Showing papers on "Epinephrine published in 1975"

Dobutamine: development of a new catecholamine to selectively increase cardiac contractility.

Abstract: We systematically modified isoproterenol's chemical structure to reduce chronotropic, arrhythmogenic, and vascular side effects. Experiments on dogs showed that the resulting drug, dobutamine, had an inotropic efficacy as great as that of epinephrine due to a direct action on beta1 cardiac receptors. However, unlike epinephrine, dobutamine's effect on alpha and beta2 vascular receptors was slight. At equivalent inotropic doses, dobutamine had less than a fourth of the chronotropic effect of isoproterenol. Desmethylimipramine (DMI), which blocks the sympathetic nerve fiber uptake mechanism, had no effect on dobutamine's actions. In contrast, DMI antagonized dopamine's inotropic effect, and marked chronotropic and pressor responses occurred when we used doses of dopamine large enough to elicit a direct inotropic effect. Dobutamine increased the contractility of isolated cat papillary muscles more but the automaticity less than did isoproterenol. In ischemic dog hearts, dobutamine lacked significant arrhythmic activity, whereas dopamine, norepinephrine, and isoproterenol caused severe ectopic activity. In dogs with experimentally induced low cardiac contractility, low cardiac output, and hypotension, dobutamine produced dose-related increases in cardiac contractility and output, restored arterial blood pressure, and reduced total peripheral resistance slightly. In contrast, isoproterenol failed to restore blood pressure, had only a meager effect on cardiac contractility and output, cuased extreme tachycardia, and lowered peripheral resistance more than did dobutamine. Norepinephrine, which did not increase cardiac contractility or output as much as dobutamine, excessively elevated peripheral resistance and arterial blood pressure.

Central and peripheral adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats.

Abstract: The role of the sympathetic nervous system in the development of deoxycorticosterone-sodium chloride (DOCA-saline) hypertension was investigated by measuring plasma levels of norepinephrine, total catecholamines, and dopamine-beta-hydroxylase activity at intervals after the initiation of the DOCA-saline regimen. Plasma norepinephrine was significantly higher in DOCA-saline-treated rats at 4 and 7 weeks and in rats treated with saline alone at 4 weeks compared with that in untreated controls. Total plasma catecholamine levels (epinephrine and norepinephrine) and dopamine-beta-hydroxylase activity were similar in hypertensive rats, untreated controls, and rats that received either DOCA or saline alone. The increases in plasma norepinephrine levels may have resulted from centrally mediated increases in peripheral sympathetic neuronal activity, since the destruction of central catecholaminergic neurons with intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) prevented both the DOCA-saline-induced rise in blood pressure and the increases in plasma norepinephrine. Rats treated with 6-OHDA consistently drank less water or saline than did vehicle-treated controls. The actions of centrally administered 6-OHDA on blood pressure and plasma norepinephrine levels were not secondary to a reduction in salt intake, however, since intact rats given a similar reduced saline intake became hypertensive and demonstrated elevated plasma norepinephrine concentrations. Chronic salt loading may cause a centrally mediated increase in peripheral sympathetic neuronal activity with raised plasma concentrations of norepinephrine. The increased adrenergic activity in the presence of mineralocorticoid-induced sodium retention leads to the development of hypertension.

Sex and estrogens and responsiveness of terminal arterioles to neurohypophyseal hormones and catecholamines.

Abstract: It has been generally assumed that reactivity (or responsiveness) of mammalian microcirculatory blood vessels to vasoactive hormones is not influenced by sex. In view of the paucity of knowledge in this area, the present in vivo studies were initiated to determine the quantitative dose-response relationships (by means of a high magnification image-splitting television microscope recording system) of catecholamines, selected sympathomimetics, neurohypophyseal hormones (NHPH), serotonin and angiotensin on mesenteric arterioles of unpretreated male and female rats and male rats pretreated with single low doses of 17 beta-estradiol (2 and 10 mug/100 g s.c.). The results indicate: 1) dose-response curves for the constrictor catecholamines (epinephrine and norepinephrine) and NHPH (vasopressin, oxytocin, vasotocin) in female rats are significantly shifted in parallel manner to the left of those obtained in male rats; 2) pretreatment of male rats with estrogen results in an enhancement of the constrictor actions of catecholamines, NHPH and phenylephrine; 3) the maximal arteriolar contractile responses (i.e., lumen narrowings) to norepinephrine and phenylphrine were enhanced by pretreatment with estrogen; and 4) dose-response curves for arteriolar constrictions induced by dopamine, serotonin or angiotensin were not affected by sex or estrogen pretreatment. The sex-linked differences, observed in this study, thus appear to be specific for NHPH and certain alpha adrenergic agonists. Overall, these findings reinforce the concept that sex hormones may play a role in control of peripheral blood flow and reactivity of arteriolar smooth muscle.

Role of Adrenergic Stimuli in Parathyroid Hormone Secretion in Man

Abstract: The role of adrenergic stimuli in the secretion of parathyroid hormone (PTH) in man was evaluated. Intradermal injections of isoproterenol, 0.15 mg, or epinephrine, 0.3 mg, caused significant prompt increases in serum PTH levels. These increases were not accompanied by any changes in serum calcium (Ca) during the period of observation. Phenylephrine, 1.5 mg, intradermally, did not cause any significant changes in serum PTH or serum Ca. Propranolol infusion alone significantly inhibited the basal secretion of PTH. This inhibition by propranolol was overcome by isoproterenol administration. The results indicate that 1) beta adrenergic agents increase PTH secretion whereas alpha adrenergic agents have no effect, 2) beta adrenergic stimuli probably play an important physiological role in basal PTH secretion in man.

Neurogenic influence on local cerebral blood flow. Effect of catecholamines or sympathetic stimulation as correlated with the sympathetic innervation.

Abstract: Local cerebral flow was measured continuously in conscious rabbits (thermoclearance technique), and PaO2 and PaCO2 were recorded by mass spectrometry. Though inhalation of CO2 increased flow in caudate nucleus and lateral geniculate body, catecholamines only had effect on caudate nucleus where isoproterenol enhanced and epinephrine and norepinephrine reduced flow. Reduction by electrical stimulation of the neck sympathetic trunk was particularly evident in the caudate. Blood flow increased markedly in both regions after preganglionic conduction blockade. The effects were correlated with a significantly lower degree of sympathetic arteriolar innervation (fluorescence histochemistry) in the lateral geniculate body compared with the caudate nucleus.

Effect of vasoactive agents on intestinal oxygen consumption and blood flow in dogs.

Abstract: A comparison study of several vasoconstrictor and vasodilator agents was conducted measuring changes in intestinal blood flow and oxygen consumption during 10-min periods of intra-arterial infusion. Blood flow was measured in a branch of the superior mesenteric artery of anesthetized dogs with an electromagnetic blood flow meter, and the arteriovenous oxygen content difference across the gut segment was determined photometrically. Vasopressin (4 x 10(-3) and 7x 10(-4) U/kg-min) diminished blood flow 60 and 28% and reduced oxygen consumption 54 and 22%, respectively (all P less than 0.001). In a dose which did not lower blood flow, vasopressin still caused a decline in oxygen consumption (P less than 0.01). Epinephrine (5 x 10(-2) mug/kg-min) decreased blood flow 19% (P less than 0.001) but did not reduce oxygen consumption. After beta-adrenergic blockade, however, the same dose of epinephrine decreased blood flow 41% and oxygen consumption 33% (both P less than 0.001). Responses to angiotension II, calcium chloride, and prostaglandin F2alpha resembled effects of vasopressin rather than those of epinephrine, namely decreased blood flow and decreased oxygen consumption. The vasodilator agents, prostaglandin E1, is isoproterenol, and histamine, increased (P less than 0.001) both blood flow (130, 80, and 98%, respectively) and oxygen consumption (98, 64, and 70%, respectively). Vasopressin, angiotensin II, calcium chloride, and prostaglandin F2alpha appear to contract arteriolar and precapillary sphincteric smooth muscle indiscriminately to evoke both intestinal ischemia and hypoxia. Epinephrine is the exceptional constrictor in this case, producing diminished blood flow without a reduction in oxygen uptake.

Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro.

Abstract: Controversy exists regarding the mechanism by which catecholamines stimulate renin secretion in vivo. A sensitive rat kidney slice system was utilized to study the direct effects of adrenergic agonists and antagonists on renin release in vitro. Catecholamines were protected from degradation by the addition of ascorbic acid to the incubation medium. Significant dose-related stimulation of renin release was observed with epinephrine and norepinephrine in concentrations from 1.5 times 10(-9) to 1.5 times 10(-7)M and with isoproterenol in concentrations from 2 times 10(-9) to 2 times 10(-7)M. No significant stimulation was seen with 10(-10)M concentrations of the three agents. Methoxamine (10(-6)M) stimulated renin release significantly (P less than 0.01). The stimulation observed with epinephrine, norepinephrine, or isoproterenol was blocked by d,l- and l-propranolol (2 times 10(-4)M) but not by d-ropranolol (2 times 10(-4)M) or phentolamine (9 times 10(-4)M). Methoxamine-induced stimulation was abolished by d,l-propranolol but not by phentolamine. These data that the in vitro kidney slice system is responsive to physiological concentrations of catecholamines when they are protected from degradation. The results further demonstrate a direct stimulatory role for beta-adrenergic agents on renin release and suggest that alpha-adrenergic effects seen in vivo are mediated indirectly by hemodynamic, vascular, or functional changes in the kidney.

Biochemical and functional evaluation of the sympathectomy produced by the administration of guanethidine to newborn rats

Abstract: The administration of guanethidine to newborn rats has been shown by morphological criteria to destroy sympathetic neurons. Newborn rats were injected with guanethidine (50-100 mg/kg/day for 20 days). Upon maturation (at 10 weeks old), the degree of destruction of the sympathetic nervous system (sympathectomy) was assessed. Marked decreases (80-98%) in the norepinephrine concentration in several tissues (heart, spleen, intestine, mesentery, kidney, uterus, vas deferens) were observed in the guanethidine-treated rats when compared to saline-treated controls. No changes were observed in the epinephrine concentration in the adrenals or in the norepinephrine levels in whole brain. Analysis of brain areas showed no change in the norepinephrine levels in brain stem and cerebrum and a small (18%) decrease in the cerebellum. Stimulation of the sympathetic vasomotor outflow in the pithed rat preparation produced almost no response in guanethidine-treated animals. Periarterial nerve stimulation of the isolated perfused kidney preparation also produced essentially no response in guanethidine-treated animals. Isolated intestinal preparations from guanethidine-treated animals responded to nerve stimulation with contractions rather than relaxation as seen in preparations from control animals. Isolated vas deferens preparations responded normally to nerve stimulation despite a 95% decrease in tissue norepinephrine concentration. These data indicate that administration of guanethidine to newborn rats produces a more complete peripheral sympathectomy, especially of the vasculature, than immunosympathectomy or neonatal administration of 6-hydroxydopamine and does so with no significant effect on central noradrenergic neurons.

Potentiation of the Adrenergic Beta-Receptor-Mediated Insulin Secretion in Pertussis-Sensitized Rats

Abstract: The increase in blood insulin level induced by adrenergic beta-stimulants, glucose and tolbutamide was strongly exaggerated in pertussis-sensitized rats. Moreover, the decrease in blood insulin caused by the alpha-receptor-mediated action of epinephrine in glucose- or tolbutamide-treated rats was effectively reversed by pertussis sensitization. The rise of blood insulin concentration due to adrenergic alpha-blockade was also enhanced by pertussis sensitization. It is concluded that the secretion of insulin resulting from the stimulation of adrenergic bate-receptor is enhanced by pertussis sensitization, probably due to activation of a process occurring in the chain of events leading to the discharge of insulin from the pancreatic beta-cell.

Halothane-epinephrine-induced cardiac arrhythmias and the role of heart rate.

Abstract: The authors previously showed that cyclopropane-epinephrine-induced bigeminal arrhythmias can best be explained by a re-entrant mechanism. They have now obtained evidence for re-entry in bigeminal arrhythmias during infusions of epinephrine (.5–3 μg/kg/min) in dogs anesthetized with .8 per cent halo

Hormonal influences in the development of the hypermetabolic state of the liver produced by chronic administration of ethanol.

Abstract: Chronic administration of ethanol to rats, either in liquid diets as the only source of food or by gastric intubation while the animals are fed ad libitum, leads to the development of a hypermetabolic state of the liver. This hypermetabolic condition of the liver can be observed independently of the feeding state of the animals. The calorigenic effects produced by ethanol in the liver, as measured in liver slices, could be reproduced by a single large dose of epinephrine. Oxygen consumption by liver slices of animals given a 2-mg/kg dose of epinephrine bitartrate increased by 40 to 50 percent. In these livers all the extra oxygen consumption, but not the basal respiration, could be abolished by ouabain, an inhibitor of the sodium pump. Dinitrophenol did not affect the respiratory rate in the liver of epinephrine-treated animals while markedly increasing that in controls. In the liver of treated animals, the activatory effect of dinitrophenol could be recovered in the presence of ouabain. The calorigenic effect of epinephrine in the liver was found to be completely abolished by phentolamine (alpha adrenergic blocker) but was not modified by DL-propranolol (beta adrenergic blocker). Also, the calorigenic effects produced by epinephrine could not be seen in thyroidectomized animals or by incubating the liver slices in a calcium-free medium. Thyroidectomy and administration of phentolamine markedly reduced and adrenalectomy completely abolished the hypermetabolic state produced in the liver of rats by chronic administration of ethanol.

Release of Catecholamines

Abstract: The cornerstone of the neurohumoral theory of synaptic transmission (Elliott, 1905; Dixon, 1907) is the ability of nerves to release an active neurotransmitter on stimulation. The experiments of Loewi demonstrated the release of Vagusstoff (later shown to be acetylcholine) or a sympathin (later shown to be epinephrine) on stimulation of frog cardiac nerves and the effect of these substances to slow or accelerate, respectively, a second isolated heart (e.g., Loewi, 1921). These experiments were later applied to the mammalian heart by Rylant (1927), and made more specifically pertinent to sympathetic nerves by Cannon and his colleagues (Cannon and Uridil, 1921; Cannon and Rosenblueth, 1937). These classical experiments in neuropharmacology were essentially the application of sensitive and quite specific bioassays to demonstrate the release of active hormone on stimulation of a peripheral nerve. The identity of neural “sympathin” in mammalian sympathetic neurons (norepinephrine) as the desmethylated congener of the catecholamine originally extracted from the adrenal gland (e.g., Abel, 1899) (epinephrine) was suspected in the 1920s and 1930s (e.g., Bacq, 1934), but depended on the application of suitable quantitative biochemical and bioassay methods for its definitive demonstration, notably by von Euler (1946).

Desensitization of Beta Adrenergic Receptors in Human Fibroblasts in Tissue Culture

Abstract: The ability of isoproterenol, epinephrine, norepinephrine, and salbutamol to desensitize the beta receptor-coupled cyclic 39,59-AMP response of human diploid fibroblasts in tissue culture correlates well with their activity as beta stimulants. Partial desensitization of the cells results in a marked fall in the maximal cyclic AMP response to isoproterenol: fully desensitized cells are totally unresponsive to isoproterenol. Recovery of beta adrenergic sensitivity is a slow process and is delayed by extremely low concentrations of isoproterenol (picomolar). Recovery is also inhibited by concentrations of puromycin, cycloheximide, and actinomycin D that inhibit protein or RNA synthesis.

Calcium-induced Insulin Release in Monolayer Culture of the Endocrine Pancreas

Abstract: SUMMARY The role of Ca2+ on insulin release has been studied by the use of ionophore A23187. The ionophore complexes divalent cations and permits Ca2+ entry into cells by acting as a carrier in the plasma membranes. Cultured cells ob- tained by enzymatic digestion of pancreases from newborn rats were studied on the 3rd day of culture. With Ca2+ in the incubation medium the ionophore induced sustained in- sulin release even in the absence of glucose. Optimal ef - fects of the ionophore were observed at 3 and 10 pg per ml in the presence of 0.3 to 1.0 mM Ca2+. Under these condi- tions the insulin release was greater than that caused by 16.7 mM glucose. A graded response was observed to changes in Ca2+ concentration from 0.1 to 1.0 mM Ca2+. Higher Ca2+ concentrations caused a large amount of insulin to be released promptly, but the release was not sustained. Mg2+ and Sr2+ were not found to substitute for Ca*+. Ba2+ at 0.3 mM stimulated insulin release even in the absence of ionophore. Cyclic adenosine 3’: 5’-monophosphate was able to increase ionophore-induced insulin release. The CY- adrenergic effect of epinephrine to inhibit insulin release was not observed in the presence of Ca2+ and the ionophore, and a stimulatory effect of epinephrine was seen. This unusual stimulatory effect of epinephrine was blocked by propranolol indicating a P-adrenergic mechanism for epinephrine. It is concluded that Ca*+, which plays an essential role in the stimulus-secretion coupling, can alone initiate and cause sustained insulin release. Calcium is known to play an important role in hormone secre- tion of eudocrine glands.

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

Abstract: 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.

Catecholamines in sympathetic ganglia of rat: effects of dexamethasone and reserpine.

Abstract: — The superior cervical sympathetic ganglion of rats contains a finite amount of epinephrine all of which is of ganglionic origin. Treatment of new-born rats with dexamethasone for 8 days results in a 112-fold increase in the epinephrine concentration, whereas the norepinephrine and dopamine are increased by only 1·4- and 1·9-fold respectively. This epinephrine increase in newborn rats is reversible if treatment is discontinued, and it fails to occur in adult animals. The epinephrine store of normal and dexamethasone treated animals is resistant to the depletion by reserpine. There is no increase in the epinephrine content in organs innervated by axons emanating from the ganglion. The data presented support the localization of epinephrine in small intensely fluorescent cells in the ganglion and we propose that epinephrine may be released from these cells and function as a modulator of ganglionic transmission.

Inter-relations between beta-adrenergic receptors, adenylate cyclase and calcium.

Abstract: THE catecholamines are a group of hormones that affect most tissues, not only in human beings, but in almost all animal phyla.1 Whether they are released locally by certain nerve endings or into the general circulation by the adrenal medulla, circulating catecholamines, such as epinephrine and norepinephrine, may regulate basic cellular processes like ion transport, enzyme secretion, glycogenolysis, lipolysis and muscle contraction.2 An understanding of their action is therefore needed for an understanding of a variety of cellular activities. In early studies, extracts of the adrenal medulla were injected into intact animals, and physiologic responses such as blood pressure were . . .

The development of sympathetic innervation and the functional state of the cardiovascular system in newborn dogs.

Abstract: The present study in dogs indicates that the peripheral sympathetic fibers develop mostly after birth and reach a full maturity at about 2 months of life. The norepinephrine content of the heart, spleen, intestine, salivary glands, and adrenal glands increased from birth to 56 days of age. In contrast, the content of the stellate ganglia decreased during this period. In most of the organs studied, the uptake of [3H] norepinephrine developed in parallel with the norepinephrine content, except in the right atrium and salivary glands where it was fully developed soon after birth. During development, the systemic blood pressure increased from 40 to 100 mm Hg. Bilateral adrenal vessel clamping failed to induce a fall in blood pressure in growing dogs which indicates that the adrenal medulla or the baroreceptors did not fully compensate for the lack of peripheral sympathetic fibers and for the lower blood pressure in newborn animals. Although cardiac norepinephrine content was still very low in 10-day-old animals, cardiovascular responses to direct and reflex sympathetic stimulation were similar to those observed in 56-day-old animals. These results indicate that the sympathetic nervous system becomes functional before the fibers reach their full maturity.

Role of cyclic AMP in the actions of catecholamines on hepatic carbohydrate metabolism.

Abstract: Studies using perfused rat liver and isolated liver parenchymal cells show that low concentrations of epinephrine, norepinephrine, and phenylephrine can activate glycogenolysis and gluconeogenesis by a mechanism mediated by alpha-adrenergic receptors and not involving accumulation of cAMP. The glycogenolytic and gluconeogenic activites of epinephrine, norepinephrine, and phenylephrine are inhibited by the alpha-adrenergic receptor antagonists phentolamine and dihydroergotamine, but are negligibly affected by the beta-adrenergic receptor antagonist propranolol. Epinephrine, norephinephrine, and the beta-adrenergic receptor agonists isoproterenol, soterenol, and salbutamol increase cAMP accumulation; and this effect is antagonized by propranolol. Isoproterenol, soterenol, and salbutamol activate glycogenolysis and gluconeogenesis, but are less effective than epinephrine or norepinephrine. The data are interpreted as indicating the existence of both alpha- and beta-adrenergic receptors in rat liver. Activation of the alpha-adrenergic mechanism appears to be more important than the beta-adrenergic receptor-cAMP system in the physiologic effects of epinephrine and norepinephrine on carbohydrate metabolism in rat liver.

Evidence for noradrenaline and adrenaline as sympathetic transmitters in the chicken

Abstract: 1 The concentrations of noradrenaline and adrenaline in various organs, arterial plasma and venous outflow from isolated hearts of adult chickens have been determined. 2 The relative adrenaline concentrations (percentage of the sum of noradrenaline and adrenaline) in the heart (33%), spleen (16%) and brain (26%) were higher than those found in mammalian organs. Chemical sympathectomy by pretreatment with 6-hydroxydopamine caused a decrease of the noradrenaline and adrenaline concentrations in the heart to 20 and 23% and in the spleen to 16 and 29%, respectively. 3 Stimulation of the right sympathetic nerves, infusion of tyramine or infusion of a modified Tyrode solution containing 108mM K+ and 44 mM Na+ caused an output of both noradrenaline and adrenaline into the perfusate of isolated hearts. The relative adrenaline concentration in the perfusate (20-28%) was not significantly different from the relative adrenaline concentration remaining in these hearts (19-22%). In the individual experiments, the noradrenaline: adrenaline ratios of the stimulation perfusates were positively correlated with the ratios found in the hearts. 4 The effects of noradrenaline and adrenaline on cardiac rate and tension development were studied in spontaneously beating right atria and electrically driven left atria, respectively. In addition, the arterial pressure rise in response to noradrenaline or adrenaline was;measured in chickens. It was found that the cardio-vaseart rate, cardiac tension development and arterial blood pressure, was not significantly different from that of adrenaline. 5 It is concluded that, in the chicken heart and spleen, both noradrenaline and adrenaline act as sympathetic neutrotransmitters.