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PubMed1963

THE EFFECTS OF GANGLION-BLOCKING AND POSTGANGLIONIC SYMPATHOLYTIC DRUGS ON PREPARATIONS OF THE GUINEA-PIG VAS DEFERENS.

The contractions of the guinea-pig isolated vas deferens elicited by electrical stimulation of the hypogastric nerve were completely blocked by the following drugs: guanethidine, bretylium, dimethylphenylpiperazinium hydrochloride, nicotine, pempidine, hexamethonium, hemicholinium, D-tubocurarine and procaine. However, when the vas deferens was stimulated through an electrode in its lumen, the contractions in response to frequent, short stimuli (50 shocks/sec, 1 msec duration) were blocked by guanethidine, bretylium and dimethylphenylpiperazinium, but were not affected by the remaining drugs, except that procaine and hemicholinium each caused some reduction in the responses. When the preparation was stimulated transmurally with shocks of 200 msec duration at 1 shock/sec, the contractions were unaffected by any of the above drugs, except hemicholinium which again caused a slow reduction of up to 50% of the original response. It is concluded that nicotine, pempidine, hexamethonium, D-tubocurarine and hemicholinium probably block the response to stimulation of the hypogastric nerve by acting on peripheral ganglia in its pathway. Hemicholinium appears to have an additional effect in depressing the responses of the smooth muscle of the vas deferens to direct electrical stimulation, and procaine may act both on the ganglia and at the nerve terminals.

Animals↗
PubMed1970

Synaptic potentials recorded by the sucrose-gap method from the rabbit superior cervical ganglion.

1. Compound ganglionic potentials evoked by stimulation of the preganglionic nerves to the superior cervical ganglion of the rabbit were recorded by the sucrose-gap method.2. When the distal part of the ganglion was bathed in flowing isotonic sucrose solution or sodium-deficient solutions, ganglionic action potentials were no longer evoked, only large synaptic potentials.3. The compound synaptic potential, which remained unaltered for more than 1 h, originated in a population of cells at the interface between the Krebs and sucrose solutions. Hexamethonium reduced the size but did not alter the time course of the synaptic potential.4. It is suggested that a higher concentration of sodium ions is required for the generation of ganglionic action potentials than for either conduction in the postganglionic axons or production of synaptic potentials.5. When lithium replaced sodium in the solution bathing the distal part of the ganglion, the synaptic potential was greatly reduced in amplitude. Impulse propagation in the postganglionic axons was only slightly impaired when lithium replaced sodium in the solution bathing the axons.6. A quantitative assessment of the potency of the ganglion-blocking drugs nicotine, pentolinium, hexamethonium and pempidine was made by measuring the depression of the synaptic potentials produced by bathing the distal part of the ganglion in flowing isotonic sucrose solution. The concentrations which produced a 50% depression were 8.1 muM nicotine, 26.5 muM pentolinium, 111 muM hexamethonium and 22.2 muM pempidine.

Animals↗
PubMed1974

Effects of cholinomimetic agents given into the brain of fowls.

1 Effects of cholinomimetic agents, given into the IIIrd ventricle of adult fowls (Gallus domesticus) or infused into the hypothalamus of young chicks, were tested on behaviour, respiratory rate and body temperature.2 Carbachol evoked behavioural and electrocortical arousal but lacked postural and respiratory effects. Contrariwise, pilocarpine increased respiratory rate and induced postural changes, i.e. abduction of the wings, but lacked other behavioural effects and did not alter electrocortical activity. Benzoylcholine induced tachypnoea, postural changes and brief electrocortical arousal. Acetylcholine was ineffective unless given with physostigmine, when electrocortical arousal, postural changes and tachypnoea developed. Methacholine induced tachypnoea and postural changes.3 Effects of carbachol and pilocarpine were prevented by hyoscine and those of benzoylcholine by pempidine; hyoscine and pempidine were required together to prevent the effects of methacholine and to attenuate those of acetylcholine with physostigmine.

Acetylcholine↗
PubMed1975

An investigation of the tachycardia produced by intracerebro-ventricular injections of isoprenaline in mice.

1. Isoprenaline, 3.5-20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose-dependent tachycardia. 2. Pretreatment with either reserpine or pempidine blocked nervously-mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated. 3. Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline. 4. When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose-dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation. 5. This was confirmed by the appearance of a late-developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice. 6. It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.

Adrenal Glands↗
PubMed1974

A microinjection study of the control of antidiuretic hormone release by the supraoptic nucleus of the hypothalamus in the cat.

1. The release of antidiuretic hormone (ADH) has been studied in the chloralose anaesthetized cat after microinjection of various agents directly into the brain, in particular the supraoptic nucleus of the hypothalamus (SON). The concentration of ADH in jugular venous blood was determined using the waterloaded, alcohol anaesthetized rat assay. The position of the microinjection cannula was located post mortem in stained brain sections.2. Nicotine, noradrenaline (NA) and hypertonic saline caused release of ADH, whereas microinjections of isotonic saline did not affect the blood level of the hormone.3. Nicotine administered to other sites in the central nervous system (C.N.S.) could also cause ADH release. Hypertonic saline proved to be an ineffective stimulus at all the tested sites outside the supraoptic region.4. The ganglion-blocking agents hexamethonium and pempidine inhibited the releasing action of nicotine at the SON in most of the experiments. These blocking drugs had no effect on osmotic release. When administered alone, both hexamethonium and pempidine had variable, but analogous effects on the hormone output.5. The alpha-adrenoreceptor blocking drug, phentolamine, stimulated ADH release, but the beta-receptor blocking drug, propranolol, had no such effect. Both drugs appeared to have inhibitory action on noradrenergic release of ADH, but neither had a consistent effect on the osmotic release of the hormone.

Animals↗
PubMed1975

Drinking behaviour in the cat induced by renin, angiotensin I, II and isoprenaline.

1. Angiotensin I, II and hog renin, infused into the lateral cerebral ventricles (I.C.V.) of water replete cats, each induced water drinking behaviour. 2. Intravenous infusion of high doses of angiotensin I or II also elicited a drinking response. The dipsogenic effect of I.V. renin was not marked. 3. Drinking in response to I.C.V. angiotensin II was abolished after autonomic ganglion blockade with I.V. hexamethonium or pempidine and was significantly reduced after I.V. atropine methonitrate. 4. The dipsogenic response to I.C.V. angiotensin II was unaffected by either peripheral adrenergic neurone blockade with I.V. bethanidine, alpha-adrenoceptor blockade with phentolamine or beta-adrenoceptor blockade with sotalol. 5. Atropine, atropine methonitrate, hexamethonium and pempidine given I.C.V did not inhibit the diposgenic response to I.C.V. angiotensin II. 6. Bethanidine I.C.V. produced a dose related reduction in the dipsogenic response to I.C.V. angiotensin II. 7. The alpha-adrenoceptor blocking agents tolazoline and phenoxybenzamine given I.C.V did not affect angiotensin induced drinking but the response was regularly inhibited by phentolamine I.C.V. 8. The beta-adrenoceptor blocking agents propranolol and practolol given I.C.V. each inhibited angiotensin induced drinking. The L-isomer of propranolol was a more effective blocker than the D-isomer. 9. Isoprenaline given I.C.V induced drinking in ten of sixteen cats. Subcutaneous administration of isoprenaline also elicited drinking but the onset of the response was delayed and the amount consumed slightly less than after I.C.V infusion.

Angiotensin II↗
PubMed1989

Cholinergic synapses and the organization of contrast detection in the crayfish optic lobe.

The actions of acetylcholine (ACh) were examined on 4 classes of multicolumnar interneurons whose dendrites lie in close proximity to the putative cholinergic transmedullary neurons described in the companion report. ACh-elicited responses in each cell type resemble visually elicited synaptic events and persist following synaptic blockade with 20 mM CoCl2. Tangential cells exhibit a hyperpolarizing response to ACh that resembles the visual response in reversal potential and dependence on extracellular chloride. The visual response is potentiated by the anticholinesterase, neostigmine (0.1 mM). Visual and carbachol-elicited responses are blocked by nicotinic ganglionic antagonists (e.g., 10(-6) M pempidine) that are 10-100 times more potent than D-tubocurarine. Medullary amacrine cells exhibit depolarizing responses to ACh (10(-6) M) and light with similar reversal potentials. The visual response is potentiated by neostigmine. Dimming fibers respond to light and ACh with a hyperpolarization that inhibits the maintained discharge. The sustaining fiber response to ACh reflects both direct responses and indirectly elicited synaptic actions. The direct action is a hyperpolarization possibly related to the visual "off-response." It is associated with an increased conductance and a reversal potential negative to the dark potential. The off-response is abolished by curare and pempidine and potentiated by neostigmine. ACh appears to orchestrate several aspects of the dual-channel contrast detection system of the optic lobe. The actions of ACh on tangential cells, amacrine cells, and dimming fibers are all consistent with the effects of a spatially localized increment in light intensity and a corresponding local release of ACh in the retinotopic columnar array.

Acetylcholine↗
PubMed1962

Effects of some guanidine derivatives on neuromuscular and ganglionic transmission.

The anticurare activity of some guanidine derivatives has been studied using the fowl sciatic nerve-gastrocnemius muscle preparation and the cat sciatic nerve-gastrocnemius and tibialis anterior muscle preparations. Among the compounds tested, and in decreasing order of potency, were NN-dimethylguanidine, N-methylguanidine, guanidine and N-aminoguanidine which antagonized or prevented tubocurarine or gallamine triethiodide-induced paralysis. None of the derivatives antagonized the effects of suxamethonium or decamethonium. NN-Dimethylguanidine, N-methylguanidine and guanidine antagonized or prevented the curare-like effects of magnesium without altering the activity of hemicholinium. At high doses NN-dimethylguanidine induced a decamethonium-like spastic paralysis in the fowl sciatic nerve-gastrocnemius muscle preparation. NN-Diethylguanidine, however, induced a tubocurarine-like flaccid paralysis. The derivatives possessing anticurare activity were also studied using the cat superior cervical ganglion-nictitating membrane preparation to check their possible effects against ganglionic blocking agents. Only guanidine antagonized or prevented the effects of hexamethonium, pentolinium and mecamylamine; it had no effect on the actions of pempidine and chlorisondamine. NN-Diethylguanidine was the only compound in the series to show a ganglionic blocking action.

Animals↗
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

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↗
PubMed1985

Mediation of passive avoidance learning by nicotinic hippocampo-entorhinal components in young rats.

Young rats, 11, 16, and 20 days of age, received bilateral injections of three antinicotinic agents into the posteroventral hippocampo-subiculo-entorhinal area, and were trained to learn a cool-draft-stimulus, passive-avoidance task shortly after (17 min). Gallamine triethiodide had no action at low doses and provoked convulsions at higher concentrations. Pempidine tartrate produced age- and dose-dependent impairments of the passive avoidance, and was much more effective in younger groups (11 and 16 days) than at 20 days. alpha-bungarotoxin also induced dose-dependent deficits. These results, together with the mecamylamine-induced deficits already reported, suggest that nicotinic cholinergic synapses located in the posteroventral part of the hippocampal complex play a role in passive-avoidance learning in the young rat as soon as this type of conditioning is possible, but become relatively less important at older ages, when muscarinic mechanisms also become involved.

Age Factors↗
PubMed1996

Pharmacological characterization of a nicotinic autoreceptor in rat hippocampal synaptosomes.

The modulation of [3H]ACh release by nicotinic compounds was studied in superfused rat hippocampal synaptosomes loaded with [3H]choline, (-)-Nicotine (0.1-10 microM) evoked a dose-dependent increase in [3H]ACh release; higher concentrations were less effective. Nicotine-evoked release was Ca(2+)-dependent, and blocked by the nicotinic antagonists dihydro-beta-erythroidine, mecamylamine, and pempidine. The alpha 7-selective antagonist methyllycaconitine did not inhibit nicotine-evoked release when tested at 1 microM, although at 10 microM some attenuation of the response was observed. Six agonists tested were equally efficacious in stimulating [3H]ACh release, as judged by the maximum responses, and gave the following EC50 values: (+/-)-epibatidine 0.12 microM; (+)-anatoxin-a 0.14 microM; (-)-nicotine 0.99 microM; (-)-cytisine 1.06 microM; ABT-418 2.6 microM; isoarecolone 43 microM. Each agonist generated a "bell-shaped" dose response curve, suggesting desensitisation at higher concentrations. This is supported by analysis of repetitive stimulation with (-)-nicotine and (-)-cytisine: S2/S1 ratios declined sharply with increasing concentration, whereas subsequent KC1-evoked release remained constant. These results are discussed in terms of possible nicotinic receptor subtypes that might be present on hippocampal nerve terminals.

Acetylcholine↗
PubMed1986

Inhibition by neosurugatoxin of nicotine-induced antinociception.

We have found a selective inhibition of nicotine-induced antinociception in mice by neosurugatoxin (NSTX, 0.4-3.8 nmol/kg), a neurotoxin with a high affinity for ganglionic nicotinic receptors (ED50 = 0.65 nmol/kg). The toxin also reduced specific [3H]nicotine binding in mouse brain membranes (IC50 = 95 nM). The anti-nicotinic activity of NSTX was markedly greater than that of mecamylamine and pempidine. These data indicate that NSTX may block functional nicotinic cholinoceptors possibly in the central nervous system.

Animals↗
PubMed1988

Surgical and pharmacological reductions in sympathetic nerve activity increase the neuropeptide Y-immunoreactivity content of the rat iris but not the vas deferens.

Decentralization of the superior cervical ganglion (S.C.G.) of the rat elevated the neuropeptide-Y immunoreactivity (NPY-ir) content of the ganglion on day 1 (+43%) but not on day 3 post-surgery. The content of NPY-ir in the iris was increased by decentralization (+40%) 3 days post-surgery, and treatment with clonidine (+43%), and pempidine (+82%). The levels of NPY-ir in the rat vas deferens were not affected by either surgical or pharmacological treatment. These results suggest NPY is released from sympathetic nerves in the iris but not vas deferens during normal sympathetic activity.

Animals↗
PubMed1992

Functional heterogeneity of the matrix compartment in the cat caudate nucleus as demonstrated by the cholinergic presynaptic regulation of dopamine release.

Previously, using a new in vitro microsuperfusion procedure, we have demonstrated marked differences in the cholinergic presynaptic regulation of the release of [3H]dopamine continuously synthesized from [3H]tyrosine in two close striosomal- and matrix-enriched areas of the cat caudate nucleus. A tetrodotoxin-resistant stimulatory effect of acetylcholine mediated by muscarinic receptors was observed in both compartments. However, in addition, two opposing types of tetrodotoxin-sensitive acetylcholine-evoked regulation of [3H]dopamine release were only seen in the matrix: one facilitatory, involving nicotinic receptors located on as yet unidentified neurons, and the other inhibitory, mediated by muscarinic receptors located on dynorphin-containing neurons. In the present study, using the same approach, a functional heterogeneity was demonstrated in the matrix. Indeed, in various conditions the effects of acetylcholine (50 microM) on the release of [3H]dopamine were different in a matrix-enriched area (matrix 2) distinct from that previously investigated (matrix 1); these areas being characterized by the presence or absence of islands of striatonigral cells, respectively. As in matrix 1, acetylcholine induced a short-lasting stimulation of [3H]dopamine release in matrix 2 but, in contrast to that observed in matrix 1, the acetylcholine-evoked response in matrix 2 was not modified in the presence of tetrodotoxin (1 microM). Experiments made in the presence of the tetrodotoxin and atropine (1 microM) indicated that both muscarinic and nicotinic receptors are located on dopaminergic nerve terminals in matrix 2 while muscarinic receptors are only present in matrix 1. In the absence of tetrodotoxin, the short-lasting stimulation of [3H]dopamine release was transformed into a long-lasting response in the presence of pempidine (50 microM), in matrix 2 but not in matrix 1 while prolonged responses were seen in both matrix areas in the presence of atropine. Finally, the acetylcholine short stimulatory effect on [3H]dopamine release was transformed into a long stimulatory response in the presence of bicuculline (50 microM) but not naloxone (1 microM) in matrix 2 while the reverse was observed in matrix 1. By providing further evidence for a functional heterogeneity of the matrix, our results suggest that depending on the matrix area investigated, dynorphin- or GABA-containing neurons are involved in the indirect cholinergic inhibitory control of dopamine release.

Acetylcholine↗
PubMed1997

[3H]benzylpempidine, a new radioligand for probing a putative channel site on nicotinic cholinergic receptors.

A study was undertaken to assess the receptor binding characteristics of [3H]4-benzylpempidine to an allosteric site on calf brain membranes associated with nicotinic cholinergic receptors and to compare the binding affinity of novel arylpempidine analogs with their ability to antagonize the behavioral effects of nicotine in mice. Scatchard analysis of the binding yielded a K(d) of 20 nM and a B(max) of 330 fmols/mg membrane protein. [3H]4-benzylpempidine appears to be a more satisfactory ligand than [3H]mecamylamine, since it possessed a 50-fold greater affinity and its binding was far less sensitive to inorganic ions and Tris. Among the arylpempidine analogs 4-m-chlorobenzylidenepempidine and 4-benzylidenepempidine had the lowest K(i) values (1.4 nM and 5.0 nM, respectively) and were the most potent in antagonizing nicotine-induced seizures in mice. Although the K(i) values for pempidine and mecamylamine were 1-2 orders of magnitude greater than any of the arylpempidines, the dose required to antagonize nicotine-induced seizures in mice was comparable to the arylpempidines. One explanation for this apparent discrepancy in the correlation of binding affinity and nicotine antagonism is the lower brain penetration of arylpempidines compared to mecamylamine, following their systemic administration to mice.

Animals↗
PubMed1979

The effect of praziquantel on Schistosoma mansoni.

3 x 10(-6)M praziquantel fails to completely paralyse miracidia and cercariae in a short time but they are not infective when maintained in the solution. 3 x 10(-5)M praziquantel prevents infected snails shedding cercariae but does not kill daughter sporocyts or developing cercariae. As the action of praziquantel on adult worms is not blocked by 10(-2)M mecamylamine, pempidine or carbachol, but is reduced by calcium depletion, it is suggested that praziquantel may act by permitting calcium influx to muscle cells causing them to contract.

Animals↗
PubMed1989

Distinct presynaptic control of dopamine release in striosomal and matrix areas of the cat caudate nucleus.

By use of a sensitive in vitro microsuperfusion method, the cholinergic prsynaptic control of dopamine release was investigated in a prominent striosome (areas poor in acetylcholinesterase activity) located within the core of cat caudate nucleus and also in adjacent matrix area. The spontaneous release of [3H]dopamine continuously synthesized from [3H]tyrosine in the matrix area was found to be twice that in the striosomal area; the spontaneous and potassium-evoked releases of [3H]dopamine were calcium-dependent in both compartments. With 10(-6) M tetrodotoxin, 5 x 10(-5) M acetylcholine stimulated [3H]dopamine release in both striosomal and matrix areas, effects completely antagonized by atropine (10(-6) M), thus showing the involvement of muscarinic receptors located on dopaminergic nerve terminals. Experiments without tetrodotoxin revealed a more complex regulation of dopamine release in the matrix: (i) In contrast to results seen in the striosome, acetylcholine induced only a transient stimulatory effect on matrix dopamine release. (ii) Although 10(-6) M atropine completely abolished the cholinergic stimulatory effect on [3H]dopamine release in striosomal area, delayed and prolonged stimulation of [3H]dopamine release was seen with atropine in the matrix. The latter effect was completely abolished by the nicotinic antagonist pempidine (10(-5) M). Therefore, in the matrix, in addition to its direct (tetrodotoxin-insensitive) facilitatory action on [3H]dopamine release, acetylcholine exerts two indirect (tetrodotoxin-sensitive) opposing effects: an inhibition and a stimulation of [3H]dopamine release mediated by muscarinic and nicotinic receptors, respectively.

Acetylcholine↗