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1.
Summary In the rat vas deferens, DMPP is a substrate of uptake, (Krn = 11.5 mol/I). After block of vesicular uptake, monoamine oxidase and catechol-O-methyl transferase, after loading of the tissue with 3H-noradrenaline, and in calcium-free solution (i. e., when axoplasmic 3H-noradrenaline levels were high and when depolarization-induced exocytotic release was impossible), DMPP induced a pronounced outward transport of 3H-noradrenaline. On the other hand, when, in similar experiments, vesicular uptake and monoamine oxidase were intact (i.e., when axoplasmic 3H-noradrenaline levels were low), DMPP induced very little outward transport of 3H-noradrenaline. This discrepancy indicates that DMPP has little ability to mobilize vesicularly stored 3H-amine.When the medium contained calcium (catechol-O-methyl transferase inhibited, all other mechanisms intact), 100 (but not 10) mol/l DMPP induced a hexamethonium-sensitive release of 3H-noradrenaline of short duration. Hence, in the presence of extracellular calcium, 100 mol/l DMPP elicits exocytotic release via activation of hexamethonium-sensitive nicotinic acetylcholine receptors.DMPP inhibits the monoamine oxidase of rat heart homogenate with an IC50 of about 100 mol/l.Abbreviations COMT
catechol-O-methyl transferase
- DMPP
dimethylphenylpiperazinium
- DOMA
dihydroxymandelic acid
- DOPEG
dihydroxyphenylglycol
- MAO
monoamine oxidase
- NMN
normetanephrine
- OM-fraction
column chromatographic fraction containing all O-methylated 3H-metabolites
- OMDA
fraction containing O-methylated and deaminated metabolites
Supported by the Deutsche Forschungsgemeinschaft (SFB 176)
Send offprint requests to U. Trendelenburg at the above address 相似文献
2.
Summary 1. The neuronal release by 100 mol/l veratridine of preloaded 3H-noradrenaline was studied in the rat vas deferens, the MAO, COMT and vesicular uptake of which were inhibited. To prevent any exocytotic release of the 3-Hamine, all solutions were calcium-free. Veratridine induced an early and a late peak of tritium efflux. The early peak was abolished by the presence of 1 mol/l desipramine, the late peak was abolished by 1 mol/l tetrodotoxin (administered subsequently to the first peak). The administration of veratridine plus 1 mmol/l ouabain resulted in only the early peak of efflux. 2. The peak response to veratridine plus ouabain was increased by a very early administration of veratridine plus ouabain (after 40 min of wash-out instead of the usual 130 min) (i. e., when the relative size of the axoplasmic distribution compartment was increased). However, very high axoplasmic 3H-noradrenaline levels (after loading with 37 instead of the usual 0.2 mol/l) reduced the height of the peak (when expressed as a FRL). 3. Substantially similar responses to vcratridine plus ouabain were obtained after loading with 3H-noradrenaline, 3H-adrenaline or 3H-dopamine. 4. As the second peak of veratridine-induced release is ouabain-sensitive, it appears to be caused by exhaustion of neuronal ATP stores; this, in turn, raises the intravesicular pH and induces efflux of 3H-noradrenaline from the vesicles into the axoplasm. The first peak, on the other hand, represents outward transport of 3H-noradrenaline from the axoplasmic compartment. Evidently, a pronounced vesicular distribution of 3H-noradrenaline takes place even after inhibition by reserpine of the vesicular uptake. 5. In preparations with intact vesicular uptake (MAO and COMT inhibited) a plateauresponse was obtained; in the presence of 10 mol/l Ro 4-2184 (a reserpine-like compound) a peak response was restored after loading with 0.2 mol/l3H-noradrenaline, less so after loading with 37 mol/l. 6. It is confirmed that veratridine (plus ouabain) exerts a reserpine-like effect when applied to tissues with intact vesicular uptake and intact MAO.Abbreviations COMT
catechol-O-methyl transferase
- DOMA
dihydroxy mandelic acid
- DOPEG
dihydroxyphenylglycol
- DOPAC
dihydroxyphenylacetic acid
- FRL
fractional rate of loss
- MAO
monoamine oxidase
- 5-HT
5-hydroxytryptamine
with technical assistance of Marianne BablSupported by the Deutsche Forschungsgemeinschaft (Bo 521 and SFB 176)
Send offprint requests to: H. Bönisch 相似文献
3.
A. Langeloh H. Bönisch U. Trendelenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(6):602-610
Summary 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. K
m-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 mol/l 3H-(–)-noradrenaline. The IC50 ranged from 0.35 mol/l (for (+)-amphetamine) to 44.3 mol/l (for 5-HT). The V
max (determined for 8 substrates) was substrate-dependent. 2. Tissues were loaded with 0.2 mol/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 K
m. Moreover, the EC50 for release greatly exceeded K
m. It is proposed that this discrepancy between EC50 and K
m is indicative of the fact that at least four factors (each one in strict dependence on K
m) contribute to the initiation of outward transport of 3H-noradrenaline: 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 K
m 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, V
max. 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. Apparently, inward diffusion of the substrates can lead to partial saturation of the inside carrier. Moreover, if release is expressed as a FRL (fractional rate of loss), loading with 37 mol/l 3H-(–)-noradrenaline decreased the releasing effect of various substrates. In this case the inside carrier appears to be partially saturated by the high axoplasmic concentration of 3H-noradrenaline. 5. Very high concentrations (especially of highly lipophilic substrates) were able to induce an additional intraneuronal release mechanism, presumably by increasing the pH inside storage vesicles.Abbreviations COMT
catechol-O-methyl transferase
- DOMAA
dihydroxymandelic acid
- DOPEG
dihydroxyphenylglycol
- FRL
fractional rate of loss (rate of efflux/tissue tritium content)
- 5-HT
5-hydroxytryptamine
- MAO
monoamine oxidase
- OM-fraction
sum of all O-methylated metabolites of noradrenaline, deaminated or not
This study was supported by the Deutsche Forschungsgemeinschaft (Bo 521, Tr 96 and SFB 176). Some of the results were presented to the German Pharmacological Society (Langeloh 1986)A. L. was the recipient of a fellowship of the Humboldt-Foundation
Send offprint requests to: U. Trendelenburg 相似文献
4.
E. Schömig U. Trendelenburg I. Azevedo D. Moura 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(1):41-46
Summary The rat vas deferens was incubated with 0.2 mol/l 3H-noradrenaline for 60 min, washed out with amine-free solution for 100 min and then prepared for autoradiography (same tissues as presented by Azevedo et al. (1990) Naunyn-Schmiedeberg's Arch Pharmacol 342: 245 – 248). The autoradiography images were then digitized, and grain density was determined as a function of the distance from the surface of the tissue. When neither monoamine oxidase nor vesicular uptake was impaired, i. e. under control conditions, grain density declined monophasically exponentially towards the centre of the tissue. This decline amounted to 0.017 m–1 or 0.124 varicosity–1, since the average distance between varicosities was calculated to be 7.4 m. After inhibition of monoamine oxidase and vesicular uptake the rate constant was significantly reduced, and the grain density in close proximity of the surface of the tissue was also reduced.It is proposed that the distribution of grain density observed in controls reflects the steady-state concentration gradient that is generated by uptake1 during the incubation with 3H-noradrenaline.During spontaneous efflux of 3H-noradrenaline one has to distinguish between re-uptake of the 3H-amine into the leaking varicosity and uptake en passant (during diffusion through the extracellular space). On the basis of the present results, the extent of uptake en passant was calculated (with a computer-assisted model) for the spontaneous efflux of heterogeneously distributed 3H-noradrenaline (after wash-out). Uptake en passant into varicosities located between the source of efflux and the medium amounted to about 55% of the net leakage of 3H-noradrenaline from all varicosities. Earlier experiments had indicated that the sum of the two uptake processes was responsible for the neuronal uptake of 90% of the gross leakage of 3H-noradrenaline from varicosities. Hence, the following appears to take place: about 78% of the gross leakage of noradrenaline from a varicosity are subject to re-uptake into the same varicosity. During diffusion to the medium, about 55% of the 3H-noradrenaline escaping re-uptake is then subject to neuronal uptake en passant.
Send offprint requests to E. Schömig at the above address 相似文献
5.
Summary After loading the isolated nerve-muscle preparation of the cat nictitating membrane with 3H-(±)-noradrenaline the effects of exogenous dopamine and (-)-noradrenaline were determined on 3H-transmitter overflow elicited by nerve stimulation in the presence of cocaine, 29 M. Dopamine, 0.20 M, and (-)-noradrenaline, 0.18 M, inhibited 3H-noradrenaline release elicited by nerve stimulation at 4 or 10 Hz. Similar results were obtained with apomorphine 0.03 or 0.1 M. Chlorpromazine, 1 M, or pimozide, 1 M, antagonized selectively the reduction in 3H-noradrenaline release obtained with dopamine or apomorphine, without affecting the inhibition obtained with (-)-noradrenaline. Phentolamine, 1 M, antagonized more effectively the inhibitory effects of (-)-noradrenaline than those of dopamine. Phenoxybenzamine, 0.29 M, prevented the inhibition of 3H-transmitter overflow obtained with (-)-noradrenaline, dopamine or apomorphine. In the absence of cocaine neither chlorpromazine nor pimozide were able to increase 3H-transmitter overflow during nerve stimulation. In contrast to these results, block of -adrenoceptors by phentolamine or phenoxybenzamine resulted in an increase 3H-transmitter overflow during nerve stimulation. Inhibition by dopamine of 3H-transmitter overflow appears to be mediated through dopamine receptors probably located in the outer surface of adrenergic nerve endings. These dopamine receptors differ from the prejunctional -adrenoceptors that mediate the negative feed-back regulatory mechanism for noradrenaline release by nerve stimulation. The prejunctional inhibitory dopamine receptors are not involved in an endogenously mediated regulatory mechanism for noradrenaline release by nerve stimulation under normal conditions. The possibility that these dopamine receptors are involved in the hypotension commonly observed in patients with chronic l-Dopa treatment is discussed. 相似文献
6.
E. Schömig I. Azevedo D. Moura U. Trendelenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(5):541-543
Summary After inhibition of extraneuronal uptake by corticosterone, isolated right atria and lengthwise halved vasa deferentia of the rat were incubated with 0.2 mol/l 3H-noradrenaline for 60 min, washed out for 100 min and then prepared for autoradiography. The autoradiographic images were digitized, and silver grain density was determined as a function of the distance from the surface.Silver grain density declined towards the centre of the tissue; the decline was monophasic exponential and significantly steeper in the vas deferens (0.016 m–1) than in the less densely innervated right atrium (0.011 m–1). Silver grain density at the surface of the tissue was higher in vas deferens than in right atrium.The results show that the extracellular steady-state concentration gradient for 3H-noradrenaline (generated by uptake, during the incubation with this amine) largely depends on the density of the adrenergic innervation.Supported by the Deutsche Forschungsgemeinschaft (SFB 176), by the Alexander von Humboldt-Stiftung (AvH-Forschungskooperation Europa funded by the BMFT) and by INIC (FmP1)
Send offprint requests to E. Schömig at the above address 相似文献
7.
F. Brandão E. Rodrigues-Pereira J. Guilherme Monteiro R. Davidson 《Naunyn-Schmiedeberg's archives of pharmacology》1981,318(2):83-87
Summary Dog saphenous vein strips obtained from untreated or reserpine-pretreated animals were incubated with 1,4 mol/l 3H-(–)noradrenaline for 60 min after inhibition of the noradrenaline-metabolizing enzymes and of extraneuronal uptake. At the end of the incubation period the strips were perifused during 200 min. Some strips were exposed to tyramine from the 100th to the 200th min of perifusion. A compartment analysis of spontaneous or tyramine-induced efflux of 3H-noradrenaline was made. The spontaneous efflux of strips obtained from untreated animals had a long half time (t/2=269 min), and most of the 3H-noradrenaline which accumulated in the strips did not participate in the efflux (bound fraction, representing 85% of tissue activity at the 100th min of perifusion). The strips were exposed to five concentrations of tyramine, ranging from 0.49–3,240 mol/l. At all concentrations, tyramine mobilized only one noradrenaline compartment. The increase of tyramine concentration decreased the bound fraction, which became negligible for the highest concentration of tyramine. The half time of 3H-efflux induced by tyramine decreased from 278–106 min when the tyramine concentration was increased from 0.49–40 mol/l. However, further increases of the concentration of tyramine up to 3240 mol/l did not result in a significantly lower half time.Strips obtained from reserpine-pretreated animals were characterized by a low accumulation of 3H-noradrenaline (403 ng/g vs. 1,374 ng/g for strips obtained from unpretreated animals, at the 100th min of perifusion), the efflux had a half time of only 122 min and the bound fraction was smaller than in strips obtained from unpretreated animals (bound fraction representing 47% of tissue activity at the 100th min of perifusion). Reserpine-pretreated strips were exposed to 40 mol/l tyramine. Under these experimental conditions there was no significant bound fraction. The 3H-efflux induced by tyramine decayed according to a two-compartment model, with half times of 8 and 50 min.The results support the view that in preparations from unpretreated animals the size of the noradrenaline pool available for release by tyramine is dependent on the concentration of the latter amine. Furthermore, the half time of the efflux evoked by tyramine in strips with intact vesicular stores is dependent on a rate-limiting process, probably of vesicular location.Results presented to the 4th Meeting on Adrenergic Mechanisms (Porto 1980). This work was supported by a grant from Instituto Nacional de Investigação Cientifica (Centro de Farmacologia e Biopatologia Química da Universidade do Porto) 相似文献
8.
D. Moura M. J. Vaz-da-Silva I. Azevedo F. Brandão S. Guimarães 《Naunyn-Schmiedeberg's archives of pharmacology》1993,347(2):186-191
Summary 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 mol/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 mol/l cocaine (to inhibit uptake1), 41 mol/l hydrocortisone (to reduce uptake2) and 50 mol/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. This difference in the evoked fractional release therefore cannot be ascribed to any difference in the efficacy of the inactivation pathways between neonates and adults. On the other hand, the difference also cannot be ascribed to a different alpha2-adrenoceptor-mediated inhibition of 3H-noradrenaline release since, as previously shown, this mechanism is as effective in newborns as in adults.It is concluded that the evoked fractional release of 3H-noradrenaline is higher in neonates than in adults because in neonates the majority of varicosities (and vesicles) is situated closer to the surface of the tissue such that both uptake from the surrounding media into the stores and release from the stores into the surrounding media become easier in the neonates.Abbreviations COMT
catechol-O-methyl transferase
- DOMA
3,4-dihydroxymandelic acid
- DOPEG
3,4-dihydroxyphenylglycol
- HPLC
high pressure liquid chromatography
- MAO
monoamine oxidase
- NMN
normetanephrine
- OMDA
3-methoxy-4-hydroxyphenylglycol (MOPEG) plus 3-methoxy-4-hydroxymandelic acid (VMA)
- U-0521
3,4-dihydroxy-2-methyl propiophenone
Correspondence to D. Moura at the above address 相似文献
9.
Maria Margarida Caramona Juan Vicente Esplugues Walter Osswald 《Naunyn-Schmiedeberg's archives of pharmacology》1985,331(2-3):181-185
Summary FLA 668(+)[(S)-(+)-4-amino-2, -dimethylethylphenethylamine (+)-hydrogen bitartrate] selectively inhibited MAO type A in homogenates of dog saphenous vein, with a IC50 of 1 mol/l for MAO A and >1 mmol/l for MAO B.At concentrations of 1 mol/l and higher, FLA 668(+) progressively decreased the formation of deaminated metabolites by saphenous vein strips incubated with3H-noradrenaline, with a preferential action on DOPEG formation. Normetanephrine formation increased but this increase did not wholly compensate for the reduction in the formation of deaminated metabolites.FLA 668(+) caused increased reactivity of saphenous vein strips to noradrenaline and markedly reduced the accumulation of3H-noradrenaline in the incubated tissue; both effects were still evident in the presence of clorgyline. After cocaine, FLA 668(+) caused no further increase in sensitivity.It is concluded that FLA 668(+) is, in the saphenous vein of the dog, a selective inhibitor of MAO type A and that it exerts a cocaine-like effect.Part of the results were presented to the Amine Oxidases: a Cambridge workshop (Caramona et al. 1984). Supported by INIC (Centro de Farmacologia e Biopatologia Quimica da Universidade to Porto)with a grant from the Portuguese-Spanish Academic Exchange Service 相似文献
10.
Arie H. Mulder Cees D. J. de Langen Victoria de Regt François Hogenboom 《Naunyn-Schmiedeberg's archives of pharmacology》1978,303(2):193-196
Summary The effects of oxymetazoline and noradrenaline (in the presence of desipramine) on the release of 3H-noradrenaline from rat brain cortex synaptosomes were studied using a superfusion technique. Both drugs (at 1M concentrations) were found to reduce the depolarization-induced (15 mM K+) release of 3H-noradrenaline. The release-modulating effect of noradrenaline was antagonized by phentolamine and yohimbine.The data provide direct evidence for the hypothesis that -receptors modulating the release of noradrenaline are localized on varicosities of central noradrenergic neurones. 相似文献
11.
P. Fischer A. Burger K. H. Graefe U. Trendelenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1989,339(1-2):79-84
Summary 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 mol/l. Dobutamine inhibited uptake, of 3H-noradrenaline in PC-12 cells (with an IC50 of 0.38 mol/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 mol/l) released tritium from rat vasa deferentia preloaded with 3H-noradrenaline. Equi-inhibitory concentrations of dobutamine and desipramine (against uptake1) were equireleasing. On the other hand, when MAO and vesicular uptake were intact, dobutamine (15 mol/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.Abbreviations COMT
catechol-O-methyl transferase
- DOPEG
dihydroxyphenylglycol
- DOMA
dihydroxymandelic acid
- MAO
monoamine oxidase
Supported by the Deutsche Forschungsgemeinschaft (Gr 490/5 and SFB 176)
Send offprint requests to P. Fischer at the above address 相似文献
12.
In inhalation chambers, 5-week-old male Wistar rats of the strain TNO-W-74 were continuously exposed to submicron aerosols of sodium dichromate in concentrations from 25 (low level) to 200 g/m3 Cr (high level). Subacute exposure (28 days) to 25 and 50 g/m3 Cr resulted in activated alveolar macrophages with stimulated phagocytic activities, and significantly elevated antibody responses to injected SRBC's. After subchronic (90 days) low level exposure there was a more pronounced effect on activation of the alveolar macrophages, with increased phagocytic activities. However, at high Cr (VI) exposure level (200 g/m3), inhibited phagocytic function of the alveolar macrophages was seen. In rats which were exposed to this chromium aerosol concentration for 42 days, the lung clearance of inert iron oxide was reduced significantly. The humoral immune system was still stimulated at subchronic low chromium aerosol concentrations of 100 g/m3, but significantly depressed at 200 g/m3 Cr. These results show that respiratory defence and immunologic functions were stimulated or inhibited depending on dose and time of chromium (VI) inhalation.This paper was presented in part at the International Seminar on the Immunological System as a Target for Toxic Damage, November 6–9, 1984, Luxembourg 相似文献
13.
Summary The effects of GABA were studied on the release of 3H-noradrenaline (3H-NA) evoked by potassium or by tyramine from slices of the rat occipital cortex and on the release of 3H-NA elicited by nerve stimulation from the cat nictitating membrane.GABA (30–1000M) facilitated the potassium-evoked release of 3H-NA in a concentration dependent manner. This facilitatory effect was not antagonized by bicuculline (1–100 M) or by picrotoxin (1–100 M). Exposure to the GABA agonist muscimol (1–100 M) did not affect either the spontaneous or the potassium-evoked release of 3H-NA.The facilitatory effect of GABA on the release of 3H-NA elicited by potassium was observed when the occipital cortex slices were exposed to 20 mM K+ during 1 min. When depolarization was induced by 35 mM K+ exposure to GABA failed to enhance the release of the neurotransmitter. GABA 300 M did not affect the release of the labelled neurotransmitter evoked by exposure to tyramine 0.6 M.In the cat nictitating membrane prelabelled with 3H-NA, the stimulation evoked release of the labelled neurotransmitter was not affected by GABA (10–300 M).In conclusion, GABA has a facilitatory effect on the calcium-dependent, potassium evoked release of 3H-NA when the depolarization is of moderate degree. This effect of GABA appears to be selective for the central nervous system.Some of the findings described in this paper have been presented at the Meeting of the British Pharmacological Society (March, 1978, Guildford, U.K.) 相似文献
14.
The heterogeneity of the neuronal distribution of exogenous noradrenaline in the rat vas deferens 总被引:3,自引:0,他引:3
E. Schömig C.-L. Schönfeld T. Halbrügge K.-H. Graefe U. Trendelenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(2):160-170
Summary After loading of the incubated rat vas deferens with 0.2 mol/l 3H-noradrenaline (followed by 100 min of wash-out with amine-free solution), the efflux of endogenous and exogenous compounds was determined by HPLC with electrochemical detection and by column chromatography with scintillation counting. Two different types of heterogeneity of labelling were found. The first one is due to the preferential labelling of varicosities close to the surface of the tissue, the second one to the preferential labelling of vesicles close to the surface of loaded varicosities. As diffusion distances within the tissue and within varicosities are then longer for endogenous than for exogenous amine and metabolites, the composition of spontaneous efflux of exogenous compounds differed from that for endogenous compounds. Because of preferential neuronal and vesicular re-uptake of endogenous noradrenaline, the percentage contribution by noradrenaline to overall efflux was: endogenous < exogenous. While 3H-DOPEG was the predominant exogenous metabolite, DOPEG and MOPEG equally contributed to the endogenous efflux.Desipramine abolished the consequences of the first heterogeneity of labelling, i.e., it increased the efflux more for endogenous than for exogenous noradrenaline; moreover it decreased the efflux of 3H-DOPEG, but increased that of 3H-MOPEG. The reserpine-like compound Ro 41284, on the other hand, abolished the consequences of the second type of heterogeneity; it reduced the specific activity of total efflux (i.e., of the sum of noradrenaline + DOPEG + MOPEG) to the specific activity of the tissue noradrenaline. The degree of heterogeneity of labelling was reduced after inhibition of monoamine oxidase and also when the tissues were loaded with 2 or 20 mol/l 3H-noradrenaline.It is proposed that the various compartments and pools of noradrenaline described in the literature reflect the two heterogeneities described here.Abbreviations COMT
catechol-O-methyl transferase
- DOMA
dihydroxymandelic acid
- DOPEG
dihydroxyphenylglycol
- FRL
fractional rate of loss (= rate of efflux/tritium content of tissue measured at onset of collection period)
- HPLC
high performance liquid chromatography
- MAO
monoamine oxidase
- MOPEG
methoxyhydroxyphenylglycol
- NMN
normetanephrine
- VMA
vanillylmandelic acid
Send offprint requests to E. Schömig at the above addressThis study was supported by the Deutsche Forschungsgemeinschaft (SFB 176, Gr 490/5 and Scho 383/1). Some of the results were presented to the German Pharmacological Society (Schönfeld 1990; Trendelenburg 1990) 相似文献
15.
Summary Intra- and extraneuronal compartments of rat hearts were selectively labelled by perfusion with 3H-noradrenaline in the presence of corticosterone 87 M or cocaine 30 M, respectively. The subsequent outflow of 3H-compounds was examined. As little as 1 nM amezinium diminished the outflow of intraneuronally formed 3H-DOPEG. This effect was antagonized by cocaine. Amezinium 1 M was necessary to diminish the outflow of extraneuronally formed 3H-DOPEG. This effect was not counteracted by corticosterone. The results indicate that amezinium is both a potent and, at low concentrations, selective inhibitor of intraneuronal MAO.Abbreviations used DOMA
3,4-dihydroxymandelic acid
- DOPEG
3,4-dihydroxyphenylglycol
- MAO
monoamine oxidase (EC 1.4.3.4)
- NA
noradrenaline
- NMN
normetanephrine
- OMDA
O-methylated deaminated metabolites 相似文献
16.
M. Vidal P. E. Hicks S. Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1986,332(4):384-390
Summary The effects of ,-methylene-adenosine triphosphate, (,-methylene ATP, a P2-receptor desensitising agent) have been evaluated on vasoconstrictor responses elicited by exogenous agonists or electrical field stimulation in isolated perfused SHR or WKY tail arteries and on tritium release elicited by electrical field stimulation in SHR-tail arteries pre-labeled with 3H-noradrenaline.Exposure to ,-methylene ATP (0.1 mol/l) significantly inhibited vasoconstrictor responses to electrical field stimulation in SHR tail arteries. These inhibitory effects were not further increased at a higher concentration of ,-methylene ATP (1 mol/l). In WKY tail arteries, ,-methylene ATP (1 mol/l) failed to significantly inhibit vasoconstrictor responses to electrical stimulation.In SHR tail arteries prelabelled with 3H-noradrenaline, ,-methyleneATP (1 mol/l) did not inhibit the stimulation evoked release of tritium. However, at this concentration, ,-methylene ATP significantly antagonized the vasoconstrictor responses of SHR tail arteries induced by exogenous ATP (1 mol/l), ,-methylene ATP (30 mol/l), a stable agonist at P2-receptors, or 60 mmol/l KCl. These effects of ,-methylene ATP on contractile responses to KCl were not observed in WKY-tail arteries.In tail arteries obtained from reserpine pretreated SHR, despite a 85–95% decrease in endogenous noradrenaline tissue content, the vasoconstrictor responses induced by periarterial field stimulation were greatly diminished, but not abolished. These residual responses to periarterial field stimulation were not antagonized by prazosin (0.1 mol/l), but were practically abolished by the addition of ,-methylene ATP (1 mol/l).In tail arteries from WKY rats pretreated with reserpine, exposure to prazosin (0.1 mol/l) further reduced the residual responses elicited by electrical field stimulation. In these WKY-tail arteries, addition of ,-methylene ATP (1 mol/l) did not further inhibit the remaining vasoconstrictor response obtained in the presence of prazosin.While our results suggest a significantly greater cotransmitter role for ATP with noradrenaline in tail arteries of SHR compared with control normotensive WKY rats, additional effects of ,-methylene ATP not involving P2 receptors cannot be entirely excluded. 相似文献
17.
Summary 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 mol/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 reserpinelike 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 < PU < 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).Abbreviations COMT
catechol-O-methyl transferase
- DOMA
dihydroxymandelic acid
- DOPEG
dihydroxyphenylglycol
- FRL
fractional rate of loss
- MAO
monoamine oxidase
Supported by the Deutsche Forschunesgemeinschaft (SFB 176)
Send offprint requests to E. Schömig 相似文献
18.
H. Fuder R. Siebenborn E. Muscholl 《Naunyn-Schmiedeberg's archives of pharmacology》1982,318(4):301-307
Summary Isolated rat hearts with the right sympathetic nerves attached were perfused at a constant flow rate of 7 ml/min with Tyrode's solution. (-)-3H-Noradrenaline (final concentration 10–13.9 nM) was infused for 10 min to label the noradrenaline stores. After wash-out the sympathetic nerves were stimulated electrically (3 Hz, 180 impulses, 1 ms, 20–30 mA) three times (S1–S3) at intervals of 15 min. 3H-Noradrenaline and its metabolites were determined by liquid scintillation counting according to Graefe et al. (1973).Both, nicotine 50 M and p-aminophenethyltrimethylammonium (PAPETA) 30 M, enhanced the 3H-noradrenaline overflow in the absence of nerve stimulation. The effect of PAPETA was biphasic and was still observed in the presence of N-methylatropine 0.1 M. Hexamethonium 10 M abolished the first phase only, but cocaine 10 M antagonized both phases.The decline of the stimulation-evoked overflow of 3H-noradrenaline from the first to the third stimulation period was similar in the absence and in the presence of cocaine 10 M starting before S1 and perfused throughout. Cocaine 10 M added before S2, however, enhanced the evoked overflow by 77%.PAPETA 30 M increased the stimulation-evoked overflow by 67% in the absence, and by 73% of the respective control in the presence, of hexamethonium 10 M. PAPETA 30 M failed to enhance the evoked overflow in the presence of cocaine. Hexamethonium (added before S2) did not modify the effectiveness of nerve stimulation.Nicotine, neither when perfused from 6 min before S2, nor when added to the perfusion fluid simultaneously with the onset of nerve stimulation, caused changes in the 3H-noradrenaline output upon S2.Upon stimulation a rather discrete increase in 3H-DOPEG overflow was observed. This increase was abolished by cocaine and/or PAPETA.It is concluded that nicotine and PAPETA stimulate the output of 3H-noradrenaline from the rat heart sympathetic nerves by activation of nicotine receptors. However, the amount of transmitter released is small. Neither drug appeared to modulate the output of 3H-noradrenaline upon electrical nerve stimulation via nicotine receptors.PAPETA, like cocaine, appears to block the reuptake of released transmittsrs thereby enhancing the 3H-noradrenaline overflow and reducing the overflow of 3H-DOPEG (formed intraneuronally from recaptured noradrenaline after nerve stimulation).Abbreviations used DOMA
3,4-dihydroxymandelic acid
- DOPEG
3,4-dihydroxyphenylglycol
- MOPEG
3-methoxy-4-hydroxy-phenylglycol
- NA
noradrenaline
- NMN
normetanephrine
- OMDA
O-methylated deaminated metabolites (sum of MOPEG and VMA)
- PAPETA
p-aminophenethyltrimethylammonium
- VMA
3-methoxy-4-hydroxymandelic acid 相似文献
19.
D.G.A. KasteleijnNolst Trenité K.G.P.M. Gilissen Th. W Rentmeester F.B.J. Scholtes L.R. Arends A. Schlosser 《Pharmacy World & Science》2001,23(1):1-5
Purpose: Evaluation of daily clinical practice in prescribing lamotrigine in refractory epilepsy patients.Methods: A collaborative, retrospective, perimarketing study was performed in in and outpatients attending one of the three Dutch epilepsy centres. Analysis of both patients' and doctors' information was performed in 520 patients using questionnaires and medical files.Results:After one year of treatment 76% of patients maintained LTG treatment, an intentiontotreat analysis showed >= 50% seizure reduction in 23% of patients; 2050% seizure reduction in 23% of patients. Six percent of patients became at least three months seizure free. In about 20% of patients seizures became less severe and shorter of duration, while in 6% an increase was found.After three months a significant decrease in number of concomitant antiepileptic drugs was found (change from mean 1,8 to 1,5 AEDs) (p=< 0.01). After twelve months the mean number of AEDs was 1,4 per patient. Overall percentage of side effects appeared to be significantly higher if patients' questionnaire data were used. Epilepsy patients considered side effects as an important factor in the choice of medication and in withdrawal of medication. Future developments of new AEDs should take this into account. Conclusion: This perimarketing study gives insight information about longterm daily use of lamotrigine, with emphasis on effectiveness. Patients complained in the questionnaires much more about sideeffects, than was known according to the medical file. Therefore, it seems necessary to perform perimarketing studies more systematically. 相似文献
20.
B. Szabo L. Hedler H. Ensinger K. Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1986,332(1):50-56
Summary Effects of dynorphin-(1–13), Leu5-enkephalin,d-Ala2,d-Leu5-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of experiments, the sympathetic outflow was stimulated electrically via the pithing rod at 2 Hz twice for 3 min each (S1, S2). Drugs were administered before S2. Bremazocine 10 g/kg+2g/kg/h and 100 g/kg+20 g/kg/h, dynorphin 1 and 3 g/kg/min, Leu5-enkephalin 100 g/kg/min and DADLE 10 and 30 g/kg/min all diminished the electrically-evoked increase in plasma noradrenaline and MAP. The effects were antagonized by naloxone. In the second series, an infusion of noradrenaline (2 g/kg/min) was given twice for 3 min each (N1, N2). Drugs were administered before N2. Bremazocine 100 g/kg+20 g/kg/h slightly enhanced the pressor effect of exogenous noradrenaline, whereas dynorphin 3 g/kg/min, Leu5-enkephalin 100 g/kg/min and DADLE 30 g/kg/min caused no significant change. In the third series, the sympathetic outflow was stimulated continuously at 2 Hz, and the interaction of dynorphin and DADLE was studied. Dynorphin 1 g/kg/min and DADLE 10g/kg/min initially decreased MAP to a similar extent. The effect of DADLE faded with time. When, during continuous infusion of DADLE 10 g/kg/min, and after return of MAP to the pre-DADLE level, dynorphin 1 g/kg/min or DADLE 10 g/kg/min was infused additionally, the effect of dynorphin was unchanged, whereas that of DADLE was almost abolished. We conclude that the opioid peptides as well as bremazocine decrease action potential-evoked release of noradrenaline and, secondarily, blood pressure. They act at peripheral sites, presumably prejunctional opioid receptors at postganglionic sympathetic axons. Dynorphin on the one hand, and Leu5-enkephalin and DADLE on the other hand, appear to act at different receptors, dynorphin probably at a - and DADLE and Leu5-enkephalin at a -receptor. 相似文献