The antihistamine and antiadrenaline properties of a series of N-naphthylmethyl-2-haloethylamine derivatives.
Explore the source record for details and available documents.
Anti-Allergic Agents↗
SEARCH · Search PubMed
Results for “SYMPATHOLYTICS”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Effect of antisympathomimetic drugs on the plasma concentrations of catechol amines.
Intravenous injection of phenoxybenzamine, choline 2,6-xylyl ether bromide (xylocholine, TM 10), piperoxane or dihydroergotamine increases the vasopressor activity of blood plasma, collected from cats under chloralose anaesthesia. The increased vasopressor activity that follows the administration of piperoxane is due to an increase of adrenaline and noradrenaline in the plasma. Cross-circulation experiments show that catechol amines are liberated from the spleen by piperoxane.
Amines↗
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.
Animals↗
Adrenergic neurone blockade and other acute effects caused by N-benzyl-N'N"-dimethylguanidine and its ortho-chloro derivative.
N-Benzyl-N'N"-dimethylguanidine sulphate (BW 467C60) and its ortho-chloro derivative (BW 392C60) had adrenergic neurone blocking and sympathomimetic effects resembling those of bretylium and guanethidine in cats, dogs and monkeys, but they were more potent in blocking adrenergic mechanisms in the cat. BW 467C60 was more active than its chloro derivative. Each compound inhibited release of noradrenaline during stimulation of the splenic nerve of cats, and increased smooth muscle responses to adrenaline and noradrenaline. Pressor responses to standard doses of tyramine were also increased except when large doses of BW 467C60 or BW 392C60 were given. The adrenergic neurone block by BW 467C60 was inhibited by dopamine, cocaine and amphetamine in situations in which these amines inhibit the effects of bretylium and guanethidine. In contrast to guanethidine, BW 467C60 and BW 392C60 did not lower the pressor amine content of the iris of cats 24 hr after administration of single doses of the compounds. BW 467C60 depressed the slope of curves relating the frequency of stimuli applied to the cervical sympathetic nerves and the resulting contraction of the nictitating membrane, but the effects of the lower rates of stimulation were preferentially inhibited. Large intravenous doses of BW 467C60 and BW 392C60 blocked autonomic cholinergic mechanisms and caused neuromuscular paralysis of voluntary muscle. These effects were brief, in contrast to the adrenergic neurone blockade. Both BW 467C60 and BW 392C60 were well absorbed from the alimentary tract. In contrast to guanethidine, BW 467C60 did not cause diarrhoea in guinea-pigs.
Adrenergic Agents↗
Vasodepression induced by acetylcholine in the atropinized dog.
The pressor response to acetylcholine in the atropinized dog resulted from an increase in cardiac output. The pressor response was attributed solely to the release of adrenaline from the adrenal medulla. After giving compound P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea) to these dogs, acetylcholine lowered blood pressure, owing to a decrease in total peripheral resistance in the absence of an increase in cardiac output. P-286 presumably blocked the liberation of adrenaline from the adrenal glands by acetylcholine. The blood vessels contributing to the fall in peripheral resistance were not in the intestines. The fall in blood pressure was not blocked by dichloroisoprenaline and it was still present in dogs treated with reserpine. It is suggested that the fall in blood pressure was due to stimulation of ganglion cells subserving vasodilatation.
Acetylcholine↗
Mechanism whereby halothane reverses the pressor responses to acetylcholine.
The initial and secondary components of the biphasic pressor response to acetylcholine in the atropinized dog were analysed separately. Deep halothane anaesthesia reversed the initial pressor response to acetylcholine owing to a decrease in total peripheral vascular resistance in the absence of an increase in cardiac output. The secondary pressor response was not reversed but was suppressed owing to a marked reduction of the increase in cardiac output responsible for this pressor response; total peripheral resistance increased. Conversely, halothane anaesthesia did not block the increase in blood glucose concentration resulting from the injection of acetylcholine. Thus, the change induced by halothane in the secondary pressor phase was apparently a consequence of cardiac depression rather than of adrenal medullary blockade. Compound P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea), which produces a change in the pressor response to acetylcholine similar to that induced by halothane, prevents the hyperglycaemia due to acetylcholine. In some experiments, deep halothane anaesthesia depressed the cardiac inotropic but not the chronotropic response to acetylcholine. Such selective blocking action is believed to have a bearing on production of arrhythmias.
Acetylcholine↗
THE INCREASE IN THE TOXICITY OF YOHIMBINE INDUCED BY IMIPRAMINE AND OTHER DRUGS IN MICE.
In mice, yohimbine appears to accentuate the normal "alarm" reactions (alerting, flight) to external stimuli. Imipramine increases this effect and at the same time converts a non-lethal dose of yohimbine into a lethal one. The effect of imipramine is greatly reduced by adrenalectomy or by treatment with reserpine, syrosingopine, ganglion-blocking drugs or adrenaline antagonists acting on sympathetic beta-receptors. Hypnotic, anti-convulsant or anaesthetic agents, tetrabenazine or antagonists of 5-hydroxytryptamine do not reduce the imipramine effect. A variety of drugs which, like imipramine, are known to interfere with the tissue binding of noradrenaline also increase the toxicity of yohimbine. Yohimbine significantly reduces brain noradrenaline content; adrenal catechol amines are slightly reduced. The results suggest that yohimbine releases noradrenaline from stores or nerves as a consequence of increased central sympathetic activity. Imipramine increases the actions and toxicity of yohimbine by increasing the effects of the released noradrenaline on beta-receptors. The lethal effects of a high dose of yohimbine alone are not reduced by any of the treatments tested, and appear not to result from activation of sympathetic mechanisms.
Adrenal Glands↗
THE ACTION OF HISTAMINE ON THE ISOLATED HEART.
A method is described for recording the coronary flow and the rate and the amplitude of contraction of an isolated heart maintained at constant temperature. Both histamine and noradrenaline increased the contractility of the guinea-pig heart. Pronethalol antagonized noradrenaline but not histamine. Mepyramine, 10-(2-pyrrolidin-1'-ylethyl)phenothiazine hydrochloride (pyrathiazine) and diphenhydramine reduced the contractility of the guinea-pig heart but did not antagonize the action of histamine. The influence of histamine and noradrenaline on coronary flow was variable but when the contractility of the heart increased there was a concomitant increase in coronary flow. Histamine decreased the contractility of the rat heart and the domestic fowl heart.
Animals↗
THE EFFECTS OF PRONETHALOL, DICHLOROISOPRENALINE AND DISOPYRAMIDE ON THE TOXICITY TO THE HEART OF OUABAIN AND ANAESTHETICS.
An intermittent infusion of ouabain, 4 mug during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea-pigs. The beta-receptor blocking drug, pronethalol (5 mg/kg), increased the dose of ouabain required to produce extrasystoles, completely prevented fibrillation, and significantly raised the lethal dose of ouabain. Dichloroisoprenaline had similar effects, but a dose of 15 mg/kg was required. When fibrillation had already been produced by ouabain, pronethalol (3 to 4 mg) administered slowly restored a regular rhythm, but rapid injection sometimes produced cardiac arrest. As much as 20 to 25 mg/kg of pronethalol could be given to animals deeply anaesthetized with urethane or pentobarbitone, but with light chloroform or ether anaesthesia, 5 mg/kg of pronethalol caused a large fall in blood pressure and complete heart-block.
Anesthetics↗
A COMPARISON OF THE ANTIFIBRILLATORY ACTIONS AND EFFECTS ON INTRACELLULAR CARDIAC POTENTIALS OF PRONETHALOL, DISOPYRAMIDE AND QUINIDINE.
A quantitative comparison of the effects of quinidine, pronethalol and gamma-di-isopropylamino-alpha-phenyl-alpha-pyrid-2-ylbutyramide (disopyramide) has been made on rabbit isolated atria. All three drugs raised the electrical threshold and reduced the contractions, the conduction velocity and the maximal frequency at which the atria would follow a stimulus. The descending order of potency was pronethalol, quinidine and disopyramide, but the range was small, pronethalol having about twice the activity of disopyramide. Both the new compounds affected intracellular potentials in the same way as quinidine, causing little change in the resting potential or duration of the action potential, but reducing the overshoot potential and slowing the rate of rise of the action potential. These results support the view that interference with depolarization is an essential feature of antifibrillatory activity.
Action Potentials↗
STUDIES ON THE HYPERGLYCAEMIA INDUCED BY CHLORPROMAZINE IN RATS.
Chlorpromazine induces in rats a marked and long-lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.
Adrenal Medulla↗
ACTIONS OF SYMPATHOMIMETIC DRUGS ON THE SMOOTH MUSCLE AT THE JUNCTION OF THE BILE DUCT AND DUODENUM STUDIED IN SITU.
The actions of adrenaline, noradrenaline, phenylephrine and isoprenaline have been examined on flow through the terminal bile duct and on the tone of the duodenum in the vicinity of the terminal bile duct. These drugs were injected intravenously, or intra-arterially into the blood supply of the junction of the bile duct and duodenum. The effects of the antagonistic drugs, dibenamine and dichloroisoprenaline, were also tested. Isoprenaline always relaxed the duodenum and increased the flow through the bile duct. Adrenaline, noradrenaline and phenylephrine relaxed the duodenum, but had variable effects on the flow through the bile duct. It is concluded that adrenaline acts directly on the smooth muscle of the bile duct to contract it, but the influence of the neighbouring duodenal muscle may nevertheless result in an increase in flow through the duct.
Animals↗
INNERVATION OF THE LARGE INTESTINE OF THE TOAD (BUFO MARINUS).
The morphology, physiology and pharmacology of the innervation of the toad (Bufo marinus) large intestine have been studied. The large intestine can be divided into the regions colon, rectum and cloaca, on morphological grounds, but acts as a unit in response to nerve stimulation. Of the right and left nerves, each appears to supply the entire large intestine. Autonomic innervation of the large intestine of Bufo marinus is as follows: (1) The 9th and 10th spinal nerves (pelvic) contain predominantly excitatory preganglionic cholinergic fibres, but some inhibitory adrenergic fibres are also present in most preparations. (2) The splanchnic nerves contain inhibitory postganglionic adrenergic fibres from the 3rd to 5th sympathetic ganglia, and a small number of excitatory cholinergic fibres. The pathway of adrenergic inhibitory fibres to the large intestine alongside the posterior mesenteric artery as seen in mammals is rarely present in the toad. Several nonspecific actions of autonomic drugs on the large intestine are discussed. The functional organization of the autonomic innervation of the toad large intestine is similar to that in mammals, that is the large intestine is controlled by antagonistic cholinergic and adrenergic nerves. However, the separation of these two types of nerve fibres into anatomically distinct nerves does not appear to be as complete as in mammals. It is suggested that inhibitory autonomic control of the alimentary canal in vertebrates first appears in the hind-gut region.
Acetylcholine↗
A PRELIMINARY INVESTIGATION OF THE PHARMACOLOGY OF THE HUMAN ISOLATED TAENIA COLI PREPARATION.
The effects of drugs on smooth muscle strips of human taenia coli, obtained from operation specimens, were studied in vitro. Both nicotinic and muscarinic sites of action of acetylcholine were demonstrated, the nicotinic effect being a relaxation. The sympathomimetic amines, adrenaline, noradrenaline, and isoprenaline produced a relaxation of the tissue by an action on adrenaline alpha- and beta-receptors. The presence of both types of receptor was demonstrated by selective adrenergic blockade with pronethalol or Hydergine. Pronethalol in high concentrations gave a nonselective adrenergic blockade. The ganglion-stimulating agents nicotine and dimethylphenylpiperazinium produced a relaxation of the tissue in all concentrations. This relaxation was inhibited by pronethalol or physostigmine but no contractile component to ganglion stimulation was revealed when these two drugs were present together. These results indicate the presence of either sympathetic ganglia in the intrinsic nerve plexuses, or adrenergic stores in the bowel wall. There is no pharmacological evidence for parasympathetic ganglia in human sigmoid colon. Histamine produced relaxant, contractile or biphasic responses. The type of response was independent of the "tone" of the preparation. The responses were not modified by procaine, hyoscine or pronethalol, which result indicates that both the contractile and relaxant responses to histamine were due to a direct action of the drug on smooth muscle. 5-Hydroxytryptamine produced either a contraction or a relaxation of the tissue. The relaxation was due to a direct effect of the drug, since hexamethonium, procaine or pronethalol did not affect the response. No conclusions have been drawn regarding the mechanism of the contractile response to 5-hydroxytryptamine. The nature of the responses of the tissue to drugs was independent of the disease for which the specimen of colon was removed.
Acetylcholine↗
DISTRIBUTION OF (2-BROMOETHYL)ETHYL(NAPHTH-1-YMETHYL-(14C))AMINE HYDROBROMIDE IN THE RAT.
(2-Bromoethyl)ethyl(naphth-1-ylmethyl)amine hydrobromide (SY28) is a halogenoalkylamine related to dibenamine. A dose of 10 mg/kg injected intravenously into rats antagonizes the pressor response to adrenaline for 36 hr. If this amount of SY28 labelled with (14)C in the 1-methyl position is administered, specific radioactivity is present in blood and tissues many days after the antagonism of adrenaline is relieved. The (14)C is excreted in bile and in urine, but not in expired air. It is present in fat but not to a greater extent than it is in other tissues. It does not cross the placental barrier. There is no evidence that slow release from a lipid depot accounts for the long duration of action.
Adipose Tissue↗
INHIBITION OF SYMPATHOMIMETIC EFFECTS ON THE HEART.
The adrenaline beta-receptor blocking drug, pronethalol, and the sympathomimetic amines, (-)-ephedrine, (-)-amphetamine, dexamphetamine, (-)-Psi-ephedrine and tyramine, inhibited the sympathomimetic effects of butyrylcholine and tyramine on the guinea-pig isolated atrium. Being reversible and noncompetitive, this antagonism was unspecific and not due to blockade of adrenaline receptors, although pronethalol inhibited the effect of noradrenaline competitively.
Amphetamine↗
THE EFFECTS OF DRUGS ON THE UPTAKE OF AMINES BY MAST CELLS.
Neoplastic mast cells, taken from an ascitic tumour in mice and incubated in vitro, took up (14)C-labelled 5-hydroxytryptamine and histamine from the medium. Uptake during the first hour gave an approximate measure of the initial rate. The amount of each amine taken up in this time was determined by bioassay and by radioactivity, the two methods giving similar results. The curves obtained by plotting initial rate of uptake against concentration in the medium suggested that the uptake of 5-hydroxytryptamine was by an active process and also by diffusion, whereas uptake of histamine was by diffusion only. The cells also took up (14)C-labelled (+/-)-noradrenaline and tryptamine, apparently by diffusion. The active uptake of 5-hydroxytryptamine was inhibited by lowering the temperature to 25 degrees C or by increasing the pH to 8.9, procedures which had little effect on histamine uptake. The effects of cocaine, imipramine, chlorpromazine, mepyramine, promethazine, phenoxybenzamine, lysergic acid diethylamide, bromolysergic acid diethylamide, methysergide, guanethidine, dichloroisoprenaline and pronethalol on the uptake of amines were examined. In general, any antagonist which inhibited uptake of 5-hydroxytryptamine had little effect on uptake of histamine, and vice versa. Possible ways in which these antagonists produce their effects on amine uptake are discussed. A high concentration of 5-hydroxytryptamine, of tryptamine or of noradrenaline inhibited uptake of histamine, but only tryptamine decreased uptake of 5-hydroxytryptamine. These results, together with those from experiments with antagonists, suggest that there are specific binding sites for 5-hydroxtryptamine in these cells.
Amines↗
THE ADRENERGIC-NEURONE BLOCKING ACTION OF SOME COUMARAN COMPOUNDS.
Ethyldimethyl(7-methylcoumaran-3-yl)ammonium iodide (SK&F 90,109) and its guanidine analogue [N-(7-methylcoumaran-3-yl)guanidine nitrate] (SK&F 90,238) abolish the effects of adrenergic nerve stimulation in cats, as do xylocholine and bretylium. SK&F 90,109 has slight sympathomimetic actions; these are less marked than in SK&F 90,238. Large doses of SK&F 90,109 have an action, dependent on local noradrenaline stores, that delays the appearance of adrenergic-neurone blockade in conscious cats. Responses to adrenaline are, in general, enhanced by each drug, but SK&F 90,238 transiently antagonizes tachycardia induced by adrenaline and isoprenaline. Both drugs inhibit the release of noradrenaline from the spleen during splenic nerve stimulation, but the release of catechol amines from the adrenal glands, in response to electrical or chemical stimulation, is unimpaired. In contrast to the prolonged adrenergic-neurone blocking action, any inhibition of the effects of cholinergic nerve stimulation is transient. Large intravenous doses produce neuromuscular blockade. The compounds have a slight central depressant action. In contrast to reserpine and guanethidine the noradrenaline content of rat hearts is not appreciably lowered 24 hr after a single dose of either drug. Unlike xylocholine they are not local anaesthetics. Related compounds also block the effects of adrenergic-nerve stimulation. The possible modes of action of these drugs are discussed.
Adrenergic Agents↗