Adrenergic Neurone Blocking Action Research Articles

Pharmacodynamic effects of dehydroemetine.

Abstract The pharmacodynamics of dehydroemetine were studied in isolated preparations and in whole animals. Dehydroemetine had no effect on the guinea-pig isolated ileum but non-specifically antagonized the spasmogenic effect of histamine, acetylcholine and nicotine on this tissue. Dehydroemetine in small concentrations inhibited relaxations of the guinea-pig and rabbit ileum produced by stimulating the sympathetic nerve without inhibiting the effect of noradrenaline. Twitches of the guinea-pig ileum elicited by transmural stimulation were blocked by dehydroemetine while higher doses of the drug also inhibited the indirectly elicited contractions of the isolated rat diaphragm. In vivo, neuromuscular blocking action could not be demonstrated for dehydroemetine while toxic doses were required to demonstrate the presence of an adrenergic neuron blocking action. Dehydroemetine had no anaesthetic action when applied locally to the rabbit cornea. Concentrations of the drug which caused local anaesthesia when injected intradermally into guinea-pigs also caused skin necrosis. It is concluded that dehydroemetine lacks any specific adrenergic neuron blocking action or neuromuscular blocking action or local anaesthetic action. It is suggested that the effects demonstrated are due to non-specific action at the nerve endings.

Adrenergic neuron blocking action of dehydroemetine.

Adrenergic neuron blocking action of dehydroemetine.

Effect of amphetamine on the uptake, release and effectiveness of xylocholine in the guinea-pig vas deferens.

Abstract Amphetamine sulphate will both reverse and prevent the adrenergic neuron blocking action of xylocholine (TM10 bromide) on the response of the guinea-pig isolated vas deferens to transmural electrical stimulation. A concentration of amphetamine sulphate capable of reversing the effect of xylocholine does not produce a significant reduction in the tissue concentration of 14C-TM10 iodide in the vas deferens. Although amphetamine reduces the rate of uptake of xylocholine, it does not prevent uptake. Comparisons of tissue concentrations with the degree of blockade produced in the normal and the amphetamine-treated vas deferens suggest that if the actions of amphetamine are to be accounted for entirely by displacement of xylocholine or by changes in uptake of xylocholine, only a very small percentage of the total tissue content of xylocholine can be involved in the production of its effects.

An adrenergic neuron blocking action of propranolol in isolated tissues

Abstract Propranolol was tested for adrenergic neuron blocking activity in three isolated sympathetically-innervated smooth muscle preparations; the rat vas deferens, rabbit ileum and rabbit ear artery. In each preparation propranolol impaired the responses to sympathetic stimulation without reducing the responses to added noradrenaline. This blocking action of propranolol resembled that of guanethidine in time of onset and persistence of blocking activity but, unlike blocking by guanethidine, was not reversed by (+)-amphetamine. Desipramine and noradrenaline also failed to reverse the blocking action of propranolol. In the rat vas deferens preparation lignocaine had a weaker and more transient sympathetic blocking action than propranolol. It is suggested that the sympathetic blocking action of propranolol may contribute to its antihypertensive effect in man.

An Adrenergic Neurone Blocking Action of Dimethylphenylpiperazinium

An Adrenergic Neurone Blocking Action of Dimethylphenylpiperazinium

Increased release of xylocholine (TM10) from guinea-pig vas deferens treated with amphetamine sulphate.

Abstract Although both NN-diethyl- and NN-dimethyl-, N-methyl-[14C]-2-(2,6-xylyloxy) ethylammonium iodide (14C-1DE10 iodide and 14C-TM10 iodide; xylocholine) are taken up by guinea-pig vas deferens to a similar extent in vitro, only TM10 reduced the response of the vas deferens to electrical stimulation. Prior incubation of vas deferens with 14C-1DE10 iodide or with 14C-TM10 iodide followed by measurement of the amount of each of these compounds eliminated from the tissue by repeated washing with Krebs solution, shows both compounds to be strongly retained by the tissue. Incorporation of 10−5 g/ml amphetamine sulphate in the wash fluid failed to modify the release of 14C-1DE10 iodide but produced a short-lived increase in the amount of 14C-TM10 iodide eliminated which reached a maximum approximately 10 min after administration of amphetamine. The additional 14C-TM10 iodide eliminated by amphetamine was about 5% of the total tissue 14C-TM10 iodide content; the possible role of this fraction is discussed in relation to the adrenergic neuronblocking action of 14C-TM10 iodide.

The actions of bretylium: adrenergic neurone blocking and other effects. 1959.

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare‐like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. A drenergic. nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5‐hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea‐pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.

The distribution of (-)-propranolol in the isolated rabbit iris.

It has been postulated that propranolol lowers the intraocular pressure by adrenergic neurone block. However, in the isolated iris of albino rabbits, there was only a small degree of cocaine-sensitive (i.e., neuronal) accumulation of 3H-(-)-propranolol, and none at all after pretreatment of the animals with reserpine. Moreover, after preloading of the iris with 3H-(-)-propranolol, veratridine failed to release any labelled material. Hence, any adrenergic neurone blocking action of propranolol is highly unlikely. Albino and pigmented irides were first exposed to 3H-(-)-propranolol and then washed out. The results and their compartmental analysis indicated an extensive binding of 3H-(-)-propranolol in or at pigment cells; the binding is characterized by a low dissociation constant. It is very likely that the initial binding and the subsequent slow dissociation from pigment cells explains the long duration of action of beta-adrenoceptor antagonists in human therapy.

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.

Recent studies of the actions of cholinomimetic drugs on adrenergic nerves and their implications for the cholinergic link hypothesis.

This review analyzes the results of recent studies of the actions of cholinomimetic drugs on adrenergic nerve terminals and their implications for the cholinergic link hypothesis. Thus far, evidence suggests that the only possible action of endogenous acetylcholine (ACh) present near noradrenaline (NA) stores is an inhibition of the release of NA from the adrenergic nerve terminals and that NA is released only when the action of acetylcholinesterase is inhibited. Nicotinic agents have been shown to act on adrenergic nerve terminal membranes, a finding that casts doubt on the proposed intraneuronal cholinergic sites for the action of endogenous ACh. Evidence also indicates that the mode of adrenergic neurone blocking action of bretylium and guanethidine is independent of the proposed cholinergic process in NA release. Current findings do not support the proposal that nicotinic agents in higher concentrations interfere with adrenergic neurotransmission. It is therefore concluded that nicotinic agents, in causing the release of NA from adrenergic nerve terminals, are merely exhibiting a pharmacological action and not mimicking the physiological function of ACh, as proposed by the cholinergic link hypothesis.

Adrenergic neuron blocking action of dehydrocorydaline isolated from Corydalis bulbosa

Dehydrocorydaline, an active principle of Corydalis bulbosa alkaloids, in concentrations of 10(-5) M to 5 x 10(-5)M inhibited relaxation and the concomitant release of (3H)-noradrenaline caused by 10(-4)M nicotine and electrical perivascular nerve stimulation in the taenia caecum of guinea pig. The same inhibitory effects were observed on contraction and release of (3H) noradrenaline in the sympathetic nerve-pulmonary artery preparation of rabbit. On the other hand, neither relaxation nor contraction caused by exogenously applied noradrenaline was affected. These results suggest that the inhibitory action of dehydrocorydaline on the relaxation or contraction, produced by nicotine and electrical nerve stimulation, is due to blockade of noradrenaline release from the adrenergic nerve terminals in both the taenia caecum and pulmonary artery. Participation of the adrenergic neuron blocking action of dehydrocorydaline in preventing experimental ulceration is discussed.

THE EFFECT OF PROPRANOLOL ON VASCULAR RESPONSES TO SYMPATHETIC NERVE STIMULATION

1. In an attempt to clarify the role of the sympathetic neurone in the antihypertensive action of propranolol, the effect of this drug on responses to lumbar sympathetic nerve stimulation has been studied in the perfused hind-limb of the dog. 2. No consistent reduction of maximal or submaximal responses to nerve stimulation was produced by propranolol (10 to 100 mug/kg). In contrast, potentiation of nerve-evoked response, as well as those to injected noradrenaline, usually occurred. Dexpropranolol (50 mug/kg) had no effect. 3. When neuronal uptake of noradrenaline was inhibited by desmethylimipramine or cacaine, no reduction in responses to sympathetic nerve stimulation was observed with propranolol. 4. No evidence was found, using alpha-adrenoceptor blocking drugs, that released transmitter stimulates beta-adrenoceptors in the blood vessels of the hind-limb. 5. No evidence has been found for the existence of an adrenergic neurone-blocking action of propranolol that might contribute to the antihypertensive activity in man.

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.

The relation between the adrenergic neurone-blocking and noradrenaline-depleting actions of some guanidine derivatives.

1 The effects of some guanidine derivatives, (-)-N-(1-phenylethyl) guanidine (PEG), guanethidine and debrisoquine have been investigated on the content and subcellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline from this organ during stimulation of the splenic nerve.2 PEG and guanethidine, at a dose of 5 mg/kg, produced adrenergic neurone blockade within 15 min and the same dose of debrisoquine produced blockade within 30 minutes.3 All three compounds produced a decrease of similar magnitude in the noradrenaline content of the high-speed particulate (P(2)) and supernatant (S) fractions of splenic homogenates; these actions were temporally correlated with the adrenergic neurone-blocking action of the compounds.4 PEG did not produce any further decrease in the noradrenaline content of the subcellular fractions at times up to 18 h after its administration; adrenergic neurone blockade was maintained throughout this period but had disappeared after 7 days when the noradrenaline content of the subcellular fractions was restored to control levels.5 Guanethidine, in contrast, caused a marked progressive loss of the transmitter from all subcellular fractions-an effect which was maximal 18 h after its administration but continued, as did the adrenergic neurone-blocking action, for at least 72 hours. This additional loss of noradrenaline, over and above that seen after 15 min, is unlikely to be connected with the adrenergic neurone-blocking action of the drug.6 Dexamphetamine both prevented and antagonized the neurone blockade and the subcellular noradrenaline-depleting action of PEG and guanethidine. The restoration of nerve function after administration of dexamphetamine to animals pretreated with 5 mg/kg of either of these compounds was temporally correlated with a selective repletion of the noradrenaline content of the supernatant fraction of the spleen.7 Larger doses (15 mg/kg) of PEG or guanethidine produced a selective depletion of noradrenaline in only the supernatant fraction of the spleen. This depletion was temporally correlated with the adrenergic neurone-blocking action of these compounds. The lack of effect of the compounds at this dose level on the noradrenaline contained in the P(2) fraction may be due to ;stabilization' of the store of noradrenaline in vivo which gives rise to this fraction on homogenization.8 It is suggested that the guanidine-type adrenergic neurone-blocking agents displace the noradrenaline which is readily available for release by nerve impulses, and that it is this action that may account for their sympathomimetic properties.9 The ability of these guanidines to impair the release of noradrenaline by nerve impulses could occur because whilst they are present within the neurone the ;nerve-releasable store', which may in these experiments appear in the supernatant fraction after homogenization, may be unable to refill with transmitter.

Possible role of adrenergic mechanisms in the systemic anti-inflammatory activity of acetic acid in rats

An attempt was made to determine whether or not the systemic anti-inflammatory activity of acetic acid, exerted upon either carrageenin or yeast-induced paw oedema in rats, was mediated via adrenergic mechanisms. It was found that the anti-inflammatory activity of acetic acid was unaffected by both α- and β-adrenoceptor antagonists, prior depletion of catecholamine stores, acute denervation of the hind paw, and by adrenergic neurone blockade. The reduction, by guanethidine, of the inhibitory effect of acetic acid on carrageenin-induced oedema appeared to be unrelated to the adrenergic neurone-blocking action. The results that adrenergic mechanisms play no significant role in the anti-inflammatory activity of acetic acid.

Some characteristics of the adrenergic neurone blocking action of dehydroemetine

The uptake of dehydroemetine by adrenergic neurones was studied indirectly by testing the ability of various procedures to prevent or reverse adrenergic neurone blockade in the periarterially stimulated rabbit isolated ileum. Adrenergic neurone blockade was prevented but not reversed by equilibration with dehydroemetine at low temperature (0 degrees C), in the absence of sodium or in the presence of tetrodotoxin. Noradrenaline, cocaine, potassium deprivation and potassium excess did not modify the adrenergic neurone blocking action of dehydroemetine.

Some factors affecting the neuron blocking action of guanethidine, xylocholine, bretylium and debrisoquin.

The uptake of guanethidine (3.3×10-5 M), debrisoquin (8.4×10-4 M), bretyliun (5.0×10-4 M) and xylocholine (1.0×10-3 M) by adrenergic neuron was studied indirectly by testing the ability of noradrenaline (NA) regarding low temp. or sodium-deprivation to prevent or reverse adrenergic neuron blocking action in the indirectly stimulated guinea-pig hypogastric nerve vas deferens preparations. NA (3.0×10-3 M) completely prevented the neuron blocking action of all the four blockers but reversed only that of bretylium. Exposure of preparations to a low temp. (0°C) prevented the neuron blocking action of all the four blockers but did not reverse that of anv one blocker. The adrenergic neuron blocking action of guanethidine was partially prevented but was not reversed by sodium-deprivation. Sodium-deprivation neither prevented nor reversed the neuron blocking action of the other three blockers. It is concluded that guanethidine shares the uptake mechanism of NA for transport across the neuron while debrisoquin, bretylium and xylocholine appear to be transported differently.

Quantitative analysis on isolated organs of the autonomic blocking properties of indoramin hydrochloride (Wy 21901).

1. Indoramin is a competitive alpha-adrenoceptor blocking agent on the guinea-pig isolated vas deferens and aortic strip; the pA(2) value on the aorta is 7.4.2. Indoramin is devoid of beta-adrenoceptor blocking activity on the guinea-pig isolated trachea (10(-4)M) and the Langendorff preparation of the rabbit heart (10(-6)M). It also has no adrenergic neurone blocking action on the Finkleman preparation of the rabbit small intestine (10(-5)M).3. On the Langendorff preparation of the rabbit isolated heart, indoramin (above 10(-6)M) has cardio-inhibitory properties similar to those of propranolol.4. On the guinea-pig isolated ileum (10(-5)M) and trachea (10(-6)M), indoramin is devoid of anticholinergic activity, but has a potent antihistamine action which satisfies the criteria for competitive antagonism; the pA(2) value for this antagonism on the ileum is 8.2.5. Indoramin antagonizes 5-hydroxytryptamine on the rat isolated fundus and ileum; the pA(2) value for the antagonism on the ileum is 6.0.

Modification by AZ-55, Guanethidine and Bretylium of Responses of Atria and Aortic Strips to Transmural Stimulation

A new antihypertensive drug (1), l-cyclohexyl-3-guanidinoazetidine sulfate (AZ-55), structurally resembles guanethidine. It is widely known that guanethidine depresses peripheral adrenergic nerve function by preventing release ot adrenergic nerve transmitters (reviewed by Boura and Green, 2). Bretylium also possesses the adrenergic neuron blocking action, but accumulated data point to the fact that bretylium and guanethidine fail to share all mechanisms of the blocking action (2).

MODIFICATION BY AZ-55, GUANETHIDINE AND BRETYLIUM OF RESPONSES OF ATRIA AND AORTIC STRIPS TO TRANSMURAL STIMULATION

Abstract A new antihypertensive drug (1), l-cyclohexyl-3-guanidinoazetidine sulfate (AZ-55), structurally resembles guanethidine. It is widely known that guanethidine depresses peripheral adrenergic nerve function by preventing release ot adrenergic nerve transmitters (reviewed by Boura and Green, 2). Bretylium also possesses the adrenergic neuron blocking action, but accumulated data point to the fact that bretylium and guanethidine fail to share all mechanisms of the blocking action (2).