dark cells may be regarded as developmental stages in a single β-cell-type. Increased nuclear volumes were recorded in chromaffin tissue in the earlier stages of hypoxia and after glucose loading, but were not observed in hypophysectomised animals. No nuclear enlargement was seen in the interrenal tissue under hypoxic conditions, but a slight increase in mean volumes occurred after glucose loading. In adrenalin injected animals, nuclear hypertrophy was very pronounced, probably accompanied by hyperplasia. Although hypophysectomy inhibits the hyperglycaemic and behavioural responses to hypoxia, it does not prevent the hydropic degeneration of the islet tissue. While there is some evidence for a pituitary influence on chromaffin tissue activity, it remains in doubt whether this is mediated through glucocorticoid activity of the interrenal tissue.

The influence of substances changing the intracellular concentration of cyclic adenosine 3?5?-monophosphate on interferon synthesis in chick embryo cell culture

The influence of cyclic 3'5'-adenosine monophosphate (cAMP), adrenalin and theophylline on interferon synthesis induced by influenza B virus (Lee strain) in chick embryo cell cultures was studied. In 5-day-old cell culture, theophylline was shown to enhance the inhibiting effect of exogenous cAMP and adrenalin on interferon synthesis and in 1-day-old culture, on the contrary, to enhance interferon production whereas adrenaline under these conditions had no effect on interferon synthesis at all. In 5-day-old cultures the activity of adrenalin and theophylline was manifested when they were added to the maintenance medium not later than 4 hours postinfection, and was not associated with the influence on interferon inducer adsorption on to cells or on virus multiplication in sensitive systems. Treatment of cells with these substances had no effect on interferon release from the cells. In the concentration used, adrenalin and theophylline exerted no cytotoxic effect. Theophylline inhibited incorporation of 3H-uridine and 14C-leucine into the acid insoluble fraction of the infected cells in 1-day-old cultures, while in 5-day-old cultures this was observed only when adrenalin and theophylline were used together. It is suggested that endogenous cAMP is essential for control of interferon synthesis and that different cAMP levels in cells of different ages may be one of the causes of the varying potency for interferon synthesis in young and old cell cultures.

Acute and chronic effects of nicotine on synthesis and storage of catecholamines in the rat adrenal medulla

Nicotine (1 mg/kg or 10 mg/kg) was administered twice daily to rats and the adrenals were analyzed for catecholamines (CA), tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and for the ability of isolated storage vesicles to incorporate 3H-epinephrine. Four hours after the first dose, there were few alterations at 1 mg/kg, but at 10 mg/kg, there was 30% depletion of CA, accompanied by a slight reduction in DBH and a decline in the number of functional vesicles (determined by uptake). Chronic administration of either dose produced elevations in both TH and DBH; at 10 mg/kg, CA levels and functional vesicles continued to decline for at least 4 days, but were at or above normal after 2 weeks of treatment. At 1 mg/kg, CA levels were never significantly below normal, and were elevated after 2 weeks. After 2 weeks at either dose level, a defect appeared in the abilities of vesicles to incorporate exogenous epinephrine relative to endogeneous CA content; this alteration also appeared if nicotine was discontinued. These data suggest that chronic nicotine administration can produce long-term alterations in CA release, synthesis and storage, and that these alterations can occur even at a dose which has little or no acute effect.

Dissociations between changes in myocardial cyclic adenosine monophosphate and contractility.

The relationship between changes in the myocardial concentration of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and cardiac contractility was studied in guinea pig and rat myocardium. When isolated perfused guinea pig heart were perfused with 10-5-M papaverine, a potent inhibitor of cyclic AMP phosphodiesterase activity, myocardial cyclic AMP concentration increased significantly from 1.7 plus and minus 0.2 (SE) pmoles/mg protein (N equal 12) to 3.3 plus and minus 0.2 pmoles/mg protein (N equal 12), and the percent of phosphorylase aual 6) (P less than 0.01). However, perfusion with papaverine had no effect on contractility in the absence or the presence of exogenous epinephrine. In perfused rat hearts, 10-5 M glucagon increased myocardial cyclic AMP concentration from 1.5 plus and minus 0.1 pmoles/mg protein (N equal 12) to 2.6 plus and minus 0.1 pmoles/mg protein (N equal 12) (P less than 0.001). In contrast, cyclic AMP levels did not increase detectably in guinea pig heart perfused with glucagon. Glucagon increased adenylate cyclase activity more than twofold in rat myocardial broken cell preparations but failed to stimulate the enzyme in preparations from guinea pigs. Despite these differences, the positive inotropic effects of glucagon on rat and guinea pig hearts were very similar over a wide dose range. Thus, with both papaverine and glucagon, changes in cardiac contractility were dissociated from stimulation of adenylate cyclase activity, increases in myocardial cyclic AMP levels, and conversion of phosphorylase b to phosphorylase a in perfused hearts.

Local anesthesia in otolaryngology. A re-evaluation.

Almost a half century following attempts to ban its use, cocaine remains at the pinnacle of topical anesthesia in otolaryngology. To understand how nonaddicting synthetic substitutes such as procaine, dibucaine, tetracaine and lidocaine have not totally supplanted cocaine, requires an in-depth analysis of its unique pharmological properties, untoward effects and potential substitutes. Almost all of the reported cocaine deaths occurred after subcutaneous injection; when used topically, cocaine's toxicity has been confined to an occasional reaction. Certain variables under physician control may be manipulated to reduce the chance of reaction to a minimum. For example, intermittent application of a particular dosage results in lower blood levels, and allowing sufficient time between doses reduces the amount necessary to obtain the desired anesthesia. If total dosage is kept below 200 mg there are few reactions. A singular advantage of cocaine over other topical anesthetics is its inherent ability to cause vasoconstriction, thus retarding its own absorption. The addition of a topical vasoconstrictor such as epinephrine is thus redundant, and may actually be harmful as cocaine sensitizes the patient to exogenous epinephrine. Finally, the usual preoperative dosages of barbiturates are entirely inadequate to prevent or treat cocaine reactions. Why, then, have synthetic local anesthetics not replaced cocaine? Inherent differences in topical effectiveness, duration of anesthesia and toxicity provide the answer. Of other local anesthetics possessing topical effectiveness tetracaine is about six times more toxic than cocaine. Dibucaine is as toxic as tetracaine, and lidocaine, while relatively nontoxic, provides only a 15 minute duration of topical anesthesia. A review of cocaine and its potential substitutes thus leads to the conclusion that cocaine is still a vital and necessary instrument in the otolaryngologist's armamentarium, singularly providing excellent topical anesthesia of usable duration, vasoconstriction, and shrinkage of mucous membranes, all with a quite acceptable margin of safety.

Mechanisms of hyperglycemic response to chlorpromazine administered into lateral ventricle in rats—II: Secretion of epinephrine from adrenal medulla

An injection of chlorpromazine(CPZ) into the lateral ventricle caused hyperglycemia in intact rats, but not in adrenal-demedullated rats. However, the hyperglycemic response to CPZ was not blocked by hypophysectomy or pretreatment with dexamethasone. Beta-adrenergic blocking and ganglionic blocking both prevented CPZ-induced hyperglycemia. Furthermore, injection of CPZ did not potentiate the hyperglycemic response to exogenous epinephrine in demedullated rats. From these results, it is suggested that CPZ causes hyperglycemia mainly by the release of epinephrine from adrenal medulla stimulated by impulses from the central nervous system.

Autoradiographic studies on the role of adrenaline in stress by using H3 adrenaline.

The site of action and the pathways of adrenaline after stress have been studied by using H3 labeled adrenaline.In this study the stress was induced in rats by producing fractures of the long bones and also by administering exogenous adrenaline in different doses. Animals were sacrificed at the interval of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after producing stress.All animals were injected with 25 microcuries of radioactive adrenaline intraperitoneally before the production of stress.After sacrificing the animals, the brain, all the endocrine glands, the heart, the liver and the kidney were subjected to microautoradiography.We could localize the particular cells in the hypothalamus (PVN) which could be responsible for the endocrine and metabolic changes in the body after stress. The radioactive adrenaline granules could be seen in the various tissues at different intervals, including the thyroid gland, adrenal gland, heart muscle, liver, kidney, etc., suggestin...

Lack of immediate response of liver tyrosine-α-ketoglutarate transaminase to exogenous adrenaline in the adrenalectomized rat

Es wird eine Steigerung der Tyrosin-α-Ketoglutarat-Transaminase-Aktivitat in der Rattenleber durch Adrenalin bestatigt und eine Verminderung der Transaminase-Aktivitat nach Adrenalektomie durch Adrenalin nachgewiesen.