Action Of Guanethidine Research Articles

Antagonism of guanethidine by dexamphetamine and other related sympathomimetic amines.

Abstract Dexamphetamine and certain other indirectly acting sympathomimetic amines prevent or reverse the sympathetic nerve blocking action of guanethidine in anaesthetised cats and dogs. Noradrenaline and dopamine do not antagonise the blocking action of guanethidine. These observations are discussed in relation to the mode of action of guanethidine and to a possible clinical significance of these findings.

Effects of fenfluramine on the adrenergic system.

Abstract The influence of fenfluramine on sympathetic transmission has been examined in various intact and isolated preparations. Fenfluramine both facilitated and inhibited the responses elicited by the sympathetic stimulation according to the dose administered and the preparation used. Fenfluramine, to a lesser extent than amphetamine, antagonized, in some preparations, the neuron blocking action of guanethidine. Fenfluramine did not antagonize the sympathomimetic effects elicited by amphetamine in the isolated atria and the isolated vas deferens unless very high concentrations of both drugs were used.

The effects of calcium on adrenergic neuron blockade.

Abstract The effects of increasing extracellular calcium were investigated on the responses to sympathetic nerve stimulation of three isolated organs; rabbit ileum, guinea-pig vas deferens and rabbit ear artery. A rise in the calcium concentration increased the responses of the ileum to low frequency stimulation, the maximum increase being obtained at 8.8 mM calcium. After partial blockade by guanethidine of the responses of the ileum to high frequency stimulation, raised calcium concentrations again increased the responses. The increase was similar in guanethidine-treated and untreated preparations and the maximum increase in both was obtained using 8.8 mM calcium. In the vas deferens and rabbit ear artery preparations an increase in extracellular calcium did not antagonize the blocking action of guanethidine. These experiments do not therefore support the theory that guanethidine acts by preventing the entry of calcium into the sympathetic nerve endings.

The pressor action of guanethidine in the spinal cat.

Abstract Guanethidine has a marked pressor action in the spinal cat. Doses of 2–4 mg./kg. produce a greater increase in blood pressure than doses of 8–16 mg./kg. Large doses of guanethidine (16 mg./kg.) inhibit the pressor action of small doses (2 mg./kg.). Guanethidine potentiated the pressor action of noradrenaline but inhibited that of tyramine. The degree of inhibition of tyramine increased with the dose of guanethidine, but was inversely related to the pressor action of guanethidine.

The effect of guanethidine and local anesthetics on the electrically stimulated mouse vas deferens.

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. 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.

Role of ganglionic cotransmission in sympathetic control of the isolated bullfrog aorta.

1. The relation between preganglionic activity and arterial tone was studied in preparations of bullfrog lumbar sympathetic ganglia 7-10 and the dorsal aorta. 2. Two or more stimuli evoked contractions when applied to the preganglionic C, but not the B pathway. Contractions were blocked when transmission in ganglia 9 and 10 was disrupted by cutting the sympathetic chain or adding (+)-tubocurarine. Contractions were antagonized by postganglionic action of guanethidine, but not by phentolamine or suramin. 3. Aortic responses to short trains (10-100 stimuli) were half-maximal at 0.3-0.5 Hz, saturated near 1 Hz and had a minimum latency of 8.9 s. By contrast, responses to 300 stimuli were half-maximal at 1 Hz and became 2.5-fold larger at 10 Hz. 4. Exogenous luteinizing hormone releasing hormone (LHRH) potentiated preganglionically evoked contractions. Endogenous LHRH mediated contractions evoked by 10 Hz stimulation in (+)-tubocurarine. These responses had a longer latency than in normal Ringer solution and were blocked by [D-pGlu1, D-Phe2, D-Trp3.6]-LHRH. The LHRH antagonist did not alter contractions evoked by continuous stimulation in normal Ringer solution or by bursts of stimuli in hexamethonium. 5. Exogenous neuropeptide Y (NPY) potentiated neurogenic contractions and responses to adrenaline. Benextramine blocked contractions produced by nerve stimulation, adrenaline and NPY, but not ATP. 6. The results show that contractions of the isolated aorta are tuned to physiological frequencies of activity in sympathetic C neurones. Peptidergic cotransmission in the ganglia can increase arterial tension, but not during synchronous activation of primary nicotinic synapses. It is suggested that the physiological role of LHRH arises from interactions with subthreshold nicotinic EPSPs and that postganglionic release of NPY shifts frequency tuning of the circuit during prolonged activity.

Prejunctional and postjunctional inhibition of adrenergic transmission in the rat-isolated anococcygeus muscle by cimetidine.

1. Cimetidine and ranitidine can inhibit various cholinergic sites, which can account for some of their clinically documented adverse effects; ranitidine can also inhibit adrenergic transmission, closely resembling the action of guanethidine. The effects of cimetidine on adrenergic transmission in the rat isolated anococcygeus muscle (Acm) were therefore investigated. 2. The contractile (motor) responses of the Acm to electrical field stimulation (EFS; 20-30V, 10 s, 1 ms pulse width, every 2 min) at varying frequencies (Hz: 5, 10, 20) and to 3 microM noradrenaline (NA) were inhibited in a concentration-dependent manner by cimetidine (mM: 1, 2, 4, 8). Inhibition of the EFS-induced responses was inversely related to the stimulation frequency. 3. Cimetidine (nM: 2, 4, 8) produced a concentration-dependent and non-parallel shift of the NA cumulative log concentration-response curves (CRCs; curves 2, 3, 4) to the right of the control curve (curve 1); at the highest concentration (8 mM) used, cimetidine produced a 4.3-fold shift of curve 4 accompanied by a decline of 9.4 +/- 1.5% in the maximal response to NA (compared to essentially no change in maximal responses for the corresponding CRCs in the NA control series). Cimetidine therefore inhibited the postjunctional alpha-adrenoceptor sites. 4. The contractile responses of the Acm to EFS (i.e. prejunctionally mediated responses) were more sensitive to inhibition by cimetidine than the NA-induced (postjunctionally mediated) responses: 8 mM cimetidine inhibited the responses to EFS by about 97%, whereas the responses to NA were inhibited by only 41 +/- 5%.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of topical guanethidine in the relief of dentine hypersensitivity: a controlled study

After a pilot study had indicated that the topical application of guanethidine might be of value in the treatment of tooth dentine hypersensitivity, a double-blind study was undertaken to investigate whether guanethidine was more effective than a distilled water control in alleviating dentinal pain. In 39 adult subjects, who had complained of dentine hypersensitivity, a 1 sec blast of air from a dental 3-in-1 syringe was directed onto sensitive root dentine at an angle of 90° from a distance of 1 cm. The severity of the resulting pain was indicated by the subject on a 10 cm visual analogue scale (VAS). One droplet of either 1% guanethidine monosulphate (Ismelin, Ciba-Geigy) or distilled water, allocated at random, was applied to the dentine for 1 min. The tooth was re-tested with the standardised air blast and a second VAS was marked by the subject. In total, 19 patients received guanethidine and 20 received water. VAS scores before treatment in the 2 groups treated with either guanethidine or water (means: 6.5 ± 2.2 and 6.0 ± 2.5, respectively) were not significantly different (Mann-Whitney, P = 0.48) whereas the VAS scores in the 2 groups after treatment with guanethidine or water (means: 2.7 ± 2.4 and 4.8 ± 2.9, respectively) were significantly different (Mann-Whitney, P < 0.02). It was concluded that guanethidine reduced dentinal hypersensitivity more effectively than distilled water. Within-group comparison of the pre- and post-treatment VAS scores, using the Wilcoxon matched-pairs test, showed that distilled water had also produced a significant improvement ( P < 0.01), probably attesting the operation of a placebo effect; the improvement produced by guanethidine reached a greater level of significance ( P < 0.001). This beneficial analgesic action of guanethidine may offer a novel, simple method of relieving the discomforts of dental conservation and restoration and lead to a better understanding of the hitherto obscure aetiology of dentinal pain.

Are mechanical and cold allodynia in mononeuropathic and arthritic rats relieved by systemic treatment with calcitonin or guanethidine?

The putative antinociceptive action of guanethidine and calcitonin systemically injected has been compared in 2 rat models of persistant experimental pain: Freund's adjuvant-induced arthritis (n = 29) and mononeuropathy induced by 4 loose ligatures around the sciatic nerve (n = 24). Guanethidine (30 mg/kg, i.v.) and calcitonin (0.125 mg, s.c.) were injected once a day over 1 week, when hyperalgesia was fully developed. The antinociceptive action was gauged using nociceptive tests based on mechanical or cold stimuli (vocalization threshold to paw pressure and struggle latency to 10°C, respectively), and the score of spontaneous pain-related behavior was measured on the basis of the abnormal hind paw position. No antinociceptive action was observed in calcitonin-compared to saline-injected rats, either in arthritic or neuropathic animals. Guanethidine treatment was ineffective on hyperalgesia exhibited in arthritic rats but was able to reduce reliably and even suppress the abnormal reactions to cold stimulus in neuropathic animals. The lack of hypoalgesic action of calcitonin versus its beneficial action in bone repair, as well as the possible role(s) of the sympathetic system in neuropathic versus arthritic pain and in hyperalgesia versus physical signs of inflammation, are discussed.

Alterations of drug toxicity in neuropsychiatric disease states.

Potentially adverse alterations in drug response in patients with neuropsychiatric disease can be divided into two categories: those arising from the pathological state itself (e.g., enhanced responsiveness to phenylephrine in patients with chronic autonomic failure) and those arising from interactions with the pharmacological treatment used for such disease (e.g., reversal of the antihypertensive action of guanethidine by imipramine). Sound knowledge of the pharmacological profile of individual compounds and of the pathophysiology of the disease is essential if drug therapy is to be used safely and effectively in these patients.

Cytofluorometric study of small highly fluorescent cells in rat auricles after a single injection of guanethidine

Small highly fluorescent cells (SHF cells) in the tissue of the mammalian auricles have been found close to vessels and nerves in zones of distribution of autonomic intramural ganglia [7]. Two types of SHF cells are distinguished: type I) single cells with wellmarked outgrowths; type II) round cells, grouped in clusters. According to Bjorklund et al. [3], SHF cells in rat auricles contain dopamine. Type I SHF cells have been classed by some workers as interneurons, whereas type II cells are generally regarded as performing an endocrine function. Activity of type I cells may evidently be regulated by the parasympathetic innervation, for cholinergic synapses have been found on some of them [6]. Type II cells may probably be under the influence of the sympathetic nervous system. Investigations by Jacobowitz [4] have demonstrated changes in fluorescence of auricular SHF cells by Falck's method after injection of reserpine. It is interesting to study how parameters characterizing catecholamine metabolism in SHF cells depend on the sympathetic mediator level in the heart. The absence of any marked effect of the cytotoxic action of guanethidine on SHF cells and the sharp fall in the noradrenalin (NA) level in the heart after a single injection of guanethidine indicate that this is a suitable model for use when assessing how SHF cell function depends on the sympathetic innervation.

Cardiac arrhythmias induced by guanethidine in cats anesthetized with halothane

Rapid i.v. administration of guanethidine provokes severe and susteined ventricular arrhythmieas in cats anesthetized with halothane. The arrhythmias premature ventricular exciations, multifocal ventricular rhythm, bigeminy, trigeminy and ventricular tachycardia. They begin in about 20 sec and last from 4 to 19 min. By comparison, a standard dose of noradrenaline (10 ωg/kg) induces ventricular arrhythmias which develop in about 12 sec and continue for 1–2.5 min. Pretreatment with β-adrenoceptor blocking drugs prevents arrhythmias from both drugs, and pretreatment with imipramine or reserpine prevents arrhythmias from guanethidine but not noradrenaline. The adrenergic neuron blocking action of guanethidine does not alter the arrhytmogenic action of guanethidine since arrhythmias can still be produced after adrenergic neuron blockade. These results indicate that guanethidine causes arrhythmias by releasing noradrenaline from cardiac adrenergic neuron storage sites and, therefore, point out the vulnerability of the heart to arrhythmias when noradrenaline-releasing drugs interact with halogenated hydrocarbon anesthetics.

Guanethidine-induced vasodilatation in the rabbit, mediated by endogenous histamine.

1 The effects of guanethidine (0.5-4 mg/kg i.v.) on arterial pressure, hindlimb blood flow and hindlimb vascular resistance (HVR) were studied in unanesthetized rabbits subjected to "total" autonomic block. 2 Evidence that this response was mediated by histamine release was that (a) 3H-labelled histamine levels in the hindlimb venous blood rose substantially after guanethidine; (b) infusion of exogenous histamine caused an inhibition of the guanethidine-induced vasodilatation; and (c) competitive antagonism of the response was obtained with the H2-antagonist burimamide. 3 There was good correlation between the [3H]-histamine ;elease and the time course of the vasodilator response. Glyceryl trinitrate infusions that lowered HVR substantially, did not cause release of histamine. 4 Reserpine, desipramine and indomethacin pretreatment did not alter the vasodilator response to guanethidine. 5 The guanethidine vasodilator response was not influenced by the H1-antagonist mepyramine or by the other H2-antagonists, metiamide or cimetidine. The vascular receptors stimulated by endogenous histamine may be distinctive from those stimulated by exogenous histamine, or the action of guanethidine may involve greater production of histamine at an intracellular site that is more readily reached by burimamide than by the other H2-antagonists.

88) - Studies on the mechanism of guanethidine action. VIII. Inhibitory action of guanethidine on output of noradrenaline induced by sodium reduction in rabbit ventricular slices

88) - Studies on the mechanism of guanethidine action. VIII. Inhibitory action of guanethidine on output of noradrenaline induced by sodium reduction in rabbit ventricular slices

1) - Adrenergic neuron blocking agents: Mode of action of guanethidine

1) - Adrenergic neuron blocking agents: Mode of action of guanethidine

Multiclinic controlled trial of bethanidine and guanethidine in severe hypertension.

One hundred and eight patients with initial diastolic blood pressure in the range of 100-124 mm Hg while taking hydrochlorothiazide were assigned randomly and double-blind to hydrochlorothiazide plus either bethanidine or guanethidine. The average reduction of the fifth and sixth months' diastolic blood pressure was 18.4 mm Hg for guanethidine and 13.6 mm Hg for bethanidine (P less than 0.01). The distribution of the individual values was such that 68.8% of guanethidine treated patients achieved a diastolic level below 90 mm Hg, compared to only 45.5% of the bethanidine treated group (P less than 0.025). The degree of orthostatic fall in blood pressure was greater with bethanidine than with guanethidine (P less than 0.05). The diurnal variation of blood pressure was slightly greater with bethanidine than with guanethidine. The results significantly favor guanethidine. This study failed to demonstrate that the shorter action of bethanidine confers significantly better control of blood pressure than the longer action of guanethidine.

57) - Studies on the mechanism of guanethidine action. VII. Effects of guanidine derivatives on release of noradrenaline from rabbit ventricular slices Induced by sodium reduction

57) - Studies on the mechanism of guanethidine action. VII. Effects of guanidine derivatives on release of noradrenaline from rabbit ventricular slices Induced by sodium reduction

Peripherally and centrally mediated bradycardiac effects of clonidine in anesthetized or spinal rats.

The bradycardia-inducing effects of clonidine were examined in anesthetized or spinal rats by injecting the drug intracisternally (i.c.) or intravenously (i.v.). Clonidine (1-25mug i.c.) caused a bradycardia dose-dependently in anesthetized rats. The bradycardia in response to clonidine (5mug i.c.) was significantly reduced after a treatment with phentolamine (100 mug i.c.), but not influenced with atropine (1 mg i.v.) or sectioning bilateral cervical vagal nerves. In spinal rats, an acceleration in heart rate by electrical stimulation of cervical sympathetic nerves was frequency-dependent and that due to desmethylimipramine (DMI) was dose-dependent. Clonidine (30 mug i.v.) significantly inhibited the acceleration induced by electrical stimulations only at a low frequency (0.3-3 Hz) or DMI (0.3 mg i.v.). This inhibition by clonidine was antagonized by phentolamine (5 mg i.v.). Clonidine (30 mug i.v.) did not significantly influence the acceleration in heart rate of spinal rats induced by norepinephrine (1 mug i.v.), tyramine (100 mug i.v.) or 1,1-dimethyl-4-phenylpiperazinium (DMPP, 50 mug i.v.). Therefore, it is suggested that clonidine causes a bradycardia by stimulating both peripheral and central alpha-adrenoceptors, the sympathetic trunk is the main pathway, and that the peripheral mechanism for clonidine-induced bradycardia is different from the action of guanethidine or hexamethonium on a release of catecholamines from the cardiac nerve terminals.

29) - Studies on the mechanism of guanethidine action VI - Effects of guanethidine and calcium on release of noradrenaline from rabbit hearts induced by sodium reduction

29) - Studies on the mechanism of guanethidine action VI - Effects of guanethidine and calcium on release of noradrenaline from rabbit hearts induced by sodium reduction

Comparative Pharmacological Studies on Butriptyline and Some Related Standard Tricyclic Antidepressants

Butriptyline was compared with imipramine and other tricyclic antidepressants for its ability to modify: (a) contractions of the cat nictitating membrane induced by noradrenaline (NA) and 5-hydroxytryptamine (5-HT), (b) the adrenergic neuron blocking action of guanethidine in the guinea pig vas deferns, (c) the rabbit's electroencephalogram (EEG) and physostigmine arousal, and (d) the sleep pattern of the rat. Imipramine and amitriptyline potentiated the NA and 5-HT effects on the nictitating membrane and antagonized the inhibitory actions of guanethidine in the guinea pig vas deferens, whereas iprindole and butriptyline were ineffective. These results are consistent with the ability of these drugs to block the neuronal uptake of catecholamines. Butriptyline was a potent blocker of the arousal reaction induced by physostigmine. Butriptyline (20--30 mg/kg) and amitriptyline (10--20 mg/kg) reduced rapid eye movement sleep with a conmitant increase in non-rapid eye movement sleep. This may be a reflection of the dual activity observed in the clinic with these compounds, namely, antidepressant and antianxiety effects.