The effect of phenoxybenzamine has been determined on the physiological response to sympathetic stimulation in two preparations, the rabbit isolated ileum and the guinea-pig isolated vas deferens. In both preparations phenoxybenzamine increased the response to stimulation of low frequency, the response being inhibitory in the one and motor in the other. This increase was large. As the stimulus frequency was raised, phenoxybenzamine caused a progressively smaller increase in the response, and at high frequencies phenoxybenzamine decreased the response. These observations agree with those of earlier workers who showed that antiadrenaline substances have more than one property. They not only block the motor effects of adrenaline and noradrenaline, but at the same time they may increase the response to sympathetic stimulation. The observations which have been made are not consistent with the interpretation which has been placed by others on the effect of phenoxybenzamine on the amount of noradrenaline appearing in the splenic vein following sympathetic stimulation; this interpretation assumes that phenoxybenzamine will decrease the response to sympathetic stimulation at low frequency. The mode of action of phenoxybenzamine is discussed, and fresh evidence that it has an anticholinesterase action is given.

Animals↗

PubMed1964

THE PART PLAYED BY CALCIUM IN DETERMINING THE RESPONSE TO STIMULATION OF SYMPATHETIC POSTGANGLIONIC FIBRES.

The inhibition of the pendular movements in a loop of rabbit ileum caused by stimulating the periarterial nerves in the mesentery depends on the calcium concentration in the bathing fluid. The inhibition is small when the concentration is low, and increases as the concentration rises. In the lower ranges of calcium concentration there is rarely any change in the response to noradrenaline, so that the increase in inhibition is due to an increase in the amount of noradrenaline released. The effect of calcium is antagonized by magnesium. In the presence of hyoscine, nicotine inhibits the ileum, and this inhibition also depends on the concentration of calcium. Acetylcholine can sometimes be shown to cause inhibition, and again this inhibition depends on the concentration of calcium. These and other experiments show a close similarity between the release of catechol amines from the adrenal medulla by acetylcholine and the release of noradrenaline from the postganglionic fibre by stimulation or by nicotine. In both instances the calcium concentration plays a decisive part.

Acetylcholine↗

PubMed1964

THE SYMPATHETIC POSTGANGLIONIC FIBRE AND THE BLOCK BY BRETYLIUM; THE BLOCK PREVENTED BY HEXAMETHONIUM AND IMITATED BY MECAMYLAMINE.

Acetylcholine, in the presence of atropine, has an action like that of sympathetic stimulation. When injected into the splenic artery it causes contraction of the spleen, but this action is blocked by hexamethonium; stimulation of the splenic nerves, however, is still effective. Thus hexamethonium distinguishes between sympathetic nerve stimulation and the action of acetylcholine. If bretylium is used instead of hexamethonium, there is no such distinction, for bretylium blocks the response to nerve stimulation as well as that to acetylcholine. It appeared that hexamethonium might block the action of acetylcholine by preventing its entry into the sympathetic fibre. Acetylcholine has some structural similarity to bretylium, since acetylcholine is a derivative of trimethylammonium and bretylium is a derivative of dimethylethylammonium. It has been found that hexamethonium, pentolinium and hemicholinium (HC-3), which are all bis-quaternary compounds, block the action of bretylium, presumably by preventing its entry into the fibre. Consistent with the view that ability to enter the fibre is important is the observation that mecamylamine and pempidine, which are ganglion-blocking agents, but not either mono- or bis-quaternary compounds, often abolish the response to stimulation of the sympathetic postganglionic fibre.

Acetylcholine↗

PubMed1963

QUATERNIZED SYMPATHOMIMETIC AMINES.

Explore the source record for details and available documents.

Cats↗

PubMed1963

The effect of eserine on the response of the vas deferens to hypogastric nerve stimulation.

In experiments in which the vas deferens together with the hypogastric nerve of the guinea-pig was studied as an isolated preparation, the relation between frequency of electrical stimulation of the nerve and the height of contraction was determined. The optimal frequency was 20 shocks/sec. This value was the same when hyoscine was present to exclude the direct effect of any acetylcholine which might be released. When eserine was added to the bath in the presence of hyoscine, the response to stimulation at a frequency of 5 shocks/sec gradually increased until it became many times greater; the response to a frequency of 10 shocks/sec also increased, though to a less extent, but eserine decreased the amplitude of the contraction at a stimulus frequency of 20 shocks/sec. Neostigmine had the same effect as eserine. These findings indicate that, in the presence of hyoscine, eserine increased the noradrenaline released by low frequency stimulation, but decreased it for high frequency. If this is so, the results are compatible with the belief that there is a cholinergic link in the release of noradrenaline by hypogastric nerve stimulation.

Acetylcholine↗

PubMed1963

The adrenergic mechanism in the nictitating membrane.

The contractions of the nictitating membrane in response to postganglionic nerve stimulation have been studied in experiments in which cats' heads were perfused. When eserine was added to the perfusion fluid there was a rapid increase in the size of the contractions. In the presence of eserine the contractions produced by injecting acetylcholine into the perfusion fluid were greatly increased. When atropine was injected into the perfusion fluid the contractions caused by postganglionic nerve stimulation returned to the size before eserine was added. In experiments with cats anaesthetized with chloralose, atropine or hyoscine was given first and the effect of eserine on the response to submaximal postganglionic nerve stimulation was determined. Eserine slowly increased the responses to stimulation without increasing the contraction produced by injecting noradrenaline. In other experiments in which maximal stimuli were used, the relation of stimulus frequency to height of contraction was determined. The optimal frequency was low, being 5 to 10 shocks/sec. In the presence of hyoscine, eserine or neostigmine increased the response to stimulation; this increase was greater at lower frequencies, and lessened as the frequency rose to the optimal value.

Acetylcholine↗

PubMed1963

The action of substances which block sympathetic postganglionic nervous transmission.

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.

Acetylcholine↗

PubMed1963

THE RELEASE OF ACETYLCHOLINE BY SYMPATHETIC NERVE STIMULATION AT DIFFERENT FREQUENCIES.

Supramaximal stimulation of the periarterial nerves in the mesentery to the rabbit isolated ileum causes inhibition which is increased when hyoscine is added to the bath. This increase is, however, usually seen only when the stimulus frequency is low, and the addition of hyoscine usually makes no difference when the frequency is 10 shocks/sec or more. The observations suggest that, at low frequency, stimulation releases both acetylcholine and noradrenaline, but that at higher frequencies only noradrenaline is released. Similar observations have been made for the nictitating membrane of the cat. When the postganglionic fibres from the superior cervical ganglion were stimulated supramaximally, the contractions of the membrane increased in size as the frequency rose. In the presence of hyoscine the contractions were smaller, the greatest difference being for the lowest stimulus frequency, the difference diminishing as the frequency rose. These observations are consistent with the view that sympathetic cholinergic fibres in many situations release acetylcholine to act directly only at low frequencies, and that at higher frequencies the acetylcholine is almost entirely used to release noradrenaline.

Acetylcholine↗

PubMed1963