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Per Juul - One of the best experts on this subject based on the ideXlab platform.
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the effects of Guanethidine pre and postganglionic nerve division on the rat superior cervical ganglion cholinesterases and catecholamines histochemistry and histology
Pharmacology & Toxicology, 2009Co-Authors: Jens Jensenholm, Per JuulAbstract:Guanethidine administered intraperitoneally in a dose of 20 mg/kg for 5 to 14 days induced a considerable reduction of histochemically demonstrable specific and non-specific cholinesterases. The loss initially involved the cytoplasm of the ganglion cells, but following prolonged administration there was a complete loss which also involved the nerve fibres. After Guanethidine 1–25 mg/kg an increasing degree of chromatolysis of the sympathetic ganglion cells was observed accompanied by infiltration of small cells. The increased number of small cells caused an increase in ganglionic size of approximately 50 % (Guanethidine 20 mg/kg for 14 days). The increased number of small cells mainly consisted of small lymphocyte — like cells, some of which showed pyroninophilia, and of macrophages. Mitoses were not observed, and the number of Schwann cells appeared unchanged. The possibility of an immunological process is discussed. The changes appeared to be specific, as only sympathetic ganglion cells were involved. These changes were partly reversible, though a number of ganglion cells had undergone complete degeneration. The ganglionic noradrenaline was partially depleted by Guanethidine. The alterations induced by Guanethidine resembled those resulting from postganglionic axotomy, but they developed independently of previously performed pre- or postganglionic nerve division. It is suggested that Guanethidine has a direct effect on the ganglion cells.
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Determination of Guanethidine in sympathetic ganglia.
Acta pharmacologica et toxicologica, 2009Co-Authors: Per Juul, Ole SandAbstract:: Guanethidine sulphate was administered intraperitoneally in a dose of 10-60 mg/kg for up to two months to adult male rats and the content of Guanethidine in the superior cervical ganglia was determined fluorometrically after combination with ninhydrin in alkaline solution. Guanethidine was shown to concentrate in the superior cervical ganglia. Twenty four hours after the discontinuation of Guanethidine sulphate 20 mg/kg for 14 days, the mean total gang-lionic content of Guanethidine base was 50 ng/ganglion (S.D. 8.8, n = 10) corresponding to 83 μg/g dry weight or 17 μg/g wet weight. Following a single injection of Guanethidine sulphate and following discontinuation of prolonged administration of the drug the ganglionic Guanethidine declined with a half-life of 35 hours. Most of the ganglia were excised 24 hours after discontinuation of administration of the drug at which time the decline in ganglionic Guanethidine was exponential. Desmethylimipramine largely prevented the accumulation of Guanethidine in the ganglia indicating a mainly intraneuronal localization of Guanethidine, a localization which was confirmed by microautoradiography. Reserpine only lowered the content to a small extent possibly indicating a mainly extragranular localization of Guanethidine in the nerve cells. The selective morphological effects of Guanethidine on sympathetic ganglia previously demonstrated were almost completely prevented by desmethylimipramine but only to a small extent by reserpine. SKF-525-A potentiated the ganglionic effects of Guanethidine. It is assumed that the ganglionic effects are due to a cytotoxic effect of Guanethidine concentrating selectively in the sympathetic ganglion nerve cells with the major part being located outside the noradrenaline storage granules as opposed to a mainly intragranular localization in the peripheral sympathetic terminals.
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The effect of Guanethidine pretreatment on transmission in the superior cervical ganglion.
Acta pharmacologica et toxicologica, 2009Co-Authors: Oliver A. Downing, Per JuulAbstract:: Isolated superior cervical ganglia from rats pretreated with Guanethidine sulphate intraperitoneally in single daily doses of 20-40 mg/kg for 5-21 days showed transmitted action potentials of normal form but diminished amplitude following single or repetitive stimulation of the preganglionic nerve. Curves relating the relative reduction in ganglionic action potential height with increasing frequency of stimulation were similar in preparations from control and Guanethidine pretreated rats. Ganglia from Guanethidine pretreated rats had the same sensitivity to exogenous acetylcholine as those from the controls as judged by doseidepolarization response curves. The absolute values of depolarization were, however, diminished. No impairment of the conduction of impulses in the preganglionic nerve or of the effect of antidromic stimulation was observed. The addition of Guanethidine to the bath fluid resulted in an acute reversible ganglion block. A 50 % reduction of the ganglionic action potentials following single stimuli was observed at a concentration of 2 × 10−5 M. At Guanethidine concentrations of 5 × 10−5 M maximum depolarizations obtained with acetylcholine or carbachol were reduced by approximately 50 % but the doselresponse curves were not shifted. Recovery was complete after washing. Retractions of the cat nictitating membrane following repetitive stimulation of the preganglionic nerve after pretreatment with Guanethidine 5-40 mg/kg for 14 days were preferentially decreased at low stimulus frequencies. The nictitating membrane was hypersensitive to intravenous adrenaline or noradrenaline. Contralateral ganglia from both rats and cats exhibited profound structural changes consisting of chromatolysis of the nerve cells and infiltration of small cells. The effects of Guanethidine on the neurophysiological parameters are probably the result of a dose dependent inactivation of the majority of the ganglion cells.
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Effect of immunosuppressive agents on the Guanethidine-induced sympathectomy in athymic and euthymic rats.
International journal of immunopharmacology, 1992Co-Authors: Hans Petter Hougen, P. Thygesen, Henning Bjørn Christensen, Jørgen Rygaard, Ove Svendsen, Per JuulAbstract:Abstract Guanethidine sulphate causes destruction of peripheral sympathetic neurons and infiltration of mononuclear inflammatory cells in the sympathetic ganglia of both athymic nude ( rnu/rnu ) and euthymic LEW/Mol rats. The effect of guanethidinde is believed to be an autoimmune reaction. To determine the effect of immunosuppressive drugs concurrently with Guanethidine treatment both athymic nad euthymic rats were treated with Guanethidine 40 mg/kg i.p. daily for 14 days, cyclophosphamide 100 mg/kg i.p. on days 1 and 8, methylprednisolone 10 mg/kg and cyclosporin A 10 mg/kg daily from days 1 to 7, and then every other day from days 8 to 14. The number of neurons in the sympathetic ganglia was counted and four subpopulations of mononuclear inflammatory cells were identified by monoclonal antibodies MHC II, CD8 T-cells/NK-cells, CD5 T-cells, CD4 T-cells/macrophages. Our results show that the immunosuppressive drugs used were unable to prevent the Guanethidine-induced reduction of sympathetic neurons, although the number of neurons following Guanethidine-methylprenisolone treatment was significantly higher compared with Guanethidine alone in both athymic and euthymic rats. The identification of mononuclear cells in the sympathetic ganglia showed that the CD8/NK and CD5 populations were the populations primarily responding to Guanethidine treatment. Both CD8/NK and CD5 populations were absent without Guanethidine, but increased significantly following Guanethidine in both athymic and euthymic animals. None of the immunosuppressive drugs used could prevent the Guanethidine-induced rise in the CD8/NK population in neither athymic not in euthymic rats. The rise in the CD5 population was suppressed following treatment with all immunosuppressive drugs in athymic rats, but only following methylprednisolone in euthymic animals. These results indicate that Guanethidine induces proliferation of T-cells in euthymic rats and non-functional CD5 positive pre T-cells in athymic animals. The CD5 population in both athymic and euthymic animals appears relatively more sensitive to immunosuppressive drugs than the NK-cell population also activated by Guanethidine. This relatively resistant NK-cell population seems to play an important role in the Guanethidine-induced destruction of sympathetic neurons and can explain why the Guanethidine-induced immunological reaction could not be fully prevented by the immunosuppressive drugs used. The conclusion is that Guanethidine induces destruction of sympathetic neurons by a NK-cell-mediated reaction.
David G. Lambert - One of the best experts on this subject based on the ideXlab platform.
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The Effect of Guanethidine and Local Anesthetics on the Electrically Stimulated Mouse Vas Deferens
Anesthesia and analgesia, 2002Co-Authors: Philip I. Joyce, David J. Rowbotham, Daniela Rizzi, Girolamo Calo, David G. LambertAbstract:UNLABELLED Complex regional pain syndrome is often treated with the sympatholytic Guanethidine and a local anesthetic in a Bier's block. The efficacy of this treatment has been questioned. Because local anesthetics inhibit the norepinephrine uptake transporter, we hypothesized that this variable efficacy results from the local inhibiting the uptake of Guanethidine. In this study, we tested this hypothesis by using a sympathetically innervated mouse vas deferens preparation. Organ bath-mounted mouse vasa deferentia were electrically stimulated in the absence and presence of Guanethidine, prilocaine, procaine, and cocaine in various combinations. Prilocaine (1 mM) induced an immediate inhibition of twitch response (maximum 100% after 2 min) that fully reversed after washing. Guanethidine (3 microM) also inhibited twitching by 95% +/- 3% in 15 min, but this effect was only partially reversed after 1 h of washing (33% +/- 12% of control). When prilocaine and Guanethidine were added in combination, a reversal of 80% +/- 13% (at 1 h) was observed. Procaine (300 micro M) produced a transient increase (152% +/- 14%) in response. When co-incubated with Guanethidine (3 microM), the twitch was reduced to 24% +/- 4% of control and was reversed to 77% +/- 7% after 1 h. Cocaine (30 microM) inhibited the twitch response to 53% +/- 8%, which was fully reversed by 1 h of washing. When co-incubated with Guanethidine, the response was reduced to 39% +/- 6% of control and was reversed to 86% +/- 10% after 1 h. In all cases, the reversal produced by the combination was significantly more intense (P < 0.05) than that produced by Guanethidine alone. Local anesthetics reduce the sympatholytic actions of Guanethidine, and this may explain the variable efficacy of Guanethidine in the treatment of complex regional pain syndrome. IMPLICATIONS In this study, with a sympathetically innervated vas deferens preparation, local anesthetics reduced the efficacy of the sympatholytic Guanethidine, questioning its co-administration in the pain clinic.
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Interaction of local anaesthetic agents with the endogenous norepinephrine transporter in SH-SY5Y human neuroblastoma cells
Neuroscience letters, 2001Co-Authors: P.i. Joyce, R. Atcheson, R.j. Marcus, A.m. Heffernan, David J. Rowbotham, David G. LambertAbstract:Abstract Use of intravenous Guanethidine for the treatment of complex regional pain syndrome type I is of variable efficacy. Guanethidine injection is painful, so local anaesthetic is co-administered. We hypothesize that local anaesthetic inhibits uptake of Guanethidine and hence reduces its efficacy. In this study we have examined the effects of a range of local anaesthetic agents on the uptake of [ 3 H]norepinephrine ([ 3 H]NE) (as a surrogate for Guanethidine) and the binding of [ 3 H]nisoxetine to the NE transporter in cultured SH-SY5Y human neuroblastoma cells. All local anaesthetic agents inhibited NE uptake with a rank order cocaine>tetracaine>procaine(esters), dibucaine>bupivacaine>prilocaine>lidocaine (amides). In addition all anaesthetic agents displaced [ 3 H]nisoxetine with a rank order cocaine>tetracaine>dibucaine>procaine>prilocaine>bupivacaine>lidocaine. There was a positive correlation between [ 3 H]NE uptake and [ 3 H]nisoxetine binding. Our data suggest that when local anaesthetic and Guanethidine are co-administered the former may reduce uptake of the latter and hence reduce the clinical efficacy of Guanethidine.
Timothy J Bartness - One of the best experts on this subject based on the ideXlab platform.
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novel method for localized functional sympathetic nervous system denervation of peripheral tissue using Guanethidine
Journal of Neuroscience Methods, 2001Co-Authors: Gregory E Demas, Timothy J BartnessAbstract:A simple technique for local chemical sympathectomy of peripheral tissues is described using Guanethidine. Multiple microinjections of Guanethidine were made into inguinal or epididymal white adipose tissue (IWAT and EWAT) pads or spleens of hamsters. Guanethidine virtually abolished the sympathetic innervation of both EWAT and IWAT, as measured by the absence of significant norepinephrine (NE) tissue content two weeks later and as suggested by the two-fold increase in IWAT mass characteristic of surgically induced WAT denervation. These measures were not affected in the contralateral pads given equivolumetric injections of saline. Guanethidine injections into the spleen lead to a functional sympathectomy, as indicated by significant depletions of NE content. Because Guanethidine treatment did not decrease body mass, induce ptosis, or spread to closely associated adjacent tissue (contralateral EWAT pad), no chemical-induced malaise or global sympathetic denervation was suggested. Guanethidine was more effective than two other local sympathectomy treatments, injections of the sympathetic neurotoxin anti-dopamine-β-hydroxylase saporin or surgical denervation, in decreasing IWAT NE content and increasing IWAT pad mass. Collectively, these results suggest that locally applied, chemical sympathectomy with Guanethidine provides an effective, restricted method for sympathectomizing WAT, spleen and likely other peripheral tissues.
Gregory E Demas - One of the best experts on this subject based on the ideXlab platform.
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novel method for localized functional sympathetic nervous system denervation of peripheral tissue using Guanethidine
Journal of Neuroscience Methods, 2001Co-Authors: Gregory E Demas, Timothy J BartnessAbstract:A simple technique for local chemical sympathectomy of peripheral tissues is described using Guanethidine. Multiple microinjections of Guanethidine were made into inguinal or epididymal white adipose tissue (IWAT and EWAT) pads or spleens of hamsters. Guanethidine virtually abolished the sympathetic innervation of both EWAT and IWAT, as measured by the absence of significant norepinephrine (NE) tissue content two weeks later and as suggested by the two-fold increase in IWAT mass characteristic of surgically induced WAT denervation. These measures were not affected in the contralateral pads given equivolumetric injections of saline. Guanethidine injections into the spleen lead to a functional sympathectomy, as indicated by significant depletions of NE content. Because Guanethidine treatment did not decrease body mass, induce ptosis, or spread to closely associated adjacent tissue (contralateral EWAT pad), no chemical-induced malaise or global sympathetic denervation was suggested. Guanethidine was more effective than two other local sympathectomy treatments, injections of the sympathetic neurotoxin anti-dopamine-β-hydroxylase saporin or surgical denervation, in decreasing IWAT NE content and increasing IWAT pad mass. Collectively, these results suggest that locally applied, chemical sympathectomy with Guanethidine provides an effective, restricted method for sympathectomizing WAT, spleen and likely other peripheral tissues.
Julius Axelrod - One of the best experts on this subject based on the ideXlab platform.
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The Uptake and Release of Catecholamines and the Effect of Drugs
Progress in Brain Research, 2008Co-Authors: Julius AxelrodAbstract:Publisher Summary The chapter analyzes the uptake and release of Catecholamines and the effect of drugs. In this respect, the uptake of Circulatjng Catecholamines has been discussed and illustrated with the help of a number case studies. Monoamine oxidase inhibitors, bretylium, uanethidine, and reserpine are the hypotensive drugs that affect the uptake, release, and metabolism of catecholamines. The actions of reserpine and monoamine oxidase inhibitors on noradrenaline have been described in the chapter. It is found that many drugs such as cocaine, Guanethidine, bretylium, imipramine, chlorpromazine, and Dibenzyline cause supersensitivity to catecholamines. All of these drugs prevent the uptake of circulating catecholamines by tissues. These drugs prevent the inactivation of hormones by binding and a higher concentration of the free and active catecholamines present at the receptor site. Chronic denervation of sympathetically innervated organs also cause supersensitivity to catecholamines. When the nerves degenerate, the vesicles, which bind and inactivate noradrenaline, are destroyed. Consequently, the amount of unbound and active catecholamines in the vicinity of the receptors in denervated tissues are expected to persist for longer periods—resulting in supersensitivity.
