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PubMed1985

Norepinephrine alone versus norepinephrine plus low-dose dopamine: enhanced renal blood flow with combination pressor therapy.

Six normotensive, anesthetized dogs were infused intravenously with short-term, incremental infusions of norepinephrine (NE) with or without the addition of iv dopamine (DA) (4 micrograms/kg X min). The infusion of NE alone and in combination with low-dose DA produced similar, significant increases in mean arterial pressure. During the infusion of pressor doses of NE, the addition of DA resulted in significantly higher renal blood flow (p less than .001) and lower renal vascular resistance (p less than .001) than infusions of NE alone. Thus, the renal vasodilating action of low-dose DA persisted despite infusions of NE, a potent vasopressor which decreases renal blood flow. This suggests that shock patients receiving therapy with NE should be good candidates to receive low-dose DA to enhance renal blood flow.

Animals↗

PubMed1988

Irreversible binding and recovery of the norepinephrine uptake system using an alkylating derivative of norepinephrine.

The effects of bromoacetylaminomenthylnorepinephrine (BAAN) on the sodium-dependent, high-affinity norepinephrine (NE) uptake system in rat brain synaptosomes and CNS neuronal cultures were investigated. BAAN inhibited [3H]NE uptake into synaptosomes in a dose- and time-dependent manner (IC50, 6.5 microM). Pretreatment of cortical synaptosomes or neuronal cells with BAAN alone, followed by washing to remove free drug, reduced the Vmax but did not alter the Km value for [3H]NE uptake. The BAAN-induced reduction in Vmax was attenuated by concurrent pretreatment with desipramine and blocked by the reaction of BAAN with dithiothreitol or cysteine. In contrast, BAAN was 19-fold less potent at inhibiting [3H]dopamine uptake in striatal synaptosomes, and no change in the Vmax or Km value for [3H]dopamine uptake was observed after a pretreatment with BAAN followed by washing. Furthermore, the irreversible beta-antagonist, bromoacetylalprenololmentane, was equipotent to BAAN for inhibiting [3H]NE uptake into cortical synaptosomes, but did not alter the Vmax or Km for [3H]NE after pretreatment. In neuronal cultures, BAAN inhibited sodium-dependent uptake of [3H]NE (IC50, 5.6 microM) with no effect on sodium-independent uptake. After pretreatment of cultures with 30 microM BAAN followed by washing, there was a 74% decrease in the Vmax for [3H]NE uptake. Following a 24-h lag period, uptake recovered to the control level within 48 h; however, recovery was completely blocked by cycloheximide. The data indicate that BAAN irreversibly binds to the [3H]NE uptake system in both CNS synaptosomes and neuronal cultures and may be a useful probe for studying the turnover of the [3H]NE uptake system.

Adrenergic beta-Antagonists↗

PubMed1983

Role of norepinephrine in seizurelike activity of hippocampal pyramidal cells maintained in vitro: alteration by 6-hydroxydopamine lesions of norepinephrine-containing systems.

Perfusion of 50 microM norepinephrine (NE) produced a marked, reversible decrease (range 20-28%) of the extracellular population spike and excitatory postsynaptic potential (EPSP) responses of the CA1 region evoked by stratum radiatum stimulation in the rat hippocampal slice preparation. The effects of NE were dramatically altered in slices obtained from animals which were previously treated with intracerebral or intraventricular injections of 6-hydroxydopamine (6-OHDA) to destroy forebrain catecholamine systems. In the latter preparations NE produced a reduction in the inhibition of the EPSP (50%), enhancement of the population spike amplitude, and multiple spike discharges characteristic of ongoing epileptiform activity. The reversal of NE-induced inhibition and the generation of seizurelike activity in 6-OHDA-treated animals suggests that NE may, in part, act upon interneurons to produce a disinhibition of CA1 pyramidal cells.

Animals↗

PubMed1989

Plasma norepinephrine in humans: limitations in assessment of whole body norepinephrine kinetics and plasma clearance.

To investigate catecholamine residence in plasma, constant intravenous infusions of increasing duration (20, 40, and 80 min) of [3H]norepinephrine [( 3H]NE), [3H]isoproterenol [( 3H]IP) IP) and a reference substance: 131I-labeled hippurate were performed in six normal volunteers. In contrast to [3H]IP and 131I-hippurate, whole body clearance from plasma of [3H]NE, as obtained from infusion rate divided by plasma concentration of tracer [1.74 +/- 0.64 (SD) 1/min] was significantly higher than the value obtained by total tracer infusion divided by total plasma area of tracer (1.27 +/- 0.51, P less than 0.01). Mean residence time in plasma (theta) after stopping the infusion of [3H]NE increased along an almost straight line with progressive infusion time, theta of 131I-hippurate increased less, and constant values were recorded after 40 min infusion of [3H]IP. Our results suggest the presence of a very large (cellular) pool from which a reversible transport of [3H]NE back into plasma takes place. The plasma clearance of tracer NE, as determined from infusion rate and plasma concentration of tracer, includes transport to and accumulation in this large store. Thus the "final metabolic clearance," reflecting irreversible removal of NE, is smaller than previously estimated due to recycling through the plasma space. Attention has been drawn to limitations of [3H]NE kinetics.

Adult↗

PubMed1981

Release of [3H]norepinephrine from nerves in rat colonic mucosa: effects of norepinephrine and prostaglandin E2.

Release of [3H]norepinephrine ([3H]NE) from noradrenergic nerves innervating rat colonic mucosa was studied by superfusion of a muscle-stripped preparation of rat colon. After a period of incubation with [3H]NE, the tissue was superfused with different releasing agents. Depolarization of the tissue with a medium containing 50 mM K+ evoked the release of [3H]NE. Veratridine (5 X 10(-5) M) also stimulated the efflux of [3H]NE; this was blocked by tetrodotoxin (2 X 10(-7) M). Tyramine, which releases NE by a nondepolarizing mechanism, also evoked [3H]NE release from the colonic mucosal preparation, and this release was not decreased in the absence of calcium. Exogenous NE (10(-7) M) inhibited the high K+-evoked release by 50% in the presence of desmethylimipramine, a NE uptake inhibitor. In addition, prostaglandin E2 (1 X 10(-7) M) significantly reduced the K+-evoked release to less than 50% of control. Pretreatment with 6-hydroxydopamine, which selectively destroys NE neurons, reduced the K+-evoked release of [3H]NE to 40% of control. This study suggests that colonic mucosa of the rat contains noradrenergic nerves that function in a manner characteristic of the noradrenergic nerves in other tissues.

Animals↗

PubMed1990

Effects of oophorectomy, sympathetic denervation and sex steroids on uterine norepinephrine content and myometrial contractile response to norepinephrine in the guinea pig.

Studies were performed in guinea pigs to elucidate alterations in endogenous uterine norepinephrine (NE) levels and changes in the contractile response to exogenous NE following local sympathetic denervation, oophorectomy, or treatment with sex steroids. Both in intact and oophorectomized animals the myometrial NE concentration was reduced after sex steroid treatment (0.5 microgram 17-beta-estradiol, or 0.1 microgram estradiol plus 2 mg progesterone, during 2 weeks), mainly as a result of increased uterine weight. After surgical removal of the hypogastric nerves and section of the suspensory ligaments, a similar response to sex steroids was seen if the animals had previously been oophorectomized. The myometrial contractile activity induced by exogenous NE was measured in vitro. The EC50 values (NE concentration giving 50% of the maximal response) showed a similar pattern of variations after hormonal treatment and oophorectomy as did the concentration of endogenous NE. Thus, exposure to the steroids leading to a reduction of neuronal NE also caused an increased sensitivity of the myometrial smooth musculature to exogenous NE, and in the various experimental groups the two parameters showed a close and significant relationship. The underlying mechanism may induce a denervation supersensitivity to NE induced by exposure to estrogen and progesterone.

Animals↗

PubMed1994

Physical conditioning decreases norepinephrine-induced vasoconstriction in rabbits. Possible roles of norepinephrine-evoked endothelium-derived relaxing factor.

BACKGROUND: Physical activity can reduce sympathetic tone and may be beneficial to human health. Whether the vascular responses to norepinephrine (NE), an adrenergic vasoconstrictor, could be altered by chronic exercise was unclear. We therefore conducted this study to investigate the effects of endurance exercise training on NE-induced vasoconstrictive response in healthy rabbits. Possible mechanisms were also studied. METHODS AND RESULTS: Twenty-four male New Zealand White rabbits were used for this study. They were divided into two groups: control and training. The training group was trained on a treadmill with running speed of 0.88 km/h at a 0 degree grade for 10 to 60 minutes per day, for 5 days a week for a total of 8 weeks. At the end of the experiments, thoracic aortae (3 mm long) were isolated. The vascular tension was measured with a force transducer. The dose-response relation of NE-induced vasoconstriction was determined and compared for control (n = 5) and trained (n = 6) groups. To verify the possible involvement of endothelium-derived relaxing factor (EDRF) in the alteration of NE-induced vasoconstriction after exercise training, we compared the vascular responses to NE in endothelium-intact, N omega-nitro-L-arginine (L-NNA, 10(-4) mol/L)-pretreated, or denuded vessel segments (n = 4 for each experiment of each group). EDRF release in the presence or absence of NE was also evaluated by the increased tension induced by hemoglobin (10(-5) mol/L), an EDRF scavenger (n = 6 for the control group and n = 8 for the trained group). In addition, vascular responses to some specific adrenergic agonists (ie, phenylephrine, an alpha 1-agonist, and clonidine, an alpha 2-agonist) were also studied to see if a specific adrenergic receptor was involved (n = 4 for each experiment of each group). Our results indicated that (1) [NE]ED50 of the thoracic aorta was elevated by exercise training; (2) in the presence of NE, EDRF release from the thoracic aorta, assessed by addition of hemoglobin or L-NNA, was higher in the trained group than in the control group; (3) both phenylephrine (10(-8) mol/L) and clonidine (10(-6) mol/L) could evoke vasorelaxation that would be inhibited by L-NNA; and (4) in addition to causing vasoconstriction, NE could stimulate EDRF release, possibly via alpha 1- and alpha 2-receptors of endothelial cells. CONCLUSIONS: Our data suggest that exercise training may decrease NE-induced vasoconstrictive response and may increase NE-stimulated EDRF release.

Animals↗

PubMed2005

Ischemia-induced norepinephrine release, but not norepinephrine-derived free radicals, contributes to myocardial ischemia-reperfusion injury.

BACKGROUND: Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemia -reperfusion, so the influence of sympathetic denervation on myocardial ischemia - reperfusion injury was investigated in the present study. METHODS AND RESULTS: Cardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously administered 10 min before the coronary occlusion. The left coronary artery was occluded for 30 min and thereafter reperfused. Cardiac interstitial fluid was collected by a microdialysis probe and free radicals in dialysate were determined by electron paramagnetic resonance (EPR) spin trapping, using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. The ratio of infarct size to the ischemic area at risk (I/R) was decreased in both the phenol and atenolol groups compared with control (28.5+/-11.3, 31.8+/-10.7 vs 50.6+/-14.7%, p<0.05). During the coronary occlusion, concentrations of interstitial NE increased markedly in the control and atenolol groups, but was unchanged in the phenol group. EPR signal intensity (relative value to internal standard) was maximal at 1 h after reperfusion and was similar in the phenol and control groups (0.32+/-0.15 vs 0.45+/-0.19). CONCLUSIONS: Cardiac denervation protected myocyte against ischemia-reperfusion injury through decreasing direct NE toxicity, but not through decreasing NE-derived free radicals.

Animals↗

PubMed1981

The distribution of plasma norepinephrine concentration and the relation of plasma norepinephrine concentration to pulmonary arterial pressure in heart disease.

Plasma norepinephrine (NE) concentration was measured in blood samples from the pulmonary artery (PA), the superior vena cava (SVC), the inferior vena cava (IVC) and the femoral artery (FA) in 34 patients undergoing diagnostic cardiac catheterization. In patients with pulmonary hypertension, the mean plasma NE concentrations in PA, SVC and FA were significantly higher than that of IVC, but no such difference was found in patients without such hypertension. Except in IVC, the plasma NE concentration in patients with pulmonary hypertension was significantly higher than in others. Furthermore, the plasma NE concentration was positively correlated with the mean pulmonary arterial pressure and inversely related to pulmonary arterial oxygen saturation in patients without a shunt. These results suggest the possibility that vasoconstriction by the sympathetic nervous system may contribute to the development of pulmonary hypertension in patients without the shunt.

Adolescent↗

PubMed1982

Alteration of norepinephrine release from [3h]-norepinephrine preloaded basilar artery by naphthalenesulfonamides.

The effects of W-7, W-5, No. 233, and chlorpromazine on sympathetic nerve transmitter efflux were compared in superfused canine basilar arterial preparations preloaded with [3H]-norepinephrine. In vitro experiments suggest that these agents are selective calmodulin antagonists. The electrical transmural stimulation-induced efflux of tritium was reduced by W-7 and W-5, although they were unexpectedly equipotent since W-5 is a chloride-deficient derivative of W-7 and has a lower affinity for calmodulin than does W-7. The median inhibitory concentration (IC50) of W-7 for stimulation-induced efflux was 3.4 X 10(-6) M. The addition of No. 233 at relatively high concentrations (3 X 10(-5) M and 5 X 10(-5) M) caused a reduction in stimulation-induced efflux. Chlorpromazine produced a dual effect on the efflux: enhancement at low concentrations (below 1 X 10(-6) M) and reduction at high concentrations. The IC50 values of No. 233 and chlorpromazine were 3.5 X 10(-5) M and 2.5 X 10(-5) M, respectively. The additions of these four agents also caused a significant elevation in the spontaneous basal efflux of tritium from the preparations. The concentrations of the agents that elevated the spontaneous efflux to the level of half the stimulation-induced efflux were closely fitted to the IC50 values for stimulation-induced efflux. This finding indicates that the elevation in spontaneous efflux is directly proportional to the reduction in electrical stimulation-induced efflux. From these findings, it is concluded that naphthalenesulfonamides including W-7 have a direct effect on sympathetic nerve terminals which is independent of the effect on calmodulin.

Animals↗

PubMed1999

LLC-PK(1) cells stably expressing the human norepinephrine transporter: A functional model of carrier-mediated norepinephrine release in protracted myocardial ischemia.

In myocardial ischemia, adrenergic terminals undergo ATP depletion, hypoxia, and intracellular pH reduction, causing the accumulation of axoplasmic norepinephrine (NE) and intracellular Na(+) [via the Na(+)-H(+) exchanger (NHE)]. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter (NET), triggering massive carrier-mediated NE release and, thus, arrhythmias. We have now developed a cellular model of carrier-mediated NE release using an LLC-PK(1) cell line stably transfected with human NET cDNA (LLC-NET). LLC-NET cells transported [(3)H]NE and [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)) in an inward direction. This uptake was abolished by the NET inhibitors desipramine (100 nM) and mazindol (300 nM) and by extracellular Na(+) removal. Na(+)-gradient reversal induced an efflux of (3)H-substrate from preloaded LLC-NET cells. Desipramine and mazindol blocked this efflux. Because of its greater intracellular stability and higher sensitivity to Na(+)-gradient reversal, [(3)H]MPP(+) proved preferable to [(3)H]NE as an NET substrate; therefore, only [(3)H]MPP(+) was used for subsequent studies. The K(+)/H(+) ionophore nigericin (10 microM) evoked a large efflux of [(3)H]MPP(+). This efflux was potentiated by the Na(+),K(+)-ATPase inhibitor ouabain (100 microM), was sensitive to desipramine, and was blocked by the NHE inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; 10 microM). In contrast, EIPA failed to inhibit the [(3)H]MPP(+) efflux elicited by the Na(+) ionophore gramicidin (10 microM). Furthermore, [(3)H]MPP(+) efflux induced by the NHE-stimulant proprionate (25 mM) was negatively modulated by imidazoline receptor activation. Our findings suggest that LLC-NET cells are a sensitive model for studying transductional processes of carrier-mediated NE release associated with myocardial ischemia.

1-Methyl-4-phenylpyridinium↗

PubMed1975

Nerve stimulation-meditated overflow of norepinephrine and dopamine-beta-hydroxylase. III. Effects of norepinephrine depletion on the alpha presynaptic regulation of release.

A frequency-dependent increase in the overflow of norepinephrine (NE), 3-H-NE, total 3-H and dopamine-beta-hydroxylase (DBH) activity per nerve impulse was obtained after electrical stimulation of the isolated, perfused cat spleen. Over the range of frequencies studied, a proportional increase in the overflow of transmitter and DBH activity was observed, suggesting that an increase in the exocytotic release of NE is the primary mechanism by which the overflow of transmitter is enhanced with increasing frequencies of stimulation. The effects of 3 muM phenoxybenzamine (PBA) on the nerve stimulation-mediated overflow of NE, total 3-h, 3-h-ne and DBH activity were studied at two frequencies of stimulation, 1 and 5 Hz, in spleens from control and alpha-methyl-p-tyrosine-treated cats. Similarly, release of DBH activity was studied in spleens of reserpine-treated cats. In spleens from control cats, PBA produced a marked increase in the overflow of transmitter and DBH activity. This enhancement was more pronounced at 5 Hz than at 1 Hz. It was estimated that only 10 and 25% of the overflow of NE obtained in the presence of PBA at 1 and 5 Hz, respectively, could be accounted for by increased exocytosis. Depletion of tissue NE (80%) by pretreatment with alpha-methyl-p-tyrosine considerably reduced the effectiveness of PBA in enhancing the nerve stimulation-mediated overflow of NE, 3-H-NE, total 3-H and, particularly, of DBH activity. After reserpine treatment, the tissue NE content was reduced by more than 99%, yet the nerve stimulation-mediated release of DBH activity was similar to control spleens. PBA failed to enhance the nerve stimulation-mediated overflow of DBH activity after reserpine treatment. Thus it appears that the enhancement in the exocytotic release of transmitter by nerve stimulation observed in the presence of PBA is related to the concentration of NE in the synaptic space. Therefore, the present study is in favor of the notion that presynaptic alphareceptors may form part of a negative feedback control mechanism by which the transmitter may inhibit its own release.

Animals↗

PubMed1989

Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis.

We have examined the impact of partial injury to central noradrenergic terminals on whole tissue norepinephrine (NE) content in hippocampus and on the concentration of NE and 3,4-dihydroxyphenylacetic acid in extracellular fluid of that structure (using microdialysis perfusion). Partial unilateral depletions of hippocampal tissue NE content were produced by administration of 6-hydroxydopamine (2-10 micrograms) into the dorsal noradrenergic bundle, and 2 weeks later microdialysis probes were placed in hippocampus ipsilateral to the lesion. The resting concentration of NE in hippocampal dialysates was unaffected by the lesion unless the reduction of tissue NE content exceeded 50%. In contrast, the basal concentration of 3,4-dihydroxyphenylacetic acid in hippocampal dialysates declined in proportion to tissue NE content. Tail shock or local perfusion with excess K+ increased NE in dialysates from sham-lesioned animals and produced equivalent changes in NE in dialysates from animals with moderate (less than or equal to 50%) depletions of tissue NE content. No significant increases of NE in dialysates were observed in response to these stimuli in animals with depletions of tissue NE content greater than 50%. To the degree that transmitter level in dialysates is representative of extracellular transmitter concentration, the results suggest that compensatory processes exist by which a normal extracellular concentration of transmitter can be maintained under both basal and stimulated conditions despite the loss of up to one half of a neuronal population. (ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Effects of estradiol on norepinephrine-induced contraction, alpha adrenoceptor number and norepinephrine content in the female rabbit urethra.

Several studies have revealed that estrogen treatment increases the reactivity to catecholamines of various tissues. In the present study it was found that estrogen treatment caused an increased sensitivity to norepinephrine (NE) of the isolated female rabbit urethra. There was a 3-fold shift to the left of the concentration-response curve for longitudinal tension in perfused urethras and for tension in urethral ring preparations. Possible mechanisms for this increase in sensitivity were investigated by studying radioligand binding to the alpha adrenoceptors and by measuring the NE content of the urethras. Using [3H]dihydro-alpha-ergocryptine as a marker for alpha adrenoceptors, a more than 2-fold increase in the receptor number was found after estrogen treatment. This is suggested to be attributable to a selective increase in the number of alpha-2 adrenoceptors. No significant change was found in the affinity of [3H]dihydro-alpha-ergocryptine to the receptor. The total NE content in the urethra was not changed by estrogen treatment. However, if calculated per milligram of wet weight, the NE content was reduced to half in estrogen treated animals. It is suggested that in the rabbit urethra the estrogen-induced increased sensitivity to the contractant effects of NE, at least in part, is attributable to an increase in the number of postjunctional alpha-2 adrenoceptors.

Animals↗

PubMed1984

The neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of [3H]norepinephrine from rat cortical slices.

The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with [3H]NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

Amines↗

PubMed1984

[Effects of continuous pure tone stimulation on blood pressure, plasma norepinephrine and urinary norepinephrine concentration in stroke-prone spontaneously hypertensive rats].

The present study was undertaken to elucidate the effect of pure tone stimulation on sympathetic nerve activity in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were exposed to a pure tone stimulation of 4 KHz at 60 dB SPL tone burst which was interrupted at a frequency of one second and continued for one hour a day for either one 10 day course period or two 10 day course periods. Over a period of 10 days, Group A received one hour-long stimulation daily. Group B received the same type of stimulation for two separate 10 day course periods and Group C did not receive any tone stimulation. Group A and Group C did not show any significant changes in blood pressure, heart rate or body weight. However, an increase in urinary norepinephrine (NE) (p less than 0.02) which returned to pretreatment levels after tone stimulation was observed in Group A. Group B showed a significant increase in blood pressure as compared with Group A (p less than 0.02): the systolic blood pressure of Group B was 233.2 +/- 36.1 mmHg; the systolic blood pressure of the sex-age matched Group A was 193.0 +/- 25.7 mmHg. Group B displayed an increase in plasma NE concentration as compared with Group A (p less than 0.05). These findings demonstrated that the summation of two 10 day course pure tone stimulations produced a larger increase in blood pressure and plasma NE concentration than one 10 day course stimulation. These increase in blood pressure and plasma NE concentration occurred via an increase in sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1983

Release of norepinephrine from organ-cultured superior cervical ganglia: effects of the norepinephrine uptake inhibitor xylamine.

After preloading with [3H]norepinephrine (NE), organ-cultured superior cervical ganglia released increased amounts of [3H]NE when incubated with depolarizing K+ concentrations, tyramine or amphetamine. K+-induced release was Ca++-dependent, whereas tyramine- and amphetamine-induced release were not. Analysis of the released radioactivity by high-pressure liquid chromatography showed that these releasing stimuli caused primarily an increase in NE release, with little increase in the release of NE metabolites. Incubation with 10 microM xylamine, an irreversible inhibitor of NE uptake, caused a small increase in [3H]NE efflux, but no reduction in the endogenous NE and dopamine levels in superior cervical ganglia. After xylamine treatment, tyramine-induced release was greatly inhibited, whereas release by amphetamine and K+ was not. The neuronal uptake inhibitor desipramine (1 microM), affected K+-, tyramine- and amphetamine-induced release in a manner similar to xylamine. It is concluded that xylamine is a very weak releasing agent in this tissue and that its effects on other release processes are consistent with its action as a NE uptake inhibitor. Amphetamine-induced release appears not to require the NE uptake system for either the uptake of amphetamine, as shown by the accumulation of [3H]amphetamine, or the efflux of NE.

Animals↗

PubMed1980

Evidence that there are subcellular pools of norepinephrine and that there is flux of norepinephrine between these pools.

d-Amphetamine evokes blood pressure responses that are dose-dependent in magnitude and in shape. At a high dose, d-amphetamine evokes a response that decays biphasically. Response decay is not due to receptor desensitization or to decreasing plasma levels of drug. The first component of the biphasic decay (early, transient response) has an apparent peak of approximately 56 mm Hg and a rate constant for decay of approximately 0.043-min-1. The second component (late, relatively stable response) has an apparent peak of approximately 27 mm Hg and a rate constant for decay less than 0.0043-min-1. Chronic reserpine treatment diminishes the blood pressure response to a high dose of d-amphetamine, but it exerts a differential effect on the two components of the response. The ID50 for reducing the early, transient response is greater than 800 micrograms/kg; the ID50 for reducing the late, relatively stable response is approximately 100 micrograms/kg. Acute reserpine treatment enhances blood pressure responses to d-amphetamine, mainly by enhancing the early, transient response. In addition, acutely administered reserpine reverses the tachyphylactic effect of d-amphetamine. The data are used to construct a model for norepinephrine storage in postganglionic sympathetic nerves and to propose a model for d-amphetamine-induced tachyphylaxis.

Adrenalectomy↗