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1.
Enhancement of noradrenaline depletion in the cat spleen by phenoxybenzamine and phentolamine
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The noradrenaline content of the microsomal fraction of cat spleen was reduced by nerve stimulation. The reduction was greater in the presence of phenoxybenzamine and phentolamine, but was not affected by the presence of cocaine. The results suggest that phenoxybenzamine and phentolamine are able to increase the impulse-evoked release of noradrenaline. 相似文献
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Summary Isolated rabbit atria were perfused with Tyrode solution containing (+)-amphetamine. Electrical stimulation of the right postganglionic sympathetic fibres caused an output of noradrenaline which was significantly decreased by simultaneous stimulation of the vagus nerves.This work was supported by the Deutsche Forschungsgemeinschaft. 相似文献
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S. M. Kirpekar Arun R. Wakade J. C. Prat 《Naunyn-Schmiedeberg's archives of pharmacology》1976,294(1):23-29
1. | The effect of tetraethylammonium (TEA) and barium on release of noradrenaline (NA) from the cat spleen by nerve stimulation or potassium was investigated. |
2. | In spleens perfused with normal Krebs solution, the NA output at 5 Hz was barely detectable, and the output at 30 Hz was about 5-fold greater than the output at 5 Hz. |
3. | TEA (1 mM) or barium (2.5 mM) increased NA output at 5 Hz by 5-fold, but did not enhance it at 30 Hz. A maximal effect of TEA was obtained at about 1–3 mM. Enhancement of NA release by TEA was readily reversible. Output of NA induced by high potassium was not affected by TEA or barium. |
4. | The effect of TEA on release was related to the external calcium concentration. Insignificant outputs obtained at 5 Hz in 0.1 and 0.5 mM calcium-Krebs solutions were markedly increased by TEA, and were 2- and 5-fold greater than the control output at 5 Hz in normal Krebs solution containing 2.5 mM calcium. TEA enhanced release at all calcium concentrations up to 5 mM, but maximum output was still obtained at 2.5 mM. |
5. | Increasing the potassium concentrations of normal Krebs solution to 10, 15 and 20 mM depressed NA outputs at 5 Hz by 50, 55 and 75%, respectively. TEA (1 mM) partially antagonized the inhibitory effect of potassium on release, and in zero potassium-Krebs solution it increased output by about 50% over that obtained in normal Krebs solution. |
6. | The ratio of NA outputs at 30 and 5 Hz during perfusion with Krebs solution containing TEA was about 0.6, and it approached the normal value as the calcium concentration of the perfusion medium was reduced. TEA facilitated release even at 30 Hz in low-calcium solutions. |
7. | It is suggested that the enhancement of NA release by TEA and barium is due to the greater influx of calcium ions into the sympathetic nerves during the course of an action potential. |
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Release of noradrenaline and dopamine by nerve stimulation in the cat spleen perfused with 3 H-dopamine
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1. Recovery of (3)H-dopamine and (3)H-L-dopa infused intra-arterially at a constant rate of 20 ng/min into the cat spleen perfused with Krebs bicarbonate solution was 52.6+/-3.8% and 90.5+/-3.1% respectively. Recovery of (3)H-dopamine in spleens treated with alpha-methyl-p-tyrosine was 67.7+/-6.7% and was not significantly different from untreated spleens.2. Release of (3)H-dopamine by nerve stimulation after an infusion of (3)H-dopamine resembled release of endogenous noradrenaline. Release of (3)H-L-dopa and (3)H-L-tyrosine after their infusion did not occur in any consistent manner by nerve stimulation.3. Preferential release of (3)H-noradrenaline formed from (3)H-dopamine was not observed during continuous nerve stimulation. Specific activity of released (3)H-noradrenaline remained constant during any single stimulation period with or without (3)H-dopamine infusion. Treating the cats with alpha-methyl-p-tyrosine did not change the time course of (3)H-noradrenaline release.4. Output of noradrenaline expressed as a percentage of the first minute output in both normal and alpha-methyl-p-tyrosine treated spleens was not significantly different at various times during continuous nerve stimulation.5. Specific activity of released noradrenaline formed from (3)H-dopamine was always greater than the specific activity of the spleen in normal spleens and spleens treated with alpha-methyl-p-tyrosine.6. It is concluded that newly synthesized or infused noradrenaline initially mixes with a more rapidly turning pool and only slowly with the entire tissue store. During continuous nerve stimulation there is no further preferential release of newly synthesized noradrenaline. Released noradrenaline truly represents the state of the releasable pool and will vary with the latter. 相似文献
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Summary After loading the isolated nerve-muscle preparation of the cat nictitating membrane with 3H-(±)-noradrenaline the effects of exogenous dopamine and (-)-noradrenaline were determined on 3H-transmitter overflow elicited by nerve stimulation in the presence of cocaine, 29 M. Dopamine, 0.20 M, and (-)-noradrenaline, 0.18 M, inhibited 3H-noradrenaline release elicited by nerve stimulation at 4 or 10 Hz. Similar results were obtained with apomorphine 0.03 or 0.1 M. Chlorpromazine, 1 M, or pimozide, 1 M, antagonized selectively the reduction in 3H-noradrenaline release obtained with dopamine or apomorphine, without affecting the inhibition obtained with (-)-noradrenaline. Phentolamine, 1 M, antagonized more effectively the inhibitory effects of (-)-noradrenaline than those of dopamine. Phenoxybenzamine, 0.29 M, prevented the inhibition of 3H-transmitter overflow obtained with (-)-noradrenaline, dopamine or apomorphine. In the absence of cocaine neither chlorpromazine nor pimozide were able to increase 3H-transmitter overflow during nerve stimulation. In contrast to these results, block of -adrenoceptors by phentolamine or phenoxybenzamine resulted in an increase 3H-transmitter overflow during nerve stimulation. Inhibition by dopamine of 3H-transmitter overflow appears to be mediated through dopamine receptors probably located in the outer surface of adrenergic nerve endings. These dopamine receptors differ from the prejunctional -adrenoceptors that mediate the negative feed-back regulatory mechanism for noradrenaline release by nerve stimulation. The prejunctional inhibitory dopamine receptors are not involved in an endogenously mediated regulatory mechanism for noradrenaline release by nerve stimulation under normal conditions. The possibility that these dopamine receptors are involved in the hypotension commonly observed in patients with chronic l-Dopa treatment is discussed. 相似文献
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M. A. Luchelli-Fortis S. Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1975,287(3):261-275
Summary The metabolism of 3H-noradrenaline released by nerve stimulation in the isolated nerve-muscle preparation of the cat nictitating membrane was determined under control conditions and in the presence of hydrocortisone, 28 M, a concentration which inhibits the high affinity extraneuronal uptake of noradrenaline in this tissue. in the controls the main fraction in the overflow elicited by stimulation at 10 Hz during 2 min was the deaminated glycol, 3H-DOPEG (3,4-dihydroxyphenylglycol), which accounted for 45.2±2.96% of the total radioactivity. Under these conditions, 3H-noradrenaline represented 30.8±1.92%, while 3H-normetanephrine accounted for 14.5±0.94% of the total overflow of radioactivity. During exposure to hydrocortisone there was a selective inhibition in 3H-normetanephrine formation from 3H-noradrenaline released by stimulation while the other fractions were not affected significantly. In contrast to these results, there were no changes in the spontaneous outflow of 3H-normetanephrine during exposure to hydrocortisone. The results obtained support the view that 3H-normetanephrine in sponteneous release originates from the activity of prejunctional catechol-O-methyltransferase. On the other hand, 3H-normetanephrine formed during transmitter release elicited by nerve stimulation is due to the activity of extraneuronal catechol-O-methyltransferase. Access of 3H-noradrenaline released by nerve stimulation to extraneuronal catechol-O-methyltransferase is mediated through the high-affinity, hydrocortisone-sensitive extraneuronal uptake mechanism. 相似文献
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The role of calcium in the effects of noradrenaline and phenoxybenzamine on adrenergic transmitter release from atria: no support for negative feedback of release 总被引:5,自引:5,他引:0
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S Kalsner 《British journal of pharmacology》1981,73(2):363-371
1 The relation of calcium ion influx into nerve terminals to presynaptic adrenoceptor function and the possible masking, by desensitization due to intraneuronal calcium accumulation, of the effects of adrenoceptor agonists and antagonists on presynaptic alpha-adrenoceptors was investigated in guinea-pig atria previously incubated with [(3)H]-noradrenaline.2 Atria were stimulated with 100 pulses at various frequencies (1 to 15 Hz) in standard (2.3 mm), low (0.26 mm) and high (6.9 mm) calcium-Krebs solution in the absence and then the presence first of noradrenaline and subsequently phenoxybenzamine.3 The per pulse overflow of tritium was directly related to the calcium concentration of the Krebs solution, being much reduced and substantially increased in 0.26 and 6.9 mm calcium-Krebs solutions respectively.4 Noradrenaline inhibited the overflow of tritium in low calcium-Krebs solution, to a relatively constant extent, independently of frequency. In addition, the agonist had a greater maximal inhibitory effect in standard than in reduced calcium-Krebs. The catecholamine was as effective an inhibitor of overflow at the lowest and highest frequencies in high as it was in standard calcium-Krebs solution. Phenoxybenzamine invariably increased the tritium overflow but was generally less effective both in low and in high calcium-Krebs solution. The patterns of inhibition and enhancement of stimulation-induced tritium overflow by these two agents do not indicate an intimate relationship between calcium influx and adrenoceptor activation; nor does desensitization appear to be an adequate explanation of the relationship between frequency of stimulation and the intensity of agonist and antagonist effect in the three different calcium concentrations.5 It is concluded that the perineuronal levels of adrenergic transmitter do not establish the magnitudes of effect of exogenous adrenoceptor agonists and antagonists on tritium overflow and that a negative feedback regulation of release by transmitter is exceedingly unlikely under ordinary conditions of neurotransmission. 相似文献
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Influence of reserpine-induced depletion of noradrenaline on the negative feed-back mechanism for transmitter release during nerve stimulation 总被引:6,自引:5,他引:1
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1. The effects of depletion of endogenous noradrenaline by reserpine-pretreatment on [(3)H]-noradrenaline overflow elicited by nerve stimulation were determined in the isolated nerve-muscle preparation of the cat's nictitating membrane.2. Reserpine pretreatment (0.3 mg/kg, s.c., 4 days prior to the experiment) reduced the noradrenaline levels in the smooth muscle of the nictitating membrane to about 10% of the control values while granular retention of [(3)H]-noradrenaline had recovered to nearly 40% of the controls.3. In the reserpine-pretreated tissue the fraction release per shock induced by nerve stimulation was 2.2-fold higher than the value obtained in the untreated tissues. This effect was correlated with the degree of depletion of the noradrenaline stores rather than with the decrease in the response of the effector organ.4. Phenoxybenzamine, 2.9 muM reduced the responses to nerve stimulation to the same extent in control and in reserpine-pretreated tissues. Yet, this concentration of phenoxybenzamine increased by 13-fold the overflow of the labelled transmitter in the controls and only by 3-fold in reserpine-pretreated tissues.5. The decrease in effectiveness of phenoxybenzamine in enhancing transmitter overflow after reserpine-pretreatment appears to be due to the decrease in the total release of the transmitter.6. The results obtained support the view that in reserpine-pretreated tissues decreased transmitter output reduces the activation of the presynaptic alpha-adrenoceptors which mediate the negative feed-back mechanism that regulates transmitter release by nerve stimulation. 相似文献
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Alice Habermeier-Muth E. Muscholl 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(2):164-172
Rabbit atria were isolated with the extrinsic right sympathetic and vagus nerves attached and perfused with Tyrode solution. Acetylcholine overflow was determined after labelling of the transmitter stores with [14C]choline and fractionation of the radioactivity on cation exchange columns. Sympathetic nerve stimulation (SNS, 2 Hz, 3 min) carried out together with vagus nerve stimulation (VNS, 2 Hz, 3 min), but each SNS pulse preceding a vagal one by 19 ms, caused a facilitation of acetylcholine overflow of about 60% versus independent controls in the absence of SNS. Antagonists of putative neurotransmitters were tested to find out the prejunctional mediator involved in the facilitation.The facilitation was not significantly reduced by prazosin, rauwolscine, idazoxan, or propranolol, excluding mediation by - or \-adrenoceptors. However, guanethidine abolished evoked noradrenaline release and facilitation, suggesting that it is due to a compound co-released with noradrenaline from postganglionic noradrenergic nerves. Pretreatment of rabbits with reserpine which reduced noradrenaline content of atria and SNS evoked overflow by 94% did not affect the facilitation of acetylcholine release which, due to the cardiostimulatory action of SNS being absent, resulted in enhanced depression of atrial force. We conclude that the facilitation is due to release of a reserpine-resistant co-transmitter from sympathetic nerves.Possible mediation of the facilitation by ATP through P2X- or P2Y-purinoceptors was excluded by ineffectiveness of , \-methylene ATP-preperfusion, of suramin and cibacron blue, respectively. However, the selective A2 adenosine receptor antagonist CP 66,713 reduced the facilitation by 25% whereas DPCPX (A1-selective) had no effect. Of the non-subtype-selective antagonists only 8-phenyltheophylline but not XAC decreased the facilitation by 40%. Mediation of the facilitation by tachykinin-, angiotensin-, opioid, AMPA/kainate-, M1 muscarinic, 5-hydroxytryptamine 5-HT1–4-receptors, or by nitric oxide, was excluded by administration of respective antagonists or inhibitors. Thus, whilst adenosine seems to be responsible for about one-fourth of the effect of sympathetic nerve stimulation, the major part of the facilitation of acetylcholine release remains unexplained.Under conditions of a low rate of evoked acetylcholine overflow prazosin enhanced the facilitatory action of SNS, suggesting an 1-adrenoceptor mediated prejunctional inhibition of acetylcholine release. 相似文献
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The effects of prazosin, phentolamine and phenoxybenzamine on inhibitory alpha-adrenoceptors in the guniea-pig isolated ileum.
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1 The relaxant effect of noradrenaline on strips of guinea-pig isolated terminal ileum was blocked by pretreatment with prazosin, phentolamine, yohimbine and phenoxybenzamine. 2 The presence of a very high concentration of noradrenaline (50 micrometers) during exposure to the blocking agent protected against the blocking effect of the drugs. 3 Yohimbine, prazosin and phentolamine partially protected against irreversible blockade by phenoxybenzamine. 4 Spontaneous release of acetylcholine in the unstimulated ileum was blocked by noradrenaline (0.05-5.9 micrometers) this effect of noradrenaline was antagonized by phentolamine (0.13-26 micrometers) and yohimbine (0.051-0.51 micrometers) but not prazosin (0.53-5.3 micrometers) or phenoxybenzamine (4.2-42 nm). All four antagonists reversed the noradrenaline-induced relaxation of the ileum. 5 Acetylcholine output in the transmurally stimulated ileum was inhibited by noradrenaline. This effect of noradrenaline was antagonized by phentolamine and yohimbine but not by prazosin or phenoxybenzamine. The first two antagonists blocked the noradrenaline-induced inhibition of evoked twitches of the ileum while the last two had no effect. 6 The results show (a) that prazosin has no effect on presynaptic alpha-adrenoceptor located on cholinergic nerve endings in the guinea-pig ileum and (b) that prazosin, phentolamine and phenoxybenzamine act on the same subgroup of postsynaptic alpha-adrenoceptors on the smooth muscle of the guniea-pig ileum. 相似文献
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Effects of GABA on noradrenaline release and vasoconstriction induced by renal nerve stimulation in isolated perfused rat kidney. 总被引:2,自引:0,他引:2
S Fujimura H Shimakage H Tanioka M Yoshida M Suzuki-Kusaba H Hisa S Satoh 《British journal of pharmacology》1999,127(1):109-114
We examined effects of gamma-aminobutyric acid (GABA) on vasoconstriction and noradrenaline (NA) release induced by electrical renal nerve stimulation (RNS) in the isolated pump-perfused rat kidney. RNS (1 and 2 Hz for 2.5 min each, 0.5-ms duration, supramaximal voltage) increased renal perfusion pressure (PP) and renal NA efflux. GABA (3, 10 and 100 microM) attenuated the RNS-induced increases in PP by 10-40% (P<0.01) and NA efflux by 10-30% (P<0.01). GABA did not affect exogenous NA (40 and 60 nM)-induced increases in PP. The selective GABA(B) agonist baclofen (3, 10 and 100 microM) also attenuated the RNS-induced increases in PP and NA efflux, whereas the RNS-induced responses were relatively resistant to the selective GABA(A) agonist muscimol (3, 10 and 100 microM). The selective GABA(B) antagonist 2-hydroxysaclofen (50 microM), but not the selective GABA(A) antagonist bicuculline (50 microM), abolished the inhibitory effects of GABA (10 microM) on the RNS-induced responses. The selective alpha2-adrenoceptor antagonist rauwolscine (10 nM) enhanced the RNS-induced responses. GABA (3, 10 and 100 microM) potently attenuated the RNS-induced increases in PP by 40-60% (P<0.01) and NA efflux by 20-50% (P<0.01) in the presence of rauwolscine. Prazosin (10 and 30 nM) suppressed the RNS-induced increases in PP by about 70-80%. Neither rauwolscine (10 nM) nor GABA (10 microM) suppressed the residual prazosin-resistant PP response. These results suggest that GABA suppresses sympathetic neurotransmitter release via presynaptic GABA(B) receptors, and thereby attenuates adrenergically induced vasoconstriction in the rat kidney. 相似文献
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Atrial natriuretic factor inhibits norepinephrine release evoked by sympathetic nerve stimulation in isolated perfused rat mesenteric arteries 总被引:4,自引:0,他引:4
The effect of atrial natriuretic factor (ANF) on [3H]norepinephrine release evoked by sympathetic nerve stimulation was examined in the isolated perfused rat mesenteric arteries. ANF (1 nM to 0.1 microM) caused a dose-dependent inhibition of [3H]norepinephrine release during nerve stimulation. The present result indicates that ANF inhibits noradrenergic neurotransmission in the rat mesenteric arteries through a prejunctional mechanism. This prejunctional effect of ANF may in part contribute to its vasodilation action. 相似文献