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Results for “Norepinephrine”

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At least 145 records · Page 8Linked to original sources

PubMed1993

Cardiac sympathetic nervous activity in congestive heart failure. Evidence for increased neuronal norepinephrine release and preserved neuronal uptake.

BACKGROUND: Increased concentrations of norepinephrine in coronary sinus plasma reported in congestive heart failure (CHF) could result from increased cardiac sympathetic nerve firing and norepinephrine release or from failure of neuronal uptake mechanisms to recapture released norepinephrine. We have applied neurochemical indexes of cardiac sympathetic nerve function in heart failure patients to delineate the underlying neural pathophysiology. METHODS AND RESULTS: Cardiac norepinephrine synthesis, assessed from the cardiac overflow of the norepinephrine precursor dihydroxyphenylalanine (DOPA), intraneuronal metabolism estimated from the overflow of the intraneuronal metabolite dihydroxyphenylglycol (DHPG), neuronal norepinephrine reuptake assessed from the fractional extraction of plasma-tritiated norepinephrine and production of tritiated DHPG across the heart, and norepinephrine spillover to plasma were examined in eight patients with CHF caused by coronary artery disease (left ventricular ejection fraction of 26 +/- 5%, mean +/- SEM) and 14 age-matched healthy subjects. Cardiac norepinephrine spillover was increased eightfold in CHF subjects (127 ng/min versus 14 ng/min in healthy subjects; standard error of the difference [SED], 8 ng/min; P < .002), and cardiac DOPA was increased twofold (P < .02). The fractional extraction of tritiated norepinephrine across the heart was marginally less in CHF subjects (0.63 versus 0.73 in normal subjects; SED, 0.02), but the extent to which pharmacological neuronal uptake blockade with desipramine reduced the cardiac extraction of tritiated norepinephrine (by 71% versus 73% in normal subjects) and reduced the production of tritiated DHPG derived from uptake and intraneuronal metabolism of tritiated norepinephrine was similar in CHF patients and healthy subjects. CONCLUSIONS: The marked increase in norepinephrine spillover from the heart in CHF attributable to coronary artery disease results primarily from an increase in sympathetic nerve firing and neuronal release of norepinephrine, not from faulty neuronal reuptake of norepinephrine.

Coronary Disease↗

PubMed1991

Effect of digitalis glycosides on norepinephrine release in the heart. Dual mechanism of action.

The effect of ouabain on exocytotic and nonexocytotic norepinephrine release was investigated in perfused rat and guinea pig hearts. The overflow of endogenous norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylethyleneglycol (DOPEG) was determined by high-pressure liquid chromatography. DOPEG served as the indicator of free axoplasmic norepinephrine concentrations. The overflow of the norepinephrine cotransmitter neuropeptide Y (NPY) was determined by radioimmunoassay and NPY was used as marker for exocytotic release. Electrical stimulation of the left stellate ganglion resulted in exocytotic norepinephrine release in rat and guinea pig hearts. Ouabain caused an increase in stimulation-induced norepinephrine overflow from rat and guinea pig hearts by 40%. However, overflow of NPY was decreased by 40%, indicating a reduced exocytosis rate. Ouabain increased both norepinephrine and NPY overflow, suggesting enhancement of exocytosis, when neuronal catecholamine uptake (uptake1) was blocked by desipramine or when presynaptic alpha 2-adrenoceptors were inhibited by yohimbine. The results demonstrate an interaction of ouabain with both calcium-dependent exocytosis and uptake1 of norepinephrine. Under calcium-free conditions, ouabain or potassium-free perfusate resulted in norepinephrine release from hearts when the axoplasmic norepinephrine concentration was elevated by the reserpinelike agent Ro 4-1284. This release was independent from neural activity, not accompanied by NPY overflow, and suppressed by the uptake1 blocker desipramine. These findings are in keeping with carrier-mediated nonexocytotic norepinephrine release that is caused by reversal of the transport direction of the uptake1 carrier. During myocardial ischemia nonexocytotic norepinephrine release was accelerated and enhanced by inhibition of Na+,K(+)-ATPase before ischemia. This study demonstrates the potential of digitalis glycosides to interact both with transmitter exocytosis and with the neuronal catecholamine transport system by Na+,K(+)-ATPase inhibition. Interaction with the catecholamine transport system involves both inhibition of norepinephrine inward transport and induction of norepinephrine outward transport, resulting in nonexocytotic norepinephrine release.

Animals↗

PubMed1997

Regulation of norepinephrine release from the rat bed nucleus of the stria terminalis: in vivo microdialysis studies.

The microdialysis technique was used to study the in vivo extracellular levels of norepinephrine in the bed nucleus of the stria terminalis. A basal level of 2.34 +/-0.25 fmol/microl of norepinephrine was observed. Desipramine (2 and 10 microM), a norepinephrine uptake blocker, significantly increased extracellular levels of norepinephrine. Reversed perfusion with high potassium in the presence of 2 microM desipramine induced the release of norepinephrine. Instead, in the presence of 10 microM desipramine, a significant decrease in the induced release of norepinephrine was observed. Clonidine, an alpha2-adrenergic agonist, significantly decreased basal extracellular levels of norepinephrine and the K+-induced release of norepinephrine. In contrast, yohimbine and RX821002, two alpha2-adrenergic antagonists, significantly increased basal extracellular levels of norepinephrine but not the release of norepinephrine induced by 70 mM K+. Perfusion of tetrodotoxin through the probe located in the bed nucleus of the stria terminalis significantly decreased both the basal extracellular level and the K+-induced release of norepinephrine. Furthermore, perfusion of tetrodotoxin through a microdialysis probe implanted in the medial forebrain bundle also decreased basal extracellular levels of norepinephrine in the bed nucleus of the stria terminalis. The results show that in vivo there is a significant noradrenergic tonic activity in the bed nucleus of the stria terminalis. This tonic activity depends on the impulse flow through medial forebrain bundle nerve fibers. Under these conditions, extracellular levels of norepinephrine in the bed nucleus of the stria terminalis are regulated by the magnitude of norepinephrine uptake and by presynaptic alpha2-adrenergic receptors.

Animals↗

PubMed1999

Norepinephrine stimulates in vitro growth but does not increase pathogenicity of Salmonella choleraesuis in an in vivo model.

Norepinephrine stimulates growth of Escherichia coli, Yersinia enterocolitica, and Pseudomonas aeruginosa in serum-supplemented media, and in vivo increases in norepinephrine may be important in the pathogenesis of sepsis by gram-negative bacteria. Because salmonellosis often is associated with stress, the effects of norepinephrine on in vitro growth, and in vivo pathogenicity of the swine pathogen Salmonella choleraesuis were investigated. When RPMI 1640 with and without pig serum was inoculated with fewer than 100 S. choleraesuis/ml and incubated overnight, bacterial numbers were 10(4) to 10(6) lower in RPMI containing serum. Norepinephrine restored bacterial growth in RPMI with serum to normal levels, but it did not increase growth in serum-free RPMI. Similar results were obtained with SAPI, a nutrient-poor medium previously used to study the effect of norepinephrine on growth of gram-negative bacteria. Conditioned media were produced by growing S. choleraesuis in RPMI containing serum with and without norepinephrine and filter sterilizing. Conditioned medium produced with norepinephrine stimulated growth of S. choleraesuis but not E. coli, whereas conditioned medium produced without norepinephrine stimulated growth of both bacteria. To determine the in vivo effects of norepinephrine, rats were implanted with tablets that secrete norepinephrine for 20 to 24 hours or with identical tablets without norepinephrine and infected intraperitoneally with graded doses of S. choleraesuis. The LD-50 of S. choleraesuis was the same in both groups, and norepinephrine did not affect the carrier rate at 30 days after infection. We concluded that although norepinephrine stimulates in vitro growth of S. choleraesuis in serum-based media, the increase in norepinephrine levels in the present in vivo system was probably not sufficient to influence the pathogenesis of S. choleraesuis infection.

Animals↗

PubMed1993

Altered release and metabolism of norepinephrine in superfused canine saphenous veins in the presence of halothane and hypoxia.

BACKGROUND: Hypoxia and halothane are both known to have different effects on the release and disposition of norepinephrine at sympathetic nerve terminals during neurotransmission. In adverse clinical situations, both conditions may be present, but the effects of halothane and hypoxia together are not known. Therefore, studies were made of the effects of low partial pressures of oxygen and of halothane on the release, action, and metabolism of norepinephrine at sympathetic nerve endings in isolated segments of a blood vessel in which halothane is known to affect norepinephrine release and action profoundly. METHODS: Saphenous veins were removed from dogs, suspended for superfusion with Krebs-Ringer solution, and stimulated electrically. The veins were exposed to either 0%, 0.75%, or 1.5% halothane in the presence of 95% O2, 5% CO2, or 5% O2, 5% CO2, and 90% N2. Superfusates were collected under basal conditions, during and after electrical field stimulation, and poststimulation. Norepinephrine and its intraneuronal metabolite, 3,4-dihydroxyphenylglycol, were measured in superfusates and in the tissues after superfusion using high-performance liquid chromatography with electrochemical detection. RESULTS: Halothane decreased 1) evoked release of norepinephrine, 2) contractile response of the smooth muscle to nerve stimulation, 3) formation of 3,4-dihydroxyphenylglycol, and 4) tissue content of norepinephrine. However, hypoxia 1) increased evoked release of norepinephrine but decreased 2) contractile response during nerve stimulation, 3) formation of 3,4-dihydroxyphenylglycol, and 4) tissue content of norepinephrine. When halothane and hypoxia were present together, their effects on 3,4-dihydroxyphenylglycol formation, tissue content of norepinephrine, and the contractile responses appeared to be additive, but norepinephrine release was decreased compared with control concentrations. CONCLUSIONS: Although halothane and hypoxia had similar and additive effects on the intraneuronal metabolism of norepinephrine and on the postjunctional responses of smooth muscle to nerve stimulation, they had opposite effects on norepinephrine release from sympathetic nerve endings. The halothane-induced decrease in norepinephrine release overrode the increased release of norepinephrine caused by hypoxia.

Animals↗

PubMed1998

Effects of low-dose dopamine on renal and systemic hemodynamics during incremental norepinephrine infusion in healthy volunteers.

OBJECTIVES: To assess the effects of low-dose dopamine on norepinephrine-induced renal and systemic vasoconstriction in normotensive healthy subjects. DESIGN: On separate days, either a low-dose dopamine (4 microg/kg/min) or a placebo (5% glucose) infusion was added in a single, blinded, randomized order to incremental norepinephrine infusions of 40, 80, and 150 ng/kg/min over a 60-min period each. SETTING: Outpatient clinic of a university-affiliated hospital. SUBJECTS: Normotensive healthy volunteers. INTERVENTIONS: Infusions of norepinephrine and dopamine. MEASUREMENTS AND MAIN RESULTS: Blood pressure and heart rate were measured with a semiautomated device, and glomerular filtration rate and effective renal plasma flow were determined with constant infusions of 125I-iothalamate and 131I-hippurate, respectively. Norepinephrine alone progressively increased mean arterial pressure to pressor levels, whereas this effect was attenuated by the addition of dopamine (p < .05 vs. norepinephrine alone). Glomerular filtration rate increased during lower norepinephrine doses and did not decrease at the highest norepinephrine dose. Addition of dopamine further increased glomerular filtration rate. Effective renal plasma flow decreased with each norepinephrine alone infusion step, but this decrease was completely prevented by concomitant dopamine infusion (p < .01 vs. norepinephrine). Sodium excretion tended to decrease with norepinephrine, but increased two- to three-fold after addition of dopamine (p < .01 vs. norepinephrine alone). CONCLUSIONS: In healthy man, norepinephrine causes a large decrease in renal plasma flow but not in glomerular filtration rate. Concomitant dopamine administration prevents this decrease in renal plasma flow, increases sodium excretion, and also attenuates the norepinephrine-induced systemic blood pressure increase. These findings warrant further clinical evaluation of the effect of concomitant low-dose dopamine and norepinephrine administration in critically ill patients.

Adrenergic alpha-Antagonists↗

PubMed1997

Role of endothelium in the endothelin-1-mediated potentiation of the norepinephrine response in the aorta of hypertensive rats.

OBJECTIVE: To investigate the role of the endothelium in the functional interaction between endothelin-1 and norepinephrine in the contractile response of aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Thoracic aorta rings with and without endothelium from SHR and from WKY rats were suspended in an organ bath to record the isometric tension. After an equilibration period of 120 min, the preparations with and without endothelin-1 were subjected to single and cumulative additions of norepinephrine in different experiments. To characterize the mechanisms involved in the interaction between endothelin-1 and norepinephrine, the aortic rings were pretreated with a cyclooxygenase pathway inhibitor (piroxicam, SO29548), an inhibitor of NO synthase [NG-nitro-L-arginine (NLA)], or selective endothelin receptor blockers (BQ-123 or BQ-788). In some experiments we examined the contractile responses to norepinephrine in aortas pretreated either with angiotensin II (AII) or with U46619, an agonist of prostaglandin H2-thromboxane A2 receptors. Finally, we examined the effect of the combination of calcium-entry blockade by administration of nifedipine and treatment with either endothelin-1 or U46619 on the norepinephrine reactivity. RESULTS: Administration of 3 x 10(-10) mol/l endothelin-1 potentiated the contractile response to norepinephrine in SHR aortas with endothelium, irrespective of whether they had been treated with NLA. No endothelin-1-mediated enhancement of the response to norepinephrine was observed in SHR denuded rings and in untreated and NLA-treated WKY rat aortas. All did not affect the response to norepinephrine in SHR rings with endothelium. The amplification by endothelin-1 of the response to (1-100) x 10(-9) mol/l norepinephrine was abolished by blockade of the cyclooxygenase pathway with piroxicam or SO29548. In WKY rat and SHR denuded aortas, 10(-8) mol/l U46619 potentiated the contractile responses to norepinephrine. Administration of 3 x 10(-6) mol/l BQ-123 abolished the increase in reactivity to norepinephrine evoked by endothelin-1 in intact SHR aorta, whereas 3 x 10(-6) mol/l BQ-788 failed to modify this potentiating effect. Administration of 10(-8) mol/l nifedipine inhibited the potentiation of the norepinephrine-induced contractions evoked both by endothelin-1 in SHR aortic rings with endothelium and by U46619 in SHR denuded rings. CONCLUSION: Our results show that a low concentration of endothelin-1 induced potentiation of the contractile response to norepinephrine in SHR aortas but not in WKY rat aortas. This response was endothelium-dependent. Furthermore, our study affords functional arguments that both endothelial and smooth muscle pathways are involved in the potentiating interaction. We propose that endothelin-1 stimulates the production of endothelium- and cyclooxygenase-generated vasoconstrictor factors, which in turn may serve directly as priming stimuli at the vascular smooth muscle level, to activate the Ca(2+)-signal pathway and consequently to increase locally the vascular sensitivity to norepinephrine.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Opposing effects of plasma epinephrine and norepinephrine on coronary thrombosis in vivo.

BACKGROUND: It is well known that plasma catecholamines and myocardial infarction have a close relation and that coronary artery thrombosis is a major cause of myocardial infarction. In addition, epinephrine is known to be a prothrombogenic agent in vivo. However, the role of the other major circulating catecholamine, norepinephrine, in the development of coronary thrombosis is somewhat uncertain, although the role of norepinephrine is often considered analogous to the role of epinephrine. Therefore, the present study was designed to investigate the effect of norepinephrine and its interaction with epinephrine on coronary thrombosis. METHODS AND RESULTS: To compare the effects of epinephrine and norepinephrine on coronary thrombosis, we analyzed the frequency of cyclic blood flow reductions (CFRs) in an anesthetized canine model of coronary thrombosis (n = 25). Three experiments were used in the present study. In the first experiment with epinephrine infusion, plasma epinephrine was elevated from 0.46 +/- 0.25 to 27.7 +/- 1.85 nmol/L. The frequency of CFRs increased by more than 60%, from 7.1 +/- 0.5 to 11.5 +/- 0.7 in 40 minutes (P < .01). The second experiment included three experimental periods: control, norepinephrine infusion, and norepinephrine infusion plus epinephrine infusion. Norepinephrine was infused to raise plasma norepinephrine from 1.3 +/- 0.2 to 32.4 +/- 4.3 nmol/L. The frequency of CFRs in the dogs was markedly reduced, from 7.89 +/- 0.42 to 2.41 +/- 1.08 in 40 minutes (P < .01), whereas arterial pressure was elevated from 88 +/- 3 to 118 +/- 5 mm Hg (P < .01). However, when epinephrine infusion was added to the norepinephrine infusion, the frequency of CFRs increased from 2.41 +/- 1.08 to 7.74 +/- 1.12 in 40 minutes (P < .01). In the third experiment, a servocontrol device was used during the norepinephrine infusion to prevent rises in coronary arterial pressure. As a result of the norepinephrine infusion, the frequency of CFRs was reduced from 7.47 +/- 0.71 to 0.83 +/- 0.65 in 40 minutes (P < .01), even though the coronary arterial pressure was not altered. CONCLUSIONS: The present study demonstrated that infusion of epinephrine stimulated coronary artery thrombosis, whereas infusion of norepinephrine inhibited coronary artery thrombosis. In addition, the inhibitory effect of norepinephrine on coronary thrombosis is independent of increases in coronary arterial pressure. Therefore, the present findings suggest that epinephrine and norepinephrine have opposing effects on coronary thrombosis in dogs.

Animals↗

PubMedDate not supplied

Effects of short-term norepinephrine infusion on plasma catecholamines, renin, and aldosterone in normal and hypertensive man.

The acute responsiveness of plasma catecholamine, renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin-angiotensin activation by diuretic pretreatment in 25 normal subjects and 34 patients with borderline-to-moderate essential hypertension. Norepinephrine infusion caused increases in plasma norepinephrine (PNE) that correlated with the infused norepinephrine dose (p < 0.001); this relationship was similar in normal and hypertensive subjects and unaltered by diuretic therapy. Plasma epinephrine and dopamine levels were unchanged during norepinephrine infusion. Norepinephrine infusion at pressor doses stimulated PRA (p < 0.01). The PRA responses correlated with the dose of infused norepinephrine (p < 0.0025), and norepinephrine-stimulated PRA correlated with basal PRA (p < 0.001). These norepinephrine-PRA relationships were unaltered by diuretic treatment and similar in normal and hypertensive subjects. In both groups, norepinephrine also caused a similar increase in plasma aldosterone (p < 0.05) under placebo conditions, but not following diuretic therapy. These findings demonstrate that an acute increase in the blood levels of the adrenergic neurotransmittor, norepinephrine, causes mild but distinct stimulation of plasma renin and aldosterone levels. Renin release in response to exogenous norepinephrine is not enhanced following renin-angiotensin activation by diuretic pretreatment. The responsiveness of the renin-angiotensin-aldosterone system to an acute norepinephrine input seems to be intact in essential hypertension.

Adolescent↗

PubMed1986

Estimation of intrasynaptic norepinephrine concentrations in humans.

Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.

Adult↗

PubMed1983

Effect of desipramine and cocaine on plasma norepinephrine and pressor responses to adrenergic stimulation in pithed rats.

Sympathetic neuronally released norepinephrine appears to act at intrajunctional alpha 1-adrenoceptors, whereas administered norepinephrine acts mostly at extrajunctional alpha 2-adrenoceptors. We examined the effects of inhibition of neuronal uptake of norepinephrine by desipramine (0.3 mg/kg iv) and cocaine (5 mg/kg iv) on the pressor effects and on plasma norepinephrine levels in pithed rats after the administration of norepinephrine (0.1, 0.3, and 1.0 micrograms/kg iv) or during stimulation of sympathetic outflow (0.1, 0.3, and 1.0 Hz at 50 V for 1 minute). Desipramine and cocaine potentiated the cardiovascular effects of administered norepinephrine to a greater extent than they potentiated the effects of sympathetic stimulation. Plasma levels of norepinephrine during sympathetic stimulation or after iv administration of norepinephrine were increased significantly after either desipramine or cocaine. The cardiovascular effects of sympathetic stimulation, but not of exogenous norepinephrine, were reduced in adrenomedullectomized rats compared to intact rats. In adrenomedullectomized rats, desipramine potentiates the pressor responses and enhances the increase in plasma norepinephrine levels during sympathetic stimulation to the same extent as in intact pithed rats. The preferential potentiation of administered norepinephrine by uptake inhibition is most likely due to enhancement of accessibility of circulating norepinephrine to otherwise inaccessible intrajunctional alpha 1-adrenoceptors. The higher concentrations of norepinephrine in the region of the nerve-ending limit release of the neurotransmitter by feedback inhibition via presynaptic alpha 2-adrenoceptors, thereby masking potentiation by uptake inhibition of the postsynaptic responses to sympathetic stimulation.

Animals↗

PubMed1997

Dual effect of digitalis glycosides on norepinephrine release from human atrial tissue and bovine adrenal chromaffin cells: differential dependence on [Na+]i and [Ca2+]i.

It was the aim of the present study (1) to characterize the influence of Na+/K(+)-ATPase inhibition by the digitalis glycoside ouabain on both spontaneous and nicotine-evoked norepinephrine release from the human heart; and (2) to further investigate the role of glycoside-induced changes in [Na+]i and [Ca2+]i (determined by microfluorimetry) for catecholamine release. The latter experiments were performed in bovine adrenal medullary chromaffin cells (BCC), an established cell culture model for sympathetic nerves. Ouabain (1-1000 mumol/l) exerted a dual effect on norepinephrine release (determined by HPLC) from incubated human atrial tissue: (I) Ouabain induced a concentration-dependent increase in norepinephrine release, that was calcium-independent and almost completely prevented by blockade of the uptake1-carrier by desipramine (1 mumol/l). The characteristics of this release process are consistent with a non-exocytotic mechanism. (II) In addition, ouabain augmented the nicotine-evoked (1-100 mumol/l) calcium-dependent norepinephrine release, which can be considered to be exocytotic. Na+/K(+)-ATPase inhibition also reduced the threshold concentration of nicotine from 10 to 1 mumol/l and it delayed the rapid tachyphylaxis of its norepinephrine releasing effect in human atrial tissue. In BCC, ouabain increased [Na+]i, [Ca2+]i and [3H]-norepinephrine release in parallel. Under calcium-free conditions, not only the ouabain-induced increase in [Na+]i, but also [3H]-norepinephrine release were enhanced. The ouabain-induced [3H]-norepinephrine release was always closely related to changes in [Na+]i, indicating a key role of [Na+]i for this calcium-independent non-exocytotic norepinephrine release. In addition, pretreatment with ouabain (1 mmol/l) augmented the nicotine-evoked (0.1-10 mumol/l) increments in [Na+]i, [Ca2+]i and [3H]-norepinephrine release. As nicotine-induced norepinephrine release depends on an increase in both [Na+]i and [Ca2+]i, these findings are indicative of an ouabain-mediated facilitation of exocytosis. In conclusion, increasing [Na+]i and [Ca2+]i inhibition of Na+/K(+)-ATPase by ouabain triggers non-exocytotic norepinephrine release, and facilitates nicotine-evoked exocytotic norepinephrine release.

Adrenal Medulla↗

PubMed2005

Sperm binding, in vitro fertilization, and in vitro embryonic development of bovine oocytes fertilized with spermatozoa incubated with norepinephrine.

The final stages of sperm maturation, fertilization, and early embryonic development occur within the oviduct and are essential for successful reproduction in mammals. Norepinephrine was previously identified in native bovine oviductal fluid and its in vitro effects on bull sperm capacitation and the acrosome reaction have been determined. It was unknown how physiological concentrations of norepinephrine influence sperm binding, fertilization, and embryo development. Therefore, the objective of this study was to determine if pre-incubating bovine spermatozoa with physiological concentrations of norepinephrine prior to insemination of bovine oocytes would improve sperm-oocyte binding, fertilization, and embryonic development in vitro. Norepinephrine, in concentrations representing those measured in bovine oviductal fluid, was used to treat bovine spermatozoa prior to insemination. Spermatozoa incubated in norepinephrine were used to inseminate bovine oocytes matured in vitro, and oocytes were evaluated for sperm binding and fertilization. Additional experiments were conducted to evaluate how early in the co-incubation period oocytes were fertilized by spermatozoa pre-incubated with norepinephrine, and to test the developmental competence of those oocytes fertilized with norepinephrine-treated sperm. Sperm binding to the zona pellucida was reduced by pre-incubation with norepinephrine. Rates of fertilization and embryo development did not increase as a result of pre-incubating spermatozoa with norepinephrine, but as early as 4h after insemination, spermatozoa treated with 20 ng/ml norepinephrine fertilized more oocytes than spermatozoa incubated in medium alone. Interestingly, this concentration of norepinephrine was found to capacitate spermatozoa in previous studies. These data suggest that oocytes fertilized by spermatozoa incubated in 20 ng/ml norepinephrine fertilize earlier in vitro than sperm pre-incubated in medium alone, and provide additional support for the role of norepinephrine in sperm capacitation and the acrosome reaction.

Animals↗

PubMed2006

Norepinephrine transporter-deficient mice respond to anxiety producing and fearful environments with bradycardia and hypotension.

The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific transporter blockade. The norepinephrine transporter is crucial in limiting catecholaminergic signaling. Norepinephrine transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, norepinephrine transporter-deficient (norepinephrine transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in norepinephrine transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in norepinephrine transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in norepinephrine transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, norepinephrine transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, norepinephrine transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in norepinephrine transporter-/- mice, norepinephrine transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic norepinephrine transporter blockade with transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.

Animals↗

PubMed1999

Norepinephrine increases rat mitral cell excitatory responses to weak olfactory nerve input via alpha-1 receptors in vitro.

A rat olfactory bulb in vitro slice preparation was used to investigate the actions of norepinephrine on spontaneous and afferent (olfactory nerve) evoked activity of mitral cells. Single olfactory nerve shocks elicited a characteristic mitral cell response consisting of distinct, early and late spiking components separated by a brief inhibitory epoch. Bath-applied norepinephrine (1 microM) increased the early spiking component elicited by perithreshold (79% increase, P<0.02), but not by suprathreshold (3% decrease, P>0.05), intensity olfactory nerve shocks. The facilitatory effect of norepinephrine was due to a reduction in the incidence of response failures to perithreshold intensity shocks. Norepinephrine also decreased the inhibitory epoch separating the early and late spiking components by 44% (P<0.05). By contrast, norepinephrine had no consistent effect on the spontaneous discharge rate of the mitral cells. The effects of norepinephrine were mimicked by the al receptor agonist phenylephrine (1 microM, P<0.001). Both norepinephrine and phenylephrine modulation of mitral cell responses were blocked by the al adrenergic antagonist WB-4101 (1 microM). These findings are consistent with observations that the main olfactory bulb exhibits the highest density of alpha1 receptors in the brain. The alpha2 receptor agonist clonidine (100 nM) and the beta receptor agonist isoproterenol (1 microM) had inconsistent effects on mitral cell spontaneous and olfactory nerve-evoked activity. These results indicate that norepinephrine increases mitral cell excitatory responses to weak but not strong olfactory nerve inputs in vitro via activation of al receptors. This is consistent with recent findings in vivo that synaptically released norepinephrine preferentially increases mitral cell excitatory responses to weak olfactory nerve inputs. Taken together, these results suggest that the release of norepinephrine in the olfactory bulb may increase the sensitivity of mitral cells to weak odors. Olfactory cues evoke norepinephrine release in the main olfactory bulb, and norepinephrine plays important roles in early olfactory learning and reproductive/maternal behaviors. By increasing mitral cell responses to olfactory nerve input, norepinephrine may play a critical role in modulating olfactory function, including formation and/or recall of specific olfactory memories.

Afferent Pathways↗

PubMed1991

Release of norepinephrine from the rat ovary: local modulation of gonadotropins.

Experiments were undertaken to define the role of gonadotropins in the release of norepinephrine and the relationship with beta-receptors of the ovary. Rat ovaries were removed at different stages of the estrous cycle and incubated in [3H]norepinephrine. Subsequently, ovaries were electrically stimulated and the release of [3H]norepinephrine was recorded. There were no changes in the norepinephrine content during the estrous cycle. The ovary exhibited cyclical variation in norepinephrine-induced release during the estrous cycle. The lowest release of norepinephrine was found during diestrus; there was an increase during proestrus and estrus followed by a decline during metestrus. The release of norepinephrine changed in the opposite way to the beta-receptor number, suggesting a process involving down-regulation between norepinephrine release and beta-receptors of the ovary. Norepinephrine released from the ovary was locally regulated by gonadotropins. The presence of FSH in the superfusion medium stimulated the norepinephrine-induced release from the ovaries of rats in diestrus (by 20%) and estrus (by 40%), but no effect was found during proestrus. In addition, the presence of hCG stimulated (by 40%) norepinephrine-induced release during proestrus, but no changes were apparent during the other stages of the estrous cycle. These results suggest that the local action of gonadotropins on nerve terminals of the ovary might be one of the factors governing the changes in norepinephrine release through the estrous cycle. The changes in the norepinephrine released to the synaptic cleft might exert down-regulation on the beta-adrenergic receptor content of the ovary and in this way control the ovarian steroid secretory activity.

Animals↗

PubMed2003

Deactivation of norepinephrine by peroxynitrite as a new pathogenesis in the hypotension of septic shock.

BACKGROUND: Vascular hyporeactivity to catecholamines limits successful treatment of hypotension in septic shock. Large amounts of nitric oxide (NO) and superoxide anion (O(2)(-1).) are produced in response to bacterial endotoxins and/or inflammatory cytokines. NO reacts with O(2)(-1). to form the potentially toxic NO metabolite, peroxynitrite (ONOO(-1)). The purpose of this study was to investigate whether ONOO(-1) decreases the vasocontractile activity of norepinephrine. METHODS: Norepinephrine was treated with ONOO(-1) or 3-morpholinosydonimine-N-ethyl-carbamine (SIN-1; an ONOO(-1) producer) in a 5 x 10(-2) m sodium phosphate buffer solution at pH 7.4, and absorbance of the product was measured spectrophotometrically at 295 and 370 nm. Norepinephrine pretreated with ONOO(-1) was administered to isolated rat thoracic aortas to observe contractions in functional experiments. The rate constant between norepinephrine and ONOO(-1) was determined via a competition assay with cysteine in functional experiments. Norepinephrine pretreated with ONOO(-1) was injected intravenously into anesthetized rats to measure blood pressure. RESULTS: Norepinephrine pretreated with ONOO(-1) was confirmed spectrally as oxidized norepinephrine. Norepinephrine pretreated with ONOO(-1) decreased its vasocontractile force in an ONOO(-1) (10(-6), up to 3 x 10(-4) m) concentration-dependent manner (EC(50) = 5.1 x 10(-5) m). The decrease in its force was lower at pretreatment with ONOO(-1) in a lower pH buffer. A rate constant for the ONOO(-1)-norepinephrine reaction was 6 x 10(2) m/s. Norepinephrine (10(-7) m) incubated with SIN-1 (10(-3) m) decreased its vasocontractile force in an incubation time-dependent manner. Administration of norepinephrine pretreated with ONOO(-1) to anesthetized rats caused no significant change in arterial blood pressure. CONCLUSIONS: These results indicate that norepinephrine was oxidized and deactivated by ONOO(-1). This deactivation may, at least in part, account for the hyporeactivities of vasocontraction to norepinephrine in septic shock.

Anesthesia↗

PubMed2002

Role of adenosine A(1) receptor in angiotensin II- and norepinephrine-induced renal vasoconstriction.

We investigated the contributions of adenosine A(1) receptors to angiotensin II- and norepinephrine-induced renal vasoconstriction. Intrarenal administrations of angiotensin II (3, 10, and 30 ng) or norepinephrine (100 and 500 ng) produced dose-dependent renal vasoconstriction in anesthetized dogs. Under resting conditions, angiotensin II (30 ng) and norepinephrine (500 ng) significantly decreased renal blood flow by -43 +/- 3 and -19 +/- 2%, respectively (n = 21). Intra-arterial infusion of adenosine (5 microg/kg/min) significantly augmented renal blood flow responses to both angiotensin II and norepinephrine (-64 +/- 4 and -45 +/- 14%, n = 7). Renal blood flow responses to angiotensin II and norepinephrine were also augmented by inhibition of cellular uptake of adenosine with dipyridamole (10 microg/kg/min, n = 6). Blockade of adenosine A(1) receptors with 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902; 10 microg/kg/min) did not alter basal renal blood flow but significantly attenuated angiotensin II- and norepinephrine-induced renal vasoconstriction (-34 +/- 6 and -9 +/- 3%, n = 7). Furthermore, KW-3902 completely prevented augmentation of renal blood flow responses to angiotensin II and norepinephrine produced by adenosine or dipyridamole (n = 7 and 6, respectively). Administrations of angiotensin II (30 ng) or norepinephrine (500 ng) into the common carotid artery significantly decreased carotid blood flow by -20 +/- 5 and -41 +/- 10%, respectively; however, neither adenosine (5 microg/kg/min) nor KW-3902 (10 microg/kg/min) affected the carotid blood flow responses to angiotensin II and norepinephrine (n = 5, respectively). Adenosine concentrations in dialysates were not significantly changed by administrations of angiotensin II (from 19 +/- 3 to 24 +/- 4 nM, n = 6) or norepinephrine (from 16 +/- 3 to 19 +/- 3 nM, n = 6). These results suggest that basal interstitial adenosine levels influence both angiotensin II and norepinephrine-induced vasoconstriction via A(1) receptors in the kidney but not in the area drained by the common carotid artery. The responses of adenosine to angiotensin II- and norepinephrine-induced renal vasoconstriction may not be mediated through de novo intrarenal adenosine accumulation due to angiotensin II- and norepinephrine-induced renal vasoconstriction.

Adenosine↗