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Results for “Norepinephrine”

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PubMed1992

Effect of ketamine HCl on norepinephrine disposition in isolated ferret ventricular myocardium.

The purpose of this study was to determine if ketamine altered the release or disposition of norepinephrine at adrenergic nerve terminals in isolated ferret myocardium. In superfused right ventricular strips, the effect of ketamine on norepinephrine release and uptake was determined. Dihydroxyphenylglycol, the intraneuronally derived metabolite of norepinephrine, served as an index of neuronal uptake and was also measured in superfusate. Pharmacological manipulation of selective aspects of adrenergic transmission with corticosterone, yohimbine, clorgyline and desmethylimipramine allowed the primary site of action of ketamine to be established. Quantitation of tissue norepinephrine content after the experiments provided another means to evaluate ketamine's effect on norepinephrine release as well as to estimate the density of adrenergic innervation in ferret myocardium. Norepinephrine and dihydroxyphenylglycol were quantitated by high-pressure liquid chromatography with electrochemical detection. Ketamine increased norepinephrine overflow and decreased the efflux of dihydroxyphenylglycol in isolated myocardium. Studies in the presence of the clorgyline suggest that ketamine does not increase norepinephrine overflow by means of monoamine oxidase inhibition, and studies in the presence of desmethylimipramine and corticosterone indicate that ketamine does not augment norepinephrine release. Quantitation of tissue norepinephrine content demonstrates that ketamine does not cause depletion of myocardial catecholamines. The ketamine-induced increase in norepinephrine overflow and the observed decrease in dihydroxyphenylglycol production suggest that inhibition of the neuronal uptake of norepinephrine is the primary mechanism of ketamine's effect in isolated myocardium.

Animals↗

PubMed1988

Alkylation of alpha-1 receptors with a chemically reactive analog of prazosin reveals low affinity sites for norepinephrine in rabbit aorta.

The effect of a newly synthesized irreversible blocker of the alpha-1 receptor [1-(4-amino-6,7-dimethoxy-2-quinazolnyl)-4-(2-bicyclo[2,2,2] octa-2,5-dienylcarbonyl)-piperazine; SZL-49] has been evaluated in contractile studies in rabbit aorta and binding studies in aorta and brain. SZL-49 produced long lasting inhibition of norepinephrine-induced contractions which was apparent 21 hr after drug washout. The inhibition, which was dose and time dependent, was characterized by progressive shift to the right in the norepinephrine dose-response curve. The ED50 for norepinephrine was shifted from 10(-7) M to 8 X 10(-7), 3 X 10(-6), 1 X 10(-5) and 5 X 10(-4) M after incubation (30 min) and washout of increasing concentrations of SZL-49. Surprisingly, SZL-49, irrespective of the dose or incubation time, did not decrease the maximal response of aortic rings to norepinephrine. This resulted in a norepinephrine dose-response curve after SZL-treatment that is parallel to the control. SZL-49 had no effect on the spasmogenic actions of histamine, serotonin, KCl or CaCl2. In contrast to the inhibitory pattern seen with SZL-49, incubation with 10(-7) M phenoxybenzamine shifted the norepinephrine dose-response curve to the right in a nonparallel manner and significantly depressed the maximal response obtainable with norepinephrine. Incubation with 10(-6) M phenoxybenzamine for 30 min virtually abolished the response to norepinephrine. Phenoxybenzamine (10(-7) M) was without effect on aortic rings treated with a maximally effective dose of SZL-49. Prazosin weakly antagonized the contractile actions of norepinephrine observed after SZL-49 treatment, whereas yohimbine was without effect on these norepinephrine-induced contractions. In control binding studies [3H]prazosin bound to two classes of sites in both aorta and brain preparations. Affinities and densities for these sites were K1 = 67.5 pM, K2 = 309 pM; R1 = 38.2 fmol/mg, R2 = 46.47 fmol/mg in aorta and K1 = 29.6 pM, K2 = 182 pM; R1 = 6.6 fmol/mg and R2 = 30.4 fmol/mg in brain. Treatment with increasing amounts of SZL-49 (10(-10) to 10(-8) M) progressively reduced the number of [3H]prazosin sites without altering the affinity of the sites remaining. At 10(-7) M, SZL-49 eliminated completely all specific [3H]prazosin binding. Our results indicate that the site mediating norepinephrine contraction after treatment with SZL-49 does not possess the characteristics of an alpha-1 receptor and supports the hypothesis that a low affinity site for norepinephrine and prazosin exists in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗

PubMed1982

Contribution of depressed reuptake to the depletion of norepinephrine from rat heart and spleen during endotoxin shock.

Norepinephrine content (microgram/g) was depressed in hearts and spleens of fasted male Holtzman rats treated intravenously with Salmonella enteritidis lipopolysaccharide (14-17 mg/kg). To investigate the mechanism of norepinephrine depletion during endotoxicosis, in vivo norepinephrine reuptake was evaluated in control and severely shocked rats using the incorporation of 3H-norepinephrine into hearts and spleens. Incorporation of 3H-norepinephrine into spleens of endotoxic rats was reduced 88%, i.e., from a control of 2309 +/- 224 dpm/gm to 270 +/- 69 dpm/gm after endotoxin. In contrast, cardiac tissue incorporation of 3H-norepinephrine was not significantly impaired, i.e., control of 11838 +/- 845 dpm/gm versus severe shock of 17783 +/- 2904 dpm/gm. In vitro analysis of total norepinephrine retained in cardiac and splenic tissue slices incubated with 3H-norepinephrine yielded results consistent with in vivo experiments: Splenic norepinephrine reuptake was significantly decreased on the order of 50% in preparations from endotoxic rats, while myocardial norepinephrine reuptake was the same in both groups. The results indicate that depression of norepinephrine reuptake is a mechanism of norepinephrine depletion in spleens but not hearts of endotoxic rats.

Animals↗

PubMed2000

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

Adult↗

PubMed1982

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients.

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.

Antidepressive Agents↗

PubMed1987

Responses of rat dorsal horn neurons to natural stimulation and to iontophoretically applied norepinephrine.

Extracellular recordings were obtained of 177 neurons throughout the lumbar spinal dorsal horn of urethane- or halothane-anesthetized rats. These neurons all responded to iontophoretically applied L-glutamate and their responses to natural stimulation of the ipsilateral hindlimb were characterized. Iontophoretically applied norepinephrine was tested on 94 of these neurons. Fifty-one neurons were inhibited and 22 were excited. Norepinephrine produced a biphasic inhibitory/excitatory effect on nine neurons. Norepinephrine was exclusively inhibitory on superficial dorsal horn neurons that responded only to innocuous brush and touch and on neurons in the nucleus proprius that responded to brush, touch, and noxious skin pinch. Norepinephrine excited some superficial brush/touch/pinch neurons and produced short inhibitions that were followed by prolonged excitations of some nucleus proprius neurons that responded only to noxious skin pinch. Neurons in the base of the dorsal horn that responded to low-threshold proprioceptive stimulation were excited by norepinephrine. Both the inhibitory and excitatory effects of norepinephrine were stereoselective, but they were not blocked by receptor subtype-selective antagonists. Desensitization to norepinephrine occurred for 30% of the neurons. This study demonstrates that the inhibitory effects of norepinephrine on rat dorsal horn neurons are not restricted to neurons that are responsive to noxious stimuli and that some of these neurons are primarily excited by norepinephrine. The excitatory effects of norepinephrine on low-threshold proprioceptive neurons may contribute to norepinephrine's known enhancement of spinal flexor reflex activity.

Action Potentials↗

PubMed1988

Comparison of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) effects on mouse heart norepinephrine.

MPP+ (1-methyl-4-phenylpyridinium) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in producing marked, dose-related depletion of cardiac norepinephrine after a single oral or subcutaneous dose in mice. MPP+ was approximately 4-fold more potent than MPTP in depleting norepinephrine, but the onset of depletion was not faster for MPP+ than for MPTP. The time courses of the effects of both compounds were similar to that for 6-hydroxydopamine, with maximum depletion occurring at 1 day, partial recovery at 2 and 4 days, and full recovery of norepinephrine concentrations at 1 week. Desipramine, over a dose range that completely prevented the depletion of cardiac norepinephrine by 6-hydroxydopamine at 24 hr, did not prevent cardiac norepinephrine depletion by either MPP+ or MPTP. In a short duration experiment, one or two doses of desipramine also failed to prevent heart norepinephrine depletion by MPP+ or by MPTP, although a slight antagonism was found. EXP 561 (4-phenylbicyclo[2,2,2]octan-1-amine hydrochloride monohydrate), another uptake inhibitor with possibly longer duration of action, also did not protect against norepinephrine depletion by a single dose of MPP+ or MPTP at a dose that prevented norepinephrine depletion by 6-hydroxydopamine. In mice given four daily doses of MPTP, EXP 561 prevented the depletion of norepinephrine in the frontal cortex and of dopamine in the striatum but not the depletion of norepinephrine in heart or spleen. Thus, both MPTP and MPP+ deplete norepinephrine in mouse heart, and this effect of the two compounds is resistant to antagonism by uptake inhibitors that antagonize the effects of MPTP on brain catecholamines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Dopamine and norepinephrine in the alimentary tract changes after chemical sympathectomy and surgical vagotomy.

The aim of this study was to examine the distribution of dopamine and norepinephrine in the proximal alimentary tract of the rat and to assess the contributions of sympathetic and vagal fibers to the tissue concentrations of both catecholamines. Tissues were extracted in perchloric acid and the catecholamines were separated by high pressure liquid chromatography and detected electrochemically. In untreated rats (controls) both catecholamines were concentrated in the gastric muscle but norepinephrine levels were 6-8 times higher (corpus, dopamine 35 +/- 7 ng . g-1, norepinephrine 265 +/- 50 ng . g-1, mean +/- SE, n = 6). In the mucosa norepinephrine concentrations were 10-12 times higher (corpus, dopamine 12 +/- 3 ng . g-1, norepinephrine 140 +/- 26 ng . g-1). Chemical sympathectomy (6 hydroxydopamine, 100 mg . kg-1 ip 3 days) significantly reduced dopamine concentrations in muscle and norepinephrine in muscle, mucosa, pylorus and duodenum. In all tissues the effects on norepinephrine were greater. Surgical vagotomy significantly reduced dopamine concentrations in the gastric muscle, but not the mucosa. Norepinephrine concentrations in the stomach of vagotomized rats were significantly reduced only in the pylorus. Differences in the relative concentrations of dopamine and norepinephrine in gastric tissues of the normal rat and differences in the effects of sympathectomy and vagotomy suggest that dopamine and norepinephrine exist, to an extent, in separate populations of cells and that dopamine is not merely a precursor of norepinephrine. Gastric mucosal dopamine, which was mainly unaffected by either treatment, may exist in APUD cells.

Animals↗

PubMed1988

Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies.

The release of endogenous norepinephrine in hippocampus was studied in freely moving rats with microdialysis perfusion. Using a loop-style dialysis probe, the basal amount of norepinephrine collected in 15-min fractions averaged 12 pg/25 microliters. Correcting for recovery (21%), the concentration of norepinephrine in the extracellular fluid of hippocampus under resting conditions was estimated to be approximately 14 nM. The alpha 2 adrenoceptor antagonist yohimbine (5.0 mg/kg, i.p.) increased norepinephrine efflux to 230% of basal levels. Clonidine (0.3 mg/kg, i.p.), an alpha 2 adrenoceptor agonist, decreased norepinephrine efflux to 56% of baseline. Addition of the reuptake blocker desipramine (1.0 microM) to the perfusate had no significant effect on norepinephrine efflux. However, increasing the K+ concentration of the perfusate to 30 mM increased norepinephrine efflux to 196% of baseline, and this effect was increased nearly two-fold by the addition of desipramine to the perfusate (364% of baseline). Restraint stress and intermittent tailshock increased norepinephrine efflux to 213% and 234% of baseline, respectively. The results suggest that microdialysis is a useful way to study norepinephrine release in hippocampus and they permit several conclusions to be drawn. First, the data obtained with systemic administration of alpha 2 adrenoceptor drugs emphasize the fact that a variety of regulatory mechanisms exist that may affect transmitter levels in the extracellular fluid. Second, the ratio of extracellular to intracellular norepinephrine in hippocampal tissue is considerably higher than that reported for dopamine in striatum. Coupled with the small effect of norepinephrine uptake blockade, this suggests that nerve terminal density is an important factor in determining the concentration of catecholamines in the extracellular fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Evidence for reduction of norepinephrine uptake sites in the failing human heart.

OBJECTIVES: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.

Adult↗

PubMed2006

Effect of norepinephrine on RhoA, MAP kinase, proliferation and VEGF expression in human umbilical vein endothelial cells.

Norepinephrine is a well known major vasoconstricting factor. Recent reports suggest that norepinephrine, in addition to acting as a vasoconstricting factor, may also play several additional roles in endothelial cells. These include: 1] induction of NO release. It has been demonstrated that a small GTP-binding protein, Rho, and its downstream effecter, Rho kinase (ROCK), negatively regulate endothelial nitric oxide synthase (eNOS) production. However, it is not known whether ROCK is directly involved in norepinephrine-induced NO release. 2] Norepinephrine is reported to induce a mitogenic effect, but whether MAPKs are involved in this process is unknown. 3] Recently, we demonstrated an increase in vascular endothelial growth factor (VEGF) mRNA/protein expression in human pheochromocytoma tissue in comparison to normal adrenomedullary tissue. Thus, it is reasonable to speculate that norepinephrine may stimulate the level of VEGF mRNA. The aim of the present study was to clarify the role of norepinephrine and related endothelial adrenoceptor systems in various pathophysiological conditions, such as hypertension and in particular pheochromocytoma, using human umbilical vein endothelial cells (HUVEC). Norepinephrine-induced RhoA attenuation, through cAMP/protein kinase A (PKA) activation coupled with beta-adrenoceptors, may lead to eNOS activation in acute conditions. Norepinephrine stimulates the production of VEGF mRNA through cAMP/PKA activation coupled with beta-adrenoceptors. Norepinephrine stimulates a mitogenic effect through ERK activation coupled with the alpha(1)-adrenoceptor. In conclusion, norepinephrine stimulates eNOS activity via RhoA attenuation, VEGF mRNA synthesis and mitogenic activity in endothelial cells. We propose that an excess of norepinephrine can lead to endothelial dysfunction due to these aforementioned processes.

Blotting, Western↗

PubMed2002

Neuropeptide Y modifies the hypertrophic response of adult ventricular cardiomyocytes to norepinephrine.

OBJECTIVE: The hypertrophic response of adult rat cardiomyocytes to norepinephrine via alpha-adrenoceptor stimulation is limited by an inhibitory cross-talk of simultaneously beta-adrenoceptor stimulation. On the other hand, neuropeptide Y (NPY), known to be co-secreted with norepinephrine from intramural nerve endings of the heart, exerts an anti-beta-adrenergic effect. Therefore, it should be expected that NPY enhances the hypertrophic response to norepinephrine. This hypothesis was addressed in the present study. METHODS: Isolated adult ventricular cardiomyocytes from rats were used. As parameters of hypertrophic growth we investigated cell volume, cross-sectional area, protein mass. Protein and RNA synthesis were determined by incorporation of [(14)C]phenylalanine or [(14)C]uridine, respectively. RESULTS: Norepinephrine (1 micromol/l) did not significantly increase protein or RNA synthesis. In co-presence of NPY (100 nmol/l), however, norepinephrine increased protein synthesis by 44% and RNA synthesis by 18%. Under the same conditions, NPY enhanced the effect of norepinephrine on cell volume from +6.4 to +18.2%, its effect on cross-sectional area from +16 to +23%, and increased the protein/DNA ratio from 32.5 to 35.6 mg/mg. In parallel, norepinephrine caused a translocation of PKC-alpha and PKC-delta into the particular fractions and this effect of norepinephrine was also enhanced by co-presence of NPY. In contrast, NPY did not enhance ERK-activation caused by norepinephrine. CONCLUSION: Our study indicates the anti-beta-adrenergic effect of NPY is sufficient to modulate the hypertrophic response of adult ventricular cardiomyocytes to norepinephrine. The results suggest that the hypertrophic effect of norepinephrine via alpha-adrenoceptor stimulation can be modulated by co-release of NPY from intramural nerve endings.

Animals↗

PubMed1993

Effects of norepinephrine and dobutamine on oxygen transport and consumption in a dog model of endotoxic shock.

OBJECTIVES: Severe septic shock is associated with an imbalance between oxygen demand and oxygen supply (DO2) in the presence of an impaired oxygen extraction. Vasopressors are often used to restore a minimal perfusion pressure and inotropic agents are often used to increase myocardial contractility. However, optimal adrenergic support remains controversial. The present study investigated the effects of norepinephrine and dobutamine on DO2, oxygen consumption (VO2), and oxygen extraction in a dog model of endotoxic shock. DESIGN: Prospective, randomized, cross-over trial. SETTING: University intensive care laboratory. SUBJECTS: A total of 14 mongrel dogs anesthetized with pentobarbital and mechanically ventilated with air. INTERVENTIONS: The dogs received 2 mg/kg Escherichia coli endotoxin intravenously. After 30 mins, fluid administration with 0.9% saline was started to restore baseline filling pressures. The dogs randomly received dobutamine and norepinephrine. Each agent was infused for 20 mins followed by a drug free interval of 30 mins so that each dog could serve as his own control. Results for norepinephrine were grouped as low dose (0.1 and 0.2 micrograms/kg/min) and high dose (0.5 and 1.0 micrograms/kg/min). Results for dobutamine were also grouped as low dose (5 micrograms/kg/min) and high dose (10 micrograms/kg/min). MEASUREMENTS AND MAIN RESULTS: Norepinephrine increased both mean arterial pressure (MAP) and cardiac output without a significant change in systemic vascular resistance. Only high-dose norepinephrine increased DO2 (from 969 +/- 62 to 1240 +/- 49 mL/min [p < .001]) and VO2 (from 176 +/- 15 to 194 +/- 14 mL/min [p < .001]). Dobutamine increased both cardiac output and MAP. Both low- and high-dose dobutamine increased DO2 (from 891 +/- 91 to 1142 +/- 99 mL/min [p < .001] and from 847 +/- 54 to 1317 +/- 75 mL/min [p < .001], respectively) and VO2 (from 172 +/- 14 to 182 +/- 15 mL/min [p < .001] and from 168 +/- 13 to 184 +/- 14 mL/min [p < .001], respectively). The increase in VO2 for a given increase in DO2 was higher with high-dose norepinephrine compared with high-dose dobutamine. When all doses were taken together, DO2 increased more with dobutamine than norepinephrine. Oxygen extraction decreased with all doses for both norepinephrine and dobutamine. CONCLUSIONS: In this endotoxic shock model, both norepinephrine and dobutamine can increase DO2 and VO2 but dobutamine caused a more consistent increase in these parameters. The decrease in oxygen extraction was relatively similar with dobutamine and norepinephrine. The present study does not support a significant beneficial effect of norepinephrine on the tissue extraction capabilities in endotoxic shock.

Animals↗

PubMed1994

Endotoxin enhances norepinephrine release in the rat by peripheral mechanisms.

The study was designed to investigate the effects of endotoxin administration on norepinephrine release in vivo in the rat. The norepinephrine release rate was calculated from the steady-state concentration of endogenous norepinephrine and [3H]norepinephrine in the central venous pool after infusion of [3H]norepinephrine intra-arterially. This method corrects for both metabolism and disposition as the infused tracer closely follows the normal pathway of neuronally released norepinephrine. Measurements were made in anesthetized intact rats as well as in pithed rats with electrically stimulated sympathetic outflow (3 Hz). Comparisons were made before and for 60 min following administration of bacterial endotoxin (10 mg/kg intravenously) or an equal volume of saline (vehicle). Plasma levels of norepinephrine and epinephrine increased significantly in both anesthetized and pithed preparations after endotoxin, whereas plasma norepinephrine clearance decreased only in anesthetized rats. Norepinephrine release rates were significantly increased in anesthetized as well as in pithed rat preparations after endotoxin. Plasma epinephrine was elevated more in pithed than anesthetized rats. The blood pressure fall was more rapid in pithed compared to anesthetized rats following endotoxin, which probably indicates that the central nervous system is able to compensate to some extent for the blood pressure fall in the anesthetized rat. Heart rate was unchanged in both preparations following endotoxin. Significant increases in norepinephrine release rates induced by bacterial endotoxin in pithed rats with constant frequency sympathetic nerve stimulation suggests that some factor in endotoxicosis enhances the release of norepinephrine by an action at peripheral nerve terminals.

Analysis of Variance↗

PubMed1985

Chronic norepinephrine infusion and adrenergic function of hypertrophied hearts.

The ability of chronic subpressor norepinephrine infusion to prevent depletion of myocardial norepinephrine stores and deterioration of myocardial adrenergic nerve function in congestive heart failure was examined. Four groups of adult male Wistar rats were subjected to aortic constriction or sham aortic constriction, along with either norepinephrine infusion or infusion of vehicle alone. After 7 days of treatment, these animals were evaluated for myocardial norepinephrine content, ventricular mass, and resting hemodynamics. Chronotropic and inotropic responses to electrical stimulation of the left and right cervical sympathetic trunks and to intravenous injections of tyramine and norepinephrine were measured. Chronic norepinephrine infusion normalized myocardial norepinephrine content in aortic-constricted rats but did not significantly affect heart size or mortality. Norepinephrine infusion diminished responses to sympathetic nerve stimulation, despite apparently normal myocardial norepinephrine sensitivity. The results suggest that chronic norepinephrine infusion suppresses neurotransmission in the heart by some means unrelated to its norepinephrine store. This suppression may be compensatory and reversible.

Animals↗

PubMed1992

Increased norepinephrine spillover into the jugular veins in essential hypertension.

In essential hypertension sympathetic nerve firing is commonly increased. A central nervous system origin has been presumed but not tested directly. To estimate cerebral norepinephrine release in essential hypertension, spillover of norepinephrine into the cerebrovascular circulation was measured by isotope dilution, with high internal jugular venous sampling. Norepinephrine was released into the cerebrovascular circulation in both hypertensive patients and healthy volunteers and was present after administration of the ganglion blocker trimethaphan and in patients with sympathetic nervous failure, indicating that brain neurons and not cerebrovascular sympathetic nerves were the probable source. Although differing among hypertensive patients, norepinephrine spillover on average was higher in the hypertensive patients (153 +/- 41 pmol/min) than in healthy subjects (59 +/- 12 pmol/min; p less than 0.05), and was elevated in six of 17 patients, in whom the accompanying whole body norepinephrine spillover rate was higher than in the remaining 11 patients (p less than 0.01). To test for a possible link between brain norepinephrine release and human sympathetic nervous function, the effect of the tricyclic antidepressant desipramine (0.3 mg/kg i.v.) on both brain and whole body norepinephrine spillover was measured in healthy volunteers. Desipramine lowered the cerebrovascular spillover of norepinephrine, its precursor dihydroxyphenylalanine, and its metabolite dihydroxyphenylglycol by 50-80% and produced a mean fall of 35% in whole body norepinephrine spillover. One interpretation of these results is that human sympathetic nerve firing is dependent on norepinephrine release within the brain and that increased cerebral norepinephrine release may possibly be present in some patients with essential hypertension, underlying their higher sympathetic nerve firing rates.

Cerebrovascular Circulation↗

PubMed1992

Plasma norepinephrine responses to head-up tilt are misleading in autonomic failure.

The failure of plasma norepinephrine to rise during upright posture is accepted as a diagnostic sign of autonomic nervous failure in patients with postural hypotension. Our clinical experience has been that this test is misleading, with an increase in plasma norepinephrine commonly occurring. To test whether this might result from absent reflex postural venous constriction lowering cardiac output and plasma norepinephrine clearance, we measured norepinephrine plasma kinetics during recumbency and 30 degrees head-up tilting in six patients with pure autonomic failure and eight healthy subjects. Mean arterial pressure fell by 54 +/- 8 mm Hg with head-up tilt in the patients with pure autonomic failure. The plasma norepinephrine concentration (arterial sampling) increased 73 +/- 29 pg/ml (mean difference +/- SED, p less than 0.02), solely because of a 36% reduction in the clearance of norepinephrine from plasma (0.78 +/- 0.09 l/min, p less than 0.0001). In normal subjects, plasma norepinephrine concentration rose by 112 +/- 20 pg/ml (p less than 0.001), largely because of a 24% increase in norepinephrine spillover to plasma (190 +/- 20 ng/min, p less than 0.005). When the postural fall in blood pressure and cardiac output in the pure autonomic failure patients was prevented by the selective venoconstrictor dihydroergotamine (10 micrograms/kg i.v.), no fall in plasma clearance or rise in plasma concentration of norepinephrine occurred. Measurement of the change in plasma norepinephrine with postural stimulation in patients with orthostatic hypotension is not a reliable diagnostic test for autonomic failure because elevations can occur in the plasma concentration that are entirely attributable to reduced plasma norepinephrine clearance.

Autonomic Nervous System Diseases↗

PubMed1996

Chronic renal neuroadrenergic hypertension is associated with increased renal norepinephrine sensitivity and volume contraction.

Individuals with essential hypertension have been characterized by increased renal sympathetic vascular tone with decreased plasma volume and normal cardiac output compared with normotensive individuals. We used a servo-controlled intrarenal infusion system to evaluate the hemodynamic, renal excretory, and plasma hormonal responses to 28-day, low-level elevations in the intrarenal adrenergic neurotransmitter norepinephrine. In uninephrectomized dogs (n = 6), servo-controlled norepinephrine infusion increased mean arterial pressure from 95.6 +/- 3.1 to 115.7 +/- 4.9 mm Hg on day 1 without concomitant reductions in renal blood flow. Arterial hypertension was sustained and renal vascular resistance increased during the 28 days of servo-controlled norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine (1.49 +/- 0.23 to 0.47 +/- 0.25 mg/d) necessary to maintain renal blood flow constant. Arterial pressure returned to control values with the cessation of servo-controlled norepinephrine, whereas renal blood flow and renal vascular resistance remained slightly decreased and increased, respectively. Cumulative sodium balance exhibited a net 177 +/- 37 mmol sodium loss over the 28 days of norepinephrine infusion, indicating that the hypertension did not result from sodium retention or expansion of extracellular fluid volume. Intrarenal norepinephrine did not change plasma epinephrine, norepinephrine, or vasopressin concentrations. Atrial natriuretic factor, however, increased at 7 and 14 days of servo-controlled norepinephrine, and plasma renin activity increased on day 14 of norepinephrine infusion. We conclude that low-level elevation of intrarenal adrenergic neurotransmitter produces sustained arterial hypertension that is independent of expansion in extracellular fluid volume, increases in circulating catecholamines or plasma renin activity, or reductions in renal blood flow. This hypertension may be associated with increased renal vascular sensitivity to norepinephrine and/or other renal vasoactive factors.

Animals↗