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PubMed2000

6-NO(2)-norepinephrine increases norepinephrine release and inhibits norepinephrine uptake in rat spinal synaptosomes.

Nitric oxide has been shown to react under physiologic conditions with norepinephrine (NE) to produce 6-nitro-norepinephrine (6-NO(2)-NE), a compound that enhances NE release in the brain. Previous studies suggest that 6-NO(2)-NE is formed in the spinal cord and stimulates spinal NE release to produce analgesia. The purpose of the current studies was to examine the mechanisms by which 6-NO(2)-NE stimulates NE release in the spinal cord. Crude synaptosomes were prepared from spinal cords of male Sprague-Dawley rats and loaded with [(3)H]NE. Incubation of synaptosomes with 6-NO(2)-NE resulted in a release of NE, with a threshold of 1 microM 6-NO(2)-NE and a maximum effect of 30% fractional release. NE transporter inhibitors desipramine and nomifensine blocked NE release from 6-NO(2)-NE, and desipramine exhibited an IC(50) of 9.6 microM. NE release from 6-NO(2)-NE was dependent on external Na(+), but not Ca(2+) or the activity of guanylate cyclase. 6-NO(2)-NE also blocked uptake of [(3)H]NE into synaptosomes, with an IC(50) of 8.3 microM. These data are consistent with a direct action of 6-NO(2)-NE on noradrenergic terminals in the spinal cord to release NE. This action is independent of guanylate cyclase activation, and most likely shares a common mechanism with classic monoamine releasers such as amphetamine that cause direct release of NE from vesicles into the nerve terminal cytoplasm, leading to extracellular release by reverse transport.

Animals↗
PubMed2000

Formation of 6-nitro-norepinephrine from nitric oxide and norepinephrine in the spinal cord and its role in spinal analgesia.

Spinally released norepinephrine is thought to produce analgesia in part by stimulating alpha(2)-adrenergic receptors, which in turn leads to nitric oxide synthesis. Also, nitric oxide is known to react with norepinephrine in vivo in the brain to form 6-nitro-norepinephrine, which inhibits neuronal norepinephrine reuptake. In the present study, we tested the hypothesis that formation of 6-nitro-norepinephrine occurs in the spinal cord and that intrathecal administration of 6-nitro-norepinephrine produces analgesia by stimulating norepinephrine release. 6-Nitro-norepinephrine was present in rat spinal cord tissue and microdialysates of the dorsal horn and intrathecal space. Intrathecal norepinephrine injection increased 6-nitro-norepinephrine. 6-Nitro-norepinephrine also stimulated norepinephrine release in dorsal spinal cord in vitro. Intrathecal injection of 6-nitro-norepinephrine produced antinociception and interacted additively with norepinephrine for antinociception. Spinal noradrenergic nerve destruction increased antinociception from intrathecally injected norepinephrine, but decreased antinociception from 6-nitro-norepinephrine. These results suggest a functional interaction between spinal nitric oxide and norepinephrine in analgesia, mediated in part by formation of 6-nitro-norepinephrine. Stimulation of auto-inhibitory alpha(2)-adrenergic receptors at noradrenergic synapses decreases norepinephrine release. Paradoxically, alpha(2)-adrenergic agonist injection increases and alpha(2)-adrenergic antagonist injection decreases norepinephrine release in the spinal cord. 6-Nitro-norepinephrine may be an important regulator of spinal norepinephrine release and could explain the positive feedback on norepinephrine release after activation of spinal alpha(2)-adrenergic receptors.

Analgesia↗
PubMed1987

A role for norepinephrine in arousal, emotion and learning?: limbic modulation by norepinephrine and the Kety hypothesis.

1. Kety hypothesized that forebrain norepinephrine acted to selectively enhance cell firing in neurons receiving environmental inputs during affectively important events. He further suggested that norepinephrine could act to induce a 'persistent facilitation' of the inputs which accompany affectively important events and would thus promote a memory for these events. 2. The electrophysiological actions of norepinephrine at the time Kety proposed his hypothesis were thought to be inhibitory. More recent evidence has demonstrated that norepinephrine in neocortex and cerebellum enhances both excitatory and inhibitory evoked activity much as Kety proposed. This has been termed norepinephrine neuromodulation. 3. The locus coeruleus-norepinephrine system which gives rise to neocortical and cerebellar norepinephrine innervation also innervates, even more densely, areas of the limbic system. A review of norepinephrine actions, particularly in limbic cortex, indicates that locus coeruleus-norepinephrine also enhances transmission of evoked inputs in these structures. 4. A long-lasting enhancement of evoked inputs by locus coeruleus-norepinephrine has been demonstrated in the hippocampus. This long-lasting enhancement of inputs is reviewed in detail since it appears to directly support Kety's hypothesized 'persistent facilitation' effect of norepinephrine. It is suggested that norepinephrine-induced long-lasting enhancement may underlie numerous demonstrations of norepinephrine-dependent memory and neural plasticity in the forebrain. 5. The relationship of norepinephrine neuromodulation to possible candidate mechanisms and to activation of specific norepinephrine receptors is briefly discussed.

Animals↗
PubMed1981

Effect of norepinephrine uptake blockers on norepinephrine kinetics.

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1 1/2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2 1/2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1 1/2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1 1/2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.

Adult↗
PubMed1999

Effects of norepinephrine plus dobutamine or norepinephrine alone on left ventricular performance of septic shock patients.

OBJECTIVE: To determine the hemodynamic effects of the combination of norepinephrine-dobutamine in adult patients with septic shock. Specifically, we tested the hypothesis that norepinephrine in addition to dobutamine would improve cardiac index (CI) and stroke volume index (SVI) and increase left-ventricular afterload. DESIGN: Prospective, descriptive, interventional study with no control group. SETTING: Intensive care unit of a university hospital. PATIENTS: Fourteen patients (group 1) were transferred to the intensive care unit from other wards with septic shock not responsive to dobutamine infusion, low blood pressure (systolic blood pressure of <90 mm Hg), clinical and laboratory signs of infection, clinical signs of poor organ perfusion, and blood lactate of >2.0 mmol/L. They were enrolled and treated by the addition of norepinephrine, while the dose of dobutamine remained constant. Three of these patients required additional fluid loading to achieve adequate ventricular filling (pulmonary capillary wedge pressure [PCWP], 12-15 mm Hg). These patients were compared with 12 patients with septic shock with high CI (CI > 5/min/m2, and other signs as outlined previously) who were treated with norepinephrine alone (group 2). INTERVENTIONS: Patients in group 1 were maintained with the same dobutamine dose, and norepinephrine was added (initial dose, 0.5 microg/kg/min, and increments of 0.3 microg/kg/min) until the correction of mean arterial blood pressure (MAP > or =75 mm Hg). Patients in group 2 received norepinephrine following the same protocol. MEASUREMENTS AND MAIN RESULTS: At study entry, group 1 patients receiving dobutamine had similar MAPs but were significantly older and had significantly lower CIs and SVIs and higher systemic vascular resistance than group 2 patients. In group 1 norepinephrine, in addition to dobutamine, significantly increased MAP, CI, SVI, left ventricular stroke work index (LVSWI), and systemic vascular resistance (SVR). No change in heart rate or PCWP was observed. In group 2, norepinephrine used alone did not modify CI or SVI and it significantly improved MAP, LVSWI, and SVR. No changes in heart rate or PCWP were observed. Blood lactate was significantly decreased in both groups. Comparing the two groups, in response to norepinephrine titrated to increase MAP to a similar concentration, patients with dobutamine-resistant septic shock had a statistically significantly greater increase in CI and SVI than patients treated with norepinephrine alone. There were no other significant differences in hemodynamic and metabolic responses to norepinephrine between groups 1 and 2. CONCLUSION: The addition of norepinephrine to treatment of patients with septic shock unresponsive to dobutamine significantly improves MAP, CI, SVI, and LVSWI. A different pattern of evolution was observed if norepinephrine was used alone in younger patients with higher CI at study entry, increases in MAP and LVSWI, and no concomitant change in CI or SVI. The use of norepinephrine in dobutamine-resistant septic shock may have some beneficial implications for the treatment of patients with inadequate myocardial performance associated with low SVR.

Adrenergic alpha-Agonists↗
PubMed1999

Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock.

OBJECTIVES: To compare in the same patient with septic shock, respective effects of epinephrine, norepinephrine, and the combination of norepinephrine and dobutamine (5 microg/kg/min) on systemic hemodynamic parameters and gastric mucosal perfusion using gastric tonometry and laser-Doppler flowmetry techniques. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: University hospital intensive care unit. PATIENTS: Twelve patients with septic shock. INTERVENTIONS: Each patient received in a random succession epinephrine, norepinephrine, and norepinephrine plus dobutamine. Dosages of epinephrine and norepinephrine were adjusted to achieve a mean arterial pressure between 70 and 80 mm Hg. A laser-Doppler probe and a tonometer were introduced into the gastric lumen. MEASUREMENTS AND MAIN RESULTS: The increase in gastric mucosal perfusion detected by laser-Doppler flowmetry was higher with epinephrine and the combination of norepinephrine and dobutamine than with norepinephrine alone (p < .05). In addition, the ratio of gastric mucosal perfusion (local oxygen delivery) to systemic oxygen delivery was increased after norepinephrine plus dobutamine as compared with norepinephrine alone and epinephrine (p< .05). Although values of intramucosal pH and gastroarterial PCO2 tended to be higher with norepinephrine plus dobutamine compared with those obtained with norepinephrine and epinephrine, differences were not statistically significant. CONCLUSIONS: For the same mean arterial pressure in patients with septic shock, our study showed that administration of epinephrine increased gastric mucosal perfusion more than norepinephrine administration alone. Addition of dobutamine (5 microg/kg/ min) to norepinephrine improved gastric mucosal perfusion. This result could be explained by a vasodilating effect of dobutamine on gastric mucosal microcirculation.

Adrenergic beta-Agonists↗
PubMed2001

Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine.

BACKGROUND AND PURPOSE: Endogenous norepinephrine release induced by cerebral ischemia may lead to small areas of necrosis in normal hearts. Conversely, norepinephrine may be one of the mediators that limit myocardial infarct size by ischemic preconditioning. Because brief ischemia in kidneys or skeletal muscle limits infarct size produced by coronary artery occlusion, we investigated whether cardiac norepinephrine release during transient cerebral ischemia also elicits remote myocardial preconditioning. METHODS: Forty-one crossbred pigs of either sex were assigned to 1 of 7 experimental groups, of which in 6 groups myocardial infarct size was determined after a 60-minute coronary occlusion and 120 minutes of reperfusion. One group served as control (no pretreatment), while the other groups were pretreated with either cerebral ischemia or an intracoronary infusion of norepinephrine. RESULTS: In 10 anesthetized control pigs, infarct size was 84+/-3% (mean+/-SEM) of the area at risk after a 60-minute coronary occlusion and 120 minutes of reperfusion. Intracoronary infusion of 0.03 nmol/kg. min(-)(1) norepinephrine for 10 minutes before coronary occlusion did not affect infarct size (80+/-3%; n=6), whereas infusion of 0.12 nmol/kg. min(-)(1) limited infarct size (65+/-2%; n=7; P:<0.05). Neither 10-minute (n=5) nor 30-minute (n=6) cerebral ischemia produced by elevation of intracranial pressure before coronary occlusion affected infarct size (83+/-4% and 82+/-3%, respectively). Myocardial interstitial norepinephrine levels tripled during cerebral ischemia and during low-dose norepinephrine but increased 10-fold during high-dose norepinephrine. Norepinephrine levels increased progressively up to 500-fold in the area at risk during the 60-minute coronary occlusion, independent of the pretreatment, while norepinephrine levels remained unchanged in adjacent nonischemic myocardium and arterial plasma. CONCLUSIONS: Cerebral ischemia preceding a coronary occlusion did not modify infarct size, which is likely related to the modest increase in myocardial norepinephrine levels during cerebral ischemia. The infarct size limitation by high-dose exogenous norepinephrine is not associated with blunting of the ischemia-induced increase in myocardial interstitial norepinephrine levels.

Animals↗
PubMed1983

Plasma l-[3H]norepinephrine, d-[14C]norepinephrine, and d,l-[3H]isoproterenol kinetics in essential hypertension.

We infused tracer-labeled l-[3H]-norepinephrine, d-[14C]norepinephrine, and d,l-[3H]-isoproterenol simultaneously into patients with essential hypertension and into normotensive control subjects, in order to determine whether abnormalities in the disappearance kinetics of these substances characterized the hypertensive patients. The mean preinfusion venous plasma norepinephrine concentration was somewhat higher in the hypertensive group (260 vs. 194 pg/ml, P = 0.06), but the groups did not differ in the disappearance kinetics of l- or d-norepinephrine or of isoproterenol. Preinfusion plasma norepinephrine was significantly positively correlated with calculated spillover rates in both the hypertensive and normotensive groups, but not with norepinephrine clearances. The d/l ratio in plasma norepinephrine was the same as in the infusate during and after the infusion, even after pretreatment with the neuronal norepinephrine uptake blocker, desipramine. Because isoproterenol is not taken up by nerve endings, the ratio of [3H]isoproterenol to l-[3H]norepinephrine increased after the infusion ended. This increase was almost completely abolished by pretreatment with desipramine. These results indicate that (a) increased plasma norepinephrine levels seen in some patients with essential hypertension result from increased sympathetic neural activity and not from decreased clearance of norepinephrine, (b) changes in the isoproterenol/norepinephrine ratio after simultaneous infusion of both provide an index of neuronal norepinephrine uptake in man, and (c) neuronal norepinephrine uptake is not stereospecific.

Adult↗
PubMedDate not supplied

Effects of norepinephrine and a combined norepinephrine and dobutamine infusion on systemic hemodynamics and indices of renal function in normotensive neonatal thoroughbred foals.

BACKGROUND: Norepinephrine is a potent vasopressor that increases arterial blood pressure but may have adverse effects on renal blood flow. The combination of norepinephrine and dobutamine may lead to improved renal perfusion compared to an infusion of norepinephrine alone. The effects of these drugs in the normotensive neonatal foal have not been reported. HYPOTHESIS: Norepinephrine increases arterial blood pressure. Adding dobutamine to a norepinephrine infusion will change the renal profile during the infusions without changing the arterial blood pressure. ANIMALS: Eight conscious Thoroughbred foals were used in this study. METHODS: Each foal received norepinephrine (0.1 microg/kg/min), combined norepinephrine (0.1 microg/kg/min) and dobutamine (5 microg/kg/min), and a control dose of saline in a masked, placebo-controlled study. Heart rate, arterial blood pressure (direct), and cardiac output (lithium dilution) were measured, and systemic vascular resistance, stroke volume, cardiac index, and stroke volume index were calculated. Urine output, creatinine clearance, and fractional excretion of sodium, potassium, and chloride were measured. RESULTS: Norepinephrine and a combined norepinephrine and dobutamine infusion increased arterial blood pressure and systemic vascular resistance and decreased heart rate and cardiac index as compared to saline. The combination resulted in higher arterial pressure than norepinephrine alone. There was no significant difference in urine output, creatinine clearance, or fractional excretion of electrolytes with either infusion as compared to saline. CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest that norepinephrine and a combined norepinephrine and dobutamine infusion cause unique hemodynamic effects without affecting indices of renal function, and this effect warrants further investigation.

Animals↗
PubMed2002

Effects of norepinephrine, epinephrine, and norepinephrine-dobutamine on systemic and gastric mucosal oxygenation in septic shock.

AIM: To compare the effects of dopamine, norepinephrine, epinephrine, and the combination of norepinephrine and dobutamine on systemic and gastric mucosal oxygen metabolism in patients with septic shock. METHODS: Sixteen patients with septic shock were enrolled in the present study. Each patient received dopamine firstly, then in a random succession epinephrine, norepinephrine, or norepinephrine-dobutamine, a mean systemic arterial pressure adjusted to >9.31 kPa. After 120 min of each treatment, hemodynamic, oxygen metabolic, and gastric mucosal parameters were obtained. RESULTS: Epinephrine induced a significant increase in heart rate compared with other three groups (P <0.05), and a significant higher cardiac index compared with norepinephrine alone and norepinephrine-dobutamine (P <0.05). Oxygen extraction ratio values were lower with epinephrine infusion as compared with other three groups (P <0.05). Arterial lactate concentrations decreased significantly with norepinephrine-dobutamine as compared with dopamine and epinephrine infusions (P <0.05). As compared with epinephrine infusion, the gastric intramucosal pH values were higher with norepinephrine-dobutamine infusion (7.25+/-0.09 vs 7.14+/-0.07, P <0.05). CONCLUSION: Dopamine, norepinephrine, epinephrine, or norepinephrine-dobutamine improved blood pressure. Epinephrine and dopamine had deleterious effect on oxygen metabolism, while norepinephrine plus low dose of dobutamine improved gastric mucosal perfusion and tissue oxygen utilization.

Adrenergic alpha-Agonists↗
PubMed1992

Norepinephrine-containing glomus cells in the rabbit carotid body. II. Immunocytochemical evidence of dopamine-beta-hydroxylase and norepinephrine.

The presence of noradrenergic glomus cells in the rabbit carotid body was investigated at the light and electron microscope levels, using dopamine-beta-hydroxylase and norepinephrine immunocytochemistry as well as the chromaffin reaction. Frozen and semi-thin plastic sections showed some dopamine-beta-hydroxylase immunoreactive glomus cells either isolated in the connective tissue or, more frequently, mixed with unreactive cells. At the ultrastructural level immunopositive cells differed from immunonegative ones by the larger size of most of their dense-cored vesicles. Similar observations were made after using anti-norepinephrine antibodies. Immunoreactive cells to anti-dopamine-beta-hydroxylase and anti-norepinephrine antibodies were relatively few although their number varied from carotid body to carotid body. The immunolabelling intensity was very variable from cell to cell. Consecutive frozen sections processed for norepinephrine- and dopamine-immunocytochemistry showed many cell clusters containing both norepinephrine and dopamine-immunoreactive glomus cells. Some chromaffin glomus cells were clearly identifiable by the very strong electron opacity of their dense-cored vesicles; most of these vesicles were characterized by their large size, as the dense-cored vesicles observed in dopamine-beta-hydroxylase- and norepinephrine-immunopositive cells. These results demonstrated that dopamine-beta-hydroxylase and norepinephrine-immunopositive, as well as chromaffin cells, were identical to the cells which take up exogenous norepinephrine, described in part I of this study. However, many intermediate levels were found between norepinephrine-immunonegative and strongly norepinephrine-immunopositive glomus cells, suggesting that the distinction between these two kinds of cells is not clearcut.

Animals↗
PubMed1999

Myocardial beta-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity.

Chronic administration of norepinephrine for 8 weeks has been shown to reduce neuronal norepinephrine uptake activity and increase interstitial norepinephrine concentration in the heart. To determine whether the changes could lead to myocardial beta-adrenoceptor down-regulation or beta-adrenergic subsensitivity, we measured left ventricular contractile responses to dobutamine, myocardial beta-adrenoceptor density, beta subtype distribution, competitive inhibition agonist binding, and adenylyl cyclase activity activation by isoproterenol, 5'-guanylylimidodiphosphate, and forskolin in dogs after a norepinephrine or saline infusion for 8 weeks. We found that norepinephrine infusion reduced myocardial beta-adrenoceptor density, beta(1)-adrenoceptor subtype density, and high-affinity site for isoproterenol. Left ventricular contractile responses to dobutamine were reduced in the norepinephrine-infused animals. In addition, norepinephrine infusion decreased the basal adenylyl cyclase activity and the adenylyl cyclase responses to isoproterenol, 5'-guanylylimidodiphosphate, and forskolin. The findings indicate that a decrease in cardiac norepinephrine uptake predisposes the heart to norepinephrine-induced myocardial beta-adrenoceptor down-regulation, and that norepinephrine, when present in a sufficient amount over a long period as it is in chronic heart failure, can reduce myocardial beta-adrenergic responsiveness by both homologous and heterologous desensitization.

Adenylyl Cyclases↗
PubMed2003

Effects of norepinephrine alone and norepinephrine plus dopamine on human intestinal mucosal perfusion.

OBJECTIVES: To evaluate the effect of norepinephrine alone and norepinephrine combined with dopamine on jejunal mucosal perfusion, gastric-arterial pCO(2) gradient, and global splanchnic oxygen demand-supply relationship after cardiac surgery. DESIGN: A prospective interventional study. SETTING: A university cardiothoracic intensive care unit. PATIENTS: Eighteen patients were studied during propofol sedation and mechanical ventilation after uncomplicated coronary artery bypass surgery. INTERVENTIONS: After control measurements, each patient received norepinephrine (50+/-26 ng.kg.min) to increase mean arterial blood pressure by 30% followed by addition of low-dose dopamine (2.6+/-0.3 microg x kg x min). Postdrug control measurements were performed 120 min after discontinuation of the catecholamines. MEASUREMENTS AND RESULTS: Norepinephrine induced a 32% increase in systemic vascular resistance with no change in cardiac index. Neither jejunal mucosal perfusion, assessed by laser Doppler flowmetry, nor gastric-arterial pCO(2) gradient (tonometry) was affected by norepinephrine. Splanchnic O(2)-extraction increased ( P<0.05) and this increase was positively correlated to the individual dose of norepinephrine ( r = 0.78, P<0.0001). Splanchnic lactate extraction was increased by norepinephrine ( P<0.05). None of the patients had splanchnic lactate production during norepinephrine infusion. The addition of dopamine increased cardiac index by 27% ( P<0.001) and decreased splanchnic O(2 )extraction. Dopamine increased jejunal mucosal perfusion by 32% ( P<0.001) while the gastric-arterial pCO(2) gradient remained unchanged. CONCLUSIONS: Vasopressor therapy with norepinephrine after cardiac surgery did not jeopardize intestinal mucosal perfusion in spite of a dose-dependent increase of the global splanchnic oxygen demand-supply relationship. The addition of dopamine increased intestinal mucosal perfusion.

Aged↗
PubMed1981

Ionophore (A23187)-induced efflux of [3H]norepinephrine and endogenous norepinephrine in the rat vas deferens.

The calcium ionophore, A23187, produced a concentration-dependent increase in the release of norepinephrine from nerves in the rat vas deferens. Maximum response to A23187 (10(-6) - 10(-5) M) was delayed in onset, occurring 60-80 min after initiation of continuous superfusion with A23187. In fact. after tissue exposure to A23187 (10(-5) M) for only 5 min with subsequent superfusion in A23187-free buffer, a significant but delayed increase in norepinephrine efflux occurred. The A23187-induced increase in efflux of norepinephrine was not altered when neuronal sodium conductance was blocked with tetrodotoxin (3.1 X 10(-7) M) or when Na+, K+ -stimulated ATPase was blocked with ouabain (10(-4) M). Release of norepinephrine by A23187 was calcium-dependent since A23187-induced efflux of norepinephrine was diminished (approximately 50%), although not abolished, in calcium-free buffer. Thus, one component of A23187 action was calcium independent. A23187 caused an increased efflux of both norepinephrine formed endogenously and [3H]norepinephrine taken up into neuronal stores. However, the effects of A23187, both on rate and maximum amount of release were greater for [3H]norepinephrine than for endogenous norepinephrine. The present studies demonstrate that neurotransmitter efflux can be induced by carboxylic ionophores in a calcium-dependent process, and this approach may prove useful in studies evaluating factors that modulate neurotransmitter release processes.

Animals↗
PubMed1987

Effect of dietary lipids on myocardial norepinephrine content and field stimulation-mediated release of norepinephrine from perfused neonatal and adult rat hearts.

The effects of dietary lipids on the content and release of norepinephrine and on the overflow of norepinephrine after alpha-adrenoceptor blockade with phentolamine were investigated in isolated perfused rat hearts. Pregnant rats were fed Purina Rodent Chow (reference diet) or a semisynthetic diet containing 16% (wt/wt) of either coconut oil (saturated fatty acids) or sunflower oil (unsaturated fatty acids). Neonatal pups were exposed to the diet via maternal milk and weaned rats were maintained on the same dietary lipid supplementation. Coconut oil caused a significant decrease in cardiac norepinephrine in all age groups when compared with the reference diet (p less than 0.01). Sunflower oil caused a significant increase in cardiac norepinephrine at 14 and 21 days of age when compared with coconut oil (p less than 0.05). Hearts prelabeled with [3H]norepinephrine were stimulated with supramaximal voltage (5 Hz, 2 ms duration, 300 pulses). At 14 and 21 days, coconut oil caused a significant decrease in norepinephrine release when compared with sunflower oil (p less than 0.05). The release of norepinephrine from hearts exposed to sunflower oil diet and the reference diet were comparable. These alterations in neuronal storage and exocytotic release of norepinephrine may be due to dietary-induced membrane perturbations. Phentolamine (10(-8)-10(-6) M) caused a dose-related increase in norepinephrine release following stimulation (supramaximal voltage 2.5 Hz, 150 pulses) of adult rat hearts from all dietary groups. However, the increase above control values was highest for coconut oil and lowest for sunflower oil (p less than 0.01), suggesting changes in receptor sensitivity. It appears that dietary lipid supplementation in the developing and adult rat could affect the myocardial alpha-adrenoceptor microenvironment which could cause changes in the prejunctional alpha-adrenoceptor neuronal function.

Animals↗
PubMed1979

Vascular compartmentalization of plasma norepinephrine in normal man: the relationships between venous and arterial norepinephrine concentration and the urinary excretion of norepinephrine.

To examine whether the concentration of NE in human plasma is dependent on the vascular source of the sample and to examine the contribution of the kidney to urinary NE, 14 normal men were studied. Plasma samples were obtained from a superficial forearm vein, and radial artery and urine samples were obtained during 1 hr of recumbency and 1 hr of upright posture. The Vne was greater than Ane during both recumbency and upright posture in black males. Such differences were not seen in age-matched white subjects. Stimulation of the sympathetic nervous system by upright posture increased both Vne and Ane in all subjects. NE concentrations in simultaneously obtained arterial and venous samples were different during the time of cardiovascular adjustments to upright posture. The urinary Xne increased after standing. Endogenous CCr decreased, whereas apparent NE clearance, calculated from the Ane, increased after standing, suggesting that a major portion of the augmented urinary Xne induced by upright posture was from an intrarenal source. We conclude that the concentration of NE in human blood is related to the specific vascular bed from which the sample is obtained, and that urinary NE is not solely derived from plasma by glomerular filtration but also arises from an unidentified renal source.

Adult↗
PubMedDate not supplied

Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients.

To assess sympathetic nervous system function in essential hypertension, we measured the rates of release to and removal from plasma of the sympathetic neurotransmitter, norepinephrine. In normal subjects, disappearance of tritiated l-norepinephrine from plasma, after infusion to steady state, was biexponential, with t1 1/2 = 2.0 +/- 0.4 minutes (mean +/- standard deviation) and t2 1/2 = 33 +/- 15 minutes. The rapid component of removal seemed to represent neuronal uptake of norepinephrine: the t1 1/2 was lengthened by the selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal uptake blocker, cortisol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction (idiopathic autonomic insufficiency). In eight of 37 hypertensive patients, the t1 1/2 was greater than 2.8 minutes (range, 3.3-6.0 min), longer than in any normal subject; this appears to be presumptive evidence of the existence of defective neuronal norepinephrine uptake. In these patients the rate of spillover of norepinephrine to plasma, of transmitter escaping uptake after release, was 0.73 +/- 0.39 micrograms/m2/min (4.3 +/- 2.3 nmoles/m2/min), higher than in normal subjects, 0.36 +/- 0.14 micrograms/m2/min (2.1 +/- 0.8 nmoles/m2/min) (p less than 0.01). A defect in neuronal uptake of norepinephrine, by exposing adrenergic receptors to high local norepinephrine concentration, may be important in the pathogenesis of blood pressure elevation in some patients with essential hypertension.

Adolescent↗
PubMed1997

Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women.

Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might reduce neural cardiovascular tone. We therefore studied responses to exogenous norepinephrine and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Total body and forearm norepinephrine spillover were measured by radiotracer methodology. Forearm vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were attenuated after estrogen supplementation (P=.002). Vasoconstrictor responses to angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a significant reduction in total body spillover of norepinephrine after estrogen supplementation (pre-estrogen, 700+/-152; postestrogen, 439+/-150 ng/min; P<.05), but there was no change after placebo. Total body clearance and forearm spillover of norepinephrine were unchanged by either estrogen or placebo. Estrogen supplementation also significantly decreased both systolic and diastolic blood pressures. Therefore, estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norepinephrine spillover, which is an index of sympathetic neural activity.

Analysis of Variance↗