Adrenergic agonists induce heterologous sensitization of adenylate cyclase in NS20Y-D(2L) cells

Adenylate cyclase activity in NS20Y cells expressing D2L dopamine receptors was examined following chronic treatment with norepinephrine and epinephrine. Initial acute experiments revealed that both norepinephrine and epinephrine inhibited forskolin-stimulated cyclic AMP accumulation via D2 receptors. Furthermore, chronic 18 h activation of D2 dopamine receptors by norepinephrine or epinephrine induced a marked increase (>10-fold) in subsequent forskolin-stimulated cyclic AMP accumulation. This heterologous sensitization of adenylate cyclase activity was blocked by D2 dopamine receptor antagonists and by pertussis toxin pretreatment. In contrast, concurrent activation of Galpha(s) or adenylate cyclase did not appear to alter noradrenergic agonist-induced sensitization.     

Corticotropin-releasing factor receptor antagonist: effects on the autonomic nervous system and cardiovascular function

The corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical [Glu27]-corticotropin-releasing factor 9-41 (CRF 9-41) has been assessed for its ability to modify plasma concentrations of epinephrine and norepinephrine, mean arterial pressure (MAP) and heart rate (HR). Basal concentrations of epinephrine and norepinephrine were not altered by lateral ventricular (icv) administration of CRF 9-41. However, this CRF antagonist, given icv, attenuated the rise of plasma epinephrine following 30% hemorrhage and insulin-induced hypoglycemia. CRF 9-41 did not alter the increased plasma concentrations of epinephrine or norepinephrine following icv administration of bombesin. Icv administration of CRF 9-41 blunted CRF-induced elevation of MAP and HR in normal animals. However, this CRF antagonist did not modify the MAP or HR in spontaneously hypertensive rats. Similarly, this CRF antagonist administered to Sprague-Dawley rats neither prevented the rise of MAP or HR following electrical stimulation of the central nucleus of the amygdala, nor did it affect nitroprusside-induced hypotension and tachycardia.     

Glucocorticoid suppression of the sympathetic nervous system and adrenal medulla

Studies were performed to evaluate the effects of glucocorticoids on the activity of the sympathetic nervous system and adrenal medulla. Plasma concentrations of norepinephrine and epinephrine were measured in rats in which endogenous glucocorticoids were removed by bilateral adrenalectomy and in rats to which exogenous glucocorticoids were administered. In intact rats, dexamethasone (2.5, 25 or 250 micrograms) pretreatment suppressed ether vapor-induced elevations of norepinephrine and epinephrine concentrations in plasma. Corticosterone (3 mg/kg), similar to dexamethasone, attenuated the elevation of plasma concentrations of norepinephrine and epinephrine in rats exposed to ether vapor. Glucocorticoids did not alter the elevation of plasma catecholamines stimulated by intracerebroventricular injections of corticotropin-releasing factor or calcitonin gene-related peptide, thus demonstrating functional integrity of the sympathetic nervous system and adrenal medulla. Adrenalectomy resulted in elevation of basal plasma norepinephrine levels and accentuation of ether vapor-induced elevations of plasma norepinephrine concentrations in rats. Dexamethasone (25 ug) administration blunted the effects of adrenalectomy on both basal and ether vapor-stimulated levels of plasma norepinephrine. It is concluded that glucocorticoids acting at as yet undefined sites may be involved in the regulation of sympathetic nervous system and adrenal medullary function.     

Beta-2 adrenergic receptors are not only for circulating catecholamines in ventricular muscles of carp heart (Cyprinus carpio)

Whether beta-2 adrenergic receptors are only for the circulating catecholamines in isolated ventricular muscles of carp heart was studied. Isoproterenol, epinephrine and norepinephrine had concentration dependent positive inotropic effects. The ED50 values for isoproterenol, epinephrine and norepinephrine were 6.23 +/- 1.9, 87.3 +/- 27.3 and 4500 +/- 580 nM, respectively. Phentolamine did not alter the inotropic effects. Tyramine increases the force of contraction and this action was completely blocked by propranolol and reserpine, but not by atenolol. Norepinephrine levels, in comparison with those of epinephrine, were similar in plasma and higher in ventricular muscles. However, the norepinephrine levels in ventricular muscles of carp heart were markedly lower than those in ventricular muscles of rat heart. These results suggest that ventricular muscles of carp heart contain adrenergic neurons, and that a catecholamine released from the nerve terminals, presumably epinephrine, may stimulate beta-2 adrenergic receptors.     

Effects of exercise on plasma catecholamine levels in the toad, Bufo paracnemis: role of the adrenals and neural control

Resting plasma epinephrine (E) and norepinephrine (N) concentrations for intact toads (Bufo paracnemis) were 5.57+/-1.0 and 0.88+/-0.38 ng/ml, respectively. Exercise induced a significant increase in heart rate, blood pressure and plasma epinephrine (about 4.3 times), whereas norepinephrine remained unchanged. The resting [E]/[N] ratio was 6.3 and increased to 32.9 during exercise. Adrenal denervation did not alter the basal plasma catecholamine or norepinephrine levels after exercise, but prevented the increase in epinephrine during exercise, suggesting that in the intact toad this increase is due to adrenal secretion whereas resting norepinephrine may be liberated by extra-adrenal chromaffin tissues. This also suggests that the adrenal glands can release selectively the two catecholamines. The increases in heart rate and blood pressure in denervated toads were not significantly different from those of intact animals, suggesting that during exercise the sympathetic nerves play the main role in inducing cardiovascular responses. Spinal transection induced a significant increase in basal norepinephrine levels, which remained elevated after exercise. Since spinal toads are unable to perform spontaneous movements it is possible that this increase may be caused by this stressful condition. The increases in heart rate and blood pressure observed in spinal toads during exercise may be due to direct mechanical effects of venous return on the heart.     

Adenosine modulation of vasoconstrictor responses to stimulation of sympathetic nerves and norepinephrine infusion in the superior mesenteric artery of the cat

Vasoconstriction induced by sympathetic nerve stimulation and by norepinephrine infusion in the superior mesenteric artery of cats anesthetized with pentobarbital was inhibited by adenosine infusions in a dose-related way. The responses to nerve stimulation were not inhibited to a greater extent than the responses to norepinephrine, thus suggesting no presynaptic modulation of sympathetic nerves supplying the resistance vessels of the feline intestinal vascular bed. Blockade of adenosine receptors using 8-phenyltheophylline did not alter the degree of constriction induced by nerve stimulation or norepinephrine infusion, indicating that in the fasted cat, endogenous adenosine co-released or released subsequent to constriction does not affect the peak vasoconstriction reached. Isoproterenol caused similar degrees of vasodilation as adenosine but did not show significant antagonism of the pooled responses to nerve stimulation or norepinephrine infusion; there was no tendency for the degree of dilation induced by isoproterenol to correlate with the inhibition of constrictor responses. Thus, the effect of adenosine on nerve- and norepinephrine-induced constriction is not secondary to nonspecific vasodilation.     

Factors controlling glycogen breakdown in the alligator

1. Catecholamines were injected into normal alligators and into others pre-treated with an α blocker (phenoxybenzamine) or a β blocker (propranol).2. Liver glycogenolysis after epinephrine, norepinephrine or isoproterenol was blocked by the β blocker, and muscle glycolysis after epinephrine or norepinephrine by an α blocker. Isoproterenol-induced glycolysis was blocked by the β blocker.3. Glycolysis proceeded 10 × as fast after work as after catecholamines and it could not be blocked.4. Work had little effect on blood glucose.5. It was concluded that glycolysis from work did not involve catecholamine stimulation.     

EFFECTS OF PRE- OR POSTNATAL DEXAMETHASONE, ADRENOCORTICOTROPHIC HORMONE AND ENVIRONMENTAL STRESS ON PHENYLETHANOLAMINE N-METHYLTRANSFERASE ACTIVITY AND CATECHOLAMINES IN SYMPATHETIC GANGLIA OF NEONATAL RATS

Abstract— Injections of dexamethasone (0.1 mg/kg/day, s.c.) on the first 2–3 days of life increased the phenylethanolamine- N -methyltransferase (PNMT) activity and epinephrine content of the superior cervical ganglion (SCG) and stellate ganglion of neonatal rats; the dopamine content was unaltered while norepinephrine was slightly reduced in these ganglia. Dexamethasone did not alter the PNMT activity or epinephrine content of the salivary glands or heart. The PNMT activity and epinephrine content of the SCG remained elevated for 10–14 days. Pretreatment with 6-hydroxydopamine did not alter the dexamethasone effects.
Injections of adrenocorticotrophic hormone (ACTH) (25 munits/rat twice a day) or exposure to a cold stress (4°C, 3 times a day) on the first 2–3 days of life, elevated the plasma concentration of corticosterone, and also increased the PNMT activity and epinephrine content in SCG of neonatal rats. Injecting pregnant rats with dexamethasone or ACTH, or exposing them to cold or restraint stress on the last 3 days of gestation increased the PNMT activity and epinephrine content in the SCG of their pups. These results indicate that the actions of dexamethasone on neonatal sympathetic ganglia may be mimicked by increasing the plasma concentration of endogenous adrenocortical steroids.     

Effect of steroid hormones on serotonin,norepinephrine and epinephrine contents in the pineal-paraphyseal complex of the soft-shelled turtle (Lissemys punctata punctata)

Summary Steroids (testosterone, oestrogen, progesterone, corticosterone, dexamethasone and deoxycorticosterone) were administered intramuscularly (0.1 mg · 100 g bw^-1) on seven consecutive days to juvenile male soft-shelled turtles. Serotonin, norepinephrine and epinephrine contents of the pineal-paraphyseal complex were measured spectrofluorometrically 24 h after the last injection. Testosterone and oestrogen decreased serotonin, norepinephrine and epinephrine levels. Progesterone treatment resulted in an increase of serotonin level and a fall in norepinephrine and epinephrine levels. Corticosterone treatment caused an increase of serotonin level and a decrease of norepinephrine and epinephrine levels. Dexamethasone failed to alter serotonin content, increased norepinephrine and decreased epinephrine levels. Deoxycorticosterone decreased serotonin and elevated epinephrine content.Abbreviations 5-HIAA 5-hydroxyindole-acetic acid - 5-MTOH 5-methoxytryptophol - ANOVA analysis of variance; bw body weight - COMT catecholamine-o-methyl transferase - E epinephrine - HIOMT hydroxyindole-o-methyl transferase - MAO monoamine oxidase - MS mean sum of squares - NAT N-acetyltransferase - NE norepinephrine - SR synaptic ribbon - SS sum of squares - SV source of variation     

Cell-free synthesis of active ribulose-1,5-bisphosphate carboxylase in the mesophyll chloroplasts of Sorghum vulgare

In the presence of either methyl xanthines or adenosine deaminase, isoproterenol elicited large dramatic increases in accumulation of cyclic AMPP. In contrast, cyclic AMP accumulation in response to epinephrine or norepinephrine was not potentiated by either methyl xanthines or by adenosine deaminase. Blocking the alpha adrenergic activity of norepinephrine and epinephrine with phentolamine established synergism between these catecholamines and methyl xanthines and adenosine deaminase. The activity of the particulate phosphodiesterase was not influenced by norepinephrine suggesting that the lack of synergism between the catecholamines norepinephrine and epinephrine and methyl xanthines is unrelated to this enzyme. The data are interpreted to suggest that the alpha adrenergic activity of catecholamines prevents the potentiation of cyclic AMP accumulation that occurs when the action of endogenously produced adenosine is interfered with, either by its degradation with adenosine deaminase or by receptor blockade with methyl xanthine. Because a major action of adenosine on fat cells is to inhibit adenylate cyclase it is suggested that alpha adrenergic receptor activation limits the extent to which the enzyme adenylate cyclase can be activated in a fashion similar to that of adenosine.     

Changes in the Permeability of the Salivary Gland Caused by Sympathetic Stimulation and by Catecholamines

The permeability of the submaxillary gland of cats and dogs has been tested by determining the rates at which non-electrolytes penetrate from the plasma into the saliva. Electrical stimulation of the cervical sympathetic trunk or administration of epinephrine or norepinephrine increases the permeability of the gland enabling glucose (molecular radius, MR = 3.5 Å), sucrose (MR = 4.4 Å), raffinose (MR = 5.6 Å), polyglycol 1000 (MR = 7.2 Å), and polyglycol 1540 (MR = 8.1 Å) to penetrate into the saliva from which they are otherwise excluded. Inulin (MR = 14.7 Å) does not enter the saliva under these circumstances. Analysis of the transfer rates suggests that the molecules diffuse through a pore structure permitting free diffusion for molecules with a radius less than 5.7 Å. Close intraarterial injection of C¹⁴-glucose demonstrates that at least part of this permeability is located in the duct system of the gland. Since epinephrine does not enable sucrose to enter the cells of the gland, it appears that penetration from the extracellular space into the saliva occurs by diffusion through intercellular gaps. The characteristics of the permeability allow conclusions as to the localisation and geometry of the ultrastructural change produced.     

Interactions between catecholamines,methyl xanthines and adenosine in regulation of cyclic AMP accumulation in hamster adipocytes

In the presence of either methyl xanthines or adenosine deaminase, isoproterenol elicited large dramatic increases in accumulation of cyclic AMP. In contrast, cyclic AMP accumulation in response to epinephrine or norepinephrine was not potentiated by either methyl xanthines or by adenosine deaminase. Blocking the alpha adrenergic activity of norepinephrine and epinephrine with phentolamine established synergism between these catecholamines and methyl xanthines and adenosine deaminase. The activity of the particulate phosphodiesterase was not influenced by norepinephrine suggesting that the lack of synergism between the catecholamines norepinephrine and epinephrine and methyl xanthines is unrelated to this enzyme. The data are interpreted to suggest that the alpha adrenergic activity of catecholamines prevents the potentiation of cyclic AMP accumulation that occurs when the action of endogenously produced adenosine is interfered with, either by its degradation with adenosine deaminase or by receptor blockade with methyl xanthine. Because a major action of adenosine on fat cells is to inhibit adenylate cyclase it is suggested that alpha adrenergic receptor activation limits the extent to which the enzyme adenylate cyclase can be activated in a fashion similar to that of adenosine.     

Plasma catecholamine concentrations of newborn piglets in thermoneutral and cold environments

Plasma epinephrine and norepinephrine concentrations were measured in seventeen unanaesthetized 3 to 4 days-old piglets while in a thermoneutral environment (31.3 degrees C) and 30, 45 and 60 min after induction of environmental cold stress (19.9-23.1 degrees C). Plasma epinephrine and norepinephrine concentrations in a warm environment were 142 +/- 26 pg/ml, and 456 +/- 44 pg/ml respectively. Environmental cold stress evoked significant increases in norepinephrine values after 30 (624 +/- 58 pg/ml), 45 (626 +/- 60 pg/ml) and 60 (626 +/- 54 pg/ml) min of cold stress. Plasma epinephrine concentrations did not significantly change during environmental cold stress. Post-hoc stratification of piglets into normothermic (deep rectal temperature 38.6 degrees C-38.8 degrees C, n = 9) and hypothermic (deep rectal temperature 37.1 degrees C-37.7 degrees C, n = 7) subgroups revealed significant increases in plasma norepinephrine concentrations only in the hypothermic subgroup. We conclude that plasma norepinephrine, but not epinephrine, is increased in newborn piglets during environmental cold stress and that the changes in norepinephrine concentrations are related to body core hypothermia. We speculate that hypothermia-mediated reductions in peripheral norepinephrine breakdown and re-uptake contribute to the rise in circulating levels.     

Serum-dependent induction of plasminogen activator in human fibroblasts by catecholamines and comparison with the effects of prostaglandin E1

Human foreskin fibroblasts produce the protease plasminogen activator, as shown by the ability of cell extracts to lyse 125I-labelled fibrin in the presence of plasminogen. Cellular plasminogen activator was stimulated up to 3-fold by 0.01-10 microM epinephrine, norepinephrine, or isoproterenol. Increases in plasminogen activator were slow in onset (24 h) and long-lived (greater than 48 h), and were abolished by 10 micrograms/ml of cycloheximide or 1 microgram/ml of actinomycin D, suggesting de novo synthesis of the protease. Stimulation of plasminogen activator by catecholamines was inhibited by 10 microM propranolol but not by 10 microM phentolamine, suggesting the involvement of beta-adrenergic receptors. Catecholamines stimulated plasminogen activator only in the presence of fetal bovine serum; under serum-free conditions they were inhibitory. Serum did not appear to alter the uptake and metabolism of epinephrine during incubation with fibroblasts. The ability of fetal bovine serum to support the induction of plasminogen activator by either 1 microM epinephrine or 3 microM prostaglandin E1 was maintained following dialysis but lost on heating (70 degrees C, 10 min) or acidification (pH 2.5). Human and calf sera supported the stimulatory effects of prostaglandin E1 but not of epinephrine. These results indicate that serum may influence the synthesis of plasminogen activator in cultured cells by modifying their response to vasoactive hormones.     

Catecholamine and blood pressure regulation by gonadotropin-releasing hormone analogs in amphibians

Analogs of gonadotropin-releasing hormone (GnRH) occur in the brain, plasma, and sympathoadrenal system of anuran amphibians. The present experiments studied the effects of GnRH and [Trp7, Leu8]-GnRH on plasma catecholamines and cardiovascular function in conscious adult bullfrogs (Rana catesbeiana) and cane toads (Bufo marinus). Both GnRH analogs elicited dose-dependent (0.1-1 nmol.kg-1) increases in arterial norepinephrine, epinephrine, and blood pressure levels when injected intravenously into toads. In bullfrogs, [Trp7, Leu8]-GnRH (1 nmol.kg-1) increased arterial norepinephrine concentration approximately 10-fold without affecting the concentrations of norepinephrine sulfate, norepinephrine glucuronide, epinephrine, epinephrine sulfate, or epinephrine glucuronide. The noradrenergic response of bullfrogs to [Trp7, Leu8]-GnRH was specific to the neurohormone because it could be inhibited by [D-pGlu1, D-Phe2, D-Trp3,6]-GnRH. The sympathomimetic activities of the GnRH analogs did not depend on changes in temperature, which occur seasonally in natural habitats, because similar noradrenergic responses were observed at 4 and 22 degrees C. GnRH and [Trp7, Leu8]-GnRH (0.01-10 nmol.kg-1) did not raise arterial blood pressure in bullfrogs despite their pressor actions in toads. This interspecific difference was remarkable because cardiovascular responses to norepinephrine, angiotensin II, and vasotocin in bullfrogs were similar to those in toads. The parallels between catecholamine and blood pressure responses suggest that epinephrine is the principal mediator of the blood pressure response to native GnRH analogs in toads. In bullfrogs, [Trp7, Leu8]-GnRH mobilizes norepinephrine but not epinephrine, and the noradrenergic effect is insufficient to raise blood pressure. These observations are consistent with a physiological role for native GnRH analogs in the regulation of the sympathoadrenal system in anuran amphibians.     

Flux of catecholamines through chromaffin vesicles in cultured bovine adrenal medullary cells

Primary cultures of bovine adrenal medullary chromaffin cells were pulse-labeled with [3H]dopamine or [3H]norepinephrine and examined for radioactive and total catecholamine contents by high performance liquid chromatography after additional incubations of 15 min to 10 days. [3H]Dopamine was rapidly taken up by chromaffin vesicles in situ and converted to norepinephrine with a half-time of approximately 6 h. [3H] Norepinephrine taken up by the cells was metabolized in three phases. 1) During its brief transit through the cytoplasm, 20 to 35% of this amine was converted to [3H]epinephrine. 2) Following vesicular accumulation, 65 to 70% of the remaining [3H]norepinephrine was methylated to form [3H]epinephrine with a half-time of approximately 30 h, corresponding to the rate of vesicular catecholamine loss from reserpine-treated cells. 3) The residual [3H]norepinephrine decreased with a half-time of 5 days, probably representing loss from norepinephrine-storing cells. [3H]Epinephrine formed endogenously had a half-life in the cultures of approximately 15 days. These data suggest that leakage of norepinephrine from chromaffin vesicles into the cytoplasm limits the rate of dopamine conversion to epinephrine in the adrenal medulla. The kinetic data indicate that approximately 18% of the endogenous norepinephrine and 73% of the endogenous dopamine are present in epinephrine cells.     

Effects of adrenergic blockers on platelet aggregation.

The action of orciprenaline, tolazoline, propanolol and inpea on platelet aggregation induced by ADP epinephrine and norepinephrine was studied in vitro in human platelet-rich plasma. Orciprenaline did not significantly affect aggregation induced by ADP. Tolazoline inhibits the aggregation induced by epinephrine and norepinephrine more intensely than the beta-blockers. Inpea blocks the platelet aggregation induced by epinephrine and norepinephrine to a greater extent than propanolol at similar concentrations. The beta-blockers inhibit platelet aggregation non-specifically.     

The effect of sulfinpyrazone on the response to sympathetic nervous system stimulation

The purpose of this study was to determine if sulfinpyrazone has a direct action on sympathetic nerve endings to prevent release of the transmitter. Pre-synaptic and post-synaptic events as well as direct sympathetic nervous system stimulation were tested in 15 α-chloralose anesthetized cats before and 1 hour after sulfinpyrazone (100 mg·kg⁻¹, i.v.). Heart rate response to cardiac accelerator nerve stimulation or to increasing doses of isoproterenol was not significantly depressed by sulfinpyrazone. In addition, no alteration in the reflex activation of the sympathetic nervous system in response to histamine was observed following sulfinpyrazone. Both norepinephrine and epinephrine levels were similar to those levels reported previously by Smith and Robinson (7) for untreated cats. We conclude sulfinpyrazone has no direct depressing effect on the sympathetic nerve endings and that this mechanism cannot explain the reported beneficial effect of sulfinpyrazone on coronary occlusion induced arrhythmias.     

Changes in human plasma catecholamines and dopamine-beta-hydroxylase produced by prostaglandin F2 alpha

Clinical research was conducted into the possible interrelationships between prostaglandin (PG) F2alpha and the human sympathetic nervous system. The study also permitted comparison of the relative sensitivity of 2 indicators of sympatho-adrenal activity: 1) the determination of circulating catecholamines, epinephrine and norepinephrine; and 2) analysis of plasma dopamine-8-hydroxylase activity. Intravenous PGF2alpha infusion was administered to college students 12-18 weeks pregnant to produce abortion; the results were compared to results from nonpregnant controls. Circulating norepinephrine but not plasma epinephrine or dopamine-8-hydroxylase levels were increased in response to the PG. There was no correlation between plasma epinephrine and plasma norepinephrine levels. Plasma dopamine-8-hydroxylase activity was found not to be significantly changed by pregnancy, administration of the analgesic and antiemetic, or the PG infusion. In fact, central venous dopamine-8-hydroxylase activity did not differ significantly from that of arterial blood. The PG did not affect cardiac output or maximal expiratory flow rate. It is suggested that the nausea and diarrhea accompanying PGF2alpha infusion may put stress on the sympathetic nervous activity causing the observed increase in plasma norepinephrine concentration. Since no changes in blood pressure, heart rate, central venous pressure, or cardiac output were observed, it is unlikely that PGF2alpha causes even slight impairment of sympathetic nervous system activity.