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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.
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.
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The peripheral chemoreceptors of the trigeminal system in the nasal cavity are presumed to be free nerve endings arising from Adelta and C fibers. These fibers appear to be scattered throughout the nasal epithelium, and arise from the nasopalatine and ethmoid branches of the trigeminal nerve. In the present study, the effects of nicotinic acetylcholine receptor (nAChR) blockers on ethmoid nerve responses to nicotine and cyclohexanone were examined. Multiunit neural recordings were obtained from the ethmoid nerve of Sprague-Dawley rats. Vapor-phase nicotine (12.5 p.p.m.) and cyclohexanone (450 p.p. m.) were delivered to the rats' nares via an air-dilution olfactometer. The magnitude of the response to nicotine decreased after the administration of the nAChR blockers dihydro-beta-erythroidine hydrobromide (DHBE) and mecamylamine hydrochloride. DHBE is a competitive nicotinic receptor antagonist specific for the alpha4beta2 receptor subtype and mecamylamine is known to bind alpha3beta4 and alpha4beta2 receptors. The nAChR blockers had no effect on ethmoid nerve responses to cyclohexanone. These results suggest that the mechanism by which at least one irritant stimulates nasal trigeminal nerve endings involves the binding of irritant with a specific receptor.
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1. The electrical and pharmacologic properties of acetylcholine (ACh)-induced current (IACh) were studied in the parasympathetic neurons isolated from bullfrog heart with the use of the concentration-clamp technique, which allows intracellular perfusion and rapid change of external solution within 2 ms under the single-electrode voltage-clamp condition. 2. The IACh consisted of an initial transient peak component and a successive steady-state plateau component. Both currents increased in a sigmoidal fashion with increasing ACh concentration. The dissociation constant (Kd value) and the Hill coefficient for each component were 2.2 X 10(-5) M and 1.6, respectively. 3. In the K(+)-free solution, the reversal potential (EACh) of IACh was close to the Na+ equilibrium potential (ENa). The current-voltage (I-V) relation showed inward rectification at positive potentials. 4. Nicotine mimicked only the peak component of IACh. However both peak and steady-state components were blocked nonselectively by the nicotinic blockers d-tubocurarine and hexamethonium. 5. Carbamylcholine (CCh) mimicked the steady-state component of IACh. The steady-state component was selectively inhibited by atropine at concentrations 1,000 times lower than that required for inhibition of the peak component. The steady state was blocked equally by either pirenzepine (M1 blocker) or AF-DX-116 (M2 blocker). 6. It was concluded that the IACh consisted of a peak component having double exponential activation and inactivation, mediated through the nicotinic actions, and a steady-state component having no inactivation, mediated through the muscarinic action.
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Until now, the only well documented, fast excitatory neurotransmitter in the brain has been glutamate. Although there is evidence for adenosine 5'-triphosphate (ATP) acting as a transmitter in the peripheral nervous system, suggestions for such a role in the central nervous system have so far not been supported by any direct evidence. Here we report the recording of evoked and miniature synaptic currents in the rat medial habenula. The fast rise time of the currents showed that they were mediated by a ligand-activated ion channel rather than a second messenger system, thus limiting the known transmitter candidates. Evidence was found for the presence on the cells of glutamate, gamma-aminobutyric acid, acetylcholine and ATP receptors, but not for 5-hydroxytryptamine (5HT3) or glycine receptors. The evoked currents were unaffected by blockers of glutamate, gamma-aminobutyric acid or acetylcholine receptors but were blocked by the ATP receptor-blocker, suramin and the desensitizing ATP receptor-agonist alpha,beta-methylene-ATP. Our evidence identifies for the first time synaptic currents in the brain, mediated directly by ATP receptors.