Showing papers on "Norepinephrine (medication) published in 1975"
TL;DR: 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 β1 cardiac receptors, however, do butamine's effect on α and β2 vascular receptors was slight.
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.
616 citations
TL;DR: A procedure for measuring picogram quantities of norepinephrine has been developed utilizing partially purified bovine adrenal phenylethanolamine-N-methyl-transferase and 3 [H]-S-adenosyl-methionine, applicable to many body tissues and fluids, including brain and plasma.
497 citations
TL;DR: The behavioral and neurochemical changes that were observed after the stressful conditions studied are consistent with the hypothesis that changes in avoidance‐escape responding following exposure to these stressful events are due to changes in brain noradrenergic activity.
Abstract: A single exposure to a severe stressor (either cold swim or inescapable shock) impairs subsequent performance in a shuttle avoidance-escape task (1), a deficit attributed to reduction in brain noradrenergic activity produced by these stressors. In the present paper, two experiments are described which examine how repeated exposure to such stressors affects (a) shuttle avoidance-escape performance (Experiment 1), and (b) aspects of brain norepinephrine metabolism (Experiment 2). Experiment 1 showed that, whereas subjects receiving the single exposure to cold swim or shock showed a large avoidance-escape deficit, subjects that received repeated exposure to these stressors for 14 days performed similarly to the control group that received no stressor. Experiment 2 showed that, whereas subjects that received one session of the inescapable shock stressor showed a lower level of norepinephrine in hypothalamus and cortex than did subjects that received no shock, subjects that received repeated exposure to inescapable shock or cold swim showed neurochemical "habituation." Subjects that received repeated shock showed elevated tyrosine hydroxylase activity and no depletion of norepinephrine level, and both repeated shock and cold swim caused a decrease in uptake of 3H-norepinephrine by slices of cortex in vitro. Thus, it is concluded that the behavioral and neurochemical changes that were observed after the stressful conditions studied are consistent with the hypothesis that changes in avoidance-escape responding following exposure to these stressful events are due to changes in brain noradrenergic activity. Language: en
284 citations
TL;DR: It is concluded that PGs of the E series modulate adrenergic transmission in the kidney and that their modulatory actions are species dependent.
Abstract: In the isolated perfused rabbit kidney prostaglandins (PGS) E1 (0.02-0-1 ng/ml), E2 (0.02-0.1 ng/ml), and A2 (1-5 ng/ml) inhibited the vasoconstrictor responses to sympathetic nerve stimulation by 21-44%, 31-39%, and 20-23%, respectively, without alerting those to injected norepinephrine. In contrast, in the rat kidney PGE1 (0.5 ng/ml), PGE2 (0.5 ng/ml), and PGA2 (5 ng/ml) enhanced the vasoconstrictor responses to sympathetic nerve stimulation by 41%, 27%, and 11%, respectively; the equiconstrictor responses to injected norepinephrine remained unaltered. Higher concentrations of these agents produced vasodilation in the rabbit kidney and vasoconstriction in the rat kidney. In both species PGF2alpha produced vasoconstriction and enhanced the response to both adrenergic stumuli. In the rabbit kidney inhibitors of PG synthesis augmented the responses to sympathetic nerve stimulation without altering those to injected norepinephrine, whereas in the rat kidney inhibition of the responses to both adrenergic stimuli occurred. Arachidonic acid inhibited the vasoconstrictor responses to sympathetic nerve stimulation in the rabbit kidney, but in the rat kidney it caused augmentation of these responses. Since these effects of arachidonic acid were reduced by indomethacin, they appear to be mediated through the acid's conversion to PGS. We conclude that PGS of the E series modulate adrenergic transmission in the kidney and that their modulatory actions are species dependent.
230 citations
Journal Article•
TL;DR: The study of the effects of ethanol on the electrically stimulated release of radioactive neurotransmitters suggests that the effect of ethanol is consistent with an inhibition of the action potential by this drug, although a specific effect ofanol on the excitation-coupling process at the synapse cannot by discarded.
Abstract: Using a double label technique to preload rat brain cortex slices with different radioactive neurotransmitters (or precursor choline), we have studied the effects of ethanol on the electrically stimulated release of these transmitters. Ethanol inhibited the release of these transmitters, acetylcholine being the most sensitive and occurring at concentrations compatible with moderate to severe intoxication in the rat (IC50 equals 0.17 M). The order of sensitivity to ethanol was acetylcholine greater than serotonin greater than dopamine greater than norepinephrine greater than glutamate greater gamma-aminobutyric acid. Two higher alcohols and two barbiturates were also shown to have a greater inhibitory effect on the stimulated release of acetylcholine than of norepinephrine. The concentrations of all the drugs tested required for 50% inhibition of release of acetylcholine and norepinephrine correlated well with their lipid solubility when corrected for their molecular volumes. The effect of tetrodotoxin and of ouabain on neurotransmitter release was also studied. A comparison of the effects of these two drugs with those of ethanol suggests that the effect of ethanol is consistent with an inhibition of the action potential by this drug, although a specific effect of ethanol on the excitation-coupling process at the synapse cannot by discarded.
211 citations
TL;DR: 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-β-hydroxylase activity at intervals after the initiation of the DOCA- saline regimen.
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.
211 citations
TL;DR: 5,7-DHT treatment was found to enhance the depressant effects of 5-hydroxytryptophan on a fixed-ratio barpress response, suggesting that 5,7,DHT treated rats are supersensitive to serotonin in the central nervous system.
167 citations
141 citations
TL;DR: Endogenous prostaglandin E2 production contributes to the regulation of blood pressure by opposing the vasoconstrictor and antidiuretic actions of circulating pressor hormones, and participating in the control of extracellular fluid volume through its renal hemodynamic actions.
Abstract: Prostaglandins are primarily local or tissue hormones which have their effects at or near the site of release and are metabolized before reaching the arterial circulation. A possible exception is prostaglandin A-2, which has been proposed as a circulating hormone; however, there is no evidence that prostaglandin A-2 is biosynthesized in the mammalian kidney or even in extrarenal tissues. The prostaglandin generated and released in the kidney is predominantly E-2. Some blood vessels also synthesize prostaglandins intramurally, where their local release influences vascular tone and reactivity. Endogenous prostaglandin E-2 production contributes to the regulation of blood pressure by (1) opposing the vasoconstrictor and antidiuretic actions of circulating pressor hormones; (2) braking the release of norepinephrine from vasoconstrictor nerves; and (3) participating in the control extracellular fluid volume through its renal hemodynamic actions.
132 citations
TL;DR: The view that the decrease in angiotensin II pressor activity during salt deprivation is the result of a prior occupancy of receptor sites by endogenous hormone is supported, and a change in the number or the affinity of receptors consequent to changes in sodium balance need not be postulated to explain the phenomenon.
Abstract: The pressor responsiveness to angiotensin II and norepinephrine was examined in rats before and during blockade of coverting enzyme activity with the nonapeptide SQ 20881. Responses to angiotensin II were impaired by sodium deprivation but enhanced by sodium loading or bilateral nephrectomy. During the period of converting enzyme blockade, a twofold increase in the angiotensin II pressor response was observed in the salt-restricted rats, whereas only a small change occurred in the salt-loaded rats. Infusion of the inhibitor produced a profound fall in the blood pressure of the salt-depleted rats with a relatively minor fall in the sodium-loaded rats. Norepinephrine pressor responses were slightly potentiated in the salt-restricted rats after administration of SQ 20881, but no change occurred in the salt-loaded or the nephrectomized rats. These observations support the view that the decreased angiotensin II pressor activity during salt deprivation is the result of a prior occupancy of receptor sites by endogenous hormone. Therefore, a change in the number or the affinity of receptors consequent to changes in sodium balance need not be postulated to explain the phenomenon.
129 citations
Journal Article•
TL;DR: The findings reinforce the concept that sex hormones may play a role in control of peripheral blood flow and reactivity of arteriolar smooth muscle.
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.
TL;DR: Lead-treated rats were more active than age-matched controls, and endogenous levels of brain dopamine were unchanged, whereas norepinephrine was increased, suggesting a possible relationship between lead exposure during earliest developmental periods, increased motor activity, and brain norpinephrine, and not brain dopamine as previously postulated.
Abstract: Daily oral administration of lead to newborn rats has no adverse effect on their body growth. Lead-treated rats were more active than age-matched controls. Endogenous levels of brain dopamine were unchanged, whereas norepinephrine was increased, suggesting a possible relationship between lead exposure during earliest developmental periods, increased motor activity, and brain norepinephrine, and not brain dopamine as previously postulated.
TL;DR: In this article, the brain norepinephrine, dopamine, and cyclic adenosine 3',5'-monophosphate (cAMP) were measured in both intact and embolized hemispheres at intervals up to four hours.
Abstract: Local cerebral ischemia was produced in rats by internal carotid artery injection of 35μ carbon microspheres, and brain norepinephrine (NE), dopamine, and cyclic adenosine 3',5'-monophosphate (cAMP) were measured in embolized and intact hemispheres at intervals up to four hours. Sham-operated animals were controls. There was an instantaneous increase of cAMP. Norepinephrine was reduced within two minutes after embolization and remained low for four hours. Dopamine increased by five minutes after embolization and returned to normal after four hours. Results were qualitatively similar, but less, in the nonembolized hemisphere. Accumulation of cAMP is thought to be due to a direct effect of ischemic hypoxia and may be the initiating factor in increased glycolysis that occurs in ischemia. Decrease in NE may be secondary to its generalized release from presynaptic terminals throughout the brain and could be a factor in cortical vasoconstriction that follows embolization. Dopamine changes are a reflection of alterations in energy metabolism.
TL;DR: It is demonstrated that rearing rats on a diet low in protein, but adequate in all other respects, significantly elevates the brain amine content at most ages from birth through 300 days of age.
Journal Article•
TL;DR: Depolarization of isolated guinea pig vasa deferentia in vitro by either hypertonic KCl or veratridine resulted in a dose-dependent, proportional release of norepinephrine and dopamine β-hydroxylase, suggesting exocytosis from sympathetic nerve terminals may be elicited by depolarizing drugs as well as by electrical stimulation.
Abstract: Depolarization of isolated guinea pig vasa deferentia in vitro by either hypertonic KCl or veratridine resulted in a dose-dependent, proportional release of norepinephrine and dopamine β-hydroxylase. The ratio of norepinephrine to dopamine β-hydroxylase activity released by depolarizing agents was similar to that obtained by electrical stimulation of the hypogastric nerve. Thus exocytosis from sympathetic nerve terminals may be elicited by depolarizing drugs as well as by electrical stimulation. Incubation of vasa deferentia in vitro in the presence of reserpine or the sympathomimetic amines tyramine, d-amphetamine, or metaraminol resulted in the dose-dependent release of norepinephrine but not of dopamine β-hydroxylase. When calcium was omitted from the incubation medium, exocytotic release of norepinephrine and dopamine β-hydroxylase induced by depolarizing agents was blocked whereas norepinephrine release induced by sympathomimetic agents was not affected. Tetrodotoxin blocked veratridine but not tyramine-induced release. Colchicine, but not hexamethonium or atropine, blocked exocytotic release. None of these drugs affected tyramine-induced release of norepinephrine. In vasa deferentia from untreated animals, the ratio of supernatant (S2) to particulate (P2) norepinephrine concentration after centrifugation at 100,000 x g for 1 hr was 0.7. In animals treated with reserpine and a monoamine oxidase inhibitor this ratio increased to 1.3, suggesting a release of norepinephrine from vesicular into intraneuronal cytoplasmic stores. The release of norepinephrine by tyramine was enhanced in vasa deferentia from reserpine- and monoamine oxidase inhibitor-treated animals and resulted in a fall in the norepinephrine content of the S2 fraction. This suggests that tyramine may act by displacing norepinephrine from cytoplasmic stores into the synaptic space. After treatment of guinea pigs with reserpine alone or in combination with a monoamine oxidase inhibitor, electrical stimulation of the hypogastric nerve to the guinea pig vas deferens resulted in release of dopamine β-hydroxylase but not of norepinephrine. This suggests that release by exocytosis may occur in the presence of a depleted amine store and that the norepinephrine released by exocytosis is derived predominantly from vesicular reserpine-sensitive stores.
Journal Article•
TL;DR: The data suggest that 110140 is a specific drug for inhibiting uptake into serotoninergic neurons in the brain in rats, and suggests that reserpine does not require the membrane pump for entry into the neuron.
Abstract: 3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140), when injected into rats at i.p. doses of 1 to 10 mg/kg, prevented the lowering of brain serotonin by 4-chloroamphetamine. The duration of 110140 action was very long, significant antagonism of 4-chloroamphetamine action being apparent still at 48 hours after a single dose of 10 mg/kg of 110140. The N,N-dimethyl tertiary amine derivative was as effective as 110140 itself in antagonizing serotonin depletion by 4-chloroamphetamine, but other structurally related compounds has less activity or were inactive. Likewise, six tricyclic antidepressant drugs injected at 10 mg/kg i.p. did not antagonize the action of 4-chloroamphetamine. When injected into rats whose brain serotonin levels had already been depleted by 3-hour pretreatment with 4-chloroamphetamine, 110140 terminated the action of 4-chloroamphetamine and permitted serotonin levels to return to normal. Lilly 110140 did not antagonize the depletion of brain serotonin or norepinephrine by reserpine, which implies that reserpine does not require the membrane pump for entry into the neuron. The depletion of brain serotonin, but not norepinephrine, by alpha-ethyl-3-hydroxy-4-methylphenethylamine (H75/12) was blocked by 110140. In contrast to chlorimipramine, 110140 did not antagonize the depletion of norepinephrine levels in heart and spleen by 6-hydroxydopamine. The data suggest that 110140 is a specific drug for inhibiting uptake into serotoninergic neurons in the brain.
TL;DR: It is concluded that, in the late stages of hamster cardiomyopathy, there is a progressive and possibly specific increase in cardiac sympathetic tone which leads to a concomitant decrease in cardiac norepinephrine with the loss of sympathetic reserve, congestive failure supervenes.
Abstract: Although a reduction in myocardial norepinephrine stores in cardiac hypertrophy and congestive failure is well documented, norepinephrine turnover has been inadequately studied in such hearts. We compared norepinephrine turnover in control and cardiomyopathic hamsters by following the decline in specific activity of myocardial norepinephrine after labelling with an intraperitoneal tracer dose of 3H-norepinephrine. Adult myocardial norepinephrine concentrations were not attained until 4 weeks of age in both strains. There was no difference in the rate of constant (K) for myocardial norepinephrine turnover (0.107+/-0.004 hours-1 vs. 0.100+/-0.005 hours-1) in the two strains of hamsters during the neonatal period. In young control hamsters, K fell to 0.064+/-0.004 hours-1, but that for age-matched hamsters with mild cardiac hypertrophy was 0.102+/-0.001 hours-1 (P less than 0.001). There was little change in K as control hamsters aged. With the development of more severe hypertrophy in cardiomyopathic hamsters, cardiac norepinephrine decreased and resting K rapidly increased to approach the value obtained when hamsters were subjected to immobilization stress (0.302+/-0.013 hours-1). The maximum achievable K remained the same for both control and dystrophic hamsters even during terminal disease. Prolonged immobilization led to a reduction in cardiac norepinephrine in both strains. Ganglionic blockade of failing hamsters completely restored the levels of both cardiac norepinephrine and K to control values. Splenic noradrenergic nerves showed no change in K, norepinephrine content, or maximum K during cardiac decompensation. We conclude that, in the late stages of hamster cardiomyopathy, there is a progressive and possibly specific increase in cardiac sympathetic tone which leads to a concomitant decrease in cardiac norepinephrine. With the loss of sympathetic reserve, congestive failure supervenes.
Journal Article•
TL;DR: The data suggest that the area of the nucleus tractus solitarii is a site of action of hypotensive drugs which may act by noradrenergic receptor stimulation in the brain as indicated by the association of elevated blood pressure and brainstem serotonin depletion during treatment with para-chorophenylalanine of normotensive and genetic hypertensive rats.
Abstract: Noradrenaline and alpha-methylnoradrenaline applied to the area of the nucleus tractus solitarii of the medulla oblongata decreased arterial blood pressure and heart rate of anesthetized normotensive rats. Alpha-Methylnoradrenaline was more effective than noradrenaline. Prior administration of the alpha-adrenergic blocking agent phentolamine at the same site prevented the central inhibitory action of the two catecholamines and even reversed the effect on blood pressure. The hypotensive responses evoked by electrical stimulation or alpha-methylnoradrenaline application were found to have a common distribution of the most effective site, comprising the middle-caudal part of the nucleus tractus solitarii at the obex level. Bilateral electrolytic lesions of this area caused an immediate and severe hypertension. The data suggest that the area of the nucleus tractus solitarii is a site of action of hypotensive drugs which may act by noradrenergic receptor stimulation in the brain. In addition brain serotonin may also play an inhibitory role as indicated by the association of elevated blood pressure and brainstem serotonin depletion during treatment with para-chorophenylalanine of normotensive and genetic hypertensive rats.
TL;DR: The cerebral vasospasm produced by blood, fractions of blood, and blood-borne agents administered intracisternally was studied arteriographically to attain a better understanding of the genesis of vasospasms, and the results indicate this phenomenon is multifarious in origin.
Abstract: The cerebral vasospasm produced by blood, fractions of blood, and blood-borne agents administered intracisternally was studied arteriographically to attain a better understanding of the genesis of vasospasm. The results indicate this phenomenon is multifarious in origin, involving a number of spasmogens. Whole blood, platelets, platelet extracts, some isolated components of platelets, plasma, thrombin, histamine, serotonin and prostaglandins F1α, E2 and F2α produced a significant incidence and duration of spasm. Norepinephrine and prostaglandin E1 were inactive. Spasm produced by arachidonic acid and red blood cells was of questionable significance. Compared to whole blood, thrombin usually produced spasm which was more delayed in onset while most other active substances produced a shorter-lived spasm. However, among the pure substances tested, serotonin, prostaglandin E2 and prostaglandin F2α induced spasm in small doses which most nearly resembled that observed with whole blood. The hypothesis that the ...
TL;DR: Experiments following depletion of norepinephrine suggest that the central part of the baroreceptor reflex arc does not contain adrenergic neurons, but these findings are compatible with the view that some neurons within the reflex arc are supplied with α-adrenoceptors, and may represent a trigger mechanism for the initiation of hypertension.
Abstract: Electrical stimulation of the posterior hypothalamus is followed by an immediate increase in sympathetic nerve activity and rise in blood pressure. Destruction of hypothalamic adrenergic structures by local unilateral injection of 6-hydroxydopamine into the posterior hypothalamus reduced the blood pressure rise in response to stimulation of the lesioned side. This and numerous other findings indicate an involvement of central adrenergic neurons in the mediation of an increase of sympathetic nerve activity caused by hypothalamic stimulation. However, central adrenergic neurons do not seem to be an integral part of the sympathoexcitatory pathways originating in the posterior hypothalamus but rather facilitate their activation: after almost complete norepinephrine depletion produced by combined treatment with reserpine and alpha-methl-p-tyrosine, hypothalamic stimulation was still followed by an increase in spontaneous sympathetic nerve activity. Stimulation of an alpha-adrenoceptive site, probably located in the lower brain stem, mimics an activation of the baroreceptor reflex. The hypotensive drug, clonidine, stimulates this alpha-adrenoceptive site. In low doses clonidine facilitates the activation of the reflex, and in high doses this drug induces a state which closely resembles a pronounced activation of the reflex. Experiments following depletion of norepinephrine suggest that the central part of the baroreceptor reflex arc does not contain adrenergic neurons. However, these findings are compatible with the view that some neurons within the reflex arc are supplied with alpha-adrenoceptors. For the present it cannot be stated with certainty whether these alpha-adrenoceptors possess an innervation by adrenergic neurons projecting onto the reflex arc. In favor of such an innervation are the obsevations that alpha-methyldopa has its site of action in the lower brain stem and that the integrity of central adrenergic neurons is essential for its hypotensive effect. It seems that two central adrenergic systems exist with opposing effects on cardiovascular control. These are an excitatory hypothalamic and an inhibitory bulbar adrenergic system. Partial destruction of central adrenergic neurons by intraventricularly injected 6-hydroxydopamine prevents the development of DOCA/NaCl, renal, and neurogenic hypertension and alters the pattern of blood pressure rise in spontaneously hypertensive rats. Impairment of central adrenergic function or imbalance of the two central adrenergic mechanisms may represent a trigger mechanism for the initiation of hypertension.
TL;DR: The view that endogenous catecholamines underlie, at least partially, diencephalic mechanisms controlling food intake, including sensory, motor, or motivational components, is supported.
Abstract: The pattern of catecholamine release was studied at sites adjacent to the lateral ventricle or in the anterior, dorsomedial or ventromedial hypothalamus of the rat as it was feeding. Endogenous sto...
TL;DR: The localization within different regions of the amygdala of norepinephrine, dopamine and tyrosine hydroxylase, the enzyme that catalyzes the ratelimiting step in the synthesis of these amines, is examined.
TL;DR: Five patients with idiopathic orthostatic hypotension and defective vasoconstrictor responses to the Valsalva maneuver and to application of ice to the forehead were found to have absent vasconstriction in the forearm in response to intra-arterial administration of tyramine, suggesting norepinephrine depletion from the nerve endings and inability of the sympathetic nerve endings to take up nore Alpinephrine.
Abstract: Five patients with idiopathic orthostatic hypotension and defective vasoconstrictor responses to the Valsalva maneuver and to application of ice to the forehead were found to have absent v...
01 Jan 1975
TL;DR: Comparison of the responses of the larger pial vessels to norepinephrine and to sympathetic nerve stimulation suggests that maximal activation of sympathetic nerves achieves a concentration of released norpinephrine equal to 5.9 × 10-4 M.
Abstract: Determinants of Response of Pial Arteries to Norepinephrine Sympathetic Nerve Stimulation • Feline pial arteries larger than 100 M in diameter constricted in response to cervical sym- pathetic nerve stimulation or in response to topical application of norepinephrine. Smaller pial arteries were unresponsive to norepinephrine. This unresponsiveness persisted when norepinephrine was dissolved in CSF with high calcium ion concentration, or in CSF with both high calcium ion and zero magnesium ion concentration, or when it was dissolved in the acid fluid used by Wahl et al. and applied by constant infusion or by intermittent application. Com- parison of the responses of the larger pial vessels to norepinephrine and to sympathetic nerve stimulation suggests that maximal activation of sympathetic nerves achieves a concentration of released norepinephrine equal to 5.9 X 10 8 M. The constriction of the larger pial vessels in response to sympathetic nerve stimulation could account for modest reductions in cerebral blood flow.
TL;DR: Since the constriction induced by norepinephrine applied exogenously or released endogenously could be reduced by a concentration of phentolamine which had no vascular effect per se, it is concluded that the resting tone of the pial arteries is not influenced by an alpha-adrenergic component under experimental conditions.
Abstract: The question regarding the existence of an alpha-adrenergic component of pial arterial tone was investigated using a microapplication technique combined with the measurement of vascular diameter. Concentration-response curves for the alpha-receptor blocker, phentolamine, revealed no vascular reaction for a concentration range from 2.5 x 10(-11) to 2.5 x 10(-7) M. At higher concentrations (up to 1.3 x 10(-3) M) concentration-dependent dilations were observed. Constrictions of pial arteries induced by perivascular injection of 2.5 x 10(-6) M norepinephrine could be reduced by 38% and 73% when phentolamine was applied simultaneously in concentrations of 2.5 x 10(-7) and 2.5 x 10(-6) M, respectively, whereas constrictions due to 2.5 x 10(-4) M norepinephrine were not reduced by 2.5 x 10(-6) M phentolamine, indicating a competitive antagonism between norepinephrine and phentolamine for pial arteries. Stimulation of the cervical sympathetic chain (90 seconds, 10 v, 1.4 msec, 20 Hz) induced constrictions of pial arteries (mean 12%) which could be reduced by two-thirds during the simultaneous application of 2.5 x 10(-7) M phentolamine. Since the constriction induced by norepinephrine applied exogenously or released endogenously could be reduced by a concentration of phentolamine which had no vascular effect per se, we conclude that the resting tone of the pial arteries is not influenced by an alpha-adrenergic component under our experimental conditions. The dilations induced by high concentrations of phentolamine are believed to be nonspecific.
TL;DR: This work is the first validation in man that the functional integrity of the beta receptor is maintained even when the autonomic nerves are absent, and the intrinsic properties of the sinus and atrioventricular nodes are the keystone in stabilizing cardiac electrophysiology after denervation.
Abstract: Five patients who had received a transplanted human heart 1 to 3 years previously were studied to determine the effects of norepinephrine, isoproterenol and propranolol on the atrioventricular (A-V) conduction system. Using the His bundle technique, atrial, His bundle and ventricular electrograms were recorded, and central aortic pressure was monitored during the administration of these drugs. Norepinephrine was given by continuous infusion to four patients in doses ranging from 4 to 8 mug/min, with the systolic arterial pressure increasing by an average of 72 mm Hg. Concomitantly, there was an average increase in the rate of the donor atrium of 32 beats/min, and a reflex slowing of the recipient atrium of 23 beats/min. The A-H interval shortened by an average of 27 msec. Isoproterenol dose-response curves were performed in three patients, with the maximal dose being 5.2 mug by intravenous bolus infusion. The rate of the donor atrium increased by an average of 40 beats/min, and that of the recipient atrium by 18 beats/min. The A-H time shortened by an average of 25 msec, with a drop in systolic blood pressure averaging 23 mm Hg. Propranolol (7 mg intravenously) was given to three patients and the peak doses of norepinephrine and isoproterenol were again infused. Beta adrenergic blockade was achieved at this dose of propranolol since there was only a minimal increase in the donor atrial rate after infusion of the drug. The A-H interval was not altered by catecholamine infusion after achievement of beta blockade. However, the levels of systolic hypertension noted after infusion of norepinephrine was not altered by propranolol. The denervated transplanted human heart appears to respond normally to norepinephrine and isoproterenol, and the electrophysiologic effects of these agents are blocked by propranolol. Extensive investigative work in the denervated canine model has demonstrated the presence of the alpha and beta cardiovascular receptors. Although the automonic nervous system is important in cardiac performance, this work is the first validation in man that (1) the functional integrity of the beta receptor is maintained even when the autonomic nerves are absent, and (2) the intrinsic properties of the sinus and atrioventricular nodes are the keystone in stabilizing cardiac electrophysiology after denervation.
TL;DR: This paper found that cat pial arteries larger than 100 mu in diameter constricted in response to cervical sympathetic nerve stimulation suggests or in response topical application of norepinephrine and demonstrated that maximal activation of sympathetic nerves achieves a concentration of released nore-pinephrine equal to 5.9 x 10(-6) M.
Abstract: Feline pial arteries larger than 100 mu in diameter constricted in response to cervical sympathetic nerve stimulation suggests or in response to topical application of norepinephrine. Smaller pial arteries were unresponsive to norepinephrine. This unresponsiveness persisted when norepinephrine was dissolved in CSF with high calcium ion concentration, or in CSF with both high calcium ion and zero magnesium ion concentration, or when it was dissolved in the acid fluid used by Wahl et al. and applied by constant infusion or by intermittent application. Comparison of the responses of the larger pial vessels to norepinephrine and to sympathetic nerve stimulation that maximal activation of sympathetic nerves achieves a concentration of released norepinephrine equal to 5.9 x 10(-6) M. The constriction of the larger pial vessels in response to sympathetic nerve stimulation could account for modest reductions in cerebral blood flow.
TL;DR: These experiments show that K+ causes relaxation of venous smooth muscle constricted by sympathetic stimulation and does so by inhibiting the release of norepinephrine from nerve endings, and also inhibits the reuptake process.
Abstract: 1. In the intact organism, an increase in K+ concentration decreases the reactivity of blood vessels to sympathetic stimulation. The present experiments were designed to determine whether or not K+ interferes with adrenergic neurotransmission. 2. Helical strips cut from dogs' saphenous veins were incubated (4 hr) in Krebs-Ringer solution containing [7-3H]norepinephrine (5 times 10(-8) g/ml). The preparations were mounted for superfusion and isometric tension recording; the superfusate was collected for estimation of total radioactivity and for chromatographic separation of 3H-labelled norepinephrine and metabolites. 3. Supramaximal electric stimulation (5 Hz, 9 V, 2 msec) increased the tension and the [3H]norepinephrine efflux. Increasing the K+ concentration from 5-9 to 1, 15, and 20 m-equiv/l. caused a progressive depression of these contractions and diminished the total 3H efflux in proportion to the relaxation; the decrease in 3H efflux reflected a decrease in intact [3H]norepinephrine. The same increase in K+ concentration did not alter basal tension or basal 3H efflux. 4. Addition of tyramine (4 times 10(-6) g/ml. min) to the superfusate augmented both the tension and the efflux, but these actions were not depresesd by increasing the K+ concentration. 5. Cocaine, phentolamine, and phenoxybenzamine did not prevent the depression by K+ of the response to electric stimulation. 6. These experiments show that K+ causes relaxation of venous smooth muscle constricted by sympathetic stimulation and does so by inhibiting the release of norepinephrine from nerve endings. By contrast, K+ does not inhibit norepinephrine release in response to tyramine. 7. During submaximal electric stimulation (5 Hz, 1-8--3 V, 2 msec), increasing the K+ concentration from 5-9 to 10 and 15 m-equiv/l. potentiated the contractions and increased the [3H]norepinephrine efflux; at 20 m-equil/l, K+ caused transient increases in tension and 3H efflux followed by relaxation and decreased norepinephrine release. After addition of cocaine (10(-5) g/ml. min), K+ only caused relaxation and decrease in 3H efflux, showing that, in addition to inhibition of norepinephrine release, K+ also inhibits the reuptake process. 8. In higher concentrations (40 m-equil/l.), K+ caused both a liberation of norepinephrine and a direct activation of the smooth muscle cells.
TL;DR: A gas chromatographic-mass spectrometric method was used for the determination of biogenic amines in carotid body of adult and 10 days old rats, indicating that certain storage sites in this tissue may store dopamine while in other sites dopamine is a precursor of norepinephrine.
Abstract: A gas chromatographic-mass spectrometric method was used for the determination of biogenic amines in carotid body of adult and 10 days old rats. The method is ideally suited for this measurement since only small amounts of tissue were available (dry weight carotid body: adult 8.3 mug; infant 5.6 mug). In adult carotid body large amounts of dopamine (1 950 pmol/mg protein) and norepinephrine (1 140 pmol/mg protein) were found together with a comparatively small concentration of serotonin (505 pmol/mg protein). The carotid bodies of infant rats contained 1 065 pmol dopamine/mg protein and 410 pmol norepinephrine/mg protein. Epinephrine could not be detected. Surgical sympathetic denervation and chemical sympathectomy (6-hydroxydopamine) of adult carotid bodies did not significantly change the catecholamine content as compared to the controls. Reserpine depleted the catecholamines dosedependently. Administration of L-Dopa and pargyline (a monoamineoxidaseinhibitor) drastically increased the concentration of catecholamines. Treatment with a dopamine-beta-hydroxlase-inhibitor resulted in a decreased amount of norepinephrine without a simultaneous increase of dopamine. This may indicate that certain storage sites in this tissue may store dopamine while in other sites dopamine is a precursor of norepinephrine. Probably most of the dopamine and norepinephrine are stored in different cells.
Journal Article•