共查询到20条相似文献,搜索用时 31 毫秒
1.
C. Damase-Michel M. A. Tran M. E. Llau F. Chollet J. M. Senard B. Guiraud-Chaumeil J. L. Montastruc P. Montastruc 《European journal of clinical pharmacology》1993,44(2):199-201
Summary We have studied the sympathetic response to blockade of presynaptic 2-adrenoceptors in essential hypertension by measuring plasma concentrations of noradrenaline after a single oral dose of yohimbine, an 2-adrenoceptor antagonist.Mean baseline plasma noradrenaline and adrenaline concentrations were similar in the hypertensive and normotensive groups. Yohimbine (0.2 mg×kg–1 orally) caused a lesser increase in the plasma concentrations of noradrenaline in hypertensive patients (+67%) than in normotensive subjects (+178%) and a pressor response in hypertensive (but not in normotensive) patients.These results are consistent with an alteration in the balance of -adrenoceptors (for example presynaptic 2-adrenoceptor desensitization and post-synaptic 1-adrenoceptor hyper-responsiveness) which would help to develop and/or maintain arterial hypertension. 相似文献
2.
N. Decker J. D. Ehrhardt G. Leclerc J. Schwartz 《Naunyn-Schmiedeberg's archives of pharmacology》1984,326(1):1-6
Summary The postsynaptic -adrenoceptors in rat aorta and in pithed rat were investigated according to their sensitivity to nine -adrenergic agonists and to the selective antagonists yohimbine (2) and prazosin (1) and the non-selective one, phentolamine. In addition, in radioligand binding studies, the affinity and selectivity of the drugs were determined on rat cerebral cortex using [3H] yohimbine and [3H] prazosin.On rat aorta, prazosin is 1,000 times more potent than yohimbine against each -adrenoceptor agonist, whether 1- or 2-selective. Rat aorta probably contains only 1-adrenoceptors.Pressor effects in pithed rats are mediated by post-junctional 1- and 2-adrenoceptors. The dose-response curve for -methylnorepinephrine in the presence of prazosin, using Hofstee's plots, revealed 1- and 2-adrenoceptors, respective proportions being 80.5 and 19.5% 相似文献
3.
Ikunobu Muramatsu Tsuyoshi Ohmura Shigeru Kigoshi 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(1):2-9
The effects of a newly synthesized compound, PNO-49B, (R)-(-)-3-(2-amino-l-hydroxyethyl)-4-fluo-romethanesulfonanilide hydrochloride, on 1-adrenocepfor subtypes were examined in various tissues in which the following distribution of 1-adrenoceptor subtypes has been suggested: dog carotid artery (1B), dog mesenteric artery (1N), rabbit thoracic aorta (1B + 1L), rat liver (1B), rat vas deferens (1A + 1L), rat cerebral cortex (1A + 1B) and rat thoracic aorta (controversial subtype).PNO-49 B (0.1–100 M) produced concentration-dependent contractions in dog mesenteric artery, rabbit thoracic aorta, rat thoracic aorta and rat vas deferens; and the maximal amplitudes of contraction were almost the same as or slighly less than those of noradrenaline. By contrast, the maximal response to PNO-49 B in dog carotid artery was markedly smaller than the response to noradrenaline. In rabbit thoracic aorta, the contractile response to PNO-49 B was not affected by inactivation of the 1B subtype with chloroethylclonidine (CEC), although the response to noradrenaline was attenuated by that treatment. The dissociation constants (KA) of PNO-49 B were not different among the rat thoracic aorta, dog carotid and mesenteric arteries and rabbit thoracic aorta (CEC-pretreated). The contractile responses to PNO-49 B were inhibited competitively by prazosin, HV723 (-ethyl-3,4,5-trimethoxy--(3-((2-(2-methoxy-phenoxy)-ethyl)))-amino(propyl)benzeneacetonitrile fumarate) and by WB4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane). The estimated pA2 values were high for prazosin and WB4101 in rat thoracic aorta and for HV 723 in dog mesenteric artery, whereas the pA2 values for these three antagonists in rabbit thoracic aorta were low and were not altered by pretreatment with CEC. The binding of [3H]-prazosin to membranes prepared from rat vas deferens and liver was inhibited by PNO-49 B in a concentration-dependent manner. The resulting pK1 value for the liver was approximately 1.5 log units lower (one thirtieth in affinity) than the values for the epididymal and prostatic portions of the vas deferens. PNO-49B also inhibited biphasically [3H]prazosin binding to prazosin-high affinity sites of rat cerebral cortex membranes, and the low but high affinity sites for PNO-49B was abolished by CEC-pretreatment. PNO-49B had no effect on the prejunctional 2-adrenoceptors in rat vas deferens (prostatic portion) nor on the -adrenoceptors in rat atria. The contractile response to PNO-49 B in rat thoracic aorta was not inhibited by cimetidine, pyrilamine or ketanserin.These results indicate that PNO-49B is an 1-adrenoceptor agonist with a lower affinity and/or efficacy at the 1B subtype as compared with other 1-subtypes. 相似文献
4.
Clemens Allgaier Holger Repp Georg Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1993,348(1):14-20
Summary The question whether presynaptic 2-adrenoceptors regulating noradrenaline release in hippocampus directly couple to tetraethylammonium chloride (TEA) or -dendrotoxin (-DTX)-sensitive K+ channels was investigated. Hippocampal slices, prelabelled with [3H] noradrenaline, were superfused in the presence of (+)-oxaprotiline and electrically stimulated with 4 pulses delivered at 100 Hz, in order to avoid autoinhibition due to released noradrenaline.TEA enhanced the evoked [3H]noradrenaline release in rabbit hippocampus in a concentration-dependent manner, yielding an approximately 4-fold increase at 30 mmol/l, whereas the spontaneous outflow of tritium was only slightly affected at this concentration. The 2-adrenoceptor agonist clonidine, at 10–100 nmol/l inhibited the evoked [3H]noradrenaline release between 77% and 96%. The inhibitory effect of the 2-agonist was distinctly diminished in the presence of 30 mmol/l TEA but was restored in low Ca2+/high Mg2+ buffer. Therefore, the diminution of the 2-agonist effect by TEA observed in experiments with normal Ca2+ can be explained by an increase of the Ca2+ availability for the release process due to the prolongation of action potentials. In rabbit hippocampus -DTX (10–200 nmol/l) did neither affect the evoked release of [3H]noradrenaline nor its 2-agonist-induced modulation. However, in rat hippocampus -DTX significantly increased the evoked transmitter release and diminished the effect of clonidine.Taken together, the present data for the rabbit hippocampus exclude the possibility that activation of presynaptic 2-adrenoceptors inhibits depolarization-evoked [3H]noradrenaline release by inducing an outward K+ current through TEA- or -DTX-sensitive K+ channels. However, there are species differences between the rabbit and the rat so that in the rat the 2-adrenoceptors could actually be coupled to K+ channels — provided that the release-enhancing properties of -DTX do not account for the 2-antagonism observed.Correspondence to C. Allgaier at the above address 相似文献
5.
G. M. Drew 《Naunyn-Schmiedeberg's archives of pharmacology》1982,319(3):222-225
Summary The -adrenoceptor blocking potency of WB 4101 at 1- and 2-adrenoceptors has been investigated in pithed rats.WB 4101 was approximately 97 times more potent at antagonizing the vasopressor responses produced by the selective 1-adrenoceptor agonist phenylephrine, than those produced by the selective 2-adrenoceptor agonist M-7.A dose of WB 4101 (3 mg/kg) that caused extensive blockade of vascular 1-adrenoceptors, but little or no blockade of vascular 2-adrenoceptors, exerted no significant blockade of the presynaptic 2-adrenoceptors in the rat heart.The results support the view that WB 4101 is a highly selective antagonist at 1-adrenoceptors in vivo. 相似文献
6.
Summary Rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline were used to investigate whether the NMDA-evoked noradrenaline release is modulated by agonists or antagonists at presynaptic 2-adrenoceptors.In experiments on slices, noradrenaline and the preferential 2-adrenoceptor agonists talipexole (former B-HT 920) and clonidine inhibited the NMDA evoked tritium overflow whereas the selective 1-adrenoceptor agonists cirazoline and methoxamine were ineffective. The 2-adrenoceptor antagonists rauwolscine and idazoxan facilitated the NMDA-evoked tritium overflow whereas the preferential 1-adrenoceptor antagonist prazosin was ineffective. The concentration-response curve of talipexole for its inhibitory effect on NMDA-evoked overflow was shifted to the right by idazoxan (apparent pA2 = 7.5). The EC50 of NMDA (97 mol/l) for its stimulating effect on tritium overflow was not substantially changed by blockade of 2-autoreceptors with 1 mol/l rauwolscine (EC50 of NMDA in the presence of the 2-adrenoceptor antagonist, 155 mol/l), but the maximal overflow of tritium was increased 2.5 fold by this rauwolscine concentration. In experiments on synaptosomes, talipexole and noradrenaline inhibited the NMDA-evoked tritium overflow. The inhibitory effect of talipexole was abolished by idazoxan which, given alone, was ineffective, as was prazosin. Talipexole did also not produce an inhibition when tritium overflow was evoked by NMDA in the presence of -conotoxin GVIA 0.1 mol/l; the latter, by itself, decreased the response to NMDA by about 55%. It is concluded that the NMDA-evoked noradrenaline release in the cerebral cortex is modulated via presynaptic 2-adrenoceptors on the noradrenergic neurones. Stimulation of these autoreceptors in slices by endogenous noradrenaline does not result in a decreased potency of NMDA, but in a decreased maximum effect, in stimulating noradrenaline release. The inhibitory effect of 2-adrenoceptor agonists on the NMDA-evoked release is at least partially due to a functional interaction between the NMDA receptors and 2-autoreceptors at the level of the same varicosities. The results obtained with -conotoxin GVIA suggest that Ca2+ influx via the N-type voltage-sensitive calcium channel (VSCC) occurs in response to NMDA receptor stimulation and contributes substantially to the induction of NMDA-evoked noradrenaline release. The inhibitory effect of 2-adrenoceptor stimulation on this release appears to be ultimately due to an inhibition of the influx of Ca2+ via the N-type VSCC.
Correspondence to: M. Göthert at the above address 相似文献
7.
S. J. Bill A. Boniface F. Haroun R. P. McAdams N. Lattimer K. F. Rhodes 《Naunyn-Schmiedeberg's archives of pharmacology》1986,334(4):418-422
Summary Wy 27127 and idazoxan were approximately equipotent as antagonists at
2-adrenoceptors as estimated by their ability to block clonidine-induced inhibition of electrically-evoked contractions of the rat isolated vas deferens.Idazoxan was seven times as potent as Wy 27127, as an antagonist at
1-adrenoceptors as indicated by blockade of methoxamine-induced contractions of the rat isolated anococcygeus muscle.Thus, the
2:
1 selectivity ratio, as calculated from these tests was 407 for Wy 27127 and 76 for idazoxan.Wy 27127 and idazoxan were equipotent in enhancing stimulation-evoked overflow of tritium from rabbit isolated pulmonary arteries preloaded with [3H]-noradrenaline as expected for
2-adrenoceptor antagonists. At higher concentrations both compounds reduced the stimulation-evoked contraction of the pulmonary artery but idazoxan was 15 times as potent as Wy 27127 in this respect.Neither compound had marked antagonist actions at 5-hydroxytryptamine (D), muscarinic, presynaptic dopamine or histamine (H1) receptors or at
1-adrenoceptors.Thus, idazoxan and Wy 27127 were equipotent
2-adrenoceptor antagonists in vitro, however, the
2:
1 selectivity of Wy 27127 was considerably greater than that of idazoxan by virtue of weaker
1-adrenoceptor antagonism. 相似文献
8.
S. Boehm S. Huck H. Drobny E.A. Singer 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(5):606-609
Summary Effects of 2-adrenoceptor agonists on whole-cell Ca2+ currents and 3H-noradrenaline release were investigated by applying the patch-clamp technique and electrical field stimulation to cultured embryonic chick sympathetic neurons. A 24-h exposure of the sympathetic neurons to pertussis toxin (100 ng/ml) abolished both the 2-adrenoceptor-mediated inhibition of Ca 2+ currents and the modulation of noradrenaline release caused by noradrenaline (1 mol/l; in the presence of 10 mol/l cocaine) or the 2-adrenoceptor agonists 5-bromo-6-(2imidazolin-2-ylamino)quinoxaline (UK 14,304, 10 mol/ l) and clonidine (10 mol/l). These results suggest that the 2-autoreceptor-mediated inhibition of noradrenaline release from chick sympathetic neurons operates through the modulation of Ca2+ channels via pertussistoxin-sensitive GTP-binding-proteins.
Send offprint requests to S. Boehm at the above address 相似文献
9.
M. Raiteri G. Maura S. Folghera P. Cavazzani G. C. Andrioli E. Schlicker R. Schalnus M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(5):508-512
Summary Slices and synaptosomes from human cerebral cortex (which had to be removed to reach deeply located tumours) and, for comparison, synaptosomes from guinea-pig and rat cerebral cortex were preincubated with [3H]5-hydroxytryptamine and superfused with physiological salt solution containing an inhibitor of 5-hydroxytryptamine uptake. The effects of -adrenoceptor agaonists and antagonists on the electrically (slices) or potassium-evoked (synaptosomes) tritium overflow were studied.In human cerebral cortical slices, the electrically-evoked [3H] overflow was inhibited by noradrenaline (pIC25 value: 6.35); the non-selective -adrenoceptor antagonist phentolamine, at a concentration of 0.32 mol/l, strongly antagonized the inhibitory effect of noradrenaline (apparent pA2 value: 8.19) but did not affect the evoked overflow by itself. In synaptosomes from humans, guinea-pigs and rats, noradrenaline also inhibited the K+-evoked[3H] overflow in a concentration dependent manner; the 2-adrenoceptor clonidine (1 mol/l), but not the 1-adrenoceptor agonist methoxamine (1 mol/l), mimicked the effects of noradrenaline; the effect of noradrenaline (0.3 mol/l) was abolished by the 2-but not by the 1-adrenoceptor antagonist prazosin (1 mol/l).It is concluded that release-inhibiting adrenoceptors of the 2-subtype exist on 5-hydrpxytryptamine terminals innervating the cerebral cortex in human and guinea-pig brain.Send offprint requests to M. Raiteri at the above address 相似文献
10.
Summary Experiments were designed to unravel the relative contribution of 1- and 2-adrenoceptors to the positive inotropic effects of adrenaline and noradrenaline in isolated tissues of left ventricular myocardium of man. We also analyzed relationships between the fractions of human left ventricular 1- and 2-adrenoceptors, estimated from binding assays, and stimulation of adenylate cyclase and contractile force by adrenaline and noradrenaline. 1) Selective blockade of 2-adrenoceptors by erythro(±)-(-methyl-indan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118,551) attenuated the increase of contractile force caused by adrenaline but not by noradrenaline, suggesting some involvement of 2-adrenoceptors. Selective blockade of 2-adrenoceptors without affecting 1-adrenoceptors still enabled both adrenaline and noradrenaline to cause maximum possible increases of contractile force through 1-adrenoceptors. 2) A direct involvement of 2-adrenoceptors became manifest by selectively antagonizing 1-adrenoceptors by 1-[2((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]3-[4(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol (CGP 20712 A) without affecting 2-adrenoceptor. 2-adrenoceptors can mediate half of the maximum increase of contractile force elicited by low concentrations of adrenaline and also contribute to the increase of contractile force caused by high concentrations of noradrenaline. 3) -adrenoceptors were labelled in membrane particles with 3H-(–)-bupranolol in the absence (1 & 2) and presence of 500 nmol/l CGP 20712 A (2). 71 % of the -adrenoceptors Were 1 and 29% 2. Binding inhibition experiments with CGP 20712 A and ICI 118,551 yielded 74% 1 and 26% 2-4) With the help of ICI 118,551 and CGP 20712 A it was found that, in membrane particles, 33–36% and 64–67% of maximum stimulation of the adenylate cyclase by noradrenaline was mediated through 1- and 2-adrenoceptors, respectively. Adrenaline caused 11–25% and 75–89% of maximum cyclase stimulation through 1- and 2-adrenoceptors, respectively. 5) The contribution of 1- and 2-adrenoceptors to the positive inotropic effects of adrenaline and noradrenaline cannot be inferred straightforwardly from biochemical estimates of receptor fractions and fractional adenylate cyclase stimulation.
Send offprint requests to A. J. Kaumann, ICI Pharmaceutical Division, Mereside Alderley Park, Macclesfield, Cheshire SK10 4TG, UK 相似文献
11.
Marco Gobbi Emanuela Frittoli Tiziana Mennini 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(4):382-386
Summary The present study aimed at relating the presynaptic 2-adrenoceptors, known to modulate noradrenaline and serotonin release, with the recently described 2A- and 2B-adrenoceptor subtypes. The effects of the agonist oxymetazoline (selective for 2A subtype) and of three adrenoceptor antagonists (idazoxan, 1-(2-pyrimidinyl)piperazine (PmP) and prazosin, the last one known to be 2B selective) were evaluated on [3H]noradrenaline and [H]serotonin release in superfused synaptosomes from rat brain cortex. These drugs were also tested in [3H]yohimbine binding to human platelet membranes (containing only 2A receptors) and to neonatal rat lung membranes (containing only 2B receptors).The affinity pattern of these compounds at 2A-adrenoceptors in binding studies was oxymetazoline > = idazoxan > PmP > prazosin; at 2B-adrenoceptors it was idazoxan > = prazosin > PmP = oxymetazoline. Oxymetazoline inhibited with high and similar potencies the K+-evoked [3H]noradrenaline and [3H]serotonin release, IC50 18 and 7 nM, respectively; in the same conditions, the IC50 values of noradrenaline were 42 and 168 nM, respectively. The antagonist affinity pattern (antagonism against noradrenaline) was idazoxan > PmP > prazosin, either on [3H]serotonin release.These results indicate that presynaptic 2 auto- or heteroreceptors do not belong to the 2B subtype and suggest that the modulation of noradrenaline and serotonin release may be mediated by the 2A-adrenoceptor subtype.
Send offprint requests to M. Gobbi at the above address 相似文献
12.
J. R. Docherty J. W. Constantine K. Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1981,317(1):5-7
Summary We have investigated the residual contractile response to noradrenaline remaining after phenoxybenzamine (3×10–7 mol/l) in rabbit aorta, since it has been reported that phenoxybenzamine at low doses completely and irreversibly blocks 1- but not 2-adrenoceptors. The contraction elicited by noradrenaline slowly recovered with time after it had been almost abolished by phenoxybenzamine. This residual response was blocked by the 1-selective antagonist prazosin (3×10–8 mol/l) but not by the 2-selective antagonist rauwolscine (3×10–7 mol/l). The results confirm that the smooth muscle of rabbit aorta contains 1- not 2-adrenoceptors. 相似文献
13.
Summary Previous studies have shown that a low dose of the alkylating compound N-ethoxycarbonyl-2-ethoxy1,2-dihydroquinoline (EEDQ) reduces the density of 2-adrenoceptors in rat cerebral cortex and antagonizes the effects of an 2-adrenoceptor agonist on noradrenaline release in rat cortical slices. In the present study, a corresponding dose of EEDQ (1 mg/kg, s. c., 24 h) was shown to reduce the effect of the 2-adrenoceptor agonists clonidine and guanfacine on noradrenaline turnover in rat brain while not affecting the inhibitory effect of clonidine on locus coeruleus (LC) cell firing. When considerably higher doses of EEDQ were administered (10 and 20 mg/kg, s. c., 24 h) not only the biochemical but also the electrophysiological effects of clonidine were markedly reduced (or even reversed). The data support the notion that EEDQ decreases the responsiveness of brain 2-adrenergic receptors; moreover, they indicate that 2-adrenoceptors regulating LC activity are characterized by a larger receptor reserve or are less sensitive to the influence of alkylation than are the population of 2-adrenoceptors regulating noradrenaline utilization.
Send offprint requests to G. Engberg, at the above address 相似文献
14.
Ludwig Funk Anne-Ulrike Trendelenburg Norbert Limberger Klaus Klaus 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(1):58-66
The study was designed to classify in terms of 2A, 2B, 2C and 2D the presynaptic 2-autoreceptors, as well as the 2-receptors modulating the release of acetylcholine, in the myenteric plexus-longitudinal muscle (MPLM) preparation of the guinea-pig ileum. A set of antagonists was chosen that was able to discriminate between the four subtypes. Small pieces of the MPLM preparation were preincubated with 3H-noradrenaline or 3H-choline and then superfused and stimulated electrically.The stimulation periods used (3H-noradrenaline: 3 trains of 20 pulses, 50 Hz, train interval 60 s; 3H-choline: single trains of 30 pulses, 0.2 Hz) did not lead to 2-autoinhibition or inhibition of 3H-acetylcholine release by endogenous noradrenaline. The 2-selective agonist 5-bromo6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced the evoked overflow of tritium in both 3H-noradrenaline and 3H-choline experiments. Most (3H-noradrenaline) or all (3H-choline) of the 10 antagonists shifted the concentration-inhibition curves of UK 14,304 to the right. pKd values of the antagonists were calculated from the shifts. pKd values from 3H-noradrenaline experiments correlated with pKd values from 3H-choline experiments (r = 0.981).It is concluded that 2-autoreceptors and 2-heteroreceptors modulating the release of acetylcholine in the MPLM preparation are of the same subtype. Comparison with antagonist affinities for prototypic native 2 binding sites, binding sites in cells transfected with 2 subtype genes, and previously classified presynaptic 2-adrenoceptors — all taken from the literature — indicates that both are 2D. The results are consonant with the hypothesis that at least the majority of 2-autoreceptors belong to the 2A/D branch of the 2-adrenoceptor tree, across mammalian or at least across rodent and lagomorph species. The same may hold true for 2-adrenoceptors on non-noradrenergic neurones. 相似文献
15.
Vladimír Palatý 《Naunyn-Schmiedeberg's archives of pharmacology》1996,353(4):431-437
The macrolide antibiotic bafilomycin A1, a selective inhibitor of the vesicular H+-transporting ATPase, increased irreversibly the overflow of 3,4-dihydroxyphenylethylene glycol from isolated segments of the rat tail artery. Maximum increase in the overflow was produced by exposing the tissues to 0.5 mol/l bafilomycin As. Unless the Na–-dependent neuronal amine carrier (uptake1) was inhibited, overflow of noradrenaline was below the detection limit. The bafilomycin As-induced increase in overflow of noradrenaline from tissues with inhibited uptakes was accompanied by a significant decrease in the (noradrenaline overflow:glycol overflow) ratio. Unlike reserpine and tetrabenazine, the antibiotic did not alter the (noradrenaline overflow:glycol overflow) ratio in arteries incubated in Ca2+-free, 120 mmol/1 K+ medium.Bafilomycin A1 increased overflow of noradrenaline and normetanephrine from tissues with inhibited monoamine oxidase. Inhibitors of extraneuronal catecholamine transport (uptake2), corticosterone, 3-O-methylisoprenaline and 1,1-diethyl-2,2-cyanine, suppressed overflow of normetanephrine while increasing that of noradrenaline. Further increase in overflow of noradrenaline was produced by concomitant inhibition of uptake1. A similar effect was observed in tissues previously exposed to phenoxybenzamine. After exposure to bafilomycin As, tyramine and (+) amphetamine (10 mol/l) were equally effective in increasing overflow of noradrenaline from tissues with inhibited monoamine oxidase into corticosterone-containing medium.Bafilomycin A1 promotes leakage of noradrenaline from storage vesicles without affecting its conversion to 3,4-dihydroxyphenylethylene glycol. When uptake1 is inhibited, axoplasmic noradrenaline can be translocated effectively across the axonal membrane by the diffusional efflux. When uptakes is inhibited, spontaneous quantal release contributes significantly to overflow of noradrenaline into normal media. The diffusional efflux of noradrenaline is unaffected by inhibitors of uptake2. Even at highly elevated concentrations of axoplasmic noradrenaline, the uptake1-mediated influx of noradrenaline exceeds the uptake1-mediated efflux. Enhancement of noradrenaline overflow from tissues with inhibited monoamine oxidase by indirectly acting sympathomimetic amines depends primarily on their ability to induce leakage of the transmitter from storage vesicles rather than its translocation across the axonal membrane. 相似文献
16.
Rainer Schulz Ron J. Oudiz Brian D. Guth Gerd Heusch 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(4):422-428
Summary -Adrenoceptor-mediated coronary vasoconstriction contributes to the initiation and aggravation of experimental and clinical myocardial ischaemia. However, the extent of 1- and 2-adrenoceptor-mediated constriction has not been characterized in the porcine coronary circulation despite the frequent use of this experimental model.Fifteen swine were anaesthetized with either -chloralose, enflurane or isoflurane to determine the amount of -adrenoceptor-mediated coronary constriction elicited by either the selective 1-adrenoceptor agonist methoxamine or the selective 2-adrenoceptor agonist azepexole. The left anterior descending coronary artery was cannulated and perfused by an external pump delivering constant blood flow from the carotid artery. Following bilateral cervical vagotomy and ß-adrenoceptor blockade with propranolol (2 mg kg–1), graded dosages of either one of the -adrenoceptor agonists (9–45 g kg–1 min–1) were infused into the coronary perfusion line while coronary arterial pressure (CAP) was measured through a distal side arm of the cannula to detect changes in coronary vascular resistance. Infusion of the -adrenoceptor agonists was terminated when systemic arterial pressure increased. Sonomicrometers were used to measure anterior left ventricular wall thickening for the assessment of regional contractile function. During methoxamine infusion, no increase in vascular resistance was observed during -chloralose, enflurane or isoflurane anaesthesia, whereas the infusion of azepexole increased CAP from 103 ± 31 mmHg to 120 ± 35 mmHg (-chloralose), from 101 ± 16 mmHg to 122 ± 11 mmHg (enflurane) and from 84 ± 20 mmHg to 94 ± 19 mmHg (isoflurane), respectively. In four additional swine anaesthetized with enflurane, the intracoronary infusion of the full catecholamine agonist noradrenaline in the presence of propranolol (6 mg kg–1) increased CAP from 98 ± 10 to 105 ± 10 mmHg prior to an increase in regional left ventricular function or systemic arterial pressure.These results indicate that there are no 1- and relatively little 2-adrenoceptor-mediated coronary constrictive effects in swine. Furthermore, neither -adrenoceptor agonist produced any detectable change in regional myocardial contractile function, regardless of the anaesthesia used.Supported by the German Research Foundation (He 1320/3-2). Dr. Guth is the recipient of a scholarship from the Alexander von Humboldt-Foundation.
Send offprint requests to G. Heusch at the above address 相似文献
17.
The effects of selective and specific 2-adrenoceptor antagonists on electroshock seizure threshold in mice were investigated. Idazoxan, at low doses, efaroxan, RX811059 and RX821002 significantly lowered seizure threshold. The 1-agonist St 587 and the -agonist isoprenaline were also pro-convulsant. On the other hand the 2-agonists clonidine and UK 14,304 produced small increases in seizure threshold. Anticonvulsant effects were also produced by low doses of the noradrenaline uptake inhibitor desipramine. This compound increases levels of noradrenaline in the synaptic cleft which could subsequently act at post-synaptic 2-adrenoceptors. The pro-convulsant action of 2-adrenoceptor antagonists could be explained in terms of two mechanisms: a) blockade of endogenous noradrenaline which may normally exert a tonic anti-convulsant influence on seizure threshold, through post-synaptic 2-receptors and/or b) increased activation of 1- and -adrenoceptors by elevated synaptic noradrenaline levels following blockade of pre-synaptic 2-adrenoceptors. Of the 2-antagonists tested, idazoxan was unusual in that high doses were not pro-convulsant; this difference may be explained by 1-adrenoceptor mediated actions or be related to its recently described affinity at a non-adrenoceptor site — a function for which is currently unknown. 相似文献
18.
J. Likungu G. J. Molderings M. Göthert 《Naunyn-Schmiedeberg's archives of pharmacology》1996,354(5):689-692
The involvement of presynaptic 2-autoreceptors and imidazoline receptors in the modulation of noradrenaline release was investigated in strips from human atrial appendages preincubated with [3H]noradrenaline and superfused with medium containing desipramine and corticosterone. Electrical impulses were applied transmurally at 2 Hz. The imidazoline derivatives moxonidine and clonidine reduced the evoked tritium overflow in a concentration-dependent manner. Moxonidine was 18-fold more potent than clonidine. The concentration-response curve for moxonidine, but not for clonidine was shifted to the right by the 2-adrenoceptor antagonist rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.41. An inhibitory effect was also observed for the imidazoline derivative BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), a mixed 2-adrenoceptor antagonist/imidazoline receptor agonist; BDF 6143 was about 2-fold more potent than clonidine. Rauwolscine (1 M) did not substantially shift the concentration-response curve of BDF 6143.It is concluded that noradrenaline release in the human atrium is inhibited not only via presynaptic 2-autoreceptors but also via presynaptic non-I1, non-I2 imidazoline receptors. The failure of rauwolscine to antagonize the inhibitory effect of clonidine suggests that clonidine preferentially stimulates the presynaptic imidazoline receptors; the 2-adrenoceptor component of its action is probably suppressed by an inhibitory interaction between the two receptors. In contrast, moxonidine acts via presynaptic 2-autoreceptors, leaving the presynaptic imidazoline receptor unaffected. 相似文献
19.
R. Brückner-Schmidt R. Jackisch G. Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1981,316(1):1-7
Summary In primary cell cultures originating from rabbit splenic pulpa the effects of various adrenoceptor agonists on prostaglandin (PG)-synthesis were studied. The cells-microscopically identified as fibroblasts-released PGs into the medium: especially PGE2 besides small amounts of PGF2 and PGD2.Noradrenaline increased dose-dependently the amount of PGs released into the medium. Besides noradrenaline, only the catecholamines adrenaline and -methylnoradrenaline strongly activated PG-synthesis. Other -adrenoceptor agonists like the phenylethylamine and imidazoline derivatives were only weak agonists or completely ineffective. All adrenoceptor agonists without intrinsic activity in these cells antagonized the noradrenaline effect on PG-synthesis, the imidazolines being more potent antagonists than the phenylethylamines.The -adrenoceptor agonist isoprenaline stimulated PG-synthesis at high concentrations only. The effects of both noradrenaline and isoprenaline were inhibited by low concentrations of phentolamine and phenoxybenzamine, but not by propranolol. The preferential 2-adrenoceptor antagonists yohimbine and rauwolscine were about 50 times more potent in blocking the noradrenaline effect on PG-synthesis than the more 1-specific antagonist corynanthine. However, prazosin, another 1-adrenoceptor antagonist, was about equipotent with yohimbine.It is concluded that noradrenaline elicits PG-synthesis in rabbit splenic fibroblasts via -adrenoceptor stimulation. The -adrenoceptor involved has properties which are different from those reported so far for 1- or 1-adrenoceptors. 相似文献
20.
Clemens Allgaier Ralf Greber Georg Hertting 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(2):187-192
Summary The aim of the present study was to obtain a more detailed understanding of the interaction between presynaptic 2-adrenoceptors and A1 adenosine receptors mediating inhibition of noradrenaline release in the central nervous system. Slices of rabbit hippocampus, prelabelled with [3H]noradrenaline, were superfused in the presence of the re-uptake inhibitor (+)-oxaprotiline and electrically stimulated during superfusion. During stimulation with 36 pulses at 3 Hz the 2-adrenoceptor antagonist yohimbine induced a five-fold increase of noradrenaline release indicating a pronounced autoinhibition of approximately 80%. In these experiments the inhibition of release caused by R-PIA, a preferential A1 agonist, as well as its facilitation caused by DPCPX, a selective A1 antagonist, were smaller in comparison to the effects of these compounds on release virtually free of autoinhibition (i. e. by stimulating the tissue with 4 pulses at 100 Hz (POP-stimulation) or with 36 pulses at 3 Hz in presence of yohimbine). Clonidine, an 2-adrenoceptor agonist, was used to impose a distinct 2-adrenoceptor-mediated inhibition of release elicited by POP-stimulation. Only, however, in the presence of 30 nmol/l clonidine, causing maximum inhibition of approximately 80% of 3H-overflow, but not in the presence of 6 nmol/l clonidine, causing approximately 50% inhibition, a significant diminution of the inhibitory effect of R-PIA was seen. Similarly, the 2-adrenoceptor mechanism was affected only by 10 mol/l R-PIA causing maximum inhibition of approximately 80%, but remained unchanged in the presence of 30 nmol/l R-PIA diminishing release by 50%. In addition, the 2-adrenoceptor-mediated inhibition remained unaffected in the presence of DPCPX, indicating that the concentration of endogenous adenosine attained was not sufficient to influence the 2-adrenoceptor mechanism. In conclusion, the present results suggest that activation of the presynaptic 2 and A1 receptors inhibits depolarization-induced noradrenaline release in an additive manner. Only extensive (near maximal or maximal) activation of one receptor mechanism impairs the inhibition due to activation of the other.
Send offprint requests to C. Allgaier at the above address 相似文献