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PubMed1964

AUTONOMIC MEDIATION OF THE EFFECT OF RAISED ARTERIAL GLUCOSE UPON FREE FATTY ACIDS.

The intravenous infusion of 600 milligrams of glucose over 30 minutes caused a 17 percent fall in the concentration of free fatty acids in arterial blood of subjects who had fasted overnight. This response to glucose was abolished in subjects treated previously with ganglionic or adrenergic blocking agents. Small amounts of insulin were secreted in response to these glucose infusions, but in insulin-dependent diabetics incapable of altering plasma insulin to any great extent, the effect of glucose upon free fatty acids could be obtained provided the subjects were primed with long-acting insulin before the infusions were begun. The response of free fatty acids to doses of glucose which elevated the concentration of glucose in arterial blood by only 3 mg percent and the blockade of this response by autonomic and adrenergic blocking agents suggest that centers in the central nervous system exist which are capable of responding to elevations of arterial glucose by inhibiting the sympathetic tone partially responsible for sustaining lipolysis in fasting.

Autonomic Nervous System↗
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

THE SITE OF THE 5-HYDROXYTRYPTAMINE RECEPTOR ON THE INTRAMURAL NERVOUS PLEXUS OF THE GUINEA-PIG ISOLATED ILEUM.

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.

Acetylcholine↗
PubMed1964

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↗
PubMed1963

PREGANGLIONIC AND POSTGANGLIONIC STIMULATION OF THE GUINEA-PIG ISOLATED VAS DEFERENS PREPARATION.

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.

Acetylcholine↗