Sympathetic vasodilatation in the rabbit ear.
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Changes in the blood content of a 1 cm(2) portion of the intact rabbit's ear were studied with transillumination and a photocell. Stimulation of the post-ganglionic sympathetic nerves produced a decrease in blood content, attributable to vasoconstriction, followed by an increased blood content, attributable to vasodilatation. The vasodilatation was enhanced by eserine and decreased by atropine. Guanethidine abolished the vasoconstriction but not the vasodilatation. After the ganglion had been decentralized by degeneration of the pre-ganglionic sympathetic nerves the vessels had an increased sensitivity to acetylcholine and the vasodilatation in response to sympathetic stimulation was enhanced. It is concluded that sympathetic stimulation results in the liberation of acetylcholine which causes vasodilatation. (+info)
Mechanism of the positive inotropic responses to bretylium and guanethidine.
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Isolated, atropinized, rat atria exhibited positive inotropic responses to bretylium, guanethidine and tyramine. These responses were prevented by treatment of the animal with reserpine, or by addition of dichloroisoprenaline to the organ bath. The positive inotropic effects of these compounds on atria from reserpinized animals were restored by incubation of the tissue with noradrenaline. On the basis of these findings it is concluded that the cardiac stimulation by bretylium, guanethidine and tyramine involves the release of catechol amines. The usually reported increase in sensitivity of the myocardium from reserpinized animals to noradrenaline was not observed. The influence of bretylium and guanethidine on cardiac uptake and release of noradrenaline was also studied with the rat. Guanethidine decreased the concentration of catechol amines and inhibited the uptake of exogenous noradrenaline, while bretylium had no effect on either. The decrease in concentration of cardiac catechol amines produced by guanethidine was prevented by treatment of the animal with bretylium or with 1-phenyl-2-hydrazinopropane (pheniprazine), a monoamine oxidase inhibitor. (+info)
Effect of guanethidine, hemicholinium and mebutamate on the hypertensive response to eserine and catechol amines.
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Guanethidine, hemicholinium and mebutamate were used to study the site and mechanism of the hypertensive response to eserine in the rat. Guanethidine was found to block very effectively the hypertensive effect of eserine and to produce at the same time a very strong potentiation of the response to catechol amines. Hemicholinium, after a certain latent period, also blocked the effect of eserine, at the same time leaving the response to adrenaline and noradrenaline intact. Mebutamate was also found to block the effect of eserine. The results of the present experiments suggest that eserine produces a central adrenergic activation in the rat. (+info)
The action of guanethidine with particular reference to the sympathetic nervous system.
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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. (+info)
The cholinergic blocking action of adrenergic blocking agents in the pharmacological analysis of autonomic innervation.
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The adrenergic blocking agents tolazoline, phentolamine, piperoxan, yohimbine, phenoxybenzamine, bretylium and guanethidine block the excitatory actions both of cholinergic nerves and of added acetylcholine on a variety of vertebrate smooth muscle preparations. These cholinergic blocking actions often occurred with concentrations lower than those required to block the response of the guinea-pig vas deferens to stimulation of the adrenergic hypogastric nerve. The anti-acetylcholine activities of these drugs have been studied in detail, using the guinea-pig rectum and the toad bladder as test organs. In preparations sensitive to eserine, the anticholinesterase actions of the drugs competed with their anti-acetylcholine actions, so that either potentiation or block of responses to acetylcholine and to cholinergic nerve stimulation occurred with different concentrations. The responses of the toad bladder to acetylcholine were not potentiated by eserine. This enabled the antagonism of acetylcholine by the anti-adrenergic drugs to be estimated without interference from their anticholinesterase activity. When blocking activity was assessed on guinea-pig rectum previously treated with dyflos, the results were qualitatively similar to those on the toad bladder. Phenoxybenzamine often completely blocks responses both to added acetylcholine and to cholinergic nerve stimulation in concentrations less than those required to block adrenergic nerves. Guanethidine and piperoxan also show strong cholinergic blocking activity. Bretylium, yohimbine, tolazoline and phentolamine were less potent. However, in concentrations required to block the effect on the vas deferens of hypogastric nerve stimulation, these drugs at least halved the effects of acetylcholine and often of cholinergic nerve stimulation. It is concluded that these adrenergic blocking agents cannot be used to distinguish conclusively between adrenergic and cholinergic nerves. For reliable analysis of autonomic innervation, the substances released upon nerve stimulation must be identified by specific biochemical techniques or bioassay. (+info)
The action of substances which block sympathetic postganglionic nervous transmission.
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The substances which block sympathetic postganglionic transmission, xylocholine, bretylium and guanethidine, also block neuromuscular and sympathetic ganglionic transmission. To see if these last properties were related to the sympathetic blocking property, phenyltrimethylammonium, which blocks the neuromuscular junction (Riker, 1953), was used. It blocked the inhibition of the rabbit ileum produced by stimulating the periarterial nerves in the mesentery, though with higher concentrations the effect of stimulation was initially increased. The action was not modified by the presence of hyoscine. The blocking action was exerted on the response to stimulation of the highest frequency first, and on the response to stimulation of the lowest frequency last. This relation of block to stimulus frequency is similar to that at the neuromuscular junction when tubocurarine is used. Nine compounds have now been shown to block responses to sympathetic postganglionic stimulation, and seven of these are onium compounds. They are, however, mon-onium compounds, and not bis-onium compounds like hexamethonium and decamethonium, so that they can probably enter the postganglionic fibre, which bis-onium compounds (having a charged group at each end of the molecule) may not be able to do. Since these mon-onium compounds have some blocking action at neuromuscular junctions and at sympathetic ganglia, their block of postganglionic transmission may be essentially similar to that by hexamethonium at ganglia and to that by decamethonium at neuromuscular junctions. It is known that acetylcholine releases noradrenaline from sympathetic postganglionic terminations, and xylocholine and bretylium block this release in the vessels of the rabbit ear and in the rabbit isolated atria. (+info)
Evidence for a competitive antagonism of guanethidine by dexamphetamine.
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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. (+info)
Mediation by nitric oxide of neurogenic relaxation of the urinary bladder neck muscle in sheep.
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1. Mechanical recordings were made in vitro from circularly oriented strips of the bladder neck muscle of sheep. In the absence of drugs, electrical field stimulation at frequencies of 0.2-1 Hz evoked clear-cut relaxations throughout 1 min stimulation periods, while higher stimulus frequencies (2-8 Hz) evoked variable responses consisting of relaxation, contraction or a mixture of both. All of the responses were abolished by tetrodotoxin (10(-6) M). 2. The contractions were reduced by guanethidine (10(-6) M) and atropine (10(-6) M), so that in the presence of these drugs clear-cut relaxations were obtained at 0.2-8 Hz stimulation, indicating that the relaxations were mediated by non-adrenergic, non-cholinergic (NANC) nerves. 3. The NANC relaxations were blocked by L-NG nitro arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. The antagonism by L-NAME was reversed by L-arginine. 4. Another feature of the NANC relaxation was 'rebound contraction' which occurred when the stimulus was switched off. The rebound contraction was also blocked by L-NAME and restored by L-arginine. 5. The relaxations and rebound contractions were unaffected by either alpha,beta-methylene ATP (10(-5) M) or 2-methylthio ATP (10(-5) M). 6. S-Nitroso-L-cysteine, a substance which spontaneously releases NO at physiological pH, mimicked the relaxation and rebound contraction produced by nerve stimulation. 7. It is concluded that nerve-evoked relaxation of the bladder neck is mediated by NO, or a closely related substance such as S-nitroso-L-cysteine. (+info)