Adrenergic Neurone Blocking Research Articles

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.

A multi-centre assessment of the role of oxprenolol in the treatment of hypertensive patients

SummaryIn a multi-centre assessment of 887 hypertensive patients, treatment with the nonselective ^-receptor antagonist oxprenolol was substituted, in part or completely, for the adrenergic neurone blockers, bethanidine, debrisoquine or guanethidine. The results showed that after the gradual introduction, over approximately 10 weeks, of oxprenolol in a median daily dose of 200 mg. (range 80 mg. to 480 mg.) there was a significant reduction in blood pressure, particularly systolic levels. The incidence of troublesome side-effects associated with the three adrenergic neurone blockers, such as postural and exercise hypotension, tiredness, diarrhoea and impotence, was markedly reduced, with an accompanying improvement in the quality of the patient's life.

A NEW GUANIDINE DERIVATIVE: DISSOCIATION OF THE ADRENERGIC NEURON BLOCKING ACTIVITY FROM LOCAL ANESTHETIC ACTIVITY

AbstractEffects of 4-7-exo-methylene-hexahydroisoindoline-ethyl-guanidine hemi-sulfate (No. 865-123), a new guanidine derivative, on adrenergic neurons and its local anesthetic activity were investigated in comparison with guanethidine. Both derivatives produced in a dose-dependent manner a progressive irreversible reduction of positive chronotropic and contractile responses to postganglionic sympathetic nerve stimulation in isolated rabbit atria. The time course of the reduction by No. 865-123 was somewhat slower. In dogs administered both agents, the pressor response to carotid occlusion was reduced and that to exogenous noradrenaline was potentiated with a slight decrease in blood pressure. Noradrenaline stores in the heart and spleen of rats were also depleted to a similar extent. In the guinea pig weal method, guanethidine acted as a potent local anesthetic with a slow onset and a prolonged action as compared to procaine. No. 865-123 revealed no more anesthetic activity than did saline. It is unlikely that the local anesthetic activity of the guanidine derivatives contributes to the adrenergic neuron blocking activity.

Pharmacodynamic Actions of (S)-2-[4,5-Dihydro5-Propyl-2 (3H)-Furylidene]-1, 3-Cyclopentanedione (Oudenone)

The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furylidene]-l,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10-40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5–200 mg/kg p.o.) caused a doserelated decrease in the systolic blood pressure. The initial pressor effect was diminished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100–600 μg/kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400–800 μg/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimulation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic, -histaminergic, beta-adrenergic and adrenergic neuron blocking properties.

Effects of beta-adrenoreceptor blocking drugs on adrenergic transmission.

The peripheral actions of beta-adrenoreceptor antagonists on adrenergic transmitter mechanisms have been reviewed. In addition to receptor blockade, beta-adrenoreceptor antagonists may in high concentrations inhibit neuronal uptake of noradrenaline; inhibit monoamine oxidase; inhibit the uptake of noradrenaline into transmitter storage vesicles and inhibit the extraneuronal uptake of noradrenaline. High concentrations of beta-adrenoreceptor antagonists (threshold about 30 muM) also release noradrenaline from intraneuronal stores; however, their intrinsic sympathomimetic activity is generally attributed to their partial agonist property. Beta-adrenoreceptor antagonists possess adrenergic neurone blocking activity and quinidine-like or local anaesthetic activity. The existance of a positive feedback mechanism involving prejunctional beta-adrenoreceptors is discussed. It is suggested that bradycardia produced by beta-adrenoreceptor antagonists is due to blockade of the action of circulating catecholamines or of transmitter noradrenaline at cardiac extrajunctional beta-adrenoreceptor sites.

Pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2-(3H)-furylidene]-1,3-cyclopentanedione (oudenone).

The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furylidene]-1,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10--40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5--200 mg/kg p.o.) caused a dose-related decrease in the systolic blood pressure. The initial pressor effect was diminished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100--600 mug/kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400--800 mug/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimulation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic,-histaminergic, beta-adrenergic and adrenergic neuron blocking properties.

The effects of lysergic acid diethylamide on the response to field stimulation of the rat vas deferens and the rat and cat anococcygeus muscles.

1. The effect of lysergic acid diethylamid (LSD) on the response to field stimulation in vitro of the rat vas deferens and anococcygeus muscle was examined. 2. LSD in concentrations from 10(-9) to 10(-6) M caused an increase in tone or rhythmic activity in both tissues, effects identical to those produced by guanethidine or tyramine. The motor effects of all three drugs were abolished by phentolamine 2 x 10(-6) M. Methysergide 2 x 10(-7) M given before LSD reduced the motor effect but was ineffective once the LSD contraction had developed. 3. LSD 10(-9) to 10(-6) M reduced and eventually abolished the response to motor adrenergic nerve stimulation in the anococcygeus muscle with no effect on the response to noradrenaline (NA) and no evidence of differential sensitivity according to the number of stimulating pulses. In the vas deferens LSD abolished the initial twitch component with no effect on the secondary slow contraction. LSD had no effect on the response to inhibitory nerve stimulation in the anococcygeus. 4. These results suggest that in the anococcygeus LSD closely resembles guanethidine in its effects as an adrenergic neurone blocking drug with indirect sympathomimetic actions. In the vas deferens these properties would explain the block of the initial twitch component in the motor response to field stimulation and the increase in rhythmic activity but do not explain the resistance of the secondary slow component of the motor response.

Centrally mediated hypotension and bradycardia by methysergide in anesthetized dogs

In anesthetized dogs, methysergide (1 and 3 mg/kg i.v.) caused reductions in systolic and dialostic blood pressure, heart rate, left ventricular pressure and peripheral resistance. Cardiac output was unchanged because of an increase in stroke volume. Methysergide exhibited no α-receptor, ganglion, or adrenergic neuron-blocking properties nor did it have marked direct vasodilator action. The BCO, but not the orthostatic, reflex was severely inhibited by the drug, evidence for a central inhibitory action. Atropine, vagotomy or carotid sinus debuffering had little or no effect on the hypotension and bradycardia produced by methysergide, whereas guanethidine pretreatment essentially abolished these effects. Direct intracerebroventricular administration of small doses of methysergide (0.2 mg/kg) caused significant hypotension and bradycardia. It is concluded that methysergide causes centrally mediated hypotension and bradycardia, the mechanism of which is not clearly understood.

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 effects of drugs or denervation on thymidine uptake into rat regenerating liver

Thymidine incorporation into regenerating liver was unaffected by the α-receptor antagonist tolazoline but was inhibited by the β-receptor antagonist propanolol, by the adrenergic neurone blockers guanethidine and reserpine and by degenerative section of the hepatic adrenergic nerves. Paradoxically 6-hydroxydopamine stimulated thymidine incorporation into regenerating liver. It is concluded that catecholamines, derived at least partly from hepatic adrenergic nerves and acting on β-receptors, facilitate thymidine incorporation into regenerating liver.

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.

COCAINE-LIKE EFFECT OF KETAMINE ON VASCULAR ADRENERGIC NEURONES

The influence of ketamine on adrenergic and cholinergic responses was studied in the rabbit pulmonary artery in vitro. Ketamine and cocaine potentiated smooth muscle contractions elicited by nonadrenaline, adrenaline and transmural electrical stimulation of adrenergic neurone terminals. Arterial contractions elicited by tyramine were enhanced by ketamine, while cocaine blocked them. Ketamine moved the concentration-response curve of carbachol slightly to the right. Nicotine-induced contractions were blocked by ketamine and cocaine. The adrenergic neurone blocking effect of bretylium and dimethylphenylpiperazinium on the response to transmural stimulation was prevented by ketamine. The uptake of 3H-noradrenaline by rabbit isolated aorta was inhibited by ketamine and cocaine. It is concluded that ketamine inhibits the membrane amine pump in the terminals of postganglionic adrenergic neurones in a cocaine-like manner.

Awareness and experience of general practitioners of selected drug interactions.

The awareness of general practitioners of selected adverse drug interactions has been assessed. The drugs studied included adrenergic neurone blockers, warfarin, antidiabetic agents, and monoamine oxidase inhibitors. The findings must be interpreted with caution but they suggest that there is a clear need to improve the effectiveness of communication of information about adverse drug interactions if unnecessary iatrogenic disease is to be avoided.

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.

Cocaine-like effect of ketamine on vascular adrenergic neurones

The influence of ketamine on adrenergic and cholinergic responses was studied in the rabbit pulmonary artery in vitro. Ketamine and cocaine potentiated smooth muscle contractions elicited by nonadrenaline, adrenaline and transmural electrical stimulation of adrenergic neurone terminals. Arterial contractions elicited by tyramine were enhanced by ketamine, while cocaine blocked them. Ketamine moved the concentration-response curve of carbachol slightly to the right. Nicotine-induced contractions were blocked by ketamine and cocaine. The adrenergic neurone blocking effect of bretylium and dimethylphenylpiperazinium on the response to transmural stimulation was prevented by ketamine. The uptake of 3H-noradrenaline by rabbit isolated aorta was inhibited by ketamine and cocaine. It is concluded that ketamine inhibits the membrane amine pump in the terminals of postganglionic adrenergic neurones in a cocaine-like manner.

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.

Further studies on the adrenergic neuron blocking activity of some -adrenoceptor antagonists and guanethidine.

Abstract The effects of low (0.2) and high (20 μg ml−1) concentrations of (±)- and (+)-propranolol, (±)-, (+)- and (-)-sotalol and guanethidine were tested for their ability to reduce responses to sympathetic stimulation in the isolated vas deferens preparation from the guinea-pig. At 0.2 μf ml−1 all drugs produced a slowly developing reduction in the responses to sympathetic stimulation while responses to noradrenaline were largely unchanged. The blockade, which was similar in extent in all six compounds, was reversed by (+)-amphetamine but not by washing. With high concentrations of and (±)-propranolol and guanethidine, the block was rapid in onset and rate and responses to noradrenaline were potentiated. The block was reversed by washing and unaffected by (+)-***amphetamine. Sotalol and its isomers, which possess little non-specific depressant activity, had qualitatively similar actions at 0.2 and 20 μg ml−1. At the latter concentration responses to noradrenaline were potentiated. The results suggest that low concentrations of the β-adrenoceptor antagonists produce a blockade which is typical of guanethidine-like drugs. At high concentrations non-specific depressant (local anaesthetic) actions of propranolol and its isomers are largely responsible for the blockade. A similar mechanism may also operate when high concentrations of guanethidine are used.

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.

Drug interactions in patients on long-term oral anticoagulant and antihypertensive adrenergic neuron-blocking drugs.

The occurrence of drug interactions was studied in outpatients on anticoagulant or adrenergic neuron-blocking drugs. In the anticoagulant group (254 patients) a theoretical potential drug interaction with warfarin was noted in 33% of patients with drugs supplied by prescription and in 30% of patients with drugs taken as self-medication, though a probable adverse drug interaction was documented in only 9% of patients. The deficiency in the transfer of information about current drug therapy and the lack of awareness of patients about the hazards of anticoagulant therapy was clear.In the 64 patients on the adrenergic neuron-blocking drugs guanethidine, bethanidine, or debrisoquine a theoretical potential drug interaction was noted in 34%, but a probable adverse drug interaction was documented in only three patients. Further studies are required of other well-recognized groups of patients on drugs which are known to interact to assess the relevance and clinical importance of the formidable lists of interactions which are now available to doctors who prescribe drugs.