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Results for “Norepinephrine”

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At least 487 records · Page 27Linked to original sources

PubMed2003

Effects of enalaprilat on venoconstriction to norepinephrine: role of prostaglandins.

OBJECTIVE: Most patients with cardiovascular disease continue to receive both aspirin and an angiotensin-converting enzyme (ACE) inhibitor. This is despite the fact that ACE inhibition also inhibits the enzyme kininase II and leads to accumulation of bradykinin which increases prostaglandins. We hypothesized that in normal veins, vasodilator prostaglandins contribute significantly to ACE inhibitor dilation of norepinephrine-induced venoconstriction, and this would be blocked by cyclooxygenase inhibition. METHODS: The study was performed using the in vivo dorsal hand vein technique for measuring vascular responses directly. Venoconstriction to norepinephrine infusions (0.5-1024 ng/min) was assessed in eight normal subjects (46+/-5 years, mean+/-S.E.M.) during coinfusion of saline in one hand (control) and enalaprilat (1000 microg/min) in the contralateral hand. On a second morning (7+/-1 days apart, mean+/-S.E.M., random order), the same procedure was repeated with indomethacin (3 microg/min) coinfusion in both hands. RESULTS: Enalaprilat shifted the norepinephrine dose-response curve to the right (P=0.024) and increased the norepinephrine log ED(50) (dose required to cause 50% venoconstriction) from 1.70+/-0.08 to 2.31+/-0.11 log ng/min (P=0.001). Indomethacin shifted the norepinephrine dose-response curve to the left (P=0.018) and decreased the norepinephrine log ED(50) from 1.70+/-0.08 to 1.09+/-0.18 log ng/min (P=0.002). In the presence of indomethacin, enalaprilat caused only a small but significant increase in the norepinephrine log ED(50), from 1.09+/-0.18 to 1.29+/-0.18 log ng/min (P=0.041). CONCLUSIONS: The results suggest that vasodilator prostaglandins contribute significantly to the attenuation of sympathetic venoconstriction by enalaprilat. This may have clinical relevance in patients receiving aspirin and ACE inhibitors in the setting of increased sympathetic activity.

Adult↗

PubMed1985

Inhibitory effects of the D(-)isomer of 3-hydroxybutyrate on cardiac non-esterified fatty acid uptake and oxygen demand induced by norepinephrine in the intact dog.

The effects of ketosis on the norepinephrine-induced high rates of cardiac uptake of non-esterified fatty acids (NEFA = free fatty acids = FFA) and oxygen consumption were studied in anesthetized intact dogs. After a control infusion of norepinephrine (500 ng/kg.min into the left ventricle), the D(-) isomer or natural form of 3-hydroxybutyrate was infused intravenously as the arginine salt at rates of 20 mumol/kg.min in group A (10 dogs) and 80 mumol/kg.min in group B (10 dogs) and a second norepinephrine infusion was superimposed on the ketone treatment. At the time the effects of the second catecholamine infusion were measured, the arterial 3-hydroxybutyrate concentration averaged 1.2 +/- 0.1 mM in group A and 8.3 +/- 0.4 mM in group B, and the cardiac uptake of the ketone amounted to 17.4 +/- 0.6 and 35.8 +/- 5.3 mumol/min.100 g, respectively. Relative to the control norepinephrine infusion, the arterial NEFA concentration was reduced to 88 +/- 4% in group A and to 62 +/- 8% in group B, but the cardiac uptake of NEFA was significantly more depressed, to 65 +/- 7% in group A and to 35 +/- 8% in group B. These changes were not observed in ten non-ketotic animals under repeated norepinephrine infusion. Thus, ketosis inhibited the norepinephrine-stimulated uptake of NEFA, presumably through (1) a lowered availability of NEFA from arterial blood, attributable to a reduction of extracardiac lipolysis, and (2) competition of 3-hydroxybutyrate with NEFA for metabolism by the myocardium in the face of still high arterial NEFA concentrations, 1.7 +/- 0.1 mM in group A and 1.1 +/- 0.2 mM in group B. In both groups, the lowering of the contribution of NEFA to cardiac metabolism was associated with a reduction of the estimated oxygen demand per beat (ratio of cardiac oxygen consumption/min to the pressure-rate product), while the pressure response to norepinephrine was not modified. There was no evidence for abnormal cardiac function.

3-Hydroxybutyric Acid↗

PubMed1986

Regional reduction in ventricular norepinephrine after healing of experimental myocardial infarction in cats.

Regional ventricular norepinephrine and myosin heavy chain concentrations were measured in two models of healed left ventricular myocardial infarction in cats. One model was characterized by a well-defined dense transmural scar (discrete myocardial infarction), while the other demonstrated a pattern of nontransmural diffuse patchy fibrosis in the infarct area (diffuse myocardial infarction). Norepinephrine and myosin heavy chain concentrations were measured in the scarred area, the non-infarcted zone surrounding the scar(s), and in sites remote from the scar. Corresponding tissue sites from unoperated animals and sham operated animals served as controls. Myosin heavy chain concentration was used as an index of surviving muscle mass to express norepinephrine concentration. Norepinephrine concentration, as a function of crude tissue mass, was significantly reduced in both the scarred tissues and the non-scarred tissues surrounding the scar in the discrete infarction model but was significantly reduced only in non-scarred tissues adjacent to the dense scar when expressed as a function of myosin heavy chain. The heavily scarred area of the discrete preparation approached normal values when corrected for myosin heavy chain content. The diffuse infarct preparation demonstrated normal norepinephrine concentration at all three sites studied, whether expressed as a function of tissue mass or myosin heavy chain. These data indicate a long-term regional reduction in norepinephrine concentration specific to non-infarcted tissues adjacent to a dense transmural myocardial infarction scar. This regional reduction in norepinephrine concentration corresponds to reported regions of increased sensitivity to sympathetic nerve stimulation in the discrete myocardial infarction model.

Animals↗

PubMed1998

Impact of age on modulation of norepinephrine release from sympathetic nerves in the rat superior mesentery artery.

There is an age-related increase in stimulation-evoked fractional norepinephrine release in tail arteries of Fischer 344 rats from 6-20 months of age. Previous studies have ruled out changes in the function of uptake and subsequent metabolism mechanisms, or feedback by prejunctional alpha2-adrenoceptors. The tail artery is important in thermoregulation, and there is the possibility that the previously observed increase in sympathetic nerve activity is due to age-related changes in thermoregulation as opposed to a fundamental age-related change in the regulation of sympathetic nerves. Thus, we measured stimulation-evoked norepinephrine release in another blood vessel model, the superior mesentery artery using HPLC with electrochemical detection. In this study fractional norepinephrine release was measured under three separate conditions, drug free Krebs'; in the presence of deoxycorticosterone and cocaine; in the presence of deoxycorticosterone and cocaine and the alpha2-adrenergic receptor antagonist, idazoxan. The most significant finding was that fractional norepinephrine release in mesentery arteries from 20-month-old animals was higher as compared to 6 months regardless of treatment condition. Furthermore, the elevation in norepinephrine release cannot be accounted for by changes in norepinephrine content, uptake and subsequent metabolism mechanisms or changes in basal norepinephrine release. These data from the mesentery artery model confirm and support our previous work in the rat tail artery model. In addition, the data from this study suggest the possibility that there are common mechanisms underlying the age-related increase in peripheral sympathetic nerve activity.

Adrenergic Fibers↗

PubMed2002

Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors.

Microglial cells rapidly become activated in response to even minor damage of neurons, suggestive of the intimate interactions between neurons and microglial cells. Although mediators for microglia-neuron interactions have not been well identified, neurotransmitters are possible candidates transmitting signals from neurons to microglial cells. Among the neurotransmitters, we focused on the effects of norepinephrine and other adrenergic agonists on the functions of rat cultured microglial cells. Reverse transcriptase polymerase chain reaction studies revealed that microglial cells expressed mRNAs encoding alpha1A, alpha2A, beta1 and beta2 receptors. Norepinephrine and a beta2 adrenergic agonist terbutaline elevated intracellular cAMP level of microglial cells. Norepinephrine, an alpha1 agonist phenylephrine, a beta1 agonist dobutamine and terbutaline suppressed the expressions of mRNAs encoding pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor alpha. Release of tumor necrosis factor alpha and nitric oxide was suppressed by norepinephrine, phenylephrine, dobutamine and terbutaline. An alpha2 agonist clonidine and dobutamine upregulated the expression of mRNA encoding catechol-O-methyl transferase, an important enzyme to degrade norepinephrine. Norepinephrine, dobutamine and terbutaline upregulated the expressions of mRNA encoding 3-phospshoglycerate dehydrogenase, an essential enzyme for synthesis of L-serine and glycine, which are amino acids necessary for neuronal survival. Clonidine upregulated the expression of mRNA encoding an anti-apoptotic factor Bcl-xL. These results suggest that norepinephrine participates in the regulation of brain function at least partly by modulating the functions of microglia.

Adrenergic alpha-Agonists↗

PubMed1998

Prostatic stromal cell phenotype is directly modulated by norepinephrine.

OBJECTIVES: To evaluate the response of prostatic stromal cells in vitro to the action of the agonist norepinephrine and to examine the role of cell density in this response. METHODS: Stromal cells isolated from transurethral chippings of patients with benign prostatic hyperplasia (BPH) were seeded onto tissue culture dishes either at high density (9 x 10(3) cells/cm2) or at low density (1.5 x 10(3) cells/cm2). Norepinephrine was added at concentrations in the range of 2.5 to 50 microM. Cells were harvested at the moment of confluence, labeled with monoclonal antibodies to four cytoskeletal proteins, and analyzed by flow cytometry. RESULTS: Sparsely plated stromal cells showed a consistent biphasic response in which a small fall in immunofluorescence occurred in the range of 5 to 15 microM norepinephrine but was thereafter followed by a progressive rise in fluorescence to 50 microM, indicating increased expression of smooth-muscle-associated cytoskeletal proteins. The shape of flow-cytometric frequency-distribution histograms for smooth-muscle myosin, desmin, and talin suggested that all mesenchymal cells in the stromal cultures were similarly modulated by norepinephrine. However, the effect on smooth-muscle actin was different in that a subpopulation of hyperreactive cells was identified. Densely plated stromal cells did not show a similar biphasic response to norepinephrine but instead demonstrated an overall downward trend, indicating a progressively diminished expression of these cytoskeletal proteins. CONCLUSIONS: Norepinephrine stimulation directly modulates BPH-derived prostatic stromal cells toward a differentiated smooth-muscle phenotype as evidenced by increased expression of cytoskeletal proteins. The effect of norepinephrine on cultures is cell-density-dependent, suggesting that intercellular communication is an important factor in coordinating the differentiation responses. This study has revealed a specific interaction between physical and humoral stimuli, which influences in part the phenotype of prostatic stromal cells. Such interaction is likely to determine the development of clinical BPH, and also the response of any individuals following therapeutic intervention using selective alpha-adrenergic blockade.

Cell Count↗

PubMed1995

Effects of naloxone on regional norepinephrine content of the rabbit urinary bladder after electrical pelvic floor stimulation.

OBJECTIVES: Effect of opioid blockade on regional norepinephrine content of the rabbit urinary bladder was investigated under electrical pelvic floor stimulation. METHODS: Norepinephrine content of the bladder body and base of the rabbit was estimated by high-performance liquid chromatography in the following four subgroups: control group; group 1, treated by electrical stimulation; group 2, treated by naloxone alone; and group 3, treated by electrical stimulation and naloxone. RESULTS: Intravenous administration of naloxone (group 2) caused depletion of norepinephrine content in the bladder body (P < 0.001). Norepinephrine content in the bladder base was also reduced, although this difference was not statistically significant. Electrical stimulation to the pelvic floor musculature (group 1) increased norepinephrine content both in the bladder base and the body (P < 0.01). Such a norepinephrine elevation disappeared in the rabbit treated by electrical stimulation plus naloxone (group 3). Norepinephrine content of this group was almost the same as those treated by naloxone alone. CONCLUSIONS: Opioid blockade appeared to block the hypogastric nerve activation induced by electrical pelvic floor stimulation.

Animals↗

PubMed2001

Small GTP binding protein Ras contributes to norepinephrine-induced mitogenesis of vascular smooth muscle cells.

Norepinephrine stimulates release of arachidonic acid from tissue lipids. Arachidonic acid metabolites generated through the lipoxygenase and cytochrome P-450 pathways but not cyclooxygenase stimulate mitogen activated protein (MAP) kinase activity and proliferation of vascular smooth muscle cells (VSMC). Moreover, norepinephrine has been shown to activate the Ras/MAP kinase pathway through generation of cytochrome P450 metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE). The purpose of this study was to investigate the contribution of Ras in norepinephrine-induced mitogenesis in aortic VSMC. Farnesylation of Ras by farnesyl transferase is required for its full activation. Norepinephrine-induced DNA synthesis, as measured by [3H]-thymidine incorporation, was attenuated by inhibitors of Ras farnesyl transferase FPT III and BMS-191563. These agents also inhibited 20-HETE-stimulated [3H]-thymidine incorporation. In cells transiently transfected with dominant negative Ras (RasN17), norepinephrine, and 20-HETE-induced proliferation of VSMC was attenuated. Both norepinephrine and 20-HETE increased localization of Ras to plasma membrane and MAP kinase activity; FPT III attenuated these effects. These data suggest that VSMC proliferation induced by norepinephrine and 20-HETE is mediated by Ras/MAP kinase pathway.

Alkyl and Aryl Transferases↗

PubMed2003

Comparison of microdialysis and push-pull perfusion for retrieval of serotonin and norepinephrine in the spinal cord dorsal horn.

Both push-pull and microdialysis methods are utilized to measure norepinephrine and serotonin in the dorsal horn of the spinal cord. This experiment was designed to determine which technique is better for measurement of norepinephrine and serotonin in the spinal cord and also to determine if the samples are best collected with or without perchloric acid. Sample stability and an assay validation for precision, limit of quantification, and limit of detection were also performed. Push-pull or microdialysis catheters were placed transversely through the dorsal horn and the catheter was perfused with artificial cerebrospinal fluid. Noxious pinch (20 s/min for 10 min) was used to evoke a change in the concentration of catecholamines. Samples were collected before, during and after pinch. No basal concentrations of epinephrine and serotonin were found with microdialysis. Although basal concentrations of norepinephrine were measured by microdialysis, there was no change in response to noxious pinch. The push-pull technique coupled with collection of samples without perchloric acid showed that significant increases in serotonin and norepinephrine are measurable in response to noxious pinch. In contrast, when samples were collected with perchloric acid present there was no change in serotonin or norepinephrine in response to pinch. The stability of catecholamines is greatly affected by perchloric acid such that there is a near complete loss of ability to detect serotonin and norepinephrine by 24 h in samples collected by push-pull. In contrast, samples collected without perchloric acid showed only a 20% reduction in concentration by 24 h. Even without perchloric acid, by 1 wk there was a 50% or greater loss in the concentrations of norepinephrine in push-pull samples. Thus, to measure changes in catecholamines in the dorsal horn, push-pull collected without perchloric provides measurable, reliable and valid results if analyzed by high performance liquid chromatography within 24 h.

Animals↗

PubMed2003

Basal norepinephrine in depersonalization disorder.

In contrast to the noradrenergic dysregulation described in PTSD, little is known regarding noradrenergic function in dissociative disorders. The purpose of this preliminary study was to investigate basal norepinephrine in depersonalization disorder (DPD). Nine subjects with DSM-IV DPD, without lifetime PTSD, were compared to nine healthy comparison (HC) subjects. Norepinephrine was measured via 24-h urine collection and three serial plasma determinations. Groups did not differ significantly in plasma norepinephrine levels. Compared to the HC group, the DPD group demonstrated significantly higher urinary norepinephrine, only prior to covarying for anxiety. The DPD group also demonstrated a highly significant inverse correlation between urinary norepinephrine and depersonalization severity (r=-0.88). Norepinephrine and cortisol levels (reported in a prior study) were not intercorrelated. We concluded that although dissociation accompanied by anxiety was associated with heightened noradrenergic tone, there was a marked basal norepinephrine decline with increasing severity of dissociation. The findings are in concordance with the few reports on autonomic blunting in dissociation and merit further investigation.

Adult↗

PubMed2000

Ischemic-like condition releases norepinephrine and purines from different sources in superfused rat spleen strips.

Transmitters and cotransmitters of the sympathetic nervous system are involved in the regulation of a variety of immune cell functions. However, it is not entirely clear what stimuli lead to the release of these molecules in immune organs. In this study, we investigated whether local ischemia can cause the parallel release of norepinephrine and its cotransmitter, ATP, in the spleen. Ischemic-like conditions, simulated by transient (15 min) O(2) and glucose deprivation, elicited a reversible increase in the release of both norepinephrine and purines from superfused spleen strips preloaded with [3H]norepinephrine or [3H]adenosine. HPLC analysis of the released tritium label revealed a net increase in the amount of ATP, ADP, AMP, adenosine, inosine, hypoxanthine and xanthine in response to ischemic-like condition. Selective O(2) or glucose deprivation, and Ca(2+)-free conditions differentially affected the outflow of [3H]norepinephrine and [3H]purines, indicating that they derived from different sources. The ABC transporter inhibitors glibenclamide (100 microM) and verapamil (100 microM) as well as low-temperature inhibited [3H]purine release evoked by ischemic-like conditions. Surgical denervation of the spleen reduced endogenous catecholamine content and [3H]norepinephrine uptake of the spleen, but not that of [3H]adenosine. In summary, these results demonstrate the release of norepinephrine and purines in response to an ischemic-like condition in an immune organ. Although both could provide an important source of extracellular catecholamines and purines involved at various levels of immunomodulation, the source and mechanism of norepinephrine and purine efflux seem different.

Adenine↗

PubMed1989

The effect of norepinephrine versus epinephrine on myocardial hemodynamics during CPR.

Alpha-adrenergic agonists improve myocardial blood flow during CPR by increasing aortic diastolic pressure. Adrenergic agonists with beta-2 properties may enhance peripheral vasodilation and may prove less beneficial during CPR. The purpose of this study was to compare epinephrine (E), an alpha-1,2; beta-1,2 agonist, versus norepinephrine, an alpha-1,2; beta-1 agonist, on myocardial hemodynamics during CPR. Twenty swine were instrumented for pressure, arterial and coronary sinus oxygen content (CAO2 and CCSO2, respectively), and myocardial blood flow measurements using tracer microspheres. CAO2, CCSO2, myocardial blood flow, myocardial oxygen delivery (MDO2) and myocardial oxygen consumption (MVO2), extraction ratio, and aortic diastolic pressure were determined during normal sinus rhythm and during CPR following a ten-minute arrest. After three minutes of CPR, the animals were allocated to receive either norepinephrine 0.08 mg/kg (n = 5), norepinephrine 0.12 mg/kg (n = 5), norepinephrine 0.16 mg/kg (n = 5), or epinephrine 0.20 mg/kg (n = 5). One minute after drug administration, all hemodynamic parameters were again determined. Three and one half minutes after drug administration defibrillation was attempted. A Newman-Keuls multiple comparison procedure was used to compare differences following drug administration. During CPR, aortic diastolic pressure averaged less than 13 mm Hg, and myocardial blood flow averaged less than 6 mL/min/100 g. All doses of norepinephrine and epinephrine improved all hemodynamic parameters over those seen during CPR. The two highest doses of norepinephrine significantly improved extraction ratio compared with norepinephrine 0.08 mg/kg (P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

A brain Na+, K+-ATPase inhibitor (endobain E) enhances norepinephrine release in rat hypothalamus.

We have shown that synaptosomal membrane Na+, K+-ATPase activity is stimulated or inhibited by norepinephrine according to the presence or absence of a brain soluble fraction. Gel filtration of such soluble fraction has allowed the separation of two fractions, peaks I and II, able to stimulate and inhibit Na+, K+-ATPase activity, respectively. Peak II behaves much like ouabain, which has suggested the term endobain. From peak II, a subfraction termed II-E (endobain E), which highly inhibits Na+, K+-ATPase, has been separated by anionic exchange chromatography in a Synchropack AX-300 column. We determined the in vitro effect of endobain E obtained from rat cerebral cortex on neuronal norepinephrine release by incubating rat hypothalamic tissue in the presence of [3H]norepinephrine. Neuronal norepinephrine release was quantified as the factor above basal [3H]norepinephrine released to the medium at experimental and three post-experimental periods. Endobain E was found to increase norepinephrine release in a concentration-dependent fashion, reaching 200%, equivalent to the effect achieved with 400 microM ouabain. Ouabain effect persisted along three post-experimental periods whereas that of endobain E remained only during the first post-experimental period. These results led us to conclude that endobain increases norepinephrine release in hypothalamic neurons at the presynaptic nerve ending level, an effect resembling that of ouabain. It is postulated that endobain E may enhance catecholamine availability in the synaptic gap, leading to an increase in noradrenergic activity.

Animals↗

PubMed1999

Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.

The relationship between discharge rates of locus coeruleus noradrenergic neurons and rates of norepinephrine release was examined in the anesthetized rat. Neuronal discharge rates of locus coeruleus neurons were altered and quantified using a combined recording-infusion probe. Peri-locus coeruleus infusions of either the cholinergic agonist, bethanechol, or the alpha2-agonist, clonidine, were used to enhance or suppress neuronal discharge activity, respectively. Alterations in concentrations of extracellular norepinephrine within the prefrontal cortex were determined using in vivo microdialysis and high-pressure liquid chromatography with electrochemical detection. A linear relationship between locus coeruleus activity and norepinephrine dialysate concentration was observed between complete suppression of locus coeruleus discharge activity and approximately 300-400% of basal discharge levels (1.58+/-0.29 Hz). Above these levels, increases in locus coeruleus discharge rates were not accompanied by similar increases in dialysate norepinephrine concentrations. In general, neither activation nor suppression of locus coeruleus neuronal discharge rates appeared to alter the relationship between discharge activity and norepinephrine efflux during subsequent epochs. The one exception to this was observed during recovery from relatively high-magnitude locus coeruleus activation. In two out of three cases in which locus coeruleus discharge rates were increased greater than 450%, a recovery of norepinephrine concentrations to basal levels occurred more quickly than the recovery of locus coeruleus neuronal discharge rates to basal levels. Although limited, these latter observations suggest that dysregulation of norepinephrine release may occur following sustained activation of locus coeruleus at the highest rates examined, which may mimic those associated with intense arousal or stress.

Animals↗

PubMed2003

Ganglionic tyrosine hydroxylase and norepinephrine transporter are decreased by increased sodium chloride in vivo and in vitro.

The present study tested the hypothesis that, in normal male rats, chronic changes in salt intake alter the levels of tyrosine hydroxylase and the norepinephrine transporter in sympathetic ganglia. Increasing dietary salt (from 0.02% to 1%, 4% or 8% NaCl in rat chow) decreased (p<0.05) the mRNA levels of tyrosine hydroxylase and the norepinephrine transporter in the adrenal gland, superior cervical ganglia and celiac ganglia. In addition, tyrosine hydroxylase and norepinephrine transporter protein levels were decreased (p<0.05) in the adrenal gland. To test the hypothesis that NaCl acts directly on postganglionic neurons to suppress the expression of these proteins, it was determined if increases in NaCl concentrations, of a magnitude achieved during increases in dietary salt in vivo, suppress expression of tyrosine hydroxylase and the norepinephrine transporter in cultured sympathetic neurons in vitro. Increased dietary salt increased plasma NaCl concentrations each by up to 4-6 mEq l(-1) (p<0.05), with the greatest increases occurring at night when the rats consume most of their food. In addition, NaCl added to cultured neurons decreased tyrosine hydroxylase and norepinephrine transporter protein and mRNA levels, and norepinephrine uptake; however, the NaCl concentration increases required were 15-30 mEq l(-1). These data suggest that increased dietary salt can influence the activity of the sympathetic nervous system by suppressing the levels of tyrosine hydroxylase and the norepinephrine transporter. While increased NaCl levels can act directly on neurons to suppress these proteins, this action may occur in vivo only in severe pathophysiological states, but not during increases in dietary salt without the synergistic effect of other factors.

Adrenal Glands↗

PubMed2000

Effects of norepinephrine on the metabolism of fatty acids with different chain lengths in the perfused rat liver.

The effects of norepinephrine on ketogenesis in isolated hepatocytes have been reported as ranging from stimulation to inhibition. The present work was planned with the aim of clarifying these discrepancies. The experimental system was the once-through perfused liver from fasted and fed rats. Fatty acids with chain lengths varying from 8-18 were infused. The effects of norepinephrine depended on the metabolic state of the rat and on the nature of the fatty acid. Norepinephrine clearly inhibited ketogenesis from long-chain fatty acids (stearate > palmitate > oleate), but had little effect on ketogenesis from medium-chain fatty acids (octanoate and laureate). With palmitate the decrease in oxygen uptake was restricted to the substrate stimulated portion; with stearate, the decrease exceeded the substrate stimulated portion; with oleate, oxygen uptake was transiently inhibited. Withdrawal of Ca2+ attenuated the inhibitory effects. 14CO2 production from [1-14C]oleate was inhibited. Net uptake of the fatty acids was not affected by norepinephrine. In livers from fed rats, oxygen uptake and ketogenesis from stearate were only transiently inhibited. The conclusions are: (a) in the fasted state norepinephrine reduces ketogenesis and respiration by means of a Ca2+-dependent mechanism; (b) the degree of inhibition varies with the chain length and the degree of saturation of the fatty acids; (c) norepinephrine favours esterification of the activated long-chain fatty acids in detriment to oxidation; (d) in the fed state the stimulatory action of norepinephrine on glycogen catabolism induces conditions which are able to reverse inhibition of ketogenesis and oxygen uptake.

Acetoacetates↗

PubMed1993

Beta-adrenergic receptor-mediated release of norepinephrine in the human forearm.

Because of difficulties in separating the systemic from local effect, the role of presynaptic beta 2-adrenergic receptors in facilitating the neural release of norepinephrine has not been defined previously in humans in vivo. To determine whether stimulation of presynaptic beta-receptors alters local release of norepinephrine, we examined the effects on norepinephrine kinetics of 60 and 400 ng/min intra-arterial isoproterenol in seven healthy male volunteers. Isoproterenol, 60 ng/min, increased forearm norepinephrine spill-over sixfold from a baseline spillover of 0.45 +/- 0.08 to 2.89 +/- 0.69 ng/min (p < 0.01), whereas 400 ng/min isoproterenol increased forearm norepinephrine spillover to 13.25 +/- 2.49 ng/min (p < 0.005), a 29-fold increase above baseline. Coinfusion of 20 to 40 micrograms/min propranolol with 400 ng/min isoproterenol in four subjects significantly attenuated the isoproterenol-induced increase in local norepinephrine spillover to 2.09 +/- 0.92 ng/min (p < 0.05 versus 400 ng/min isoproterenol). This study shows that presynaptic beta-adrenergic receptors facilitate local release of norepinephrine in vivo in humans.

Adult↗

PubMed1993

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

BACKGROUND: Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. METHODS AND RESULTS: The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. CONCLUSION: Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Adult↗