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1.
Michiko Shinkai Hiroko Tsuruoka Susumu Wakabayashi Yoshihisa Yamamoto Issei Takayanagi 《Naunyn-Schmiedeberg's archives of pharmacology》1994,350(1):63-67
Effects of endothelins (ETs) were studied in the rat iris sphincter preparation. Three peptides (ET1, ET-2 and ET-3) caused contractile responses, and the rank order of agonist potency was: ET-1 = ET-2 > ET-3. The concentration-response curve to ET-1 was shifted to the right by the ETA receptor antagonist cyclo [d-Asp-l-Pro-d-Val-l-Leu-d-Trp] (BQ-123: 10–7 M), the pA2 value of which was 7.41 ± 0.09 (n = 4).ET-1 and ET-3, at the concentration of 10–9 M, potentiated cholinergic contractions evoked by electrical field stimulation (5 and 20 Hz) without affecting the postjunctional sensitivity to carbachol. This potentiating effect was not influenced by BQ-123 (10–6 M). The ET-evoked percentage increase in the stimulation-induced contraction observed at 5 Hz was significantly greater than that at 20 Hz. A release of immunoreactive ET was detected when the preparation was stimulated at 20 Hz (1.81 ± 0.36 pg/sphincter n = 6). ET release evoked by 20 Hz stimulation was completely abolished by tetrodotoxin (10–7 M).In conclusion, ET interacts with two different receptor types, ETA and non-ETA receptors (probably ETB) which exist post- and presynaptically at cholinergic neuroeffector junctions of the rat iris preparation. Stimulation of ETA receptor results in a direct muscle contraction and non-ETA receptor activation facilitates the acetylcholine output from cholinergic nerve endings. It is suggested that ET released from a tetrodotoxin-sensitive site is involved in the modulation of acetylcholine release in the rat iris sphincter preparation.
Correspondence to: I. Takayanagi at the above address 相似文献
2.
M.J. Vaz-da-Silva S. Guimarães D. Moura 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(6):640-645
This study aimed at characterizing the influence of endothelium on noradrenaline release from the canine pulmonary artery. Tritium overflow from intact or endothelium-free vessels preloaded with 0.2 mol.1–1
3H-noradrenaline was evoked by electrical stimulation (1 Hz, during 5 min) or potassium (25–100 mmol. 1–1).The fractional release of tritium evoked by electrical stimulation was increased by removing the endothelium [from 1.7 (1.2; 2.4) to 2.7(2.3; 3.2) × 10–5. pulse–1, n = 10; P < 0.05]. Neither NG-nitro-l-arginine methyl ester (l-NAME) (up to 300 mol.l–1) nor indomethacin (up to 30 ml.l–1), nor endothelin-1 (up to 30 nmol.l–1), nor suramin (up to 300 mol.l–1) changed tritium release evolved by electrical stimulation. In contrast, the selective A1-adenosine antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (3.3-33 nmol.l–1) concentration-dependently increased, and the selective A1-adenosine agonist N6-cyclopentyladenosine (CPA) (3.3–100 nmol. l–1) concentration-dependently decreased the evoked release of noradrenaline. Since the effects of DPCPX were observed in endothelium-intact tissues only, it may be concluded that adenosine secreted by the endothelium activates prejunctional release-inhibiting A1-receptors. Tetraethylammonium (TEA) (3.3–33 mmol. l–1) enhanced tritium overflow evoked by electrical stimulation more in endothelium-free than in endothelium-intact vessels, indicating that some K+-channel opener is involved in the inhibitory role of endothelium on noradrenaline release. Since it had been previously shown that A1-adenosine receptors are coupled to K+-channels, it is suggested that adenosine may inhibit noradrenaline release through the opening of K+-channels.In conclusion, the results show that in the canine pulmonary artery, adenosine is a good candidate for the endothelium-dependent inhibitory factor which is responsible for the reduction of noradrenaline release evoked by electrical stimulation. 相似文献
3.
Héry F. Bourgoin S. Hamon M. Ternaux J. P. Glowinski J. 《Naunyn-Schmiedeberg's archives of pharmacology》1977,296(2):91-97
Summary The effects of various cholinergic agonists and antagonists on the spontaneous release of newly synthetized 3H-5-HT were examined in rat hypothalamic slices. 3H-5-HT was measured in incubating medium at the end of a 30 min incubation carried out with l-3H-tryptophan in the presence of the various durgs tested. ACh (10–5 M) in the presence of eserine (2×10–4 M), and carbachol (10–5 M) stimulated the release of 3H-5-HT. In contrast, oxotremorine (10–5 M) reduced the 3H-amine release. The effect of carbachol was blocked by two nicotinic blockers, mecamylamine (10–6 M) and d-tubocurarine (10–6 M). It was not reduced by the muscarinic antagonists, atropine (10–6 M) and scopolamine (10–6 M). In fact, each of two antagonists added alone to the incubating medium enhanced 3H-5-HT release. The scopolamine (10–6 M) stimulating effect on 3H-5-HT release was suppressed by d-tubocurarine (10–6 M). Finally, the inhibiting effect of oxotremorine on 3H-5-HT release was not prevented by d-tubocurarine (10–6 M) but was in the presence of atropine (10–6 M) or scopolamine (10–6 M).In the concentrations used in the release study, the cholinergic agonists and antagonists had no effect on the total formation of 3H-5-HT and 3H-5-HIAA from l-3H-tryptophan and on the accumulation of l-3H-tryptophan in tissues. In these concentrations, except for eserine, they did not affect the uptake of exogenous 3H-5-HT in hypothalamic synaptosomes (P2 fraction).These results suggest that cholinergic receptors of the muscarinic and nicotinic type are involved in the control of 3H-5-HT release; since the stimulation of the muscarinic and nicotonic cholinergic receptors resulted in an inhibition and an activation of 3H-5-HT release, respectively. As in the case of peripheral noradrenergic and central dopaminergic neurons the cholinergic receptors could be localized on serotoninergic terminals. 相似文献
4.
Dirk H. G. Versteeg Tamás Csikós Henk Spierenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(6):595-602
Summary The periaqueductal gray is a brain region of considerable interest. It is innervated by monoamine-containing neurons as well as by a variety of peptidergic fiber systems, and it participates in the regulation of various functions. Virtually nothing is known about monoamine release in the periaqueductal gray and its receptor-mediated modulation. We therefore studied the release of radioactivity from periaqueductal gray slices preloaded with tritriated monoamines, using an in vitro superfusion method.The release of radioactivity from superfused periaqueductal gray slices after preloading of the tissue with [3H]noradrenaline increased upon electrical stimulation in a frequency-dependent manner. The stimulus-evoked release of radioactivity was Ca2+-dependent. Clonidine reduced and yohimbine enhanced the release. The inhibition curve for the effect of clonidine was shifted to the right in the presence of 10–6 M yohimbine. While phenylephrine, isoprenaline, SK&F 38393, quinpirole, carbachol, [Arg8]vasopressin, -MSH and ACTH-(1-24), at a concentration of 10–6 M, did not influence the electrically evoked release of radioactivity, [Leu5]enkephalin reduced it. The selective -opioid receptor agonists [d-Ala2,NMePhe4,Gly-ol5]enkephalin and [d-Arg2,Lys4]-dermorphin-(1–4)-amide reduced the release of radioactivity, whereas the selective opioid receptor agonist [d-Pen2,d-Pen5]enkephalin and the selective K opioid receptor agonist U-69593 had no effect. In the presence of naloxone, which by itself had no effect on the release of radioactivity, the effect of [d-Arg2,Lys4]dermorphin-(1–4)-amide was abolished. These results show that the release of noradrenaline from periaqueductal gray slices is via a Ca2+-dependent. exocytotic process, and that it is modulated through 2-adrenoceptors as well as via -opioid receptors. Though the overflow of radioactivity from slices preloaded with [3H]dopamine in the presence of desipramine was measurable, there are reasons to assume that we are dealing here with the release of tritiated catecholamines from a population of nerve endings consisting of noradrenergic and dopaminergic terminals.The release of radioactivity from periaqueductal gray slices preloaded with [3H]5-hydroxytryptamine upon elevation of the K+ concentration in the superfusion medium was much more pronounced than that induced by electrical stimulation. The K+-evoked release of radioactivity was almost completely abolished in the absence of Cat2+; showing that the release is via a Ca2+-dependent process. 5-Hydrotryptamine reduced the K+-evoked release of radioactivity in a concentration-dependent manner.Some of these data were presented at the XIth International Congress of Pharmacology, 1–6 July 1990, Amsterdam, The Netherlands (Eur J Pharmacol 183:408)
Send offprint requests to D. H. G. Versteeg at the above address 相似文献
5.
Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase 总被引:4,自引:0,他引:4
Mariaemilia Bertolazzi Stefano Caroldi Angelo Moretto Marcello Lotti 《Archives of toxicology》1991,65(7):580-585
Methamidophos causes acute cholinergic toxicity in several species, including man, and organophosphate-induced delayed polyneuropathy which has been reported in man but not in the hen. Acetylcholinesterase (AChE) and neuropathy target esterase (NTE) are thought to be the molecular targets of acute and delayed toxicity, respectively. The rate constants of inhibition (ka) and reactivation (k+3) of human and hen brain AChE and NTE by methamidophos resolved optical isomers are here reported. NTE inhibition was progressive and irreversible. Human and hen NTE ka (M–1·m–1) ford-(+) methamidophos was 88 and 59, respectively, and forl-(–) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition.d-(+) methamidophos 10–3·ka (M–1·m–1) for human and hen AChE was 0.24 and 0.13; 103·k+3 (m–1) was 0.83 and 0.69, respectively,l-(–) Methamidophos 10–3·ka (M–1·m–1) for human and hen AChE was 5.7 and 2.8, whereas 103 · k+3 (m–1) was 6.50 and 1.52, respectively.l-(–)-Inhibited AChE reactivated to about 60% for human and 30% for hen enzymes, respectively.d-(+)-Inhibited AChE reactivated to about 10–20% for both species. Maximal reactivation occurred within 4–6 h when a plateau was reached. The larger and faster reactivation of human AChE inhibited in vitro byl-(–) methamidophos suggests that a corresponding effect might be possible in vivo and therefore explain, in part, the relatively higher susceptibility of man to delayed polyneuropathy induced by racemic methamidophos which occurs, however, with doses always causing severe cholinergic toxicity.Part of this work was presented at the 29th Annual Meeting of the Society of Toxicology, held in Miami FL, USA, February 1990. 相似文献
6.
Gary T. Shearman Rüdiger Schulz Peter W. Schiller Albert Herz 《Psychopharmacology》1985,85(4):440-443
Rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and the opioid kappa receptor agonist ethylketocyclazocine. After acquisition of this discrimination, generalization tests with opioid peptides such as -endorphin, -neoendorphin, dynorphin A and some dynorphin-derived peptides were conducted. The rats dose-dependently generalized the effects of intracerebroventricularly injected ethylketocyclazocine but not -endorphin, -neoendorphin, dynorphin A1–8, dynorphin A1–13, D-Cys2-L-Cys5-dynorphin A1–13 or dynorphin A.
D-Cys2-L-Cys5-dynorphin A1–13, in contrast to dynorphin A itself, dose-dependently caused analgesia and catatonia that was reversible with naloxone. Studies into the receptor preference of this derivative, using the technique of selective tolerance, revealed that this dynorphin derivative is almost devoid of kappa-receptor activity. 相似文献
7.
The effects of nitric oxide (NO) synthase inhibitors on the electrically evoked release of [3H]acetylcho-line were studied in guinea-pig myenteric plexus preparations preincubated with [3H]choline. NG-monomethyl-l-arginine (EC50 5.3 mol l–1) and NG-nitro-l-arginine (EC50 1.3 mol l–1) concentration-dependently increased the evoked release of [3H]acetylcholine without affecting the basal outflow. The facilitatory effect of NG-monomethyl-l-arginine was prevented by l-arginine but not by d-arginine. The results suggest that endogenous NO inhibits the depolarisation-evoked release of acetylcholine.
Correspondence to: H. Kilbinger at the above address 相似文献
8.
Summary In the mouse isolated vas deferens the amplitude of excitatory junction potentials (e.j.p.s) recorded intracellularly from smooth muscle cells varied with the strength of stimulation. Receptor type selective opioids were tested in this preparation. The -agonist normorphine (2,000 nmol/l) reduced the amplitude of e.j.p.s and shifted the stimulus-response curve in a parallel way to the right. By contrast, the -agonist U-50488 (1,000 nmol/l) and the -agonist [d-Ala2,d-Leu5]-enkephalin (2 nmol/l) caused a nonparallel shift of the curve. In addition, opioids having a lower selectivity for one type of receptor were also used. The preferential -agonists ethylketocyclazocine (40 nmol/l) and dynorphin A1–13 (100 nmol/l) produced parallel and nonparallel shifts, respectively. Thus, normorphine and ethylketocyclazocine were more effective in depressing e.j.p.s evoked by low intensities of stimulation than those evoked by high intensities of stimulation. U-50488, dynorphin A1–13 and [d-Ala2,d-Leu5]-enkephalin caused an equal depression of e.j.p.s evoked by either intensity of stimulation. The preferential - and -antagonists naloxone (1,000 nmol/l) and ICI 154129 (10,000 nmol/l), reversed the action of the respective agonists normorphine and [d-Ala2,d-Leu5]-enkephalin. In addition, ICI 154129 (10,000 nmol/l) reversed the action of dynorphin A1–13, as well. The preferential -antagonist MR-2266 (1,000 nmol/l) prevented the effect of both ethylketocyclazocine and U-50488. It is concluded that under the conditions of these experiments normorphine and ethylketocyclazocine acted at -, U-50488 at -, and dynorphin A1–13 and [d-Ala2,d-Leu5]-enkephalin at -receptors. In the mouse vas deferens more excitable fibres are probably equally sensitive to all three types of opioids, whereas less excitable fibres seem to be more sensitive to - and -, than to -agonists. 相似文献
9.
T. Halbrugge K. Lutsch A. Thyen K. -H. Graefe 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(6):720-727
Summary This study in the anaesthetized rabbit aimed at determining the role of nitric oxide (NO), the putative endothelium-derived relaxing factor, in the regulation of haemodynamics and the release into plasma of noradrenaline and adrenaline. Specific inhibition of NO formation was achieved by i.v. bolus injection of l-NG-monomethyl-arginine (l-NMMA; 3–100 mg kg–1). Phenylephrine was infused i.v. at constant rates (2.5–20 g kg–1 min–1) in order to assess baroreflex-mediated changes in release due to direct peripheral vasoconstriction. Rates of noradrenaline and adrenaline release into plasma were determined by the radio-tracer technique. l-NMMA, but not d-NMMA, dose-dependently increased mean arterial pressure and total peripheral vasular resistance, whereas both heart rate and cardiac output decreased concomitantly. The corresponding ED50 values for l-NMMA ranged from 11.2 to 18.5 mg kg–1. Inhibition of NO formation by l-NMMA as well as phenylephrine infusion caused decreases in the plasma clearance of noradrenaline and adrenaline which were correlated with the drug-induced decreases in cardiac output. Both l-NMMA and phenylephrine reduced the rate of noradrenaline release into plasma as they increased total peripheral resistance. Moreover, the curvilinear relationship between these two parameters obtained for l-NMMA was virtually identical to that produced by phenylephrine, indicating that the reduction in noradrenaline release by l-NMMA is mediated solely by the baroreflex. From the l-NMMA-induced maximum inhibition of noradrenaline release, it is concluded that the counter-regulation against peripheral vasodilation by NO accounts for 69% of basal noradrenaline release. The baroreflex-sensitive component of noradrenaline release, as determined by the maximum inhibition of release induced by phenylephrine, amounted to 83% of basal release. l-NMMA also reduced the release into plasma of adrenaline; the maximum inhibition of release was 52%. However, when related to total peripheral resistance, this inhibition of adrenaline release was more pronounced than that induced by phenylephrine, suggesting that the formation of endogenous NO facilitates the release of adrenaline.This study was supported by the Deutsche Forschungsgemeinschaft (Gr 490/5-3). A preliminary account of the present results was presented to the German Pharmacological Society (Halbrügge and Lütsch 1991)
Send offprint requests to T. Halbrügge at the above address 相似文献
10.
H. Kilbinger T. Ginap D. Erbelding 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(6):500-504
The effects of GABA receptor agonists were investigated on guinea-pig isolated ileum longitudinal muscle with intact myenteric
plexus. Electrical field stimulation (1 Hz, 10 s) of the histamine (1 μM)-precontracted preparation caused a contraction followed
by a relaxation. Relaxations were inhibited by l-N
G-nitro-arginine (l-NA; EC50 3 μM) in a concentration-dependent manner. The inhibitory action of 10 μM l-NA was blocked by 10 μM l-arginine but not by d-arginine, which indicates that the relaxation was largely mediated by endogenous nitric oxide (NO). Tetrodotoxin (1 μM) reduced
the relaxation only by about 50%. GABA and the GABAB agonist, baclofen, inhibited the field stimulation-induced longitudinal muscle relaxation in a concentration-dependent manner.
The GABAB receptor antagonist, saclofen (10 μM), antagonised the effect of baclofen (apparent pA
2 of saclofen: 5.6). Muscimol (10 μM) similarly inhibited the relaxation, and this inhibition was prevented by bicuculline
(1 μM). It is concluded that nitrergic nerves of the guinea-pig myenteric plexus are endowed with GABAA and GABAB receptors which mediate inhibition of NO release.
Received: 5 February 1999 / Accepted: 22 March 1999 相似文献
11.
Guido Maura Alessandra Barzizza Susanna Folghera Maurizio Raiteri 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(3):229-236
Summary The effects of 5-hydroxytryptamine (5-HT) and of a number of 5-HT receptor agonists and antagonists on the release of endogenous aspartate were investigated in rat cerebellum slices and synaptosomes depolarized with high K+. The release of endogenous aspartate evoked from slices by 35 mmol/l KCl and from synaptosomes by 15 mmol/1 KCl was strongly (about 90%) calcium-dependent. In slices the release of aspartate was inhibited by exogenous 5-HT (0.1–100 nmol/1) in a concentration-dependent manner. The indoleamine was very potent, producing 30% inhibition at 0.1 nmol/l. The effect of 10 nmol/1 5-HT was partly but maximally counteracted by ketanserin (300–1000 nmol/1), a 5-HT2 receptor antagonist, but fully blocked by 300 nmol/1 of the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibited the K+-evoked release of endogenous aspartate in a concentration-dependent manner. The effect of 8-OH-DPAT was antagonized by methiothepin, but not by ketanserin which fully antagonized the inhibition produced by DOI. In cerebellar synaptosomes the release of endogenous aspartate evoked by 15 mmol/l K+ was inhibited by exogenous 5-HT and by 8-OH-DPAT, but not by DOI. Methiothepin (100–300 nmol/1) antagonized the inhibitory effects of 100 nmol/l 5-HT or 8-OH-DPAT. However, 1000 nmol/l of various 5-HT receptor antagonists [ketanserin, methysergide, (–)-propranolol, spiperone or ICS 205–930] did not counteract the effect of 100 nmol/15-HT.It is concluded that: (1) 5-HT projections to the rat cerebellum may exert a potent inhibitory action on the depolarization-evoked release of aspartate; (2) this inhi bition is mediated through receptors of both the 5-HT1 and the 5-HT2 type; (3) the 5-HT2 receptors appear to be sited on structures which do not survive the standard preparation of synaptosomes, while the 5-HT1 receptors are likely to be localized on Apartate-releasing nerve terminals; and (4) the 5-HT1 receptors do not conform to the pharmacological criteria defining the known subtypes of the 5-HT1-binding sites. 相似文献
12.
Shigeo Kitayama Katsuya Morita Toshihiro Dohi Akira Tsujimoto 《Naunyn-Schmiedeberg's archives of pharmacology》1990,341(5):419-424
Summary The mode by which GABA facilitates the basal and stimulation-evoked catecholamine (CA) release from cultured bovine adrenal chromaffin cells was investigated. Muscimol, a GABAA receptor agonist, facilitated 45Ca uptake in a concentration-related manner. When GABA and acetylcholine (ACh) were simultaneously applied, additive increase in 45Ca uptake was observed. Similar effect on 45Ca uptake was observed in the presence of GABA and veratridine, although 45Ca uptake induced by a rather low concentration of veratridine was more than additively enhanced by GABA. GABA-evoked CA release was also more than additively enhanced by BayK 8644 whereas there was only an additive effect on 45Ca uptake. Substitution of extracellular Cl– by sucrose (low Cl– medium) during the stimulation with GABA enhanced GABA-evoked CA release. Substitution of extracellular Cl– for more than 1 h abolished GABA-evoked CA release and 45Ca uptake. At this time, the concentration-response curve for veratridine-evoked CA release was shifted to left and GABA no longer enhanced veratridine-evoked CA release at any concentration of veratridine. GABA-induced facilitation of 45Ca uptake in the presence of low concentration of veratridine was also inhibited by long-term treatment with low Cl– medium. These results suggest that the C–-dependent process linked to GABAA receptor acts on voltage-sensitive Ca2+ channels in chromaffin cells to elicit and modulate CA release.
Send offprint requests to A. Tsujimoto at the above address 相似文献
13.
Roland Seifert Rahel Burde Günter Schultz 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(1):101-106
Summary There are controversial reports in the literature concerning the effects of opioids on superoxide (O
2
–
) formation in phagocytes, these agents being either inhibitory or stimulatory. We re-examined this issue and compared the effects of the Chemotactic peptide, N-formyl-l,-methionyl-l-leucyl-l-phenylalanine (fMet-Leu-Phe), phorbol myristate acetate (PMA), ATP, platelet activating factor (PAF), cytochalasin B (CB) and prostaglandin E1 (PGE1) with those of various opioids on O
2
–
formation in human neutrophils and HL-60 leukemic cells under defined experimental conditions. In the presence of CB, fMet-Leu-Phe and PAF concentration-dependently activated O
2
–
formation in neutrophils with EC50 values of 20 nM and 100 nM, respectively. In the absence of CB, fMet-Leu-Phe and PAF were much less effective. PAF synergistically enhanced O
2
–
formation induced by fMet-Leu-Phe. ATP at a concentration of 100 M and the opioids, methionine enkephalin, -endorphin, dynorphin, [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, [d-Ala2-d-Leu5]-enkephalin and morphine at concentrations between 10 pM to 1 M did not activate O
2
–
formation. ATP but not \-endorphin potentiated fMet-Leu-Phe-induced O
2
–
formation. O
2
–
formation induced by a maximally stimulatory concentration of PMA (100 ng/ml) was enhanced by fMet-Leu-Phe but was unaffected by methionine enkephalin or PGE1. PMA at a non-stimulatory concentration (2 ng/ml) potentiated the effect of fMet-Leu-Phe but did not induce responsiveness to PAF, ATP or -endorphin. PGE1 strongly inhibited fMet-Leu-Phe-induced O
2
–
formation, whereas morphine, methionine enkephalin and the opioid antagonist, naloxone, were without effect. In HL-60 cells differentiated with dibutyryl cAMP, fMet-Leu-Phe, PAF and ATP but not -endorphin activated O
2
–
formation. Our results show that O
2
–
formation is differentially regulated by various classes of intercellular signal molecules and that opioids do not play a role in the regulation of O
2
–
formation. The precise definition of the experimental conditions and control experiments with established modulators of O
2
–
formation are essential to evaluate the role of opioids in the regulation of this effector system.Send offprint requests to R. Seifert at the above address 相似文献
14.
Summary The effects of three different opioid agonists on contractions and [3H]-acetylcholine (ACh) release evoked by 5-hydroxytryptamine3 (5-HT3) and neurokinin-3 (NK-3) receptor activation were examined in the guinea-pig ileum longitudinal muscle-myenteric plexus strip (LMMP) preparation. The selective mu ()-opioid receptor agonist (d-Ala2,NMe-Phe4,Gly-ol]-enkephalin) (DAMGO; 1 nM–100 nM) and the selective kappa ()-opioid receptor agonist U50488 (10 nM -1 M) inhibited contractile responses to 5-HT and to the selective NK-3 receptor agonist senktide, producing a concentration-related progressive flattening of their concentration-response curves. IC50 estimates for DAMGO and U50488 were somewhat higher for inhibition of 5-HT-evoked as compared to senktide-evoked contractions, and overall lay in the range 6 nM – 51 nM. The selective delta ()-opioid receptor agonist [d-Pen2,5]-enkephalin (DPDPE) inhibited contractile responses only at the highest concentration used (1 M).
3H-overflow from LMMP preparations preincubated with [3H]-choline was measured as an indicator of [3H]-ACh release. DAMGO (1 nM –100 nM) and U50488 (10 nM -1 M) inhibited the increases in release of [3H]-ACh evoked by 5-HT (10 M) and by senktide (10 nM) in a concentration-dependant manner. IC50 estimates for DAMGO and U50488 were not significantly different for inhibition of 5-HT as compared to senktide-evoked increases in [3H]-ACh release and lay in the range 6 nM –23 nM. DPDPE again only inhibited these responses at the maximum concentration used (1 M). The inhibitory effects of DAMGO, U50488 and DPDPE on contractions and [3H]-ACh release evoked by 5-HT and senktide were completely reversed by naloxone (10 M).These results show that ACh release in the guinea-pig ileum evoked by 5-HT and senktide can be modulated to a similar extent by the opioid agonists DAMGO and U50488, but not by DPDPE. This suggests that the pathways of excitation for 5-HT3 and NK-3 receptors converge at some level susceptible to opioid inhibition, which may be mediated by - and -, but not -, opioid receptors. 相似文献
15.
T. Sakurada Y. Manome K. Katsumata H. Uchiumi K. Tan-No S. Sakurada K. Kisara 《Naunyn-Schmiedeberg's archives of pharmacology》1992,346(1):69-75
Summary [d-Arg1, dTrp7,9, Leu11]-substance P (spantide) was tested for antagonism against the licking, biting and scratching response induced by various neurokinin (NK) receptor agonists and bombesin (Bom) in mice. When co-administered with substance P (SP) intrathecally, spantide reduced the SP-induced behavioural responses in a dose-dependent manner. The duration of this antagonistic effect was approximately 30 min. Behavioural responses induced by physalaemin (Phy), [pGlu6, l-Pro9]-SP (6–11) (septide), [pGlu6, d-Pro7]-SP (6–11) (d-septide) and eledoisin (Ele) were also dose-dependently decreased by relatively small doses of spantide. Higher doses of spantide were needed to reduce the behavioural responses induced by [Sar9, Met (O2)11]-SP, neurokinin A (NK A) and neurokinin B (NK B). No significant effect of spantide was observed against the behavioural responses elicited by Bom. Pretreatment with naloxone, an opioid antagonist, resulted in a reversible effect on the behavioural reduction of NK-2 and NK-3 receptor agonists produced by spantide. However, the effect of spantide on the NK-1 receptor agonist-induced response was unchanged by naloxone. In homogenates of mouse spinal cord, competition studies confirmed that the binding of the opioid ligand [3H]naloxone was displaced by spantide with a low but measurable affinity. These results suggest that the behavioural response to NK-2 and NK-3 receptor agonists may be partially inhibited by spantide through the activation of opioid system in the mouse spinal cord.
Send offprint requests to T. Sakurada at the above address 相似文献
16.
Summary Kainic acid (a rigid conformational analogue of glutamate), N-methyl-d-aspartate (the methylated derivative of aspartate), and (-)-nuciferine (an aporphine alkaloid with a depressant effect on glutamate-induced neuronal firing), which, so far, have been examined in microiontophoretic studies, were investigated in spinal cats for their effects on some spinal cord activities after intravenous injections.At low doses, kainic acid (0.3 mg kg–1) enhanced segmental monosynaptic but not polysynaptic ventral root reflexes and increased the excitability of motoneurones, whereas N-methyl-d-aspartate (3 mg kg–1) facilitated polysynaptic but not monosynaptic reflexes. Higher doses of the two amino acids depolarized motoneurones and primary afferent endings, enhanced monosynaptic reflexes and depressed polysynaptic reflexes.(-)-Nuciferine (1–10 mg kg–1) depressed monosynaptic but not polysynaptic ventral root reflexes in a dose-dependent manner and antagonized the effects of kainic acid but not of N-methyl-d-aspartate on the spinal cord.The results are consistent with the hypothetical excitatory transmitter role of glutamate in primary afferents and of aspartate in excitatory spinal cord interneurones; the findings also suggest that (-)-nuciferine may be used as a systemically effective, rather selective blocker of central glutamate receptors. 相似文献
17.
P. C. Waldmeier P. Wicki J. -J. Feldtrauer P. A. Baumann 《Naunyn-Schmiedeberg's archives of pharmacology》1989,339(1-2):200-207
Summary The previously reported inhibitory effect of (–)-baclofen on the electrically evoked release of endogenous GABA from rat brain slices indicated the possibility of existence of GABAB autoreceptors. In this study, we have tested an alternative explanation, i. e. the possibility that (–)-baclofen reduced an excitatory glutamatergic input to GABAergic neurons by inhibiting glutamate release, by investigating the interaction of 10 mmol/1 l-glutamate with the inhibitory effect of 10 mol/1(–)-baclofen. l-Glutamate did not affect the electrically evoked release of GABA on its own and did not abolish the effect of (–)-baclofen, suggesting that the latter was not secondary to a reduction of glutamate release. On the other hand, it greatly increased the basal release of GABA and more than doubled the GABA content of the slices at the end of the perfusion, indicating a marked enhancement of GABA synthesis. This additional GABA, apparently formed from exogenous l-glutamate, was not releasable by electrical stimulation at 0.5 or 24 Hz, but at least in part by stimulation with 30 mmol/l K+. The previously reported increase of GABA release at 12 Hz as compared to 4 Hz was studied in more detail. GABA released by electrical stimulation at 8–48 Hz was Ca2+-dependent and tetrodotoxin-sensitive. No evidence was obtained for a decrease of the amount of GABA released per impulse with increasing frequency in this range. Moreover, neither (–)-baclofen nor muscimol at 10 mol/l altered the release of the amino acid at 24 Hz; the former was also tested at a low Ca2+ concentration (0.3 mmol/l) and found to be inactive under these conditions. Thirty mmol/l K+ released about 30% higher amounts of GABA than electrical stimulation at 24 Hz under comparable conditions, in a Ca2+-dependent manner. K+-induced release was not modified by 10 mol/l (–)-baclofen or muscimol. Our results suggest the existence of at least 2 different, presumably neuronally located, releasable pools of GABA. One is sensitive to electrical stimulation at 0.25–4 Hz and responds to (–)-baclofen, suggesting control by GABAB-type autoreceptors. The existence of a 2nd pool is indicated by the fact that K+ releases substantially more GABA than electrical stimulation and by the exclusive sensitivity of K+-evoked GABA release to exogenous l-glutamate. GABA released by electrical stimulation at frequencies above 4 Hz may come from a 3rd pool. Both the 2nd and the 3rd pool seem to be insensitive to (–)-baclofen and muscimol.
Send offprint requests to P. C. Waldmeier at the above address 相似文献
18.
B. P. Imbimbo T. Mant M. Edwards D. Amin N. Dalton F. Boutignon V. Lenaerts P. Wüthrich R. Deghenghi 《European journal of clinical pharmacology》1994,46(5):421-425
Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml–1 after 0, 0.5, 1 and 2 g·kg–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml–1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 g·kg–1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml–1 and 3936 ng·min·ml–1, thus indicating that the effect after the 2 g·kg–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations. 相似文献
19.
The present study assessed the discriminative stimulus effects of the delta-opioid agonist [d-Pen2-d-Pen5]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 µg [d-Pen2-d-Pen5]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [d-Ser2, Leu5, Thr6]enkephalin (DSLET) and [d-Ala2]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the mu-opioid agonists, DAMGO (0.1–3.2 µg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for deltaopioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE's discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo. 相似文献
20.
Summary Due to a lack of l-Dopa-decarboxylase, the mouse neuroblastoma clone N1E-115 contains a high intracellular Dopa-content compared to a low noradrenaline- and dopamine-content. Because of this decarboxylase deficiency, the N1E-115 clone releases more than 95% of the produced Dopa into the culture medium. After renewal of the culture medium, Dopa production of the cells can be measured by the increase of Dopa in the medium. Dopa production was linear during 2 h and varied from 50–180 g x mg prot–1 x h–1 between different subcultures. Dopa release into the medium was used as an indirect measure for the tyrosine-hydroxylase activity. Several dopaminergic agonists and antagonists were tested. Dopa production could be blocked dose-dependent by apomorphine (1×10–7–1×10–6M), but not by lisuride hydrogen maleate and bromocryptine. Several dopaminergic and adrenergic antagonists failed to reverse the apomorphine induced blockade of the tyrosine-hydroxylase activity. 相似文献