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PubMed1986

Effects of epinephrine and dopamine on norepinephrine release from the sympathetic nerve endings in hypertension.

The purpose of the present study was to analyse the regulatory mechanisms of epinephrine and dopamine on norepinephrine release from the sympathetic nerve endings in the resistance vessels in hypertension. The perfused mesenteric arteries were used for the experiment in spontaneously hypertensive rats (SHR; 7-10 weeks old) and age-matched normotensive Wistar-Kyoto (WKY) rats. Norepinephrine overflow during electrical nerve stimulation was significantly greater in SHR than in WKY rats. A low concentration of epinephrine (5.5 X 10(-9) mol/l) potentiated norepinephrine overflow from the nerve endings in SHR, and this was antagonized by propranolol, while this overflow was reduced by the same concentration of epinephrine in WKY rats. Higher concentrations of epinephrine decreased the norepinephrine overflow both in SHR and WKY rats, and this was antagonized by yohimbine. Dopamine reduced the norepinephrine overflow during electrical nerve stimulation, suppression being significantly less in SHR than in WKY rats. These results suggest that in SHR the increased norepinephrine overflow from sympathetic nerve endings may be partly caused by the facilitatory effect of epinephrine (through presynaptic beta-adrenoceptors) and impaired dopamine-mediated inhibition on the nerve terminals, which might contribute to the enhanced adrenergic activity in hypertension.

Animals↗

PubMed1987

Depletion of heart norepinephrine in mice by some analogs of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

The effects of ten analogs of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on heart norepinephrine concentration in mice were compared to those of MPTP itself. A single dose of MPTP (10 mg/kg s.c.) caused 73% depletion of heart norepinephrine 24 hrs after its injection. m-Hydroxy-MPTP caused an identical degree of depletion, and six other analogs caused statistically significant but lesser depletion. Three analogs caused no significant change in heart norepinephrine concentration. Since MPTP is oxidized by type B monoamine oxidase (MAO-B), the analogs were compared for their ability to be oxidized by mitochondrial MAO preparations from mouse brain and liver. MPTP and seven analogs were oxidized by MAO-B (oxidation was inhibited by deprenyl); three analogs were not oxidized or were oxidized only slowly and not by MAO-B. The ability of the compounds to deplete heart norepinephrine paralleled their ability to deplete striatal dopamine in the case of MPTP and seven analogs. Three analogs--the same three that were not substrates for MAO-B--depleted heart norepinephrine but not striatal dopamine. One conclusion is that the ability of an MPTP analog to be a substrate for MAO-B is a necessary but not sufficient requirement for depletion of striatal dopamine, but is not necessary for depletion of heart norepinephrine.

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

PubMed1987

Interconversion of O-methylated norepinephrine metabolites in humans.

Levo-norepinephrine labeled with tritium was used to study urinary norepinephrine metabolites as an index of whole body norepinephrine turnover. Six healthy volunteers were given intravenous infusions of [ring-2,5,6-3H] levo-norepinephrine, followed by collection of urine for 24 hours. Specific activities were determined by high-performance liquid chromatography for each of the three O-methylated metabolites of norepinephrine in the urine samples, and were then used to calculate the fraction of 4-hydroxy-3-methoxymandelic acid (VMA) formed from 4-hydroxy-3-methoxyphenylglycol (MHPG) and from normetanephrine. These values were used, in conjunction with total excretion of each of these metabolites, to calculate the fraction of MHPG and normetanephrine converted to VMA. The fraction of VMA formed from MHPG was 0.821 +/- 0.020, and that from normetanephrine was 0.179 +/- 0.020. Whereas fractional conversion of normetanephrine to VMA was 0.634 +/- 0.030, that of MHPG to VMA was only 0.507 +/- 0.025. Similar results were obtained when the experiment was repeated in three of the subjects using [8-14C] levo-norepinephrine, suggesting that isotope, specific activity, and position of the label were not determinants of the values obtained. The present results confirm the extent of conversion of MHPG to VMA described by others, and suggest that a higher percentage of normetanephrine than previously reported is converted to VMA.

Adult↗

PubMed1987

Plasma and platelet norepinephrine in normal and preeclamptic pregnancy.

Catecholamines accumulate in platelets, and platelet catecholamine concentrations may give a more stable index of sympathoadrenal activity than do random plasma values. We measured norepinephrine in plasma and platelets from normal, nonpregnant women and from normal and preeclamptic pregnant women with a radioenzymatic assay. Plasma and platelet norepinephrine was not markedly different in normal, pregnant women during the third trimester, intrapartum or postpartum when compared with those levels in nonpregnant women. Platelet norepinephrine was significantly elevated in women with mild preeclampsia, but plasma norepinephrine was not. A linear relationship existed between platelet count and platelet norepinephrine concentrations in women with preeclampsia. These findings are compatible with the hypothesis of increased sympathoadrenal activity in women with mild preeclampsia and normal platelet counts. The lower platelet norepinephrine in thrombocytopenic patients suggests that platelet activation and degranulation have occurred and indicate that platelet catecholamine concentration does not provide a stable index of sympathoadrenal activity when platelets are being consumed.

Adolescent↗

PubMed1986

Norepinephrine uptake in canine saphenous veins in the presence and absence of halothane.

Studies were done to examine neuronal and extraneuronal uptakes of norepinephrine in canine saphenous veins and to ascertain whether these uptakes were altered by halothane. Minced vein was incubated for 1 min in Krebs-Ringer solution containing L-[ring-2,5,6-3H]-norepinephrine (1, 2.5, 6, or 12 microM). After incubation, radioactivity in tissue was measured by liquid scintillation counting. Neuronal uptake at each norepinephrine concentration was determined by the difference in norepinephrine uptake between tissues in which both neuronal and extraneuronal uptakes were operative and in tissues in which only extraneuronal uptake was operative. In time studies with 1 microM norepinephrine, neuronal uptake was still dominant at 10 min; with 12 microM norepinephrine, extraneuronal uptake predominated at all incubation periods tested. In other studies, tissues were incubated in the absence or presence of halothane (2.5%). The Km values for neuronal uptake in control and halothane-treated tissues were 2.49 and 2.32 microM, respectively. Corresponding Vmax values were 0.049 and 0.060 nMol X min-1 X 100 mg-1, respectively. No significant effect of halothane on neuronal or extraneuronal uptake could be detected.

Animals↗

PubMed1985

The effects of norepinephrine and acetylcholine in the vas deferens from normal and diabetic rats: influence of ouabain and verapamil.

In vas deferens from acute and chronic diabetic rats a hypersensitivity to norepinephrine and acetylcholine was observed. The hypersensitivity to norepinephrine was markedly reduced by treatment with ouabain or verapamil. On the contrary, the response to acetylcholine was not modified by ouabain in the same concentration, but was inhibited by verapamil. Under normal conditions, ouabain and verapamil did not modify the stimulatory effect of either norepinephrine and acetylcholine; however increase of extracellular potassium concentrations potentiated the action of norepinephrine. The results suggest that ouabain-sensitive (Na+ + K+)ATPase exists in the rat vas deferens. In diabetic animals, the supersensitivity to norepinephrine is associated with an increase in membrane permeability to calcium ions that could be related to hypersensitivity of the enzyme. Under normal conditions it is possible to mimic the hypersensitivity to norepinephrine through an increase in the extracellular potassium concentration.

Acetylcholine↗

PubMed1979

[Specific activity and release of norepinephrine in isolated and perfused rabbit hearts under various oxygen pressure].

The incorporation of 3H-tyrosine into norepinephrine of rabbit hearts perfused with Krebs-Henseleit solution containing 11 mM glucose and gassed with 95% O2 - 5% CO2 (control) or 80% O2 - 5% CO2 15% N2 (hypoxic) or 95% N2 - 5% CO2 (anoxic), was studied. In the control hearts a constant specific activity of norepinephrine without any release of catecholamine into coronary effluent was measured after 5, 15, 30, 60 minutes. The hypoxic perfusion while not causing any release of norepinephrine, produced a significant increase in tyrosine incorporation into norepinephrine. The specific activity of norepinephrine and its release into coronary effluent were increased by anoxic perfusion; this effect was most evident when the glucose was replaced with a solution containing 11 mM mannitol. These results suggest that the synthesis of norepinephrine in isolated hearts, lacking of sympathetic innervation, may be affected by different condition of oxygen supply.

Animals↗

PubMedDate not supplied

[Triiodothyronine binding and norepinephrine uptake in the heart and liver].

Administration of norepinephrine to thyroidectomized rats activates sharply the [125I]triiodothyronine binding by heart mitochondria and liver nuclei. Epinephrine stimulates the binding by the heart mitochondria and decreases the intensity of this process in the liver and heart nuclei and liver mitochondria As compared to norepinephrine, adrenoxyl is weaker in activation of [125I] triiodothyronine binding by the heart mitochondria and stronger in intensification of binding by the liver nuclei. Physiological concentrations of thyroxine like adrenoxyl administered to intact animals 2h before investigations intensify the uptake of [3H] norepinephrine by sections of the auricles, myocardium and liver. Hyperthyroidization induces contrary changes inthe uptake of [3H] norepinephrine. Norepinephrine administration decreases sharply the uptake of [3H] norepinephrine by sections of the auricles and myocardium. The blocking of beta-adrenoreceptors weakens the uptake.

Animals↗

PubMed1978

[Studies on the excitation-metabolism coupling mechanism in brown adipose tissues, 2; Effects of K+ and norepinephrine on the lipolysis in brown adipose tissues (author's transl)].

This investigation was undertaken to clarify the lipolytic response caused by K+ and norepinephrine in brown adipose tissues. 1. Lipolytic response was obviously observed at the concentration of 50 mM in the K+-induced stimulation, and at 1.0 microgram/ml in the norepinephrine-induced stimulation, respectively. 2. K+- and norepinephrine-stimulated lipolysis were inhibited in the Ca2+-deficient tissues, and were inhibited by the addition of Mg2+, Mn2+ and La3+. 3. In the K+-stimulated lipolysis Ca2+ could be substituted only by Sr2+, while in the norepinephrine-stimulated lipolysis the substitution was possible with both Sr2+ and Ba2+. 4. K+- and norepinephrine-stimulated lipolysis were inhibited by the addition of propranolol and procaine. Accordingly, these positive results suggest that K+- and norepinephrine-stimulated lipolysis are dependent on the presence of Ca2+, and are related to the movements of Ca2+ and cyclic AMP system in the cells.

Adipose Tissue, Brown↗

PubMed1978

The effects of exogenous norepinephrine on ventilatory mechanics in the rat.

The effects of intravenous administration of norepinephrine on ventilatory mechanics were assessed in the anesthetized, spontaneously breathing rat. Pulmonary resistance, dynamic compliance and functional residual capacity remained unchanged during a 10-min infusion period. After paralysis, repetition of the norepinephrine infusion caused an increase in static deflation recoil pressure at lung volumes above the tidal range but maximum expiratory flow rates at corresponding lung volumes were not increased indicating an elevation in the resistance of upstream airways. Flow rate responses to low density gas breathing were not enhanced by norepinephrine suggesting peripheral airways narrowing as the cause of the increased upstream resistance. Isoproterenol protected animals against serotonin-induced bronchoconstriction whereas norepinephrine augmented the response to serotonin. It is concluded that in intact rats norepinephrine increases the flow-resistive properties of peripheral airways, does not measurably alter the caliber of central airways and possesses no discernible bronchodilator activity. The effects of norepinephrine on small airways appear to be secondary to changes in pulmonary hemodynamics rather than the result of direct stimulation of alpha adrenoceptors in airway smooth muscle.

Airway Resistance↗

PubMed1980

Norepinephrine kinetics in patients with idiopathic autonomic insufficiency.

The rates of norepinephrine release into plasma and removal from plasma were studied in patients with idiopathic peripheral autonomic insufficiency (sympathetic neuronal dysfunction), as it was thought that plasma norepinephrine concentration alone inadequately quantifies the degree of sympathetic nervous underactivity in this disorder. In four patients with autonomic insufficiency, clearance of norepinephrine from the circulation was slowed, 1.69 +/- 0.44 liters/min, compared with 2.80 +/- 0.73 liters/min in 10 normal subjects (P less than 0.05). As a consequence, despite a 60% lower norepinephrine apparent secretion rate, 0.19 +/- 0.12 microgram/m2 per min vs. 0.54 +/- 0.20 microgram/m2 per min, the plasma norepinephrine concentration was near normal. The plasma concentration of neurotransmitter does not provide a valid index of sympathetic nervous tone in this disorder in which removal of norepinephrine from the circulation is slowed.

Dysautonomia, Familial↗

PubMed1980

Central actions of norepinephrine, phentolamine and 6-hydroxydopamine in spontaneously hypertensive rats.

The effects of norepinephrine HCl, isoproterenol HCl, phentolamine and 6-hydroxydopamine HCl on mean arterial blood pressure (MABP), heart rate (HR), and pulmonary respiration were examined in 67 urethane-anesthetized, spontaneously hypertensive rats (SHR) with carotid arterial and femoral venous catheters and stereotaxically positioned intracerebral cannulae. Norepinephrine produced significant pressor responses when it was instilled into the posterior hypothalamic region and/or the pars magnocellularis region of the ventral medial thalamus. Central pretreatment with either phentolamine mesylate or phentolamine HCl, 30 min before central administration of norepinephrine, blocked the norepinephrine-induced pressor responses. Central administration of 6-hydroxydopamine HCl in the hypothalamic-thalamic region of the diencephalon produced significant depressor responses within 60 min. Neither norepinephrine nor isoprotereol produced their centrally-induced pressor and depressor responses when they were instilled centrally into the reticular formation. The results suggest that receptors that respond to norepinephrine are located in the posterior hypothalamic-ventral medial thalamic region of the diencephalon. The results also suggest that cells located in these areas send projection fibers either directly or indirectly to the vasomotor center located in the brain stem.

Animals↗

PubMed1978

Regional differences in the effects of denervation, cocaine and chronic reserpine administration on the responses of the rat vas deferens to norepinephrine and acetylcholine.

The prostatic half and epididymal half of the rat vas deferens was found to show the difference with respect to both the sensitivity (expressed as the geometric mean ED50) and maximal response to norepinephrine and acetylcholine. The epididymal half was more sensitive to both drugs than the prostatic half; the maximal response to norepinephrine was greater in the epididymal half than in the prostatic half. Effects of denervation, 10-6 M cocaine and chronic administration of reserpine (1 mg/kg/day for 5 days) on the responses to the drugs were also found to be qualitatively and/or quantitatively different between the two halves. In the epididymal half, all these procedures produced supersensitivity to acetylcholine as well as to norepinephrine. Whereas, in the prostatic half, supersensitivity to only norepinephrine was observed; the responses to acetylcholine were more or less depressed, accompanied by little change in the sensitivity, by these procedures. Degree of supersensitivity (ED50 control/ED50 treated) to norepinephrine produced by denervation was greater in the prostatic half than in the epididymal half. However, in the case of cocaine or reserpine, there was little difference in the degrees of the two halves. In both halves, the maximal response to norepinephrine was increased by denervation and cocaine, but not by reserpine. The magnitude of such increase in the prostatic half was greater and less, after denervation and cocaine, than that in the epididymal half, respectively. Only cocaine increased the maximal response of the epididymal half to acetylcholine. These results are discussed in relation to those previously obtained using whole vas deferens.

Acetylcholine↗

PubMed1994

Unmasking of activated histamine H3-receptors in myocardial ischemia: their role as regulators of exocytotic norepinephrine release.

We had previously found that histamine H3- receptors are negatively coupled to norepinephrine exocytosis in atrial tissue. We report here that in the presence of H1- and H2- receptor blockers, histamine significantly inhibits the tachycardia and norepinephrine release elicited by sympathetic nerve stimulation is isolated guinea pig hearts, an effect prevented by the H3 antagonist, thioperamide. Sympathetic nerve stimulation also caused a 1.5-fold increase in histamine overflow, which was insufficient to activate H3 receptors because thioperamide affected neither the tachycardia nor the norepinephrine release. Hence. We questioned whether H3 receptors become activated when adrenergic activity is greatly enhanced, as in myocardial ischemia. Guinea pig hearts underwent 10-min global ischemia. At reperfusion, norepinephrine exocytosis was markedly augmented and was associated with a 3.5-fold increase in histamine overflow. (R)alpha-methylhistamine, an H3 agonist, did not modify norepinephrine release, whereas thioperamide doubled it. Thus, in physiologic conditions, cardiac H3 receptors are quiescent, yet available for activation by exogenous ligands. In contrast, in the ischemic myocardium, H3 receptors appear to be fully activated by an endogenous ligand, probably histamine. Hence, cardiac H3 receptors may play an important role by negatively modulating exocytotic norepinephrine release associated with ischemic states.

Animals↗

PubMed1994

Clenbuterol increases norepinephrine release from rat brain slices by a calcium- and receptor-independent mechanism.

Clenbuterol (10-100 microM), a beta 2-adrenergic agonist, potentiated basal (unstimulated) and electrical stimulation-evoked release of 3H-norepinephrine from cerebral cortical slices in a concentration-dependent manner. The beta-adrenergic antagonists propranolol and ICI 118,551 did not antagonize the facilitatory effect of clenbuterol on basal 3H-norepinephrine efflux. Selective down-regulation of beta 2-adrenergic receptors produced by chronic administration of clenbuterol also did not alter this effect of in vitro clenbuterol, despite marked reductions in the density of these receptors. These results suggest that the increase in basal efflux of 3H-norepinephrine observed with clenbuterol was not mediated by beta 2-adrenergic receptors. The facilitatory effect of clenbuterol on basal 3H-norepinephrine efflux was Ca(2+)-independent, which may indicate an amphetamine-like mechanism of action. The enhanced basal efflux of 3H-norepinephrine produced by clenbuterol was stereoselective; there was a four-fold increase in basal 3H-norepinephrine efflux with the (+)-isomer of clenbuterol compared with that induced by the (-)-isomer; this contrasts with the stereoselectivity of the isomers for interacting with beta 2-adrenergic receptors. The present results may explain some of the behavioral actions of clenbuterol, particularly those observed after long-term treatment, and may be relevant to the antidepressant actions of this compound.

Adrenergic beta-Antagonists↗

PubMed1994

Norepinephrine utilizes alpha 1- and beta-adrenoreceptors synergistically to maximally induce c-fos expression in brown adipocytes.

In order to examine how norepinephrine stimulates proliferation and differentiation in brown fat cells, we have investigated the ability of brown fat cells to respond to norepinephrine stimulation with an increase in the expression of the proto-oncogene c-fos. Stimulation of brown fat precursor cells (isolated from young mice and grown for 4 days in culture) with norepinephrine led to a marked but transient (maximal approximately 30 min) induction of c-fos expression. The magnitude of this induction was similar in pre- and postconfluent cells. The norepinephrine effect could be blocked by both alpha 1- and beta-adrenergic antagonists. Forskolin had a small inductive ability, as had the selective alpha 1-agonist cirazoline, but with both together a high induction was obtained. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) could in itself induce c-fos expression, but pretreatment with TPA did not abolish the ability of norepinephrine to induce c-fos expression, indicating that TPA-sensitive protein kinase C was not a primary mediator in this pathway. Also the Ca2+ ionophore A23187 had in itself an inductive ability, but A23187 in combination with forskolin led to a large increase in c-fos expression, indicating synergistic interaction between a cAMP pathway and a [Ca2+]i pathway. This interaction was not proximal, i.e. alpha 1 stimulation or increase in [Ca2+]i by A23187 did not augment forskolin-induced cAMP levels, and beta stimulation or forskolin did not affect [Ca2+]i levels; and it did not require protein synthesis. It was concluded that norepinephrine, in agreement with its fundamental role in the control of brown fat cell growth and development, was able to induce c-fos expression, that this induction was not exclusively linked to promotion of either proliferation or differentiation, and that the induction was mediated via a distal synergism between beta/cAMP and alpha 1/[Ca2+]i pathways, thus conferring to the alpha 1-adrenoreceptors on the cell a potentially significant role in the control of cell growth and development.

Adipocytes↗

PubMed1994

Multifactorial mediation of post norepinephrine induced intestinal hyperemia.

We evaluated several potential endogenous mediators of post norepinephrine induced hyperemia in the mesenteric circulation. Hyperemia was elicited in the anesthetized rat anterior mesenteric artery after cessation of intravenous norepinephrine infusion at 0.125 to 1.0 x 10(-8) M/min x 4 min. Arterial blood pressure was measured with a transducer, and the velocity of arterial blood flow was determined with pulsed Doppler velocimetry. Conductance at the height of mesenteric hyperemia, the post norepinephrine hyperemia volume, and the autoregulatory escape volume were calculated from recorded measurements. The higher doses of norepinephrine increased both the hyperemia volume and peak conductance in both control and capsaicin pretreated rats. Hyperemic parameters were significantly diminished by pretreatment with either yohimbine, propranolol, adenosine deaminase, or methylene blue. Combining adenosine deaminase with propranolol further reduced peak conductance and the hyperemia volume compared with enzyme pretreatment alone. The magnitude of hyperemia was related to the escape volume but not to the extent of norepinephrine induced vasoconstriction. We conclude that post norepinephrine induced hyperemia in the rat mesenteric circulation is modulated by alpha 2 and beta 2 adrenergic receptor activation, adenosine release, and endothelial factors.

Adenosine Deaminase↗

PubMed1993

Desensitization of beta-1 and beta-2, but not beta-3, adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion.

The beta-3 adrenoceptor protein lacks most of the potential phosphorylation sites for beta adrenoceptor kinase and protein kinase A. In addition, it exhibits a lower affinity toward norepinephrine than beta-1 or beta-2 adrenoceptors. It is thus expected that beta-3 adrenoceptors could be less implicated in desensitization processes than the beta-1 or beta-2 adrenoceptors. An attempt to demonstrate the physiological relevance of this prediction was performed by using fat cells having a beta-3 adrenergic responsiveness or not (hamster and guinea pig). The influence of prolonged in vivo exposure to norepinephrine on the beta adrenoceptor-mediated lipolytic responses was investigated in both species. In control guinea pigs, isoproterenol, norepinephrine and epinephrine were fully lipolytic, whereas BRL 37344 [(R',R')-4-2[2-((2[(3-chlorophenyl)-2-hydroxyethyl]amino] propyl)phenyl]phenoxyacetic acid], CGP 12177](+-)-4-(3-tertiarybutylamino-2-hydroxypropoxy)- benzimidazole-2-on hydrochloride] and other beta-3 agonists were inefficient, whereas hamster adipocytes exhibited maximal response to the beta-3 agonists. Blockade of the lipolytic effect of isoproterenol in the guinea pig gave a rank order of beta antagonists [CGP 20712A (1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-4-(1-methyl-4-tr i-fluoro-methyl-1H-imidazol-2-yl)phenoxy-2-propanol methanesulfonate] > bupranolol > or = propranolol >> ICI 118551 [erythrodl-1-(7- methylindan-4-yloxy)-3-isopropylaminobutan-2-ol)] in agreement with that of a beta-1 effect. In contrast, the selective beta-1 antagonist CGP 20712A did not counteract the effect of BRL 37344 in hamsters and bupranolol was the best beta antagonist tested; a result arguing for the predominance of a beta-3 component in the adrenergic activation of lipolysis, as in rat fat cells. In treated guinea pigs (6-day treatment with osmotic minipumps delivering norepinephrine at the rate of 5 micrograms/min/kg), the adrenocorticotropic hormone dose-response curve was identical to that of controls, but the curves for isoproterenol, norepinephrine and epinephrine were flattened and shifted to the right. A down-regulation of beta-1 and beta-2 adrenoceptors was evidenced by a reduction in [3H]CGP 12177 high-affinity binding sites. In treated hamsters, compared to the controls, there was no change in the lipolytic response to the beta adrenergic agonists. Other protocols of chronic exposure to norepinephrine (e.g., daily injections) at different doses were also unable to reduce the beta-lipolytic effect in the hamster fat cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗