SEARCH · PubMed Health

Results for “Norepinephrine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 595 records · Page 33Linked to original sources

PubMed1988

Classification of phenoxybenzamine/prazosin-resistant contractions of rat spleen to norepinephrine by Schild analysis: similarities and differences to postsynaptic alpha-2 adrenoceptors.

The striking resistance of norepinephrine contractions of rat splenic strips to antagonism by the selective alpha-1 adrenoceptor antagonist prazosin was examined by Schild analysis. Prazosin was a simple competitive antagonist of contractions to phenylephrine indicating that this tissue possesses alpha-1 adrenoceptors. In contrast, the Schild regression for prazosin, with norepinephrine as the agonist, was nonlinear and had an overall slope of 0.24. These data indicated that norepinephrine activated a prazosin-resistant adrenoceptor in this tissue. As a working hypothesis, it was assumed that the prazosin-resistant receptor was an alpha-2 adrenoceptor; the concomitant addition of yohimbine, in concentrations below those required to block alpha-1 adrenoceptors, converted the atypical Schild regression for prazosin (norepinephrine as agonist) to a linear regression identical with that found for antagonism of phenylephrine responses. Selective alkylation of alpha-1 adrenoceptors with phenoxybenzamine (POB) eliminated responses to phenylephrine but not those to norepinephrine. After POB-alkylation and in the presence of a concentration of prazosin that was sufficient to produce a profound blockade of alpha-1 adrenoceptors, a response to norepinephrine remained. It was determined that the POB/prazosin-resistant response most likely was mediated by a homogeneous population of receptors by the finding that the Schild regressions for both yohimbine and idazoxan were identical with respect to slope and elevation when either norepinephrine or cobefrin were utilized as agonists, i.e., a difference in the regressions for these antagonists would be expected if the two agonists activated a heterogeneous receptor population.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗

PubMed1988

Inhibition of norepinephrine contractions by diltiazem on aorta and pulmonary artery from young and aged rats: influence of alpha-adrenoceptor reserve.

Inhibition of contractile responses to norepinephrine by either diltiazem (1 microM) or by reducing the extracellular calcium (from 2.5-0.25 mM) has been examined on isolated ring preparations of aorta and pulmonary artery from young (2 months old) and aged (19-21 months old) rats. On aorta, the reduction in the norepinephrine maximum contraction by diltiazem was significantly greater in aged rats (40% reduction) than in young rats (12% reduction). The results obtained by reducing the extracellular calcium were indistinguishable from those with diltiazem (reduction in norepinephrine maximum: aged, 55%; young, 19%). The potency (negative log EC50) of norepinephrine was less in aorta from aged than from young rats. This was not due to a lower affinity (pKA) of norepinephrine for the alpha adrenoceptors, but to a reduced alpha adrenoceptor reserve for norepinephrine. On pulmonary artery none of the above age-related changes was seen. It is concluded that, in aorta from aged rats, the inhibitory effect of diltiazem on norepinephrine-induced contractions is enhanced, and that this is due to the age-related reduction in alpha adrenoceptor reserve in this vessel.

Age Factors↗

PubMed1988

Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat heart.

The classical approach of displacing the dose-response curve by an alpha adrenoceptor blocker has most often failed to demonstrate a contribution of an alpha adrenoceptor-mediated component in the final inotropic response to norepinephrine unless the beta adrenoceptors are extensively blocked. To unmask and quantify the inotropic components in the response to norepinephrine, we took a different approach by studying reversal responses to appropriate adrenoceptor blockers in isolated paced rat papillary muscles maximally stimulated by norepinephrine. The inotropic response to norepinephrine was rapidly reversed by simultaneous addition of the beta adrenoceptor blocker timolol and the alpha adrenoceptor blocker prazosin. When the adrenoceptor blockers were added sequentially, both alpha and beta adrenoceptor-mediated components in the inotropic response to norepinephrine could be demonstrated: one beta adrenoceptor-mediated component (timolol sensitive only) that represented about 75% of the inotropic response and one alpha adrenoceptor-mediated component (prazosin sensitive only) that represented about 25% of the inotropic response. When one adrenoceptor population was eliminated by giving one of the adrenoceptor blockers before norepinephrine, the inotropic response in this situation could be completely reversed by the other adrenoceptor blocker. The expression of both alpha and beta adrenoceptor-mediated components was significantly less during concomitant receptor stimulation than when the respective receptor populations were stimulated separately. Thus, there was apparently a mutual inhibition of one component upon the other. Although the beta adrenoceptor-mediated inotropic component clearly was the dominating one, the present observations will explain the difficulties in demonstrating an alpha adrenoceptor-mediated component during unopposed beta adrenoceptor stimulation in the inotropic response to norepinephrine in earlier studies.

Animals↗

PubMed1985

Demonstration of an alpha adrenoceptor-mediated inotropic effect of norepinephrine in human atria.

It has been claimed by other investigators that norepinephrine does not evoke a significant alpha adrenergic inotropic effect in human atria in contrast to epinephrine and phenylephrine, indicating a limitation of a possible functional role of the cardiac alpha adrenoceptors. We therefore characterized the inotropic effects of norepinephrine in isometrically contracting muscle strips from human atria obtained during open heart surgery. Both contraction and relaxation were studied by measuring developed tension and its first and second derivatives. Both the influence of propranolol and prazosin upon the inotropic responses to norepinephrine and the qualitative characteristics of the responses revealed that norepinephrine evoked both alpha and beta adrenergic inotropic effects. The alpha adrenergic response to norepinephrine was qualitatively different from the beta adrenergic effect and qualitatively similar to the alpha adrenergic effect of norepinephrine observed in other mammalian species. Although the alpha adrenergic effect was marked, the beta adrenergic effect was the dominating one as has also been found in other species. It is concluded that also in human atria norepinephrine evokes inotropic effects through both alpha and beta adrenoceptors.

Heart Atria↗

PubMed1985

Ouabain-evoked norepinephrine release from intact rat sympathetic neurons: evidence for carrier-mediated release.

Inhibition of the Na,K-ATPase is known to cause transmitter release from many neurons. The mechanism of [3H]norepinephrine release was examined in primary cultures of sympathetic neurons. Ouabain caused [3H]norepinephrine release at concentrations that produced 80 to 90% inhibition of Na,K-ATPase activity. The effect of ouabain was compared with the effects of high K+ and the Ca2+ ionophore A23187. [3H]Norepinephrine release elicited by depolarization with high extracellular K+ was dependent on extracellular Ca2+, was unaffected by tetrodotoxin, was potentiated by reducing extracellular Na+, and was potentiated by the norepinephrine uptake inhibitor desipramine. These are the results expected if high K+ causes release by exocytosis, and if blockade of the Na+-dependent norepinephrine uptake system increases the net measurable release of the transmitter. The Ca2+ ionophore A23187 caused [3H]norepinephrine release that was not dependent on extracellular Ca2+ but which was like the release elicited by high K+ in other respects. Release elicited by ouabain was independent of extracellular Ca2+, was delayed for several hours by tetrodotoxin, was inhibited by reducing the concentration of extracellular Na+, and was inhibited by desipramine. These results suggest that the measured increase in transmitter release is secondary to a rise in the concentration of intracellular Na+. The data are consistent with the hypothesis that at high levels of pump inhibition, ouabain elicits nonvesicular [3H]norepinephrine release through reversal of the Na+-dependent plasma membrane carrier.

Animals↗

PubMed1987

[A mouse model of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism: effect of norepinephrine terminal destruction].

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)

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

PubMed1987

Circadian and other variation in epinephrine and norepinephrine among several human populations, including healthy blinded and sighted subjects and patients with leprosy.

Urinary levels of epinephrine and norepinephrine were studied in three populations: presumably healthy young men who were studied twice, 8 years apart, and in the same month to avoid seasonal influences; blinded but otherwise healthy males and females; and patients with leprosy. Determinations of epinephrine and norepinephrine were done on urine samples collected at 3-hr intervals for 72 hr from the first two groups and for 10 days from patients with leprosy. The same chemist, method, and protocol were used in all studies. In one study of the group of healthy young men, the effect of meal timing and fasting on the rhythms was investigated. From these studies several generalizations can be made. Highly statistically significant population circadian rhythms characterize both epinephrine and norepinephrine in all three groups. In general, the rhythm in norepinephrine was "noisier" than that in epinephrine; in the blind subjects, both variables were characterized by noisier rhythms than in the sighted. The overall levels of epinephrine were much higher in blind than in sighted subjects. The overall levels of norepinephrine were much higher in blind males than in blind females. In the studies done with the group of healthy young men, the overall levels of epinephrine and norepinephrine increased significantly over a 10-year period. The amplitude of the rhythm also increased significantly with time. The average age of the group was 27 years at the time of the first study and 40 years at the time of the second. The patients with leprosy also showed strong circadian variation in both epinephrine and norepinephrine, but, because many of the subjects were on medication, comparisons with the other groups are questionable. In general the data raise some questions about, but do not refute, the commonly held view that the amplitude and mesor of the circadian rhythm in epinephrine decrease with age. Additional work is needed to resolve this question completely.

Adult↗

PubMed1985

Antagonism of the positive chronotropic effect of norepinephrine by purine nucleosides in rat atria.

Adenosine has been shown previously to antagonize the positive chronotropic effects of beta adrenoceptor agonists. In the present study, the effects of adenosine and related compounds were observed on the concentration-effect curve for the positive chronotropic effect of norepinephrine in isolated spontaneously beating rat atria. Adenosine produced both a decrease in the potency of norepinephrine and a decrease in the maximal effect. The decrease in the potency was postulated to be mediated by an action on an external membrane receptor because it was also produced by the potent A1 receptor agonist N6-phenylisopropyladenosine. The effect of N6-phenylisopropyladenosine was antagonized by 8-phenyltheophylline which is known to block external adenosine receptors. When adenosine deaminase was inhibited with erythro-9-(2-hydroxy-3-nonyl)adenine, both effects of adenosine were enhanced markedly suggesting considerable metabolism of exogenous adenosine to inosine under the conditions of this study. Inosine increased rather than decreased the potency of norepinephrine while decreasing its maximal effect. The decrease in the maximal effect of norepinephrine was also produced by 2',5' dideoxyadenosine, 2' deoxyadenosine and S-adenosylhomocysteine but not by N6-phenylisopropyladenosine. This suggests that the decrease in the maximal effect of norepinephrine by adenosine analogs is related to an interaction with an internal site. Adenine had no effect on the concentration-effect curve for norepinephrine. It is suggested that adenosine may regulate cardiac function by antagonizing the chronotropic effect of norepinephrine released upon nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1984

Beta adrenoceptor mediation of the enhancing effect of norepinephrine on the murine primary antibody response in vitro.

The beta adrenoceptor has been identified in this study to be the receptor responsible for the enhanced immunoglobulin M antibody response produced by norepinephrine in mouse spleen cells immunized with sheep erythrocytes in vitro. The magnitude and kinetics of the enhanced antibody response to norepinephrine alone, or to norepinephrine in the presence of phentolamine, were more closely mimicked with a beta-2 adrenoceptor agonist (terbutaline) than with a beta-1 adrenoceptor agonist (dobutamine). Norepinephrine alone, norepinephrine in the presence of phentolamine, or terbutaline exposure produced a number of spleen cells secreting immunoglobulin M antibody that is equal to control on day 4 after immunization and which is enhanced above control on days 5, 6 and 7. Dobutamine causes no change when compared to control on days 4 and 5, but causes a delayed decline in the response on days 6 and 7. All drug responses were concentration-dependent and propranolol antagonized the enhanced response observed in the presence of terbutaline or dobutamine alone. When norepinephrine was added to immunized spleen cell cultures in the presence of propranolol, an alpha adrenoceptor-mediated component was unmasked which produced an enhanced response on day 4 after immunization and returned to control levels on days 5, 6 and 7. These results suggest that antibody responses can be modulated positively by a sympathetic neurotransmitter. This up-modulation by norepinephrine is beta adrenoceptor-mediated at the time of, and after, peak control response and alpha adrenoceptor-mediated 1 day before peak control response.

Animals↗

PubMed1984

Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses.

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.

Adenosine↗

PubMed1984

Alteration of presynaptic alpha 2-mediated inhibition of norepinephrine release in perfused mesenteric arteries of young and adult spontaneously hypertensive rats.

The present study was designed to evaluate norepinephrine release during sympathetic nerve stimulation and its inhibitory characteristics by presynaptic alpha 2-adrenoceptor in the perfused mesenteric arteries of young and old spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto rats (WKY). Sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from adrenergic nerve terminals in young SHR than age-matched WKY. Yohimbine, alpha 2-adrenoceptor antagonist, exerted a facilitatory effect on norepinephrine overflow from mesenteric vasculature. This effect was less in young SHR than in aged-matched WKY. On the other hand, in adult SHR the amount of norepinephrine overflow was somewhat reduced compared with age-matched WKY. The difference of the facilitatory effect on norepinephrine overflow by yohimbine between SHR and WKY was not so marked as that observed in young age. These results indicate that increased norepinephrine release from sympathetic nerve endings in young SHR could depend at least partly on impaired presynaptic alpha 2-mediated inhibition, while normal or reduced norepinephrine release in adult SHR might be an adaptive mechanism to prevent further increase in blood pressure in SHR.

Aging↗

PubMed1984

Reduction in norepinephrine content of sympathetic neuroeffector organs by alpha adrenergic antagonists and nerve stimulation: evidence for presynaptic control of sympathetic transmitter release in intact animal.

The purpose of the present study was to obtain evidence for the functional role of presynaptic alpha adrenergic receptors in the intact animal. This aim was approached by investigating the effects of alpha adrenergic blocking agents and other hypotensive agents on the norepinephrine content of the heart, spleen and the salivary gland of the normal and adrenalectomized rats. Intraperitoneal administration of saline, hydralazine (10 mg/kg), yohimbine (1 mg/kg), prazosin (0.5 mg/kg) or bretylium (10 mg/kg) to normal or adrenalectomized rats had no significant effect on norepinephrine content of these organs over 4 hr. A combined treatment of hydralazine plus yohimbine produced 50 and 27% reduction in norepinephrine content of the heart and spleen, respectively. The effect of hydralazine plus yohimbine was more pronounced in adrenalectomized rats (62% for the heart and 50% for the spleen). Administration of phentolamine (2 mg/kg) alone resulted in about 40% reduction in norepinephrine content of the normal rat hearts. A combination of hydralazine plus phentolamine enhanced the degree of norepinephrine depletion in the hearts (52%) and also produced a small loss (17%) in the spleen. The depleting effects of various drugs were completely prevented by prior treatment of rats with bretylium. Norepinephrine content of the salivary gland remained unchanged in all of the above-treated rats. However, transmural stimulation of the isolated salivary gland for 30 min in the presence of yohimbine caused about 50% reduction in norepinephrine content.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1980

The role of norepinephrine in the regulation of fluid absorption in the rat proximal tubule.

In order to investigate the possibility of a direct effect of adrenergic transmitter on tubular fluid absorption, we have studied the effects of norepinephrine and phenoxybenzamine on fluid absorption in the proximal convoluted tubule of the rat kidney. Net fluid absorption (Jv) was determined in the same proximal convoluted tubule before and after addition of norepinephrine or phenoxybenzamine while the tubular lumen and peritubular capillaries were simultaneously microperfused in situ. When the tubular lumen was perfused with Ringer's solution and the peritubular capillaries were perfused with albumin Ringer's solution, Jv was 2.85 +/- 0.25 nl/min X nm. Addition of 2 X 10(-6) M norepinephrine to the capillary perfusate caused at 30% increase in Jv which could be reversed by removing the adrenergic transmitter. The effect of norepinephrine was dose dependent with the maximal increase of Jv observed at a concentration of 10(-5) M. Addition of 2 X 10(-6) M phenoxybenzamine to the capillary perfusate caused a 16% decrease in Jv while the simultaneous administration of norepinephrine and phenoxybenzamine to the capillary perfusate caused a 25% decrease in Jv. On the other hand, there was no effect observed on Jv when either norepinephrine or phenoxybenzamine was added to the luminal perfusate. These results suggest that adrenergic nerves may participate in the regulation of tubular fluid absorption through the direct action of norepinephrine on alpha adrenergic receptors located on the basolateral membrane of proximal tubular cells.

Absorption↗

PubMed1982

Chronic effects of a monoamine oxidase-inhibiting antidepressant: decreases in functional alpha-adrenergic autoreceptors precede the decrease in norepinephrine-stimulated cyclic adenosine 3': 5'-monophosphate systems in rat brain.

Various antidepressant drugs (monoamine oxidase inhibitors and tricyclics) enhance norepinephrine availability and lead to adaptive changes in brain noradrenergic systems, namely, decreases in the number of beta receptors and in the responsiveness of adenylate cyclase to norepinephrine monamine oxidase inhibitor, but not after 3 days, there is an increase in norepinephrine release from rat brain microsacs in response to 43 mM KCl stimulation. Microsacs prepared from 21-day clorgyline-treated animals also show a marked decrease in the inhibition of norepinephrine release caused by the alpha 2-selective agonist clonidine. These functional changes in norepinephrine release mechanisms are accompanied by a 53% reduction in brainstem alpha 2 receptor density as measured by [3H]clonidine binding. At the same time, despite findings of a decrease in beta receptor number as determined by [3H]dihydroalprenolol binding data, no significant decrease in the responses of cyclic adenosine 3': 5'-monophosphate (cyclic AMP) systems to norepinephrine stimulation is observed. Decreases in the cyclic AMP response are observed by day 35 of clorgyline treatment. The results provide direct physiological support for a change in the norepinephrine release mechanism and an effect on autoreceptors, specifically, preceding postsynaptic adaptive changes in the instance of one antidepressant, clorgyline. Difficulties in observing such changes with other antidepressants may result from the multiple nature of alpha-adrenergic receptors, especially as measured by radioactive ligand techniques; the lack of a direct relationship between physiological changes and receptors as measured by radioligand techniques; the large doses of monoamine oxidase inhibitors used in some studies; and the possible multiplicity of antidepressant molecular mechanisms.

Animals↗

PubMed1982

Developmental changes in the accumulation of norepinephrine and the chronotropic effects of catecholamines in isolated rat atria as influenced by dietary lipid.

Pregnant rats were fed semisynthetic diets enriched in either saturated fat (coconut oil) or polyunsaturated fat (sunflower oil) and sympathetic function was observed in the resulting neonatal pups. The neuronal accumulation of [3H]norepinephrine was significantly decreased in atria from neonates (11, 24 and 37 days of age) of dams receiving dietary sunflower oil compared with coconut oil diet. The nonspecific accumulation of [3H]norepinephrine occurring in the presence of desipramine (5 X 10(-5)M) was not changed by dietary lipid treatment. No differences in the accumulation of [3H]norepinephrine were observed in atria from day 7 neonates or in atria from adults which had received the diets since birth. When the beating rate of isolated atria was studied upon exposure to norepinephrine and isoproterenol, it was observed that the EC50 for these agonists was not changed upon exposure to the diets but that the maximal effect of both agonists was increased in atria from adult animals fed coconut oil relative to the sunflower oil diet. No significant differences were observed in the chronotropic effects of either norepinephrine or isoproterenol in atria from 11-day-old rats. A developmental analysis of the chronotropic response of isolated atria to a maximally effective dose of norepinephrine (10 microM) revealed a gradual onset of the altered maximum effects found in adult rat atria. The results of this study indicate that sympathetic nerve regulation of myocardial function can be modified during development by changing the dietary fat composition. The results are discussed in reference to the perturbation of specific membrane-associated processes that may be brought about by dietary lipid treatment and the possible importance of each of these effects in the changes observed in the accumulation of norepinephrine and the chronotropic effects of catecholamines in isolated rat atria.

Animals↗

PubMed1982

Characterization of [3H]desipramine binding associated with neuronal norepinephrine uptake sites in rat brain membranes.

A variety of evidence indicates that [3H]desipramine can label neuronal norepinephrine uptake sites in brain membranes. Pretreatment of rat cerebral cortical membranes with 0.3 M KCl increases the ratio of high affinity to low affinity saturable [3H]desipramine binding. With this improved tissue preparation, we have confirmed our earlier observation that the high affinity [3H]desipramine binding component (KD = 2 to 4 nM) is associated with norepinephrine neuronal uptake sites. The potencies of various antidepressant drugs in reducing [3H]desipramine binding correlate with their inhibition of neuronal [3H]norepinephrine accumulation. Like the norepinephrine uptake system, high affinity [3H]desipramine binding is dependent both on sodium and chloride, with half-maximal stimulation by 10 mM chloride. Although bromide can substitute for chloride to stimulate binding, other anions, including iodide, fluoride, acetate, citrate, and phosphate, are inactive. Comparable sodium and anion regulation of [3H]imipramine binding to serotonin uptake recognition sites also is observed. The association of [3H]desipramine binding sites with neuronal norepinephrine uptake sites is supported further by the selective abolition of high affinity [3H]desipramine binding following the destruction of central norepinephrine neurons by intraperitoneal administration of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). In vitro incubation of cerebral cortical membranes with DSP-4 also selectively abolishes the high affinity [3H]desipramine binding, an effect which cannot be reversed by repeated washing of the membranes, suggesting that DSP-4 alkylates neuronal norepinephrine uptake sites.

Animals↗

PubMed1994

Endothelium-derived relaxing factor inhibition and the pressor response to norepinephrine in the pregnant rat.

OBJECTIVE: To determine whether endothelium-derived relaxing factor (EDRF) plays a role in the blunted pressor response to norepinephrine that is characteristic of normal pregnancy. METHODS: Eleven pregnant (mean +/- standard error of the mean 18 +/- 1 days of gestation) and 11 virgin conscious, unrestrained Sprague-Dawley rats with long-term indwelling vascular catheters were studied. Mean arterial pressure (MAP) and heart rate were measured in response to continuous infusions of either vehicle (5% dextrose) or increasing concentrations of norepinephrine (25, 100, and 200 ng/kg/minute) before and after administration of NG-monomethyl-L-arginine (LNMMA), a specific inhibitor of EDRF synthesis. RESULTS: Baseline MAP was lower in pregnant than in virgin rats (96 +/- 3 versus 105 +/- 3 mmHg; P < .05). Before LNMMA administration, the pregnant rats exhibited a significantly blunted pressor response to increasing concentrations of norepinephrine compared to that of virgin rats (P < .005). Given alone, LNMMA produced a greater increase in baseline MAP in virgin rats than in pregnant rats (rise in MAP of 44 +/- 2 versus 31 +/- 2 mmHg; P < .001). However, LNMMA abolished the blunted pressor response to norepinephrine in the pregnant animals and did not significantly affect the pressor response to norepinephrine in virgin rats. Heart rate responses to increasing concentrations of norepinephrine in the presence and absence of LNMMA were not significantly different in the two groups of animals. CONCLUSION: Stimulated EDRF production may contribute to the blunted pressor response to norepinephrine characteristic of pregnancy in the rat.

Analysis of Variance↗

PubMed1977

Production of sustained hypertension by chronic intrarenal norepinephrine infusion in conscious dogs.

The purpose of this study was to determine whether increased sympathetic nervous system activity with proportionally greater stimulation to the kidney could result in sustained hypertension. This was simulated by continuous intrarenal norepinephrine infusion. Effects of chronic infusion of norepinephrine (0.285 microng/kg per min) into the renal artery and inferior vena cava were compared in uniephrectomized conscious dogs. Ten days of intrarenal norepinephrine infusion produced a sustained rise in mean arterial pressure (25 mm Hg), and a 32-mEg positive sodium balance occurred. Inferior vena caval infusion caused a transient rise, lasting 24 hours, in mean arterial pressure which was associated with a 54-mEq natriuresis. With renal artery infusion, peripheral plasma renin activity rose from 1.0 +/- 00.2 to 4.4 +/- 0.8 ng angiotensin I/ml per hour at 1 hour (P less than 0.002) and fell to 1.4 +/- 0.4 at 24 hours (not significant). Inferior vena caval infusion produced a similar result. [Sar1,ala8]angiotensin II (6 MICrong/kg per min) produced no significant change in arterial blood pressure. (alpha-Adrenergic blockade with phentolamine normalized the blood pressure. Renal plasma flow was chronically decreased by about 25% in dogs given intrarenal norepinephrine; no significant change in glomerular filtration rate occurred. The cardiac output decreased from a control of 7.2 +/- 0.6 to 4.8 +/- 0.1 liters/min (P less than 0.01) and total peripheral resistance was increased from a control of 13 +/- 1 to 26 +/- 1 resistance units (RU) (P less than 0.0005) in dogs given intrarenal norepinephrine. The data indicate that chronic intrarenal infusion of norepinephrine in uninephrectomized conscious dogs results in sustained hypertension characterized by decreased renal plasma flow, normal glomerular filtration rate, positive sodium balance, and increased total peripheral resistance due to norepinephrine-dependent vasoconstriction.

Aldosterone↗