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PubMed1987

The aziridinium derivative of DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) accelerates the beating rate of isolated rat atria by enhancing the spontaneous release of noradrenaline.

The aziridinium derivative of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (az-DSP4) depletes endogenous noradrenaline stores and exerts neurotoxic actions on noradrenergic neurons. These effects are persistent in the central nervous system and transient in the periphery. To determine if transmitter release plays a role in the noradrenaline depletion caused by az-DSP4, the action of the compound was studied in isolated and spontaneously beating rat atria. 1. az-DSP4 enhanced atrial beating rate when present in the incubation medium at concentrations ranging from 10(-7) M to 10(-4) M but at 10(-3) M decreased that rate below basal levels. 2. Preincubation of atria for 30 min with the noradrenaline uptake blocker desimipramine (DMI, 10(-6) M) or with the beta-blocker propranolol (10(-7) M), abolished the positive chronotropic action of az-DSP4. 3. The rate-accelerating effect of az-DSP4 could be prevented by pretreating the rats with reserpine (5 mg/kg i.p. 24 h) or enhanced by pargyline pretreatment (100 mg/kg i.p. 18 h). 4. az-DSP4 stimulated the spontaneous efflux of tritium from the isolated atria previously labeled with 3H-noradrenaline (4 X 10(-7) M), an increase that was mainly accounted for by DOPEG. 5. COMT and MAO activities in atria homogenates were inhibited by az-DSP4 in a concentration-dependent manner. However, MAO inhibition did not result in a change of the metabolic pattern as could be expected. 6. The results obtained indicate that az-DSP4 enhances the rate of spontaneous beating of isolated rat atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Cocaine-sensitive O-methylation of noradrenaline in dental pulp of the rabbit: comparison with the rabbit ear artery.

Incisor pulp from the rabbit metabolises exogenous noradrenaline in concentrations between 0.12 and 1.2 mumol/l mainly to NMN. Effects of chronic sympathetic denervation indicated that in incisor pulp the NMN is extraneuronal in origin, and that DOPEG and DOMA formation, as well as a major part of the noradrenaline which accumulates in the tissue, are associated with the sympathetic nerves. NMN formation was unaffected by hydrocortisone 210 mumol/l, but was strongly inhibited by cocaine 30 mumol/l. These effects contrasted with those in the rabbit ear artery, where NMN formation was increased by cocaine 30 mumol/l and decreased by hydrocortisone 210 mumol/l. In COMT-inhibited denervated pulp, cocaine inhibited the accumulation of noradrenaline. Monoamine fluorescence histochemistry of pulp exposed to noradrenaline 50 mumol/l indicated that cocaine-sensitive uptake occurred in fibroblasts. It is concluded that O-methylation of noradrenaline in dental pulp involves prior uptake of the amine by a process resembling uptake1 but which is distinguished from uptake1 by its extraneuronal location.

Animals↗
PubMedDate not supplied

The effect of (+/-)-dobutamine on adrenergic nerve endings.

Possible effects of (+/-)-dobutamine on adrenergic nerve endings were determined in experiments with ghosts of bovine chromaffin granules, with rat phaeochromocytoma (PC-12) cells and with the rat vas deferens. Dobutamine inhibited the vesicular uptake of a mixture of 70% adrenaline + 30% 3H-noradrenaline into ghosts, with an IC50 of 1.7 mumol/l. Dobutamine inhibited uptake1 of 3H-noradrenaline in PC-12 cells (with an IC50 of 0.38 mumol/l) without being a substrate. However, dobutamine easily entered PC-12 cells by diffusion. After inhibition of MAO, COMT and vesicular uptake dobutamine (15 and 45 mumol/l) released tritium from rat vasa deferentia preloaded with 3H-noradrenaline. Equi-inhibitory concentrations of dobutamine and desipramine (against uptake1) were equi-releasing. On the other hand, when MAO and vesicular uptake were intact, dobutamine (15 mumol/l) increased the efflux of tritium from preloaded vasa deferentia much more than did an equi-inhibitory concentration of desipramine. Most of the released tritium was then 3H-DOPEG. Dobutamine is a potent inhibitor of uptake1 as well as of vesicular uptake; moreover, it easily diffuses into adrenergic nerve endings. Hence, it blocks the neuronal and the vesicular re-uptake of noradrenaline; consequently, when MAO and vesicular uptake are intact, dobutamine increases the net leakage of noradrenaline from the storage vesicles, thereby leading to an efflux of deaminated metabolites. However, dobutamine is virtually unable to release noradrenaline into the extracellular space.

Adenosine Triphosphate↗
PubMed1987

The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: multifactorial induction of outward transport.

The mechanism of action of indirectly acting sympathomimetic amines was studied in the rat vas deferens, after inhibition of vesicular uptake (by reserpine), of MAO (by pargyline) and of COMT (by U-0521). 1. Km-values for the neuronal uptake of 12 substrates were determined as the IC50 of the unlabelled substrate inhibiting the initial rate of neuronal uptake of 0.2 mumol/l 3H-(-)-noradrenaline. The IC50 ranged from 0.35 mumol/l (for(+)-amphetamine) to 44.3 mumol/l (for 5-HT). The Vmax (determined for 8 substrates) was substrate-dependent. 2. Tissues were loaded with 0.2 mumol/l 3H-(-)-noradrenaline and then washed out with amine-free solution. All 12 substrates of uptake1 induced an outward transport of 3H-noradrenaline, and equieffective concentrations were positively correlated with Km. Moreover, the EC50 for release greatly exceeded Km. It is proposed that this discrepancy between EC50 and Km is indicative of the fact that at least four factors (each one in strict dependence on Km) contribute to the initiation of outward transport of 3H-noradreanline: a) the appearance of the carrier on the inside of the axonal membrane (facilitated exchange diffusion), b) the co-transport of Na+, c) the co-transport of Cl- (both lowering the Km for 3H-noradrenaline at the inside carrier), and d) inhibition of the re-uptake of released 3H-noradrenaline (through competition for the outside carrier). 3. At least for amezinium, Vmax appears to limit the maximum rate of outward transport. 4. For some substrates (especially for the highly lipophilic ones) bell-shaped concentration-release curves were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: role of monoamine oxidase and of vesicularly stored 3H-noradrenaline.

The mechanism of action of indirectly acting sympathomimetic amines was studied in vasa deferentia of unpretreated rats (COMT inhibited), preloaded with 3H-noradrenaline. 1. Concentration-release curves were obtained for 12 unlabelled indirectly acting amines. From differences between these results and those in an accompanying report (involving tissues from rats pretreated with reserpine and pargyline), it is concluded that a "mobilisation" of vesicular 3H-noradrenaline is required for high and sustained rates of outward transport of 3H-noradrenaline from intact adrenergic varicosities. 2. Experiments with a reserpine-like compound (Ro 4-1284) supported the view that a "mobilisation" of vesicular 3H-noradrenaline is required for substantial release. 3. An atypical time course of release and abnormally high rates of release were observed in the presence of excessive concentrations of (+)-amphetamine. Such atypical effects are ascribed to the of basic amines to increase the intravesicular pH. 4. Analysis of the ratio NA/DOPEG (rate of efflux of 3H-noradrenaline/rate of efflux of 3H-DOPEG) indicated that the inward transport (by uptake) of substrates of MAO fails to achieve axoplasmic concentrations which saturate MAO. Inhibition (or saturation) of MAO is not a prerequisite for the initiation of outward transport. 5. A larger fraction of vesicular 3H-noradrenaline is accessible to equireleasing concentrations of (+)-amphetamine (an inhibitor of MAO) than of tyramine (a substrate of MAO). 6. From the present and the accompanying report it is concluded that "substantial and sustained indirect sympathomimetic effects" are to be expected for substrates of uptake which additionally mobilise vesicular noradrenaline. However, this "mobilisation" does not seem to involve a change in intravesicular pH, except at excessive concentrations.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1987

Simulation of outward transport of neuronal 3H-noradrenaline with the help of a two-compartment model.

In order to simulate the outward transport of 3H-noradrenaline induced by veratridine from adrenergic varicosities, a mathematical two-compartment model was developed in which the two compartments (representing axoplasm and storage vesicles) are arranged in series. Simulated results were compared with experimental results obtained with 100 mumol/l veratridine + 1 mmol/l ouabain and rat vasa deferentia kept in calcium-free solution (Bönisch and Trendelenburg 1987). As in experiments, the time course of efflux of 3H-noradrenaline had a pronounced and early peak under RPU-conditions, a minor peak under PU-conditions, and solely a plateau under U-conditions (where R stands for pretreatment with reserpine, P for pretreatment with pargyline, and U for inhibition of COMT by U-0521). From the width of the peak of release, it was deduced that--under RPU-conditions--about 40% of neuronal 3H-noradrenaline are distributed into the axoplasm, about 60% into the storage vesicle. However, this estimate represents an average value; the results are compatible with the view that the ratio "axoplasmic/vesicular 3H-noradrenaline" is quite variable from rat to rat. Under U-conditions, calculations confirm that reserpine-like compounds induce an efflux of tritium that consists predominantly of deaminated 3H-metabolites. The stimulation of outward transport, on the other hand, causes an efflux of tritium that consists predominantly of 3H-noradrenaline; indeed, the efflux of deaminated 3H-metabolites declines (as it did in experiments). Simulations showed further that the highest rates of outward transport of 3H-noradrenaline were achieved when there was a simultaneous induction of outward transport of 3H-noradrenaline and a reserpine-like effect (as it is known to occur when tissues are exposed to veratridine; Bönisch and Trendelenburg 1987). While there was satisfactory agreement between simulated and experimental results under various conditions, there were also two discrepancies that may be caused by a) inhomogeneous labelling of the storage vesicles in individual varicosities (RPU less than PU less than U) and b) saturation of outward transport of 3H-noradrenaline when a reserpine-like compound greatly increases the axoplasmic level of total noradrenaline (under U-conditions).

Biological Transport↗
PubMed1987

Characteristics of the cocaine-sensitive accumulation and O-methylation of 3H-(-)-noradrenaline by rabbit endometrium.

1. The extraneuronal uptake and O-methylation of 2,5,6 3H-(-)-noradrenaline was studied in segments of uterine endometrium from rabbits pretreated with 17 beta-oestradiol and progesterone. 2. The uptake of 3H-noradrenaline was measured in MAO- and COMT-inhibited tissues and obeyed Michaelis-Menten kinetics with an apparent Km of 78 mumol/l and a Vmax of 5.4 nmol/g min. Uptake was inhibited by low Na+, and by potential substrates in the order dopamine greater than (-)adrenaline greater than (-)isoprenaline = 5-hydroxytryptamine. 3. Following uptake at 1.2 mumol/l, efflux of 3H-noradrenaline was slow and appeared to be from two compartments, of which the first (I) had a t1/2 of 53 min and a capacity of 1.8 nmol/g. The presence of the second compartment (II) was inferred from the tissue content of 3H after 60 min of efflux, which was 3-4 times greater than predicted if the 3H was present in compartment I only. Following incubation with 3H-noradrenaline in the presence of cocaine 30 mumol/l the 3H efflux was rapid and the combined capacities of compartments I and II were greatly decreased. 4. 3H-NMN formation, measured in MAO-inhibited tissues, obeyed Michaelis-Menten kinetics with a half-saturating outside concentration of 12 mumol/l and a Vmax of 0.9 nmol/g X min. The formation was inhibited by the neuronal uptake inhibitors, desipramine 3 mumol/l and metaraminol 100 mumol/l (each by 80%), but was unaffected by the extraneuronal uptake inhibitor, NMN 100 mumol/l, and by oxytetracycline 100 mumol/l and methoxamine 10 mumol/l. 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Homogeneous or heterogeneous distribution of systemically administered adrenaline: organ dependence.

In incubation experiments it was shown that exogenous adrenaline or noradrenaline does not distribute homogeneously into the adrenergic varicosities of the rat vas deferens (wall with thick and compact muscle layer) but does distribute homogeneously in the rat spleen capsule (thin and loose muscle layer, containing more extracellular space than the vas deferens). To circumvent any hypothetical role of the muscular layer in the distribution of the amine, 100 micrograms.kg-1.h-1 adrenaline was administered to rats in vivo either i.v. (during 90 min) or i.p. (under pentobarbital anaesthesia, an Alzet minipump was implanted which delivered that dose during 6 days). The rats also received 100 mg.kg-1 pargyline (to inhibit MAO) and 100 mg.kg-1 tropolone (to inhibit COMT). At the end of adrenaline administration, vasa deferentia and spleen capsule were removed, washed and then exposed to 100 mumol.l-1 tyramine for 20 min. At the end of this exposure, the ratio noradrenaline/adrenaline in the tissue and in the medium was compared. In the vas deferens both after i.v. and i.p. administration of adrenaline, the ratio noradrenaline/adrenaline was about 3 times higher in the medium than in the tissue, while in the spleen capsule the ratio noradrenaline/adrenaline was not significantly different in the medium and in the tissue. We conclude that, even when the amine reaches the storage sites from the blood, it distributes homogeneously in the spleen capsule and heterogeneously in the vas deferens, perhaps because there are more than one kind of storage vesicles in the vas deferens.

Adrenergic Agents↗
PubMed1988

The handling of five amines by the extraneuronal deaminating system of the rat heart.

The handling of five amines by the extraneuronal deaminating system was studied in perfused hearts of rats (pretreated with reserpine; COMT and neuronal uptake inhibited). Hearts were perfused with 50 nmol/l 3H-noradrenaline for 30 min, in the presence of increasing concentrations of unlabelled (-)-adrenaline, (-)-noradrenaline, dopamine, tyramine and 5-HT. IC50's were determined as those concentrations of unlabelled amines which halved the steady-state rate of deamination of 3H-noradrenaline. After correction for changes in the tissue/medium ratio for 3H-noradrenaline, "half-saturating outside concentrations" were obtained. They increased in the order (-)-adrenaline (15 mumol/l) - tyramine - dopamine - noradrenaline - 5-HT (53 mumol/l). The Vmax for extraneuronal deamination was determined for 3H-(-)-adrenaline, 3H-(-)-noradrenaline and 3H-dopamine, as well as (by HPLC and electrochemical detection) for tyramine and 5-HT. It was low for (-)-adrenaline, intermediate for (-)-noradrenaline, dopamine and 5-HT, high for tyramine. For the three catecholamines the half-saturating outside concentrations of the extraneuronal deaminating system clearly exceeded those for the extraneuronal O-methylating system of the same organ (see Grohmann and Trendelenburg 1985), although the two enzymes appear to co-exist in the same cells, so that the same transport system is involved.

Animals↗
PubMed1993

Release and disposition of 3H-noradrenaline in the saphenous vein of neonate and adult dogs.

Release of 3H-noradrenaline and formation of 3H-metabolites were studied in the saphenous vein of newborn (mean age, 18 h) and adult dogs. Vein strips were incubated with 0.23 mumol/l of 3H-noradrenaline during 1 h and washed out for 110 min; thereafter, the perifusion fluid was collected in 5-min samples. Electrical stimulation was applied at 120 min (1 Hz, 2 ms, 100 V, for 5 min). In some experiments the tissues were preincubated with 1 mmol/l pargyline (to inhibit monoamine oxidase). In these experiments, 12 mumol/l cocaine (to inhibit uptake1), 41 mumol/l hydrocortisone (to reduce uptake2) and 50 mumol/l U-0521 (to inhibit COMT) were present during the perifusion. 3H-noradrenaline, 3H-DOPEG, 3H-NMN, 3H-DOMA and 3H-OMDA were separated by column chromatography. The noradrenaline content of the tissue was estimated by HPLC followed by electrochemical detection. A morphological study was also carried out by light and electron microscopy. The endogenous noradrenaline content of the saphenous vein was 4.3 times higher in adults than in neonates. The number of varicosities was similar in adults and newborns but the number of vesicles per varicosity profile was 5 times higher in adults. Hence, the endogenous noradrenaline content per vesicle was about the same in adults and newborns. The accumulation of 3H-noradrenaline per vesicle was about 5 times higher in newborns than in adults. On the other hand, the vein wall media of neonates was about 3 times thinner than that of adults. The evoked fractional release of tritium was about 10 times higher in neonates than in adults, whether the inactivation pathways were blocked or not.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1987

Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart.

Isolated rat hearts were perfused according to the Langendorff technique and both extraneuronal uptake of noradrenaline and COMT were inhibited. The noradrenergic neurones were first prelabelled with 3H-(-)-noradrenaline (13 nmol/l). Thereafter the hearts were submitted to global ischemia (perfusion rate reduced from 5 up to 0.5 ml/min) for 60 min and subsequently reperfused for 5 min. The coronary effluent was continuously collected and analyzed for the appearance of 3H-noradrenaline and its metabolites. 1. Global ischemia was associated with an early release of 3H-noradrenaline. At reperfusion a brisk increase in the FRL of 3H-noradrenaline was observed which may indicate that, on severe restriction in coronary flow, perfusion of the tissue became heterogenous and thus partially masked the amount of 3H-noradrenaline released from the noradrenergic nerve terminals. Gradual reduction in coronary flow also progressively reduced (but did not abolish) the total formation of 3H-DOPEG. 2. The maximal efflux of 3H-noradrenaline was observed during the 1st min of reperfusion whereafter the efflux declined rapidly, indicating a wash-out of transmitter trapped in the extracellular space. The efflux of the lipophilic metabolite 3H-DOPEG, on the other hand, continuously increased during the reperfusion. This was due to both new formation and "wash-out" of 3H-DOPEG retained and/or distributed into the tissue during the period of restricted flow. 3. Neither a reduction of the extracellular calcium concentration (from 2.6 mmol/l to 0.1 mmol/l) nor the presence of the calcium entry blocker verapamil (250 nmol/l) reduced the efflux of 3H-noradrenaline seen during ischemia and reperfusion. 4. Desipramine (100 nmol/l) markedly reduced the ischemia-induced release of 3H-noradrenaline and simultaneously attenuated the formation of 3H-DOPEG. 5. A moderate reduction in the ischemia-induced mobilization of 3H-noradrenaline was seen in hearts perfused with 1 mumol/l reserpine, whereas the formation of 3H-DOPEG from such hearts was markedly higher than in corresponding controls. Only minor deviations from this pattern was observed when desipramine was present in addition to reserpine. It is concluded that a severe restriction in myocardial perfusion rate is associated with an enhanced net leakage of vesicular noradrenaline. This results in a rise of the free axoplasmic noradrenaline concentration which, in combination with an altered transmembrane sodium gradient, induces an increased local release of noradrenaline partly mediated by a calcium-independent, carrier-mediated outward transport.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Uptake and metabolism of 3H-(+/-)-noradrenaline in the isolated perfused rat liver.

The influence of inhibitors of metabolism and uptake of noradrenaline on the 3H-noradrenaline removal from the perfusion fluid by the isolated rat liver was studied. Livers were perfused with 3 nmol/l 3H-noradrenaline and 3H-noradrenaline and 3H-metabolites were determined in effluent, liver and bile. After the perfusion with 14,900 +/- 920 dpm.g-1.min-1 during 90 min, cumulative removal of tritium was 323,574 +/- 63,103 dpm/g. 3H-metabolites recovered from the liver after 90 min perfusion represented 71.1 +/- 9.0% of total metabolite formation. Only the OMDA-fraction appeared in the perfusate; its approach to steady state of efflux was slow. The inhibition either of MAO or COMT changed neither the total removal of tritium nor the 3H-metabolites recovered from the liver. Cocaine (10 mumol/l) reduced the accumulation of 3H-noradrenaline in the liver. The uptake2 inhibitor corticosterone (30 mumol/l) diminished total removal of tritium and the 3H-metabolites recovered from the liver without changing the accumulation of 3H-noradrenaline. The hypothesis of two different compartments, one responsible for the metabolism and the other for the accumulation of the amine is discussed.

Animals↗
PubMed1991

Carrier-mediated outward transport of dopamine from adrenergic varicosities of the vas deferens of reserpine-pretreated rats.

In vasa deferentia of reserpine-pretreated rats a carrier-mediated (i.e., desipramine-sensitive) outward transport of endogenous dopamine was induced by either tyramine or ouabain. The dopamine taking part in the efflux induced by tyramine (and the concomitant efflux of DOPAC) was derived from ongoing synthesis of dopamine. Inhibition of MAO trebled the rate of spontaneous efflux of dopamine and reduced the spontaneous efflux of DOPAC by 90%. After inhibition of MAO, desipramine caused a further five-fold increase in the basal efflux of dopamine with no change in the basal efflux of DOPAC. Inhibition of COMT failed to affect the spontaneous efflux of dopamine but increased that of DOPAC. It is concluded that, after depletion of the noradrenaline stores by pretreatment with reserpine, an outward transport of axoplasmic dopamine is induced by the same mechanisms that (without any pretreatment with reserpine) are known to initiate an outward transport of noradrenaline.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

The force driving the extraneuronal transport mechanism for catecholamines (uptake2).

Recently, uptake2 was shown to exist in the clonal Caki-1 cell line. The aim of this study was two-fold: a) to determine, in Caki-1 cells, the intracellular fate of 3H-noradrenaline after its translocation by uptake2 and b) to analyse the force driving uptake2. Caki-1 cells have the characteristics of a "metabolizing system" in which the activity of catechol-O-methyl transferase (COMT) greatly exceeds that of monoamine oxidase (MAO). In all subsequent experiments these enzymes were inhibited. The determination of initial rates of uptake2 into Caki-1 cells at an extracellular pH between 6.9 and 7.9 indicated that the protonated species of 3H-noradrenaline is transported. Depolarization of Caki-1 cells (by three different procedures) inhibited the inward transport. Determination of the time course of the specific accumulation of 3H-noradrenaline in Caki-1 cells and of 3H-isoprenaline in the perfused rat heart (both mediated by uptake2) revealed that depolarization (by high K+) reduced the rate constant for inward transport (kIN) and increased that for outward movement (kOUT). Consequently, depolarization reduced the steady-state factor of accumulation. It is proposed that, as the protonated species of the substrates of uptake2 is transported, the membrane potential is likely to provide the driving force for uptake2. The fact that depolarization decreased kIN and increased kOUT agrees with this proposal, as do the magnitudes of the steady-state accumulation factors determined in Caki-1 cells and perfused rat heart.

Animals↗
PubMed1987

Effects of extraneuronal uptake inhibitors on the positive chronotropic response to isoprenaline and on the accumulation of isoprenaline in perfused rat heart after inhibition of catechol-O-methyl transferase.

Experiments were carried out in isolated perfused rat hearts. The presence of tropolone (100 mumol/l), an inhibitor of catechol-O-methyl transferase (COMT), significantly potentiated the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Two uptake2 inhibitors, 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l), induced a positive chronotropic response, but corticosterone (100 mumol/l) and hydrocortisone (100 mumol/l) had no such effect. 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l) enhanced the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Corticosterone (100 mumol/l) potentiated the positive chronotropic response to isoprenaline (0.1 and 1 nmol/l). Hydrocortisone (30 mumol/l) enhanced the response to 0.1 nmol/l isoprenaline but did not affect the positive chronotropic responses to 1, 3 or 10 nmol/l isoprenaline. The addition of uptake2 inhibitors (3-O-methylisoprenaline, 100 mumol/l; normetanephrine, 100 mumol/l; corticosterone, 100 mumol/l) to the perfusion medium significantly reduced the positive chronotropic response to the perfusion with isoprenaline (3 nmol/l) and tropolone (100 mumol/l). The accumulation of 3H-isoprenaline in the heart perfused with 3H-isoprenaline (1, 10 and 100 nmol/l) was significantly increased by the presence of tropolone (100 mumol/l): the accumulation for 1, 10 and 100 nmol/l of 3H-isoprenaline was 5.07, 47.0 and 500 pmol/g, respectively. The high accumulation observed during perfusion with 3H-isoprenaline (3 nmol/l) and tropolone (100 mumol/l) was significantly decreased by the addition of an uptake2 inhibitor, 3-O-methylisoprenaline (100 mumol/l), normetanephrine (100 mumol/l) or corticosterone (100 mumol/l), but not by hydrocortisone (30 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The membrane potential of vascular smooth muscle appears to modulate uptake2 of 3H-isoprenaline.

Segments of the rabbit main pulmonary artery and of its two branches were exposed for 10 min to 50 nmol/l 3H-(+/-)-isoprenaline, and the accumulation of tritium in the tissue was determined; COMT was inhibited in all experiments. 1. The accumulation of the tritium label was sensitive to 3-O-methyl-isoprenaline (OMI), showing that this vascular smooth muscle possesses uptake2. 2. In the presence of 0.01 to 1 mumol/l (-)-noradrenaline, the accumulation of tritium was depressed (in a concentration-dependent manner). This decline involved the OMI-sensitive accumulation of 3H-isoprenaline. 3. The presence of any one of three selective alpha 1-adrenoceptor antagonists (1 mumol/l prazosin, 1 mumol/l WB4101, 10 mumol/l corynanthine) prevented the effect of 1 mumol/l (-)-noradrenaline on the accumulation of tritium. However, in the absence of (-)-noradrenaline, the three antagonists failed to affect the accumulation of tritium. 4. 10 mumol/l nicorandil caused the accumulation of tritium to increase. 5. As stimulation of alpha 1-adrenoceptors is known to result in depolarization, and as nicorandil is known to hyperpolarize this smooth muscle, it is concluded that the resting membrane potential modulates uptake2.

Adrenergic alpha-Antagonists↗
PubMed1986

Immunocytochemical localization of catechol-O-methyltransferase in the oviduct and in macrophages in corpora lutea of rat.

Catechol-O-methyltransferase (COMT) (EC 2.1.1.6) was localized in rat ovary, oviduct, and uterus using immunocytochemical methods. Immunoreactive deposits were found in the cytoplasm of macrophages in the ovary, epithelial cells of the oviduct, and glandular epithelial cells of the non-pregnant uterus. The pattern of localization observed in the extraneuronal elements suggest that enzyme may function in extraneuronal inactivation of catechols in the ovary, oviduct, and uterus.

Animals↗
PubMed1991

Effect of catechol oestrogens on extraneuronal metabolism of noradrenaline by rabbit uterine endometrium and myometrium.

The effects of 2-hydroxy and 2-methoxy oestrogens on the extraneuronal O-methylation of 3H-(-)-noradrenaline were examined in progesterone-dominated, monoamine oxidase (MAO)-inhibited, rabbit uterine tissues in vitro. Both the corticosteroid-sensitive system in myometrium and the cocaine-sensitive system in endometrium were examined. In myometrial slices preincubated with nialamide to inhibit MAO and incubated with cocaine to inhibit neuronal uptake, 3H-normetanephrine (3H-NMN) formation was inhibited in the order of potency 2-hydroxy oestrone greater than or equal to 2-hydroxy oestradiol = 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone. In myometrial slices not exposed to cocaine and nialamide, inhibition of 3H-NMN formation by both 2-hydroxy and 2-methoxy oestradiol did not affect the formation of deaminated metabolites of 3H-(-)-noradrenaline by the alternative metabolising pathway. In endometrial slices preincubated with nialamide to inhibit MAO, only 2-hydroxy oestrogens inhibited 3H-NMN formation, but they were one to two orders of magnitude less potent in this regard than in the myometrium. The uptake of 3H-(-)-noradrenaline by MAO- and COMT-inhibited myometrial slices was inhibited by 2-hydroxy and 2-methoxy oestrogens in the order of potency 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone greater than or equal to 2-hydroxy oestrone greater than 2-hydroxy oestradiol. Uptake of 3H-(-)-noradrenaline by endometrial slices was not affected by either 2-hydroxy or 2-methoxy oestrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗