Norepinephrine Uptake Inhibitor Research Articles

Dopamine transporter loss in 6-OHDA Parkinson's model is unmet by parallel reduction in dopamine uptake.

The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson’s disease (PD), DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined [3H]DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against [3H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [3H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [3H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [3H]DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.

Angiotensin II, sympathetic nerve activity and chronic heart failure

Sympathetic nerve activity has been reported to be increased in both humans and animals with chronic heart failure. One of the mechanisms believed to be responsible for this phenomenon is increased systemic and cerebral angiotensin II signaling. Plasma angiotensin II is increased in humans and animals with chronic heart failure. The increase in angiotensin II signaling enhances sympathetic nerve activity through actions on both central and peripheral sites during chronic heart failure. Angiotensin II signaling is enhanced in different brain sites such as the paraventricular nucleus, the rostral ventrolateral medulla and the area postrema. Blocking angiotensin II type 1 receptors decreases sympathetic nerve activity and cardiac sympathetic afferent reflex when therapy is administered to the paraventricular nucleus. Injection of an angiotensin receptor blocker into the area postrema activates the sympathoinhibitory baroreflex. In peripheral regions, angiotensin II elevates both norepinephrine release and synthesis and inhibits norepinephrine uptake at nerve endings, which may contribute to the increase in sympathetic nerve activity seen in chronic heart failure. Increased circulating angiotensin II during chronic heart failure may enhance the sympathoexcitatory chemoreflex and inhibit the sympathoinhibitory baroreflex. In addition, increased circulating angiotensin II can directly act on the central nervous system via the subfornical organ and the area postrema to increase sympathetic outflow. Inhibition of angiotensin II formation and its type 1 receptor has been shown to have beneficial effects in chronic heart failure patients.

Cardiovascular stability and unchanged muscle sympathetic activity during xenon anaesthesia: role of norepinephrine uptake inhibition

Intraoperative hypotension is associated with increased risk of perioperative complications. The N-methyl-d-aspartate (NMDA) receptor (NMDA-R) antagonist xenon (Xe) induces general anaesthesia without impairment of cardiac output and vascular resistance. Mechanisms involved in cardiovascular stability have not been identified. Muscle sympathetic activity (MSA) (microneurography), sympathetic baroreflex gain, norepinephrine (NE) plasma concentration (high-performance liquid chromatography), anaesthetic depth (Narcotrend(®) EEG monitoring), and vital parameters were analysed in vivo during Xe mono-anaesthesia in human volunteers (n=8). In vitro, NE transporter (NET) expressing HEK293 cells and SH-SY5Y neuroblastoma cells were pre-treated with ketamine, MK-801, NMDA/glycine, or vehicle. Subsequently, cells were incubated with or without Xe (65%). NE uptake was measured by using a fluorescent NET substrate (n=4) or [(3)H]NE (n=6). In vivo, Xe anaesthesia increased mean (standard deviation) arterial pressure from 93 (4) to 107 (6) mm Hg and NE plasma concentration from 156 (55) to 292 (106) pg ml(-1), P<0.01. MSA and baroreflex gain were unaltered. In vitro, ketamine decreased NET activity (P<0.01) in NET-expressing HEK293 cells, while Xe, MK-801, and NMDA/glycine did not. Xe reduced uptake in SH-SY5Y cells expressing NET and NMDA-Rs (P<0.01). MK-801 (P<0.01) and ketamine (P<0.01) also reduced NET activity, but NMDA/glycine blocked the effect of Xe on [(3)H]NE uptake. In vivo, Xe anaesthesia does not alter sympathetic activity and baroreflex gain, despite increased mean arterial pressure. In vitro, Xe decreases the uptake of NE in neuronal cells by the inhibition of NET. This inhibition might be related to NMDA-R antagonism and explain increased NE concentrations at the synaptic cleft and in plasma, contributing to cardiovascular stability during Xe anaesthesia.

QTC Prolongation and Torsades in Bupropion Overdoses Presenting to United States Emergency Departments

Bupropion is an atypical antidepressant commonly used for depression and smoking cessation. It is structurally dissimilar to other antidepressants and is an inhibitor of norepinephrine and dopamine uptake. It is associated with QTc prolongation in therapeutic use and in overdose. There are limited data assessing QTc prolongation and torsades de points (TDP) in cases of overdose. The purpose of this study is to assess the incidence of QTc prolongation and the development of TDP in cases of bupropion overdose presenting to Emergency Departments (EDs).

Peripherally-restricted dopamine agonist but not norepinephrine uptake inhibitor alters prolactin release

Peripherally-restricted dopamine agonist but not norepinephrine uptake inhibitor alters prolactin release

Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone

Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied. Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors. Butylone, mephedrone and methylone (5-25 mg·kg(-1) ) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]dopamine uptake with IC(50) values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA. Butylone and methylone induced hyperlocomotion through activating 5-HT(2A) receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone.

Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons

Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on the measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM's effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1–1 mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg) significantly decreased early positive and negative components of the sensory-evoked LFP response. Higher doses (0.3–1 mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike-field coherence was enhanced by 1 mg/kg ATM across frequency bands. Finally, coherence between LC fields and EEG signals was generally increased by 1 mg/kg ATM, whereas 0.1 and 0.3 mg/kg respectively decreased and increased coherence values in specific frequency bands. Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may play a role in the cognitive effects of ATM.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Variable prenatal stress results in impairments of sustained attention and inhibitory response control in a 5-choice serial reaction time task in rats

Rats repeatedly exposed to variable prenatal stress (PNS) exhibit schizophrenia-like behavioral signs such as social withdrawal, elevations in amphetamine-induced locomotor activity, deficits in sensory-motor gating, as well as impairments in memory-related task performance. However, to date there have been no studies designed to test the hypothesis that variable PNS would lead to disruptions in sustained attention and inhibitory response control (i.e., symptoms also commonly observed in schizophrenia and other neuropsychiatric disorders such as attention-deficit hyperactivity disorder). In the current study, the effects of variable PNS in rats were evaluated in fixed and variable stimulus duration (VSD) as well as variable intertrial interval (VITI) versions of a 5-choice serial reaction time task (5C-SRTT). In a separate series of experiments, the glutamate (N-methyl-d-aspartate [NMDA]) antagonist, MK-801 (0.025–0.05mg/kg), and the norepinephrine reuptake inhibitor, atomoxetine (0.30–3.0mg/kg), were administered acutely to assess the sensitivity of PNS subjects to glutamatergic and noradrenergic manipulations. The results indicated that exposure to variable PNS significantly impaired accuracy in the VSD version of the 5C-SRTT and increased premature and timeout responses in the VITI version. In addition, both doses of MK-801 impaired accuracy, increased premature and timeout responses in PNS, but not control subjects. In contrast, atomoxetine decreased premature and timeout responses in both PNS and control subjects in the VITI version of the task and improved accuracy in the PNS subjects. The results suggest that exposure to variable PNS in rats results in impairments of sustained attention and inhibitory response control and that these deficits can be exacerbated by NMDA antagonism and improved by a norepinephrine uptake inhibitor. Collectively, these data further support the premise that variable PNS in rats is a valid model system for the study of neuropsychiatric disorders and their treatment.

Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats

Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats. Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment. DOV (6.25 to 50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose-dependently reduced immobility of P rats in the FST. DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.

Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabelling for NET and co-localization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 d, 15 mg/kg.d), NET-immunoreactive (ir) axons were significantly less likely to co-localize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI- and vehicle-treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labelling. Our findings encourage consideration of possible post-translational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.

Catalyst‐Controlled Diastereoselection in the Hydrogenation of Heterocycloalkyl Ketones

Abstractα‐Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2‐(4‐benzoylmorpholinyl) phenyl ketone and 3‐(1‐tert‐butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri‐sec‐butylborohydride as reducing agents affords the syn‐ and anti‐alcohols in a lower than 80:20 ratio. Hydrogenation of these ketones with a catalyst system of RuCl2(BIPHEP)(DMEN) and potassium tert‐butoxide in 2‐propanol results in the syn‐alcohols with ≥ 99:1 selectivity [BIPHEP=2,2′‐bis(diphenylphosphino)biphenyl, DMEN=N,N‐dimethylethylenediamine]. The marked difference in the diastereoselectivity suggests that the stereoselection in this hydrogenation is primarily regulated by the structure of the catalyst’s reaction field (“catalyst‐controlled diastereoselection”) but not the internal stereocontrol of the substrates. This chemistry is applied to the asymmetric hydrogenation through dynamic kinetic resolution with a RuCl2[(S)‐BINAP][(R)‐DMAPEN]/potassium tert‐butoxide catalyst [BINAP=2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl, DMAPEN=2‐dimethylamino‐1‐phenylethylamine]. A series of aryl heterocycloalkyl ketones has been converted to the alcohols in excellent diastereo‐ and enantioselectivities. The modes of catalyst‐controlled diastereoselection and enantioselection are interpreted by using transition‐state molecular models. (S,S)‐Reboxetine, a selective norepinephrine uptake inhibitor, was synthesized from one of product alcohols.

Recent Advances in the Treatment of Narcolepsy

A diagnosis of narcolepsy requires pharmacologic treatment in more than 90% of patients. Wake-promoting compounds are used to treat excessive daytime sleepiness (EDS), and anticataplectics are used for cataplexy. The treatment of EDS includes the use of amphetamine-like CNS stimulants (such as dextroamphetamine and methylphenidate), modafinil, and its R-enantiomer, armodafinil. Because of its high safety and low side-effect profiles, modafinil has become the first-line treatment of choice for EDS associated with narcolepsy. However, wake-promoting compounds do not improve cataplexy and dissociated manifestation of REM sleep, and so antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Tricyclic antidepressants potently reduce REM sleep and thus have been used for the treatment of cataplexy and REM sleep abnormalities, but these have recently been replaced by more selective serotonin and/or noradrenaline uptake inhibitors with better side-effect profiles. As sodium oxybate (the approved formula of γ-hydroxybutyrate in the United States), given at night, improves both EDS and cataplexy, the number of US patients treated with sodium oxybate is increasing, while much progress has been made in understanding the modes of action of amphetamine-like CNS stimulants.

Deamination of hordenine by monoamine oxidase and its action on vasa deferentia of the rat

The selectivity of the naturally occurring amine, N,N-dimethyltyramine (hordenine) for monoamine oxidase (MAO) and its action upon isolated vasa deferentia of the rat was investigated. Hordenine was deaminated by rat liver MAO with a Michaelis constant of 479 microM and maximum velocity of 128 nmol (mg protein)-1 h-1 compared with 144 microM and 482 nmol (mg protein)-1 h-1 for tyramine. Studies, with selective irreversible inhibitors of MAO, showed that hordenine was a highly selective substrate for MAO-B of liver and that it was not deaminated by the MAO-A of intestinal epithelium. In contrast to tyramine, hordenine did not produce contractions of isolated vasa deferentia. However, 25 microM hordenine potentiated contractile responses of vasa, from control animals, to submaximal doses of noradrenaline and inhibited responses to tyramine. It did not alter responses, to noradrenaline, of vasa denervated by chronic pretreatment of rats with guanethidine. Therefore, it appears that hordenine acted as an inhibitor of noradrenaline uptake, in isolated vasa deferentia. These results indicate that dietary-hordenine is unlikely to be deaminated by intestinal MAO as this is predominantly MAO-A. Consequently, it is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake.

Reduction of gastric acid secretion and ulcer formation by 3,3-dimethyl-1-(3-methylaminopropyl)-1-phenylphthalan (Lu 3-010); an inhibitor of noradrenaline uptake.

Abstract Lu 3–010 [3,3-dimethyl-1-(3-methylaminopropyl)-1-phenylphthalan], administered intraperitoneally, blocks the uptake of [3H]noradrenaline into the mouse and rat heart and has an activity 5 times greater than imipramine and comparable to that of desipramine. Lu 3–010 inhibits basal gastric acid secretion in the rat and is 4 and 2 times more potent than imipramine and desipramine, respectively. The drug is about 9 times more potent than desipramine in preventing the pentagastrin-induced stimulation of gastric acid secretion in the rat. Lu 3–010 reduces the incidence of stress-induced gastric lesions in the rat, exhibiting an ED50 ± s.e. of 6.3 ± 1.4 mg/kg, and at 10 mg/kg, ulcer development in the 17-hour Shay test is reduced by 50%.

Pharmacological properties of 403U76, a new chemical class of 5-hydroxytryptamine- and noradrenaline-reuptake inhibitor.

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

INHIBITION OF NORADRENALINE UPTAKE BY SYMPATHOMIMETIC AMINES.

INHIBITION OF NORADRENALINE UPTAKE BY SYMPATHOMIMETIC AMINES.

Inhibition of noradrenaline uptake by angiotensin.

Journal Article Inhibition of noradrenaline uptake by angiotensin Get access Djuro Palaič, Djuro Palaič Research Division, Cleveland Clinic Foundation, Cleveland, Ohio 44106, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Philip A Khairallah Philip A Khairallah Research Division, Cleveland Clinic Foundation, Cleveland, Ohio 44106, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 19, Issue 6, June 1967, Pages 396–397, https://doi.org/10.1111/j.2042-7158.1967.tb09567.x Published: 12 April 2011

INHIBITION OF NORADRENALINE UPTAKE BY DRUGS.

Journal Article Inhibition of noradrenaline uptake by drugs Get access L L Iversen L L Iversen Department of Pharmacology, University of Cambridge Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 17, Issue 1, January 1965, Pages 62–64, https://doi.org/10.1111/j.2042-7158.1965.tb07572.x Published: 12 April 2011 Article history Received: 09 November 1964 Published: 12 April 2011

Presynaptic α-block and inhibition of noradrenaline and 5-hydroxytryptamine reuptake by a series of compounds related to mianserin

A structure-activity relationship study was undertaken for a variety of structural analogues of the tetracyclic antidepressant mianserin. Presynaptic alpha-blocking activity in vitro was evaluated measuring the potentiation of depolarization-induced noradrenaline (NA) release from rat cerebral cortex slices. Inhibition of NA and 5-hydroxytryptamine reuptake was measured in rat hypothalamic or striatal synaptosomes, respectively. Presynaptic alpha-blockade was only found in molecules with an overall bent shape. Flat rigid molecules or flexible ones were not active. Six-membered, chair-formed D-rings (containing the -NCH3 moiety) appeared better than 5- or 7-membered ones. Heteroatom substitution, but not hydroxylation or methylation, of the bridge between the two aromatic rings left presynaptic alpha-blockade unaffected. N-Demethylation and aromatic methyl- or chlorine-substitution reduced presynaptic alpha-blockade. In pyridine ring-substituted analogues the localization of the heteroatom appeared to be crucial. 5-Hydroxytryptamine reuptake inhibitory activity was only found in desmethylmianserin. NA uptake inhibition was found in many mianserin analogues, especially those with an exocyclic-N(CH3)2 moiety. Structure activity relationships for NA reuptake inhibition differed from those for presynaptic alpha-blockade and were generally less stringent. For both properties simple additivity relationships appeared to be absent.

Antagonism by propranolol of the inhibitory effect of phenoxybenzamine on noradrenaline uptake in vivo.

Abstract The reduction of noradrenaline stores and [3H]noradrenaline concentration in the heart of mice and rats induced by phenoxybenzamine-treatment, alone or in combination with cold-stress, was prevented by propranolol. Propranolol also antagonized a similar effect induced by phentolamine but not that induced by other noradrenaline uptake inhibitors, such as desipramine, cocaine, guanethidine and reserpine. Analysis of the time-course of antagonism by propranolol indicates that it was evident only when the β-adrenoceptor blocking agent remained in the body. The inhibitory effect of phenoxybenzamine on noradrenaline stores reappeared when propranolol was excreted. Propranolol alone did not change cardiac noradrenaline stores or [3H]noradrenaline. It is concluded that the restoration of reflexly increased adrenergic discharge to normal, because of unmasking of spare α-adrenoceptors resulting from β-adrenoceptor blockade by propranolol rather than competition for binding at the active site of phenoxybenzamine, is responsible for the observed antagonism.