EFFECT OF SOME BLOCKING DRUGS ON THE PRESSOR RESPONSE TO PHYSOSTIGMINE IN THE RAT.
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Bretylium and guanethidine blocked the pressor effect of physostigmine and potentiated the responses to adrenaline and noradrenaline on the blood pressure of the rat. Morphine and atropine in small doses blocked the pressor effect of physostigmine without interfering with the actions of adrenaline and noradrenaline. Chlorpromazine in small doses (0.5 to 2.5 mg/kg) blocked the pressor effect of physostigmine and potentiated the responses to noradrenaline whilst those to adrenaline remained unaltered. 3,6-Di(3-diethylaminopropoxy)pyridazine di(methiodide) (Win 4981) blocked the pressor effect of physostigmine and, in its early stages, this block was partially reversed by choline chloride. N-Diethylaminoethyl-N-isopentyl-N'N'-diisopropylurea (P-286), in a dose that reduced the effect of dimethylphenylpiperazinium, had no effect on the pressor response to physostigmine or on the responses to adrenaline and noradrenaline. Hexamethonium, even in large doses (100 mg/kg), only blocked partially the effect of physostigmine while mecamylamine produced a complete block; the responses to adrenaline and noradrenaline were potentiated in both instances. (+info)
THE SITE OF THE 5-HYDROXYTRYPTAMINE RECEPTOR ON THE INTRAMURAL NERVOUS PLEXUS OF THE GUINEA-PIG ISOLATED ILEUM.
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Dose/response measurements were made on the guinea-pig isolated ileum with six agonists, acetylcholine, 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium, choline phenyl ether and histamine. The dose effects were repeated in the presence of each of twelve antagonists and one anticholinesterase. Acetylcholine and histamine were chosen because of their direct mode of action on smooth muscle, nicotine, dimethylphenylpiperazinium and choline phenyl ether were used as examples of drugs that act at the ganglionic acetylcholine receptor. 5-Hydroxytryptamine was the drug investigated. Hyoscine blocked the contractions caused by acetylcholine, 5-hydroxytryptamine and the ganglion-stimulants but left the responses to histamine unchanged. The anticholinesterase N,N'-diisopropylphosphorodiamidic fluoride (mipafox) potentiated all the agonists except histamine. The strength of potentiation decreased in the order 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether, and acetylcholine. The local anaesthetic procaine inhibited to the same extent contractions elicited by 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether. These results showed that 5-hydroxytryptamine, like nicotine, choline phenyl ether and dimethylphenylpiperazinium, mediated its response through the nervous plexus. Of those tested 5-hydroxytryptamine was the only specific antagonist to 5-hydroxytryptamine; lysergic acid derivatives produced spasm and prolonged changes in tone; phenoxybenzamine caused non-specific block. The diverse modes of action of a number of ganglion-blocking agents were selectively used. Thus hexamethonium, pentolinium, and nicotine in its competitive phase, blocked contractions due to nicotine, dimethylphenylpiperazinium and choline phenyl ether and left those due to 5-hydroxytryptamine, acetylcholine and histamine unchanged. The depolarizing ganglion-blocking agents, dimethylphenylpiperazinium and nicotine, inhibited the responses to all the indirectly acting drugs. Furthermore, mecamylamine, a drug with a less well-defined mode of action, partially inhibited contractions due to 5-hydroxytryptamine in a concentration that blocked those due to nicotine, dimethylphenylpiperazinium and choline phenyl ether. Pempidine, known to act like mecamylamine, did not antagonize 5-hydroxytryptamine. It is concluded that 5-hydroxytryptamine activates specific receptors sited at the intramural parasympathetic ganglion cells. (+info)
THE EFFECTS OF NEOSTIGMINE UPON GANGLION RESPONSES AFTER ADMINISTRATION OF BLOCKING DRUGS.
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The effects of block of autonomic ganglia by chlorisondamine and by hexamethonium, the administration of neostigmine and of atropine upon blood pressure, nervous transmission through the superior cervical ganglion, stimulation of autonomic ganglia by dimethylphenylpiperazinium, and the carotid occlusion reflex, have been studied in the dog anaesthetized with sodium pentobarbitone. The results of these studies have shown: (1) A ganglion blocking agent blocks synaptic transmission in the superior cervical ganglion at the same time as it lowers blood pressure. Neostigmine administered after ganglion-block raises the blood pressure without much change in the response to stimulation of the preganglionic cervical sympathetic nerve. (2) If the effects of preganglionic nerve stimulation are recorded as a contraction of the nictitating membrane, a ganglion-blocking agent also abolishes this response at the same time as it blocks the reflex rise in blood pressure produced by occlusion of both common carotid arteries. Neostigmine administered under these conditions does not affect the responses of the nictitating membrane, but restores the carotid occlusion reflex. This restoration of reflex activity is sensitive to atropine, as is the blood pressure rise. (3) At the same time that neostigmine restores the carotid occlusion reflex, there is no restoration of sensitivity of autonomic ganglia to chemical stimulation by dimethylphenylpiperazinium. In these animals atropine not only blocked the restored carotid occlusion reflex, but produced a further inhibition of the pressor response to dimethylphenylpiperazinium. It is concluded that neostigmine may raise blood pressure by partially restoring autonomic ganglionic transmission, but that total ganglionic function is not restored. (+info)
PREGANGLIONIC AND POSTGANGLIONIC STIMULATION OF THE GUINEA-PIG ISOLATED VAS DEFERENS PREPARATION.
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The isolated vas deferens of the guinea-pig contracted when stimulated transmurally with parallel wire electrodes. These contractions persisted in concentrations of hexamethonium, pentolinium, nicotine and mecamylamine which at the same time abolished the responses to hypogastric nerve stimulation. Procaine and lignocaine in local anaesthetic concentrations abolished the responses to transmural stimulation but potentiated the contractions produced by added noradrenaline. Guanethidine and bretylium in concentrations specific for adrenergic neurone blockade abolished the contractions due to transmural stimulation without impairing the responses of the muscle to added noradrenaline or acetylcholine. In contrast, high concentrations of the adrenergic-blocking agents phentolamine and dihydroergotamine were needed to block the contractions due to transmural stimulation; these concentrations also blocked the response to added noradrenaline but simultaneously reduced the responses to added acetylcholine or potassium chloride. Preparations from guinea-pigs previously treated with reserpine at first responded normally to transmural stimulation; thereafter the contractions diminished progressively but were never abolished. Hyoscine and atropine produced a small decrease in the response to transmural stimulation when present in concentrations up to 1x10(-5) and a larger decrease only in concentrations of 1x10(-4) or greater. Hemicholinium produced a small decrease of the contractions due to transmural stimulation in concentrations up to 1x10(-4); concentrations of 5x10(-4) present for 1 hr produced only a slightly greater reduction in response. These experiments show that when the guinea-pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves. (+info)
THE GANGLION BLOCKING ACTION OF PROCAINAMIDE.
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In cats and rabbits procainamide (20 to 50 mg, intravenously) produced a fall of blood pressure of 20 to 50 mm Hg which reached a maximal effect within 1 min and lasted for about 5 min. Procainamide reduced the pressor responses to nicotine and to carotid arterial occlusion and reduced the depressor response to vagal stimulation, but did not antagonize the actions of adrenaline or noradrenaline on blood vessels. The contractions of the nictitating membrane to stimulation of the preganglionic cervical sympathetic nerve were partially or completely blocked by 20 to 50 mg of procainamide given intravenously. The ganglion blocking effect was more abrupt in onset and more slow to recover than that due to hexamethonium and had about 1/250th of the activity of the latter. Procainamide (1 mg) reduced the acetylcholine output of the perfused superior cervical ganglion to below 30% of the control value and blocked transmission completely. Small doses (10 mug) reduced the acetylcholine output but hardly affected ganglionic transmission. Procainamide, injected into the perfused superior cervical ganglion, blocked contractions elicited by stimulation of the preganglionic cervical sympathetic nerve for a longer period than those produced by acetylcholine injected into the perfusion circuit to the ganglion; the reverse was true for hexamethonium. Procainamide reduced the size of action potentials recorded from the superior cervical ganglion without altering the resting potential of the ganglion. The ganglion blocking activities of procainamide and hexamethonium often potentiated each other, especially when the preparation had been set up for several hours. On the guinea-pig isolated ileum preparation, procainamide (0.5x10(-4) g/ml.) antagonized responses due to acetylcholine, histamine and, most effectively, to nicotine. On the isolated heart, procainamide (1 mg) almost abolished the bradycardia produced by acetylcholine; 10 mg slowed and weakened the heart, while 100 mg stopped it. We conclude that procainamide, like procaine, blocks ganglionic transmission by (1) depressing the release of acetylcholine from preganglionic nerve endings; and (2) competing, with the acetylcholine which is released, for receptor sites on the ganglion cells. The amounts required to produce significant effects in vivo and in vitro are comparable. The methods available for detecting this type of ganglion blocking action are discussed. (+info)
STIMULANT ACTIONS OF VOLATILE ANAESTHETICS ON SMOOTH MUSCLE.
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A number of volatile anaesthetics, and some compounds synthesized in the search for new anaesthetics, have been tested on guinea-pig intestinal smooth muscle in vitro. All the compounds produced a contractile response. This effect did not correlate well with convulsant activity in vivo among the compounds tested. Two kinds of stimulant effect were distinguishable: (1) Rapid, transient contractions, abolished by cocaine or lachesine; most of the anaesthetics in clinical use had this action. (2) Slow, sustained contractions, unaffected by cocaine or lachesine; this effect predominated among the fluorinated ring compounds. Hexamethonium and mepyramine did not affect the contractile response to any of the compounds. The first type of effect presumably represents excitation of postganglionic nerve cells, while the second type is a direct action on the muscle cell. The action of perfluorobenzene, which is of the latter kind, was studied further. Adrenaline and lack of calcium diminished the contraction in parallel with the contraction to histamine, which suggests that the cell membrane was the site of action; in contrast to the stimulant action of histamine or acetylcholine, the effect was highly temperature-sensitive, being almost abolished by cooling to 32 degrees C, and enhanced at 40 degrees C. The depressant action of anaesthetics on smooth muscle is affected very little by temperature changes. These findings are discussed in relation to other observations which suggest a stimulant action of volatile anaesthetics on excitable tissues. Protein denaturation is tentatively suggested as a mechanism of action. (+info)
EFFECTS OF AMPHETAMINE ON THE RESPONSES OF THE GUINEA-PIG ISOLATED VAS DEFERENS PREPARATION TO HYPOGASTRIC NERVE STIMULATION.
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In concentrations from 1 to 100 mug/ml., amphetamine potentiated responses of the isolated vas deferens preparation of the guinea-pig stimulated via the hypogastric nerve at rates of from 5 to 40 shocks/sec. Potentiation was more pronounced with low than with high stimulus frequencies. A concentration of 500 mug/ml. of amphetamine had a blocking action which was more pronounced at high than at low stimulus frequencies. This effect contrasted with the ganglionic blocking action of hexamethonium which had a greater effect at low than at high stimulus frequencies. (+info)
PARTICIPATION OF AN UNUSUAL GANGLIONIC PATHWAY IN THE MEDIATION OF THE PRESSOR EFFECT OF PHYSOSTIGMINE IN THE RAT.
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In spinal rats physostigmine failed to produce a pressor response even after treatment of the animals with hexamethonium, whereas noradrenaline, McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride) and AHR602 (3-acetoxy-1-benzyl-1-methylpyrrolidinium bromide) all produced large pressor effects. In rats anaesthetized with urethane, hexamethonium completely abolished the pressor effect of dimethylphenylpiperazinium but only partially blocked the pressor response to physostigmine; pressor effects of noradrenaline, McN-A-343 and AHR602 were potentiated. Combined treatment with hexamethonium and atropine and with hexamethonium and cocaine, however, completely abolished the pressor effect of physostigmine; simultaneously the pressor effects of McN-A-343 and AHR602 as well as of dimethylphenylpiperazinium were also blocked. P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea) produced an early and a late block of the pressor effect of physostigmine; the initial block was due to an adrenergic blocking action while the late block was probably due to a dual action of the drug in abolishing the effects of both the nicotinic and non-nicotinic ganglion stimulants. Pressor responses to physostigmine, McN-A-343, AHR602 and dimethylphenylpiperazinium were abolished immediately after ganglion-blocking doses of nicotine. It is suggested that an unusual ganglionic pathway participates in the mediation of the pressor response to physostigmine in the rat, especially when the established ganglionic pathways are blocked. (+info)