Action Of Guanethidine Research Articles

Studies on the dual action of guanethidine in sympathetic nerves.

P. Lundborg and R. E. Stitzel. Studies on the dual action of guanethidine in sympathetic nerves. Acta physiol. scand. 1968. 72. 100–107. Evidence is presented indicating that guanethidine inhibits both the transport of amines through the nerve cell membrane and an uptake mechanism present in amine-storing granules. In vivo the onset of membrane pump blockade is the more rapid process, but inhibition of granular uptake is more long-lasting. In vitro studies demonstrate that guanethidine can inhibit the uptake of 14C-adrenaline into bovine adreno-medullary granules. The depletion of 3H-metaraminol seen after guanethidine administration may result from a reserpine-like action on the amine storage granules and/or a protriptyline-like action on the membrane pump. It is suggested that the membrane pump inhibiting ability possessed by guanethidine, but not reserpine. may account for the sympathomimetic activity and exogenous amine potentiation which often accompanies guanethidine, but not reserpine, administration.

Antagonism of the antihypertensive action of guanethidine sulfate by desipramine hydrochloride

In five studies, the antihypertensive effect of guanethidine sulfate was significantly reversed by two antidepressants, desipramine hydrochloride and protriptyline hydrochloride. This reversal was not immediate, requiring many hours before maximum antagonism was seen. After discontinuation of desipramine, an average of five days was required for the antihypertensive action of guanethidine to reappear. Three similar studies demonstrated that the antihypertensive action of bethanidine sulfate, a guanethidine-related drug, was reversed by desipramine also. The reversal of bethanidine was more rapid than with guanethidine, with almost maximum antagonism appearing within four hours, while the delay in the reappearance of bethanidine's antihypertensive action was similar to that seen with guanethidine. A blockade by the antidepressants of the uptake of the antihypertensives to their active site within the sympathetic neuron is suggested as a mechanism for the antagonism.

Antagonism of the Antihypertensive Action of Guanethidine Sulfate by Desipramine Hydrochloride

In five studies, the antihypertensive effect of guanethidine sulfate was significantly reversed by two antidepressants, desipramine hydrochloride and protriptyline hydrochloride. This reversal was not immediate, requiring many hours before maximum antagonism was seen. After discontinuation of desipramine, an average of five days was required for the antihypertensive action of guanethidine to reappear. Three similar studies demonstrated that the antihypertensive action of bethanidine sulfate, a guanethidine-related drug, was reversed by desipramine also. The reversal of bethanidine was more rapid than with guanethidine, with almost maximum antagonism appearing within four hours, while the delay in the reappearance of bethanidine's antihypertensive action was similar to that seen with guanethidine. A blockade by the antidepressants of the uptake of the antihypertensives to their active site within the sympathetic neuron is suggested as a mechanism for the antagonism.

THE POTENTIATION OF THE RESPONSES TO NORADRENALINE AND ISOPRENALINE OF THE GUINEA‐PIG ISOLATED TRACHEAL CHAIN PREPARATION BY DESIPRAMINE, COCAINE, PHENTOLAMINE, PHENOXYBENZAMINE, GUANETHIDINE, METANEPHRINE AND COOLING

THE POTENTIATION OF THE RESPONSES TO NORADRENALINE AND ISOPRENALINE OF THE GUINEA‐PIG ISOLATED TRACHEAL CHAIN PREPARATION BY DESIPRAMINE, COCAINE, PHENTOLAMINE, PHENOXYBENZAMINE, GUANETHIDINE, METANEPHRINE AND COOLING

Interaction between acetylcholine and guanethidine on sensory C fibres

Intravenously of intra-arterially injected guanethidine and hexamethonium blocked the afferent discharge produced by acetylcholine in C fibres of the rabbit saphenous nerve, without impairing the response to touch or to KCl. In contrast, the local anaesthetic lignocaine was effective only by intra-arterial injection and all effective doses abolished responses to acetylcholine, KCl and touch. The results are discussed in relation to the adrenergic neurone blocking action of guanethidine. Saphenous nerve Saphenous nerve compound action potential response to hexamethonium response to acetylcholine response to KCI response to carbachol response to lignocaine response to dexamphetamine response to methacholine response to dimethylphenylpiperazinium response to nicotine response to guanethidine response to stroking

The actions of some adrenergic neurone blocking drugs at cholinergic junctions

The effects of some adrenergic neurone blocking drugs on the responses of isolated organs to parasympathetic nerve stimulation were examined. When the parasympathetic nerves were stimulated preganglionically, the responses were blocked by moderate concentrations of adrenergic neurone blocking drugs. However, responses to postganglionic stimulation were much less effectively blocked. The main site of this blocking action therefore appears to be at the ganglionic synapse. The action of guanethidine on the neuromuscular junction was also investigated using the hen sciaticgastrocnemius preparation, the chick biventer cervicis and the frog rectus muscle. Guanethidine was found to exert a postjunctional neuromuscular blocking action similar to that of tubocurarine. The significance of the actions of adrenergic neurone blocking drugs at cholinergic sites is discussed in relation to the mechanism of adrenergic neurone blockade.

Effects of ionic alterations on various sympathetic nerve-smooth muscle preparations.

SummaryIsolated preparations of guinea pig, rat and rabbit vas deferens, and Finkleman preparations of rabbit ileum and rat and guinea pig colon have been used to study the effects of ionic alterations on responses to added noradrenaline and to stimulation of sympathetic nerves. With vas deferons preparations it was found that, depending on the species used, these responses were affected differently by certain of the ionic alterations. Intestinal preparations from the three species behaved more consistently.Species difierences in vas deferens preparations were seen in response to the following ionic changes: (i) reduction in sodium chloride (replaced by sucrose); (ii) absence of potassium; (iii) increasing potassium to 15 and 20 mM, and (iv) raising calcium to 5–10 mM. Lowering calcium to 0·25–0·5 mM depressed the responses of vas deferers from all three species.Intestinal preparations showed a uniform depression in 7·5–10 mM calcium. Raised potassium depressed the response to sympathetic nerve stimulation in all three species, though the response to noradrenaline was affected differently with different species.The interactions of drugs and ions also showed differences with the three species. While 15 mM potassium could reverse the blocking action of both guanethidine and procaine on guinea pig vas deferens, it was almost ineffective on rat vas deferens, and on intestinal preparations raised potassium increased the blocking action of these drugs. High calcium, which enhanced the effects of sympathetic nerve stimulation in varions tissues, failed to modify the blocking action of guanethidine.

Dual actions of guanethidine on amine uptake mechanisms in adrenergic neurons

By using a technique which allows the differentiation in vitro between amine uptake mechanisms in adrenergic neurons, evidence is presented that guanethidine at 10 −4 M inhibits both a membrane amine pump and an intracellular amine-concentrating mechanism. At a low concentration of guanethidine (5 × 10 −6 M) the intracellular mechanism is preferentially inhibited. The action of guanethidine on the membrane pump is readily removed by washing. It is concluded that at clinical doses, guanethidine acts only on the intracellular mechanism, thus leading to depletion of norepinephrine.

Peripheral noradrenaline and adrenergic transmission in the rat.

Peripheral noradrenaline and adrenergic transmission in the rat.

Anti-arrhythmic action of bretylium.

THE anti-arrhythmic action of guanethidine which was found to prevent a type of clinical paroxysmal ventricular tachycardia1 and prevented experimental atrial fibrillation2 suggested that other agents which interfere with the release of catecholamines might exhibit similar effectiveness.

Effect of guanethidine and bretylium tosylate on systemic and renal hemodynamics in essential hypertension

1. 1. The acute administration of guanethidine and bretylium tosylate lowered arterial blood pressure through reduction in cardiac output. In the tilted position, mean arterial blood pressure dropped even more, because of greater diminution of cardiac output. Guanethidine also lowered total peripheral resistance in the tilted position. 2. 2. Under the long term use of guanethidine, the drop in arterial blood pressure was due to a reduction in total peripheral resistance, while under bretylium tosylate it was produced by a reduction of cardiac output and total peripheral resistance. 3. 3. Glomerular filtration rate and renal plasma flow decreased under the acute administration of both drugs. After a certain period of time under the use of bretylium tosylate, renal hemodynamics recovered their previous values while cardiac output and mean arterial blood pressure remained reduced, indicating that the changes in renal and systemic hemodynamics were independent of each other. 4. 4. The acute administration of guanethidine and bretylium tosylate increased sodium and water reabsorption probably as a result of increase aldosterone secretion. The reduction in urinary sodium-potassium concentration ratio under the action of guanethidine supports this assumption; bretylium tosylate, however, does not affect this ratio. Another explanation could be that on lowering perfusion pressure, water and sodium reabsorption are increased.

MODIFICATION OF THE EFFECTS OF GUANETHIDINE ON CARDIAC CATECHOL AMINES BY VARIOUS AGENTS.

A study has been made of the effect of injections of guanethidine in rats, in depleting catechol amines from the whole cardiac ventricles and from various subcellular fractions. Unlike reserpine, guanethidine first affected the concentration of the amines in the soluble fraction of the cell. Neither [2-(2,6-dimethylphenoxy)-propyl]trimethylammonium chloride monohydrate (beta-methyl xylocholine) nor hemicholinium affected the endogenous catechol amines or the uptake of injected noradrenaline, but each significantly reduced the action of guanethidine in depleting catechol amines. Administration of choline chloride after hemicholinium reversed its influence on guanethidine depletion. In cats, cocaine potentiated the pressor response to noradrenaline, but antagonized the response to tyramine and guanethidine, while bretylium and N-o-chlorobenzyl-N'N"-dimethylguanidine sulphate (BW392C60) potentiated the responses to noradrenaline, tyramine and guanethidine.

THE CHRONOTROPIC ACTIONS OF GUANETHIDINE AND RESERPINE ON THE ISOLATED DOG HEART.

Administration of reserpine to a heart-lung preparation about 140 min after the addition of guanethidine, when the chronotropic action of the latter had levelled off, produces a rise in heart rate with a peak equal to that observed when reserpine is given alone. Addition of reserpine to a heart-lung prepared from reserpinized dogs after partial repletion of the stores with noradrenaline does not increase the heart rate in contrast to the action of guanethidine which under the same conditions results in a marked increase in rate. These experiments indicate that guanethidine and reserpine act on different sites and lend further support to the concept that at least two noradrenaline stores exist.

Guanethidine類似化合物の薬理学的研究 (第2報)

Effects of anesthetics, sympathomirnetic amines, reserpine, phenethylhydrazine, and cocaine on hypotensive action of guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate were examined in rats.Guanethidine possessed a lasting hypotensive action in urethane anesthetized rats, whereas only temporary depression was observed in rats anesthetized with pentobarbital sodium, thiopental sodium, secobarbital sodium, or chloralose. The hypotensive action of guanethidine decreased after previous administration of reserpine and cocaine. Furthermore, guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate showed hypertensive action after pretreatment with phenethylhydrazine in rats anesthetized with urethane.The pressor action of adrenaline and noradrenaline were potentiated, but effect of tyramine was inhibited by guanethidine and [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate. These were also observed after section of the spinal cord at C1-C2.It was concluded that hypotensive action of [2-(hexahydro-1-azepinyl)ethyl]guanidine sulfate and guanethidine was mainly due to the depletion of endogeneous catecholamines from peripheral stores.

The action of guanethidine with particular reference to the sympathetic nervous system.

It has been suggested that guanethidine can release and then deplete postganglionic sympathetic nerve endings of noradrenaline. However, no release of noradrenaline from postganglionic nerve endings or from the adrenal medulla by guanethidine was found by direct experiment. Although release of noradrenaline from postganglionic sympathetic nerve endings in response to nerve stimulation was rapidly reduced and finally abolished by guanethidine, the drug did not appear to affect the release of catechol amines from the adrenal medulla in response to splanchnic nerve stimulation. The nature of the action of guanethidine is discussed, and it is concluded that it blocks the effect of postganglionic sympathetic nerve stimulation by interfering with the synthesis of transmitter and that it also has a direct sympathomimetic effect.

Evidence for a competitive antagonism of guanethidine by dexamphetamine.

After guanethidine had blocked the response of the cat nictitating membrane to sympathetic nerve stimulation, dexamphetamine restored the responses to all frequencies of stimulation. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated sympathetically innervated rabbit ileum; the evidence suggests that the antagonism was competitive. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated hypogastric nerve-vas deferens preparation of the guinea-pig. Doses of dexamphetamine, larger than those required to antagonize the blocking action of guanethidine, abolished the responses of the nictitating membrane, ileum and vas deferens to nerve stimulation. Dexamphetamine did not influence the depletion of noradrenaline by guanethidine in the heart and spleen of rabbits. The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings.

Pharmacodynamic actions of the newer autonomic drugs used in the treatment of essential hypertension ∗

The pharmacodynamic actions of the more recently available autonomie agents employed in the treatment of hypertension have been summarized. The agents discussed include guanethidine (Ismelin) and bretylium (Darenthin), both of which produce selective blockade of the sympathetic nervous system, and methyl-dopa (Aldornet), an inhibitor of aromatic amino acid decarboxylase. Available evidence indicates that guanethidine and bretylium inhibit transmission of nerve impulses over sympathetic pathways by an action located in postganglionic adrenergic neurons. This action, demonstrated directly in laboratory animals, probably occurs in man and forms the basis for their antihypertensive actions. The mode of action of guanethidine may involve a latent depletion of norepinephrine, the sympathetic transmitter, from adrenergic neurons. Bretylium, however, apparently blocks release of the transmitter in response to the nerve impulse without causing its depletion. Guanethidine may have a similar action early after its administration. Methyldopa has been demonstrated to inhibit the decarboxylation of several aromatic amino acids including dihydroxyphenylalanine and 5-hydroxytryptophan. In laboratory animals, it causes a short-lasting decrease in serotonin levels in the brain and a considerably longer-lasting decline in tissue levels of norepinephrine both in the brain and peripheral tissues. Although this action resembles effects of rcserpine and guanethidine, it is not associated with disruption in transmission over sympathetic pathways as is the case with the latter agents. The mechanism and site of the antihypertensive action of methyldopa in man or laboratory animals is unresolved at present. It is not yet clear whether its catecholamine-de-pleting or decarboxylase inhibitory activity is responsible for its antihypertensive action in some as yet undefined manner. Additional studies are required to assess the importance of these actions.

Studies on the action of guanethidine on the central nervous system and on the norepinephrine content of the brain

Studies on the action of guanethidine on the central nervous system and on the norepinephrine content of the brain

Reserpine and guanethidine action on peripheral stores on catecholamines

Reserpine and guanethidine action on peripheral stores on catecholamines

Effect of drugs on the noradrenaline content of brain and peripheral tissues and its significance.

Large single doses of methoserpidine (12 mg/kg) given to rabbits lowered the noradrenaline content of sympathetic ganglia but not that of brain; no sedation was observed. Cats responded to doses ranging from 12 to 0.5 mg/kg with loss of noradrenaline from ganglia as well as from brain, and were sedated by the drug. The effect in man resembles that in the rabbit. Only within the group of reserpine-like drugs do sedation and loss in hypothalamic noradrenaline run parallel. These effects are therefore not causally related. Guanethidine lowers the noradrenaline content of sympathetic ganglia (cats and rabbits), but this effect does not explain the blocking action of the drug on the adrenergic nerve. Effects on the noradrenaline of the brain are variable and may be caused reflexly rather than by direct central action of guanethidine. Repeated intravenous injections of dimethylphenylpiperazinium iodide for a period of 4 hr did not produce any significant change in the noradrenaline content of ganglia or brain of rabbits. In contrast, dexamphetamine (20 mg/kg) produced a small but significant mean fall in noradrenaline content of the superior cervical ganglia and in that of the brain, but the effects were not seen in every rabbit. Prolonged administration of the mono-amine oxidase inhibitors pheniprazine and phenylhydrazinobutane raised the noradrenaline content of the brain of rabbits but not that of cats, whereas it raised the noradrenaline of the ganglia of cats but not (or rarely) that of rabbits. The question of correlation between a rise in the noradrenaline content of the brain and certain clinical signs is discussed. Finally, a comparison is made in rabbits between the changes produced by drugs in the noradrenaline content of the heart and of the superior cervical ganglion. The changes run parallel and are only occasionally more pronounced in the heart.