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1.
With the aim of investigating whether exogenous noradrenaline (NA) and adrenaline (A) can modulate transmitter release via the stimulation of presynaptic beta-adrenoceptors, 3H-release from isolated portal veins was studied after pretreatment with 3H-1-NA, phenoxybenzamine, desipramine and normetanephrine. NA (10 muM) and A (0.05 muM) increased the fractional 3H-release elicited by sympathetic nerve stimulation by 30%. This effect could be blocked by d, 1-propranolol which per se reduced the release by 10%. It is concluded that NA can facilitate its own release via a presynaptic beta-adrenoceptor-mediated positive feed-back mechanism and that adrenaline can stimulate this beta-adrenoceptor-mediated mechanism. 相似文献
2.
The inhibitory actions of the Ca2+ antagonist Cd2+, morphine and noradrenaline (exogenously added + endogenously released) on electrically evoked release of [3H]noradrenaline from superfused rat neocortical slices were strongly reduced when release was enhanced by 4-aminopyridine. In the presence of 4-aminopyridine the release inhibiting effects of these drugs were restored by lowering the extracellular Ca2+ concentration. When release was enhanced by prolonging the pulse duration, only the release inhibiting effect of noradrenaline was reduced but the effects of Cd2+ and morphine were unchanged. Irrespective of the pulse duration, blockade of presynaptic alpha-adrenoceptors with phentolamine did not affect the release inhibiting effects of Cd2+ and morphine. The inhibitory effects of morphine and noradrenaline remained unchanged in Cl--free medium. Furthermore, these drugs strongly reduced the [3H]noradrenaline release induced by 20 mM K+ in the presence of tetrodotoxin. The results suggest that activation of presynaptic opiate-receptors inhibits Ca2+ entry through voltage-sensitive Ca2+ channels, whereas presynaptic alpha-adrenoceptors affect a step in the secretory process subsequent to Ca2+ influx. Moreover, the involvement of (direct) changes in Na+, K+ or Cl- permeability appears unlikely for both receptor systems. 相似文献
3.
Ravindra K. Malhotra Taruna D. Wakade Arun R. Wakade 《Naunyn-Schmiedeberg's archives of pharmacology》1985,331(2-3):220-224
Summary The effect of gallamine on spontaneous and stimulation-evoked overflow of tritium was studied in the submandibular gland of the rat. The gland was perfused retrogradely and labeled with3H-noradrenaline. The stimulation-evoked (1 Hz for 60 s) overflow of tritium was facilitated by increasing concentrations of gallamine (0.3–20 mM). None of the concentrations of gallamine increased the spontaneous overflow of the tritium. The facilitatory effect of gallamine was observed in 0.3 to 5 mM calcium medium; the maximum facilitation was observed at the normal concentration of calcium (2.5 mM). The facilitatory effect of gallamine was inversely related to the frequency of stimulation (10-fold facilitation at 1 Hz and 3-fold at 10 Hz).Stimulation of the salivary gland by a single pulse (1 ms duration) in the normal medium did not evoke an overflow of tritium; however, the same stimulus produced a marked increase in the overflow in the presence of gallamine.The facilitatory action of gallamine on the release of sympathetic transmitter is ascribed to the enhanced availability of calcium ions to the secretory process resulting from blockade of potassium conductance during nerve activity. 相似文献
4.
Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors 总被引:9,自引:0,他引:9
Eberhard Schlicker Klaus Fink Marc Hinterthaner Manfred Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(6):633-638
Summary The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with3H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl2 1.3 mmol/l (slices superfused with Ca2+-free medium containing K+ 20 mmol/l).Histamine slightly decreased the electrically evokedH overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC15 6.46). Under the latter condition, the evoked overflow was inhibited by the H3 receptor agonist R-(–)--methylhistamine and its S-(+) enantiomer (pIC15 7.36 and 5.09, respectively), but was not affected by the H2 receptor agonist dimaprit and the H1 receptoragonist 2-thiazolylethylamine (both at up to 32 µmol/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA2 8.37, 6.86 and 7.05, respectively), by the H2 receptor antagonist ranitidine (apparent pA2 4.27) and was not affected by the H1 receptor antagonist dimetindene (32 µmol/l). The inhibitory effect of R-(–)--methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked3H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine. The concentration-response curve of noradrenaline for its inhibitory effect on the evoked overflow was shifted to the right by impromidine and burimamide, but not influenced by thioperamide (apparent pA2 5.24, 5.04 and <6.5, respectively; experiments carried out in the presence of desipramine). In slices superfused with Ca2+-free K+-rich medium containing tetrodotoxin, desipramine plus phentolamine, the tritium overflow evoked by introduction of Ca2+ was inhibited by histamine; the concentration-response curve of histamine was shifted to the right by thioperamide.The present study shows that the inhibitory effect of histamine on noradrenaline release in the rat brain cortex involves presynaptic H3 receptors and that the degree of inhibition is increased in the presence of phentolamine. The H3 receptor antagonists impromidine and burimamide are weak 2-adrenoceptor antagonists.
Send offprint requests to E. Schlicker at the above address 相似文献
5.
A cumulative dose-response technique was developed for the characterization of presynaptic receptors involved in the modulation of [3H]noradrenaline (NA) release from rat hippocampus slices, using continuous K+ (20 mM) depolarization. The results obtained with this technique were compared with those obtained using a repetitive K+ stimulation procedure. The release of [3H]NA induced by continuous K+ stimulation as well as that caused by repetitive K+ stimulation was strongly Ca2+-dependent and consisted for more than 90% of unmetabolized [3H]NA. Using continuous K+ stimulation it was demonstrated that the presynaptic inhibition of 3H-NA release by exogenous NA reached a maximum 10 min after addition of NA. The inhibitory effect of NA appeared to be independent of the time of addition, suggesting that the sensitivity of the presynaptic α-adrenoceptors remained unchanged during the experiment. Cumulative dose-response curves were recorded by the successive addition, at 10 min intervals, of increasing concentrations of NA. It was shown that continuous stimulation and repetitive K+ stimulation were basically similar with regard to the characteristics of the resulting [3H]NA release as well as its presynaptic α-adrenoceptor-mediated modulation by exogeneous NA. However, the cumulative dose-response technique, which can be carried out only using continuous K+ stimulation, makes it possible to determine more rapidly and also more accurately the apparent affinities and intrinsic activities of drugs towards receptors involved in the modulation of neurotransmitter release from brain slices. 相似文献
6.
Bela Szabo Liselotte Hedler Claudia Schurr Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1988,338(4):368-372
Summary The effects of ACTH on the release of noradrenaline and the increase of heart rate produced by sympathetic nerve stimulation (1 Hz) were studied in isolated perfused rabbit hearts. ACTH-(1–24) 0.1–100 nmol/l increased the stimulation-evoked overflow of noradrenaline concentration-dependently, reversibly and up to two-fold. The basal outflow of noradrenaline, the basal heart rate and the stimulation-evoked increase in heart rate were not changed. Human ACTH-(1–39) also increased the evoked overflow of noradrenaline. The effect of ACTH-(1–24) 0.3 nmol/l persisted after blockade of -adrenoceptors with propranolol and blockade of neuronal catecholamine uptake by cocaine. ACTH-(1–24) 3 nmol/l did not change the removal of noradrenaline from the perfusion fluid, when hearts were perfused with medium containing 59 nmol/l noradrenaline. The results show that ACTH increases the action potential-evoked release of noradrenaline from cardiac postganglionic sympathetic neurones, probably by activating specific presynaptic ACTH receptors. The high potency of ACTH suggests that these presynaptic receptors may be activated in vivo by circulating ACTH under certain pathophysiological conditions.Send offprint requests to B. Szabo at the above address 相似文献
7.
G. J. Molderings K. Fink E. Schlicker M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(3):245-250
Summary In the rat inferior vena cava preincubated with 3H-noradrenaline, the effects of nine serotonin (5-HT) receptor agonists and of eight antagonists (including two -adrenoceptor blocking agents) on the electrically evoked 3H overflow were determined. 1. 5-HT, 5-carboxamidotryptamine, 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969), 5-methoxytryptamine, N,Ndimethyl-5-HT, tryptamine and 5-aminotryptamine inhibited the evoked 3H overflow. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT1B binding sites, but not with their affinities for 5-HT1A, 5-HT1C or 5-HT2 binding sites. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5HT1A receptor agonist, and ipsapirone, a partial agonist at these receptors, did not inhibit overflow. 2. Cyanopindolol facilitated the evoked 3H overflow, an effect which was abolished by propranolol. The maximum inhibition of overflow obtainable with 5-HT was diminished by cyanopindolol. 3. The concentration-response curve for 5-HT was shifted to the right by metitepine, metergoline, quipazine, 6-chloro-2-(1-piperazinyl)pyrazine (MK 212) and propranolol which, given alone, did not affect 3H overflow. The apparent pA2 values of these antagonists tended to be correlated with their affinities for 5-HT1B (but not 5-HT1A, 5-HT1c or 5-HT2) binding sites. Ketanserin, a 5-HT2 receptor antagonist, and spiperone, which blocks 5-HT2 and 5-HT1A but not 5-HT1B or 5-HT1C receptors, failed to antagonize the effect of 5-HT. These results suggest that the inhibitory presynaptic 5-HT receptors on the sympathetic nerve terminals of the rat vena cava appear to belong to the 5-HT1B subtype. Cyanopindolol may act as a partial agonist at these receptors, as it does at the facilitatory prosynaptic -adrenoceptors.This study was supported by a grant of the Deutsche Forschungsgemeinschaft
Send offprint requests to M. Göthert 相似文献
8.
Nociceptin inhibits noradrenaline release in the mouse brain cortex via presynaptic ORL1 receptors 总被引:1,自引:1,他引:0
E. Schlicker S. Werthwein M. Kathmann U. Bauer 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(4):418-422
A fourth type of opioid receptor, termed ORL1, has been cloned and nociceptin (also known as orphanin FQ) has been identified as an endogenous ligand at this receptor.
We examined whether nociceptin affects the release of noradrenaline in the brain. For this purpose, cerebral cortex slices
from the mouse, rat or guinea-pig were preincubated with [3H]noradrenaline and then superfused with medium containing desipramine and rauwolscine. Tritium overflow was evoked electrically
(0.3 Hz) or by introduction of Ca2+ 1.3 mM into Ca2+-free K+-rich (15 mM) medium. Nociceptin 1 μM reduced the electrically evoked tritium overflow from mouse, rat and guinea-pig brain cortex slices by 80, 71 and 36%, respectively. Naloxone 10 μM
did not change the effect of nociceptin. All subsequent experiments were performed on mouse brain cortex slices and in the
presence of naloxone 10 μM. The concentration-response curve of nociceptin (maximum inhibition by 80%, pEC50 7.5) was shifted to the right by the non-selective ORL1 receptor antagonist naloxone benzoylhydrazone and the selective ORL1 receptor antagonist [Phe1ψ(CH2-NH)Gly2]-nociceptin(1–13)NH2 (pA2 6.6 and 7.2, respectively). Naloxone benzoylhydrazone did not affect the evoked overflow by itself whereas [Phe1ψ(CH2-NH)Gly2]-nociceptin(1–13)NH2 caused an inhibition by maximally 35% (pEC50 7.0; intrinsic activity α 0.45). The inhibitory effect of [Phe1ψ(CH2-NH)Gly2]-nociceptin(1–13)NH2 was counteracted by naloxone benzoylhydrazone. Nociceptin also reduced the Ca
2+
-evoked tritium overflow in mouse brain cortex slices superfused in the presence of tetrodotoxin. This effect was also antagonized
by naloxone benzoylhydrazone, which, by itself, did not affect the evoked tritium overflow. In conclusion, nociceptin inhibits
noradrenaline release more markedly in the mouse than in the rat or guinea-pig brain cortex. The effect of nociceptin in the
mouse brain cortex involves ORL1 receptors, which are located presynaptically on noradrenergic neurones.
Received: 19 June 1998 / Accepted: 17 July 1998 相似文献
9.
M. Ferrer R. Galvín J. Marín G. Balfagón 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(6):619-626
Summary Experiments were performed in bovine cerebral arteries preincubated with [3H]-choline or [3H]-noradrenaline to analyze the presynaptic muscarinic receptors involved in inhibition of acetylcholine and noradrenaline release induced by electrical stimulation (4 Hz, 200 mA, 0.3 ms, 1 min). For this purpose, the actions of several muscarinic receptor antagonists on the 3H overflow and on the carbacol-induced inhibition of this overflow were assessed. The evoked [3H]-acetylcholine release and [3H]-noradrenaline release were markedly reduced by the presence of tetrodotoxin, Ca2+-free medium, and the inhibitor of both choline transport and choline acetyltransferase, AF64A. Chemical sympathetic denervation with 6-hydroxydopamine (6-OHDA) decreased the uptake of[3H]-noradrenaline, and AF64A reduced mainly the uptake of [3H]-choline, but also of [3H]-noradrenaline. Carbachol reduced the evoked [3H]-noradrenaline and [3H]-acetylcholine release; the IC50 values were 0.37 and 0.43 mol/l, respectively.Atropine and 4-DAMP, but not AF DX 116, methoctramine or pirenzepine, increased the evoked [3H]-acetylcholine release. However, these muscarinic antagonists failed to modify the evoked [3H]-noradrenaline release. Carbachol inhibited the release of both acetylcholine and noradrenaline. The inhibition was blocked by the antagonists. The rank orders of potency (based on plC50 values) were, in the case of [3H]-acetylcholine release, atropine > 4-DAMP >AF-DX 116 >- pirenzepine >- methoctramine, and, in the case of [3H]-noradrenaline release, atropine > 4-DAMP > AF-DX 116 >- methoctramine >-pirenzepine. These results suggest (1) that the prosynaptic receptors that modulate endogenous acetylcholine release are likely of the M3 subtype, whilst those involved on the effect of the exogenous agonist Carbachol are of M2 subtype, and (2) that those which inhibit noradrenaline release are probably a mixture of M2 and M3 subtypes as well. The autoinhibition of the acetylcholine release was funtionally active under our experimental conditions, while noradrenaline release does not appear to be modulated by muscarinic receptors in physiological conditions.Send offprint requests to G. Balfagón at the above address 相似文献
10.
G. J. Molderings James Likungu Manfred Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(4):440-444
Strips of human right atrial appendages were preincubated with [3H]noradrenaline and then superfused with physiological salt solution containing inhibitors of uptake1 and uptake2. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). Prostaglandin E2 (PGE2) inhibited the electrically evoked tritium overflow; at the highest concentration investigated, tritium overflow was reduced
by about 80% and the pIC50% value was 7.14. The effect of PGE2 was not affected by rauwolscine, which, by itself, increased the evoked overflow. Naproxen failed to affect the evoked tritium
overflow and its inhibition by PGE2. The inhibitory effect of PGE2 on the electrically evoked tritium overflow was mimicked by prostaglandin E1, the EP1/EP3-receptor agonist sulprostone and the EP2/EP3-receptor agonist misoprostol with the rank order of potency (pEC50%): sulprostone (7.68) > misoprostol (7.10) > PGE1 (6.39). In contrast, PGF2α, the IP/EP1-receptor agonist iloprost and the stable thromboxane A2 analogue U46619 (9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α) did not change evoked tritium overflow. PGD2 caused facilitation. These results suggest that the sympathetic nerve fibres innervating human atrial appendages are endowed
with presynaptic inhibitory EP3 and facilitatory DP-receptors. The EP3-receptors appear not to be tonically activated and do not interact with the α2-autoreceptors.
Received: 11 May 1998 / Accepted: 29 July 1998 相似文献
11.
Strips of the rabbit main pulmonary artery were preincubated with 3H-noradrenaline. 3 X 10(-8) -- 10(6) M yohimbine enhanced the overflow of tritium and the smooth muscle contraction induced by transmural sympathetic nerve stimulation. The increase of the stimulation-evoked overflow of tritium was prevented by a high concentration of oxymetazoline. The results indicate that yohimbine is more potent in blocking the presynaptic than the postsynaptic alpha-adrenoceptors of the artery. 相似文献
12.
G. J. Molderings G. Weißenborn E. Schlicker J. Likungu M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1992,346(1):46-50
Summary The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked 3H overflow was inhibited by histamine and the H3 receptor agonist R-(–)--methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by 2-adrenoceptor blockade by rauwolscine. S-(+)--methylhistamine (up to 10 mol/l) as well as the histamine H1 and H2 receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mol/l) and dimaprit (up to 30 mol/l), respectively, were ineffective. The selective histamine H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H2 and H1 receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H3 class.
Send offprint requests to M. Gothert at the above address 相似文献
13.
In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mol/l or 0.032 mol/l, respectively); S-(+)--methylhistamine (up to 10 mol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine) and the selective H2 receptor agonist dimaprit (each up to 10 mol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of -conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(–)--methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.
Correspondence to: M. Göthert at the above address 相似文献
14.
Carlos J. Perec Francisco J. E. Stefano Carlos M. Baratti Omar R. Tumilasci 《Naunyn-Schmiedeberg's archives of pharmacology》1975,289(3):257-274
Summary Six and 18 months after neonatal administration of 6-hydroxydopamine or surgical sympathetic denervation the submaxillary gland of the rat showed a marked depletion of noradrenaline stores. Six months after removal of the superior cervical ganglion the gland's endogenous noradrenaline was lowered to 0.032±0.004 g/g while after neonatal 6-hydroxydopamine the values were 0.228±0.023 g/g (controls 2.145±0.382 g/g). Eightheen months after either type of sympathetic denervation the neurotransmitter was still depleted. In rats treated with 6-hydroxydopamine the sialagogue effect of injected noradrenaline was potentiated 2.7-fold while the potentiation of the effect of noradrenaline was 3.6 times after surgical denervation. The magnitude of the supersensitivity developed to isoprenaline did not differ between both types of denervation. No supersensitivity to the cholinomimetic agent, methacholine, was observed. Cocaine administration or removal of the superior cervical ganglion slightly increased the supersensitivity to noradrenaline in rats treated with 6-hydroxydopamine. Eighteen months after surgical or chemical denervation, the activity of choline-acetyltransferase in the submaxillary gland was increased by about 50%. Of the respiratory enzymes studied, succinic dehydrogenase, fumarase and cytochrome oxidase, the activity of only the latter was markedly reduced by chronic sympathetic denervation. From the results obtained it is concluded that neonatal treatment with 6-hydroxydopamine causes a permanent and almost complete sympathectomy of the submaxillary gland of the rat.Supported partially by grant N0 3211/73, Consejo Nacional de Investigaciones Cientificas y Técnicas. 相似文献
15.
Summary Slices of rat hypothalamus (noradrenaline experiments) or rabbit caudate nucleus (dopamine experiments) were prepared, superfused, and field-stimulated using series of monophasic rectangular pulses. Noradrenaline, dopamine and the main dopamine metabolite, dihydroxyphenylacetic acetic acid (DOPAC), were determined using HPLC with electrochemical detection. Electrical stimulation was performed using the following protocols: 1) 4 pulses delivered at 100 Hz; this type of stimulation is referred to as pseudo-one-pulse stimulation (POP); its short duration of only 32 ms does not allow the development of autoinhibition; 2) 2 bursts of 4 pulses at 100 Hz, delivered 1 s apart (2-POP-stimulation); 3) 8 pulses at 1 Hz (dopamine experiments only); 4) 36 pulses at 3 Hz.
Noradrenaline experiments. The 2-adrenoceptor antagonist yohimbine (1 mol/l) did not enhance noradrenaline overflow following POP stimulation, but enhanced the overflow following 2-POP-stimulation by about 50% and that following 36-pulse-stimulation by almost 100%.
Dopamine experiments. The D2-dopamine receptor antagonist sulpiride (3 mol/l) facilitated the overflow of dopamine elicited with 2-POP-stimulation (66%), 8 pulses/1 Hz (92%), and 36 pulses/3 Hz (140%). It did not significantly facilitate the overflow of dopamine following POP-stimulation (19%). The overflow of DOPAC was not, or only slightly, increased by electrical stimulation, and its spontaneous outflow was more than three times higher than that of dopamine. Furthermore, the electrically induced overflow of dopamine did not exceed the outflow of DOPAC at any of the stimulation conditions employed.The results of the present study bear out important claims of the autoreceptor theory and confirm the data obtained in previous experiments using labelled transmitters.
Correspondence to E. A. Singer at the above address 相似文献
16.
G. J. Molderings K. Werner J. Likungu M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(4):371-377
Summary The human saphenous vein preincubated with [3H]noradrenaline was used to determine the pharmacological properties of the release-inhibiting presynaptic serotonin (5-HT) receptor on the sympathetic nerves. The overflow of tritium evoked by transmural electrical stimulation (2 Hz) was concentration-dependently inhibited by drugs known to stimulate 5-HT receptors in the following rank order: oxymetazoline 5-HT 5-carboxamidotryptamine = 5-methoxytryptamine = sumatriptan > tryptamine > N,N(CH3)2-5-HT = yohimbine = 8-hydroxy-2-(di-n-propylamino)-tetraline. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT1B and 5-HT1D binding sites, but not with those for 5-HT1A or 5-HT1C binding sites. 5-Aminotryptamine, methysergide, ipsapirone, cyanopindolol, SDZ 21009 and metergoline dit not produce a significant inhibition. Metitepine and methysergide antagonized the inhibitory effect of 5-HT, whereas spiroxatrine, propranolol, ketanserin and ICS 205-930 did not.These data exclude the idea that the inhibitory presynaptic 5-HT receptor on the sympathetic nerves belongs to the 5-HT2 and 5-HT3 receptor class; the pattern of agonist potencies suggests that the receptor is very similar to the 5-HT1D receptor subtype.
Send offprint requests to M. Gothert at the above address 相似文献
17.
Postsynaptic glutamate AMPA receptors (AMPARs) can recycle between plasma membrane and intracellular pools. In contrast, trafficking of presynaptic AMPARs has not been investigated. AMPAR surface expression involves interactions between the GluR2 carboxy tail and various proteins including glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), protein interacting with C kinase 1 (PICK1), N-ethyl-maleimide-sensitive fusion protein (NSF). Here, peptides known to selectively block the above interactions were entrapped into synaptosomes to study the effects on the AMPA-evoked release of [3H]noradrenaline ([3H]NA) and [3H]acetylcholine ([3H]ACh) from rat hippocampal and cortical synaptosomes, respectively. Internalization of pep2-SVKI to prevent GluR2-GRIP/ABP/PICK1 interactions potentiated the AMPA-evoked release of [3H]NA but left unmodified that of [3H]ACh. Similar potentiation was caused by pep2-AVKI, the blocker of GluR2-PICK1 interaction. Conversely, a decrease in the AMPA-evoked release of [3H]NA, but not of [3H]ACh, was caused by pep2m, a selective blocker of the GluR2-NSF interaction. In the presence of pep2-SVKI the presynaptic AMPARs on noradrenergic terminals lost sensitivity to cyclothiazide. AMPARs releasing [3H]ACh, but not those releasing [3H]NA, were sensitive to spermine, suggesting that they are GluR2-lacking AMPARs. To conclude: (i) release-regulating presynaptic AMPARs constitutively cycle in isolated nerve terminals; (ii) the process exhibits neuronal selectivity; (iii) AMPAR trafficking and desensitization may be interrelated. 相似文献
18.
Helga Koch I. von Kügelgen Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1998,357(4):431-440
The aim of the study was to find out whether, and if so through which receptors, nucleotides modulate the release of noradrenaline
in the rat pancreas. Segments of the pancreas were preincubated with [3H]-noradrenaline, superfused with medium containing desipramine (1μM) and yohimbine (1μM), and stimulated electrically, in
most experiments by 60 pulses/1Hz.
The adenosine A1-receptor agonist N6-cyclopentyl-adenosine (CPA; EC50 32nM), the non-subtype-selective adenosine receptor agonists adenosine (EC50 15μM) and 5’-N-ethylcarboxamidoadenosine (NECA; EC50 135nM), and the nucleotides ATP (EC50 13μM), adenosine-5’-O-(3-thiotriphosphate) (ATPγS; EC50 19μM) and adenosine-5’-O-(2-thiodiphosphate) (ADPβS; EC50 16μM) decreased the evoked overflow of tritium. The adenosine A2A-agonist 2-p-(2-carboxyethyl)-phenethylamino-5’-N-ethylcarboxamido-adenosine (CGS 21680) caused no change. The concentration-response
curve of CPA was shifted to the right by the A1-antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX 10nM; pKd 9.1) but, like the concentration-response curve of adenosine, hardly affected by the P2-receptor antagonist cibacron blue
3GA (30μM). Combined administration of a high concentration of DPCPX (1μM) and 8-phenyltheophylline (10μM) abolished the effects
of CPA and NECA. The concentration-response curves of ATP and ADPβS were shifted to the right by both DPCPX (10nM; pKd 8.7 and 8.9, respectively) and cibacron blue 3GA (30μM; pKd 5.0 and 5.2, respectively). The antagonist effects of DPCPX (10nM) and cibacron blue 3GA (30μM) against ATP were additive
in a manner compatible with the blockade of two separate receptors for ATP. In the presence of the high concentration of DPCPX
(1μM) and 8-phenyltheophylline (10μM), ATP and ADPβS still decreased evoked tritium overflow, and this decrease was attenuated
by additional administration of cibacron blue 3GA (30μM). The P2-antagonists cibacron blue 3GA, reactive blue 2, reactive
red 2, and to a limited extent also suramin and 8-(3,5-dinitro-phenylenecarbonylimino)-1,3,5-naphthalenetrisulphonate (XAMR0721),
increased the evoked overflow of tritium by up to 114%. Pyridoxalphosphate-6-azophenyl-2’,4’-disulphonate (PPADS) caused no
change. The results indicate that the postganglionic sympathetic axons of the rat pancreas possess A1-adenosine and P2-receptors. Both receptors mediate an inhibition of noradrenaline release. The presynaptic P2-receptors are
activated by an endogenous ligand, presumably ATP, during appropriate trains of action potentials. This is the first demonstration
of presynaptic P2-receptors at postganglionic sympathetic neurons that are located in prevertebral ganglia.
Received: 6 November 1997 / Accepted: 6 January 1998 相似文献
19.
The influence of oxymetazoline and phentolamine on the overflow of noradrenaline evoked by potassium, tyramine and dimethylphenylpiperazinium (DMPP) was investigated in isolated perfused rabbit hearts.Oxymetazoline decreased, and phentolamine increased, the outflow of noradrenaline evoked by potassium. In hearts previously perfused with (?)-3H-noradrenaline, oxymetazoline reduced, and phentolamine enhanced, potassium-induced overflow of both 3H-noradrenaline and total tritium. These actions closely resemble previously described effects on noradrenaline overflow evoked by electrical stimulation of sympathetic nerves. At concentrations which modified the response to potassium, oxymetazoline and phentolamine did not influence the overflow evoked by tyramine. Both drugs diminished DMPP-induced overflow.It is concluded that oxymetazoline depresse noradrenaline release evoked by potassium or orthodromic action potentials through activation of neuronal α-adrenoceptors, followed by inhibition of electro-secretory coupling. Phentolamine blocks the analogous inhibitory effect of liberated noradrenaline and thus enhances release. The action of tyramine does not involve electro-secretory coupling and therefore is not changed. The influence of oxymetazoline and phentolamine on noradrenaline release by DMPP is not related to α-adrenoceptors. 相似文献
20.
Helga Koch I. von Kügelgen Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(6):707-715
Experiments on hippocampal slices were carried out in order to find out whether the release of noradrenaline in the hippocampus
can be modulated through P2-receptors. The slices were preincubated with [3H]-nor-adrenaline, superfused with medium containing desipramine (1 μM), and stimulated electrically, in most experiments
by 4 pulses/100 Hz. The adenosine A1-receptor agonist N6-cyclopentyl-adenosine (CPA) and the nucleotides ATP, adenosine-5’-O-(3-thiotriphosphate) (ATPγS) and adenosine-5’-O-(2-thiodiphosphate)
(ADPβS) decreased the evoked overflow of tritium by up to 55 %. The adenosine A2a-agonist 2-p-(2-carboxyethyl)-phenethylamino-5’-N-ethylcarboxamido-adenosine (CGS 21680; 0.003-0.3 μM) caused no change. The concentration-response
curve of CPA was shifted to the right by the A1-antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3 nM) but not by the P2-receptor antagonists cibacron blue 3GA (30
μM) and reactive blue 2 (30 μM); the apparent pKB value of DPCPX against CPA was 9.0. In contrast, the concentration-response curve of ATP was shifted to the right by DPCPX
(3 nM), apparent pKB 8.7, as well as by ciba-cron blue 3GA (30 μM), apparent pKB 5.2, and reactive blue 2 (30 μM), apparent pKB 5.6; the antagonist effects of DPCPX and cibacron blue 3GA were additive in a manner compatible with the blockade of two
separate receptors for ATP. The same pattern was obtained with ATPγS: its concentration-response curve was shifted to the
right by DPCPX as well as by cibacron blue 3GA and reactive blue 2. Suramin (300 μM) antagonized neither the effect of ATP
nor that of ATPγS. The 5’-nucleotidase inhibitor α,β-methylene-ADP (100 μM) did not change the effect of ATP. Only cibacron
blue 3GA (30 μM) but not reactive blue 2 (30 μM), given alone, consistently caused a small increase of the evoked overflow
of tritium. Hippocampal slices degraded exogenous ATP, and this degradation was reduced by cibacron blue 3GA (30 μM), reactive
blue 2 (30 μM) and suramin (300 μM). The results indicate that the noradrenergic terminal axons of the rat hippocampus possess
P2-receptors in addition to the known A1-adenosine receptors. The presynaptic P2-receptors mediate an inhibition of noradrenaline release, are activated by nucleotides
but not nucleosides, and are blocked by cibacron blue 3GA and reactive blue 2. ATP and ATPγS act at both the A1- and the P2-receptors. An autoreceptor function of cerebral presynaptic P2-receptors remains doubtful.
Received: 20 November 1996 / Accepted: 10 February 1997 相似文献