Neuronal Blocker Research Articles

Bretylium and the degeneration contraction of the sympathetically innervated periorbital smooth muscle in the rat.

AbstractThe ability of bretylium to delay the start of the degeneration contraction of the sympathetically innervated periorbital muscle has been studied in conscious rats. The sympathomimetic and neuron blocking action of bretylium at the doses most frequently used were also tested. A low dose, 0.5 mg/kg, that induced no measurable neuron block still delayed. The delay caused by local injection into the muscle exceeded the duiation of the neuron block. These findings indicate that the bretylium‐induced delay is not caused by neuron block and that the delaying action mainly is exerted on the terminal parts of the neurons. Bretylium given repeatedly postponed the onset of the degeneration contraction at least 6 to 10 hrs. Later the processes responsible for the degeneration contraction appeared to develope despite the treatment. Within 4 hrs preceding or just including the start of the degeneration contraction the time of injection was very critical for the effect of bretylium on the time course of the contraction. An injection of bretylium during an ongoing degeneration contraction interrupted the contraction and displaced the latter part for several hrs. Before the interruption the drug seemed to enhance the transmitter release. It appeared that early during the degeneration contraction there are nerve endings at different stages of degeneration on which bretylium acts differently.

Relaxations of the isolated portal vein of the rabbit induced by nicotine and electrical stimulation

1. A pharmacological analysis of the inhibitory innervation of the isolated portal vein of the rabbit has been made.2. In untreated preparations, transmural stimulation elicited a long-lasting relaxation at low frequencies (0.2-1 Hz); at higher frequencies a contraction followed by a prolonged after-relaxation occurred. Tetrodotoxin abolished the contractions but a higher dose was required to abolish the relaxations. Veratrine lowered the threshold of stimulation for producing relaxations in the untreated vein. The relaxations were unaffected by hyoscine or hexamethonium. They were reduced or altered by antagonists of alpha-adrenoceptors for catecholamines and by adrenergic neurone blockade. They were sometimes slightly reduced by antagonists of beta-adrenoceptors.3. In the presence of antagonists of alpha-adrenoceptors, electrical stimulation elicited relaxations which increased with frequency of stimulation and became maximal at 20-30 Hz. These relaxations were partially reduced by antagonists of beta-adrenoceptors, or by adrenergic neurone block; the antagonisms were more pronounced at the higher frequencies of stimulation. Noradrenaline also caused relaxations which were abolished by beta-adrenoceptor blocking drugs. Cocaine increased the sensitivity to noradrenaline by 7-8 fold after alpha-adrenoceptor blockade but had little or no effect on the relaxations induced by electrical stimulation at high frequencies.4. In the presence of antagonists of alpha- and beta-adrenoceptors, or adrenergic neurone blocking agents, or in veins taken from rabbits pretreated with reserpine, electrical stimulation elicited rapid relaxations which were greatest at 20-30 Hz. These relaxations were increased by veratrine and abolished by tetrodotoxin or by storing the vein for 9 days at 4 degrees C. They were unaffected by antagonists of acetylcholine, or by dipyridamole.5. Prostaglandins E(1), E(2) and F(2alpha) inhibited contractions elicited by electrical stimulation and noradrenaline, but in higher doses caused contractions themselves.6. Nicotine (10(-6)-10(-5) g/ml) relaxed the portal vein; higher concentrations elicited mixed inhibitory and excitatory effects. All these effects were abolished by tetrodotoxin, cocaine, hexamethonium or storage. The contractor effects were abolished by drugs or procedures that blocked adrenergic mechanisms.7. The relaxations produced by nicotine in untreated preparations and in veins from rabbits pretreated with reserpine were mediated mainly by a non-adrenergic non-cholinergic nervous mechanism. Relaxations induced by nicotine in the presence of antagonists of a-adrenoceptors were only partially antagonized by antagonists of f3-adrenoceptors.8. It was concluded that all the effects of nicotine and transmural stimulation were mediated by nerves. Part of the inhibitory effects was mediated by non-adrenergic, non-cholinergic nerves.

Pharmacological actions of phosphocholine 2,6-xylyl ether bromide (phospho-TM10; PTM10).

Abstract PPP-Trimethyl-2-(2,6-xylyloxy)ethylphosphonium bromide (PTM10; phospho-TM10), the phosphorus analogue of xylocholine (TM10), has been found to possess local anaesthetic, α-adrenoceptor and ganglion blocking properties. It also shows a blocking action at the neuromuscular junction but has no detectable adrenergic neuron blocking properties. The relation of these results to the ‘cholinergic link” hypothesis of Burn and Rand is discussed.

The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea-pig.

1. In isolated rat mesentery preparations, intra-arterial injection of the following drugs rapidly suppressed vasoconstrictor responses to sympathetic nerve stimulation: bretylium (75-100 mug), guanethidine (10-20 mug) and bethanidine (20-30 mug); with phenoxypropylguanidine (15-30 mug) the onset of blockade was slower. The blockade caused by these or higher concentrations was rapidly abolished by intra-arterial injection of amphetamine (100 mug) as also was the blockade caused by infusing bretylium or guanethidine for 10-20 min. Partial blockade was produced by 20 mug of reserpine and this was only slightly and briefly antagonized by amphetamine.2. In mesentery preparations taken from rats 24 h after subcutaneous injection of bretylium 50 mg/kg, guanethidine 10 mg/kg, phenoxypropylguanidine 10 mg/kg or reserpine 0.1 mg/kg, responses to sympathetic nerve stimulation were greatly impaired. Only in the preparations from the bretylium-treated rats did amphetamine antagonize the blockade. The adrenergic neurone blocking effect of bethanidine 10 mg/kg was evident at 12 h but not at 24 h after injection.3. In rat mesentery amphetamine did not cause vasoconstriction but briefly potentiated the vasoconstrictor effect of sympathetic nerve stimulation. Responses to noradrenaline were not importantly affected.4. The contractile responses of the rat inferior eyelid caused by stimulation of the cervical sympathetic nerve was greatly reduced 17-27 h after subcutaneous injection of bretylium 300 mg/kg, bethanidine 30 mg/kg, guanethidine 10 mg/kg or reserpine 0.3 mg/kg. Intravenous dexamphetamine (0.5 mg/kg) powerfully antagonized the effect of bretylium, weakly antagonized the blockade by bethanidine and guanethidine and caused no change in the response of reserpine-treated animals.5. The vas deferens taken from guinea-pigs 24 h after subcutaneous injection of either bretylium or guanethidine showed greatly impaired responses to hypogastric nerve stimulation. Amphetamine largely restored the contractile response in bretylium-treated rats but caused only weak antagonism in the guanethidine-treated animals.

The effect of catecholamine infusions on myocardial blood flow, metabolic heat production and on general haemodynamics, before and after alprenolol (H56/28), in anaesthetized cats

1. In cats anaesthetized with pentobarbitone sodium, infusions of adrenaline, noradrenaline (0.5 mug/kg per min) and isoprenaline (0.25 mug/kg per min) increased myocardial blood flow, myocardial heat production, left ventricular systolic and end-diastolic pressures, left ventricular +ve and -ve dp/dt max, and calculated cardiac output, effort and oxygen consumption. These effects (apart from the effect of noradrenaline on left ventricular systolic pressure) were markedly reduced by previous administration of alprenolol (0.5 or 1.0 mg/kg).2. Infusions of adrenaline and noradrenaline increased arterial diastolic blood pressure and isoprenaline reduced it. After alprenolol the effects of adrenaline and noradrenaline were potentiated and that of isoprenaline abolished; in some experiments isoprenaline increased arterial diastolic pressure after alprenolol. Alprenolol did not influence the increases in arterial systolic pressure which followed the administration of adrenaline and noradrenaline.3. Isoprenaline-induced tachycardia was markedly reduced and adrenaline tachycardia was converted to bradycardia after alprenolol. The bradycardia which occurred during noradrenaline infusions was unaffected.4. After blockade by alprenolol, recovery of the effects of isoprenaline on left ventricular dp/dt and on heart rate occurred more quickly than recovery of the effects on arterial diastolic pressure. This suggests that alprenolol has a greater affinity for beta(2)- than for beta(1)-adrenoceptors.5. Intravenous administration of acetylcholine decreased arterial blood pressure, left ventricular pressure and +ve and -ve dp/dt max. During recovery from these effects there was a marked increase in +ve dp/dt max. which was absent after the administration of alprenolol (0.5 mg/kg). Because this dose of alprenolol is thus able to block the effects of reflex sympathetic cardiac nerve stimulation but does not completely antagonize the effects of exogenous adrenaline on dp/dt, it is suggested that alprenolol may have some adrenergic neurone blocking activity.6. Increases in liver and myocardial blood flow and heat production produced by noradrenaline, adrenaline and isoprenaline were reduced after alprenolol.7. Isoprenaline reduced air-way resistance and this effect was abolished by alprenolol; increases in air-way resistance produced by adrenaline and nor-adrenaline were augmented. All three amines inhibited intestinal smooth muscle contractions in vivo. Only the effect of isoprenaline was reduced by alprenolol.

Effect of the adrenergic neurone blocker, ?-TM10, on the depletion of noradrenaline induced by denervation or reserpine

Effect of the adrenergic neurone blocker, ?-TM10, on the depletion of noradrenaline induced by denervation or reserpine

Effect of the adrenergic neurone blocker, beta-TM10, on the depletion of noradrenaline induced by denervation or reserpine.

The noradrenaline content of the rat submaxillary gland was determined fluorimetrically as various times after sympathetic denervation as well as after the subcutaneous injection of reserpine (300 μg/kg). The effect of an adrenergic neurone blocker (β-TMIO) was compared with that of an inhibitor of monoamine oxidase (pargyline). 2 Both βTM10 (50 mg/kg s.c. given 6 hours and repeated 12 hours after the operation) and pargyline (100 mg/kg i.p. at the operation) delayed the decline of endogenous noradrenaline observed after denervation; the delay was similar for both treatments. 3. Both,β-TM10 (50 mg/kg s.c. 2 hours before reserpine) and pargyline (100 mg/kg s.c. 6 hours before reserpine), caused a similar delay in the reserpine-induced decline of endogenous noradrenaline in the sympathetically decentralized gland. 4. Reserpine induced a higher rate of depletion in normal than in decentralized glands of untreated or pargyline-pretreated rats. However, the relation of depletion rates was reversed afterβ-TM10. 5. It is concluded that the last mentioned effect is at least partly due to the adrenergic neurone blocking effect ofβ-TMIO. The antagonism byβ-TMIO of the depleting effect of sympathetic denervation and of reserpine, on the other hand, is attributed to the ability of adrenergic neurone blocking agents to block monoamine oxidase. The results confirm earlier studies and indicate that the ability of adrenergic neurone blocking agents to block intraneuronal monoamine oxidase accounts for effects which up to now have been ascribed to their ability to prevent the release of noradrenaline by nerve impulses.

Conformation of xylocholine.

THE biological activity of quaternary aryloxyethylammonium salts is critically dependent on the nature and position of the substituents in the aromatic ring1–3. Thus choline phenyl ether bromide is a potent nicotine-like ganglion stimulant2,4, whereas its 2,6-dimethyl analogue (xylocholine) is devoid of ganglion stimulant activity5 but was the first compound to exhibit adrenergic neurone blocking activity6–9. Xylocholine also has muscarine-like properties6–9.

On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquin

After injection of debrisoquin into rats, the drug was rapidly taken up into several organs, especially the heart. The drug levels then declined rapidly in most tissues for about 4 hr, followed by a period of much slower decline. Low concentrations could be detected in several organs 16 hr after injection. By the use of radioactive debrisoquin, metabolic products of the drug could be found in the heart, liver and intestine 6 hr after drug injection, but at 16 hr, metabolic products were found only in the intestine, urine and feces. About two-thirds of the drug underwent biotransformation. Distinct adrenergic neuronal blocking action, as revealed by inhibition of the physostigmine-induced pressor response, persisted for only about 1 1 2 hr after injection of 5 mg kg of debrisoquin. This short duration of sympatholytic action in the face of prolonged antihypertensive action in man and the hypertensive rat, coupled with the finding that the low residual amounts of debrisoquin are sufficient to inhibit adrenergic neuronal monoamine oxidase (MAO), suggests that the antihypertensive action of debrisoquin and other neuronal blocking agents may lie, in part, in inhibition of neuronal MAO.

Adrenergic neuron blockers and transmitter release after sympathetic denervation studied in the conscious rat.

Abstract13 to 15 hrs after excision of the superior cervical ganglion the postdenervation ptosis in the rat is reversed for about 12 hrs due to release of transmitter from degenerating nerve terminals. This degeneration contraction has been studied in unanesthetized rats. A special apparatus with an image splitting eyepiece was constructed for the measurement of the palpebral aperture at a distance. The time course of the degeneration contraction was found to correlate well with that of postdenervation transmitter depletion earlier found by other workers using biochemical and histochemical methods. Earlier findings that postdenervation depletion is delayed by bretylium were fully confirmed. It was also found that the neuron‐blockers beta‐TM 10 (10–50 mg/kg), bethanidine (10–50 mg/kg) and BW 392C60 (10–75 mg/kg) caused much less delay than bretylium at 1 to 50 mg/kg. The delayed degeneration contraction has a normal appearance and magnitude. There is no correlation between the neurone blocking action of the drugs and their “delaying effect”.

Mechanism of the antagonism between guanethidine and dexamphetamine.

1. The effects of dexamphetamine were studied on the responses of rabbit ileum, rabbit ear artery and sheep spleen to sympathetic nerve stimulation after exposure to guanethidine and in the absence of guanethidine.2. In the absence of guanethidine, dexamphetamine enhanced the responses to sympathetic stimulation and, in the spleen, this was shown to be due to an increase in noradrenaline output. However, the increase in these responses was much less than the increase obtained in preparations treated with guanethidine.3. Cocaine, in a concentration which produced the same effect on noradrenaline uptake as the concentration of dexamphetamine used, was also effective in reversing the adrenergic neurone blocking actions of guanethidine.4. It is suggested that the antagonism between dexamphetamine and guanethidine is due to a reduction in the uptake of guanethidine by the nerve endings rather than to interaction of the two drugs at the receptor site for the adrenergic neurone blocking action of guanethidine.

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.

Influence of sodium and calcium on norepinephrine uptake by isolated perfused rat hearts.

ARTICLESInfluence of sodium and calcium on norepinephrine uptake by isolated perfused rat heartsWD Horst, IJ Kopin, and ER RameyWD Horst, IJ Kopin, and ER RameyPublished Online:01 Oct 1968https://doi.org/10.1152/ajplegacy.1968.215.4.817MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByAlkali Metal Ion Transport and Biochemical Activity9 March 2007The Transport of Amines Across the Axonal Membranes of Noradrenergic and Dopaminergic NeuronesLithium Pharmacology and PhysiologyContribution of the sympathetic nervous system to the hypertensive effect of a high sodium diet in stroke-prone spontaneously hypertensive rats.Hypertension, Vol. 4, No. 6HypertonieStimulation recording of uptake and secretion of14C-noradrenalin by rat brain synaptosomesBulletin of Experimental Biology and Medicine, Vol. 91, No. 3The inhibitory effect of some monovalent cations on the stimulation by Na+ of the neuronal uptake of noradrenalineNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 309, No. 2Kinetic analysis of the interaction between noradrenaline and Na+ in neuronal uptake: Kinetic evidence for CO-transportNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 309, No. 2Noradrenaline transport by rat heart sympathetic nerves: A re-examination of the role of sodium ionsNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 302, No. 3On the brain ascorbic acid and its importance in metabolism of biogenic aminesLife Sciences, Vol. 20, No. 9False Transmitters as Antihypertensive AgentsINFLUENCE OF COCAINE AND SODIUM ON BRETYLIUM UPTAKE BY RESERPINE-TREATED GUINEA-PIG LEFT ATRIUM19 July 2012 | British Journal of Pharmacology, Vol. 53, No. 2Regulation Mechanisms of Central and Peripheral Sympathetic NeuronsInfluence of lithium chloride on adrenergic mechanisms in ventricle of frog heart and guinea-pig left atriumExperientia, Vol. 31, No. 1Ascorbic acid: Effect of high doses on brain and heart catecholamine levels in guinea-pigs and ratsExperientia, Vol. 29, No. 7The effects of changes in ionic environment and modification of adrenergic function on the vascular responses to sympathomimetic amines12 April 2011 | Journal of Pharmacy and Pharmacology, Vol. 25, No. 7Uptake kinetics and ion requirements for extraneuronal uptake of noradrenaline by arterial smooth muscle and collagen19 July 2012 | British Journal of Pharmacology, Vol. 47, No. 3Pharmacology—Lithium Absorption, Distribution, Renal Handling, and Effect on Body ElectrolytesSome Factors Affecting the Neuron Blocking Action of Guanethidine, Xylocholine, Bretylium and DebrisoquinJapanese Journal of Pharmacology, Vol. 23, No. 6In vitro Studies on the Uptake of Biogenic Amines by Rat Mast CellsActa Physiologica Scandinavica, Vol. 86, No. 2Adrenocortical steroid hormones, electrolytes, and the disposition of the catecholamines with particular reference to depressive statesJournal of Psychiatric Research, Vol. 9, No. 3Potassium Deficiency and Cardiac Catecholamine Metabolism in the RatCirculation Research, Vol. 30, No. 5Influence of serotonin on adrenergic mechanismsBiochemical Pharmacology, Vol. 21, No. 3Contractile Responses of Isolated Rabbit Aortae to Transmural Stimulation as Affected by Calcium, Strontium, Sodium and OuabainJapanese Journal of Pharmacology, Vol. 22, No. 3Possible role of sodium and calcium ions in retention and physiological release of norepinephrine by adrenergic nerve endingsBiochemical Pharmacology, Vol. 20, No. 12The fate of [14C]l-3,4-dihydroxyphenylalanine in isolated perfused rat heartsBiochemical Pharmacology, Vol. 20, No. 10Factors affecting the action of guanethidine on adrenergic neurones19 July 2012 | British Journal of Pharmacology, Vol. 42, No. 3Interactions between Adrenocortical Steroid Hormones, Electrolytes, and the CatecholaminesAn investigation of α-methyl amino-acids and their derivatives on isolated tissue preparations19 July 2012 | British Journal of Pharmacology, Vol. 40, No. 4Mechanism of transport and storage of biogenic amines. III. Effects of sodium and potassium on kinetics of 5-hydroxytryptamine and norepinephrine transport by rabbit synaptosomesBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 219, No. 1Influence of debrisoquin (Declinax) on adrenergic function and norepinephrine metabolismBiochemical Pharmacology, Vol. 19, No. 7Accumulation of debrisoquin-14C by the human plateletBiochemical Pharmacology, Vol. 19, No. 3Sodium-dependent accumulation of 5-hydroxytryptamine by rat blood platelets19 July 2012 | British Journal of Pharmacology, Vol. 37, No. 3 More from this issue > Volume 215Issue 4October 1968Pages 817-822 Copyright & PermissionsCopyright © 1968 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1968.215.4.817PubMed5676382History Published online 1 October 1968 Published in print 1 October 1968 Metrics

Hypotensive action of bretylium after central administration.

Bretylium has been found to have a central hypotensive effect independent of its peripheral adrenergic neuron blocking action. It decreases the excitability of the medullary vasoactive neurons, as shown by inhibition of vasopressor responses evoked by stereotaxic stimulation of the medulla oblongata or reflex responses mediated at the medullary level. A possible role of catecholamines in the central hypotensive action of bretylium is suggested.

Mechanisms of the pressor and depressor actions of St 155 (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride, catapres ®)

St 155 (Catapres ®) has recently been found effective in the treatment of hypertension. The mechanism of its antihypertensive action has been investigated in animal experiments. These indicate that it differs from other clinically useful antihypertensives in its mode of action. In the cat, intravenous injections of St 155 produced an initial rise in blood pressure and a contraction of the nictitating membranes. After treatment with cocaine the pressor response was unchanged, and the contraction of the nictitating membrane was not reduced after denervation of the membrane. These sympathomimetic effects of St 155 are therefore not due to the release of endogenous catecholamines. Since these effects were blocked by phentolamine, they appear to be due to an action on the α-adrenoreceptors. Following the initial pressor response, St 155 produced a long lasting reduction of the blood pressure. St 155 had no ganglion blocking or adrenergic neurone blocking activity and did not block α- or β-adrenoreceptors; the depressor response was therefore not due to impairment of peripheral sympathetic function. The fall in blood pressure was unaffected by pretreatment with atropine or by propranolol, and was therefore not due to effects on muscarinic receptors or β-adrenoreceptors. However there was no fall in blood pressure in spinal cats or in cats treated with guanethidine. It is suggested that the depressor action of St 155 may therefore be due to a central reduction of sympathetic outflow to the heart and blood vessels.

Adrenergic neurone blocking agents. II. Some dioxane-substituted derivatives of guanoxan.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAdrenergic Neurone Blocking Agents. II.1 Some Dioxane-Substituted Derivatives of GuanoxanA. M. Monro, G. W. H. Potter, and M. J. SewellCite this: J. Med. Chem. 1967, 10, 5, 880–883Publication Date (Print):September 1, 1967Publication History Published online1 May 2002Published inissue 1 September 1967https://doi.org/10.1021/jm00317a027RIGHTS & PERMISSIONSArticle Views46Altmetric-Citations8LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (522 KB) Get e-Alerts Get e-Alerts

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 relationship between adrenergic neurone blocking activity and local anaesthetic activity in a series of guanidine derivatives

The adrenergic neurone blocking potencies of a number of guanidine derivatives were assessed using three isolated sympathetically innervated organs: rabbit ileum, guinea pig vas deferens and the artery segment from the rabbit's ear. The most suitable of these preparations for making quantitative comparisons was the isolated artery segment, and the results so obtained were used as the basis for a study of structure-activity relationships. Some of these compounds were also tested for local anaesthetic activity using the guinea pig weal and mouse tail methods. It was found that the local anaesthetic activity of these compounds was unrelated to their adrenergic neurone blocking activity.

Pharmacological studies on guanethidine derivatives. V. Adrenergic neurone blocking action of 2,3,4,5-tetrahydro-1H-3-benzazepine-3-carboxamidine sulfate

Pharmacological activity of 2, 3, 4, 5-tetrahydro-1H-3-benzazepine-3-carboxamidine sulfate (GQ-2) and following results were obtained. GQ-2 suppresses the contraction of nictitating membrane of the pre-and post-ganglionic fiber of cervical sympathetic nerve in urethane-anesthetized cat. This suppression is recovered by the intravenous injection of amphetamine but GQ-2 failed to suppress the contraction of nictitating membrane caused by amphetamine. GQ-2 also suppressed the elevation of blood pressure by electrical stimulation of the great splanchnic nerve and that by carotid occlusion. On the other hand, fall of blood pressure by electrical stimulation of the peripheral end of vagus nerve was not suppressed. GQ-2 abolished the movement of the isolated ileum produced by electrical stimulation to the mesenteric nerve. neurone blocking action of GQ-2 in urethane-anesthetized cat was about 0.4 time that of guanethidine. GQ-2 sometimes showed a sympathomimetic action but this was extremely weak. GQ-2 also increased the action of tyramine as well as of norepinephrine on nictitating membrane and blood pressure in a cat. Potentiation of tyramine was considered to be the interference of monoamine oxidase by GQ-2 since the action of reserpine was reversed after administration of GQ-2.

The Adrenergic Neurone Blocking Action of [2-(Methylphenylamino)-ethyl] guanidine Sulfate. II.

The effect of [2-(methylphenylamino)ethyl]guanidine sulfate (MPG) on sympathetic nervous system was studied and the following results were obtained : 1) intravenous injection of MPG caused a fall of blood pressure and sustained contraction of the nictitating membrane in urethane anesthetized cat, 2) MPG caused a lasting depression of many excitatory responses, evoked by electrical stimulation of the peripheral sympathetic nerves, that is, inhibition of the response of the cat nictitating membrane to postganglionic sympathetic nerve stimulation and inhibition of the pressor responses in cat to the celiac ganglion or splanchnic nerve stimulation. In addition, these reduced responses were abolished by amphetamine, 3) MPG also caused the potentiation of the pressor responses to norepinephrine and epinephrine, but caused a potent antagonistic action to pressor responses produced by tyramine, dimethylphenyl-piperazinium and the occulusion of the carotid artery in cat, 4) injection of high doses of MPG caused a sympathomimetic effect on the cat nictitating membrance, the heart rate of cat and dog and the blood pressure in spinal cat. The contraction of the cat nictitating membrane by MPG was abolished by phentolamine and pretreatment with reserpine. From the results mentioned above, it is concluded that MPG has adrenergic neurone blocking action and sympathomimetic action resembling those of guanethidine and bretylium.