Interaction between hemicholinium-3 and edrophonium on the isolated taenia of the guinea-pig caecum.
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Acetylcholine↗
Biomedical subjects
F Mitchelson
Publications and source records attributed to F Mitchelson.
Differentiation between the actions of acetylcholine and tetramethylammonium on the isolated taenia of the guinea-pig caecum by hemicholinium-3.
1. Contractions of the isolated taenia of the guinea-pig caecum produced by acetylcholine and TMA were examined in the presence of various antagonists and anticholinesterases.2. Hemicholinium-3 (HC-3) (50-400 mug/ml) inhibited contractions or relaxations produced by TMA but not contractions produced by acetylcholine. The inhibition was rapid in onset and readily reversible. Contractions produced by transmural stimulation were unaffected by HC-3 but responses produced by nicotine were inhibited.3. Low concentrations of hyoscine and benzhexol inhibited responses to acetylcholine to a greater extent than those to TMA.4. Morphine, raised concentrations of Mg(++) or reduced concentrations of Ca(++) inhibited contractions produced by TMA and by acetylcholine to a similar extent.5. Edrophonium, in concentrations which preferentially inhibit acetylcholinesterase, increased contractions produced by acetylcholine and converted responses to nicotine or transmural stimulation into contractions or biphasic responses with a marked contraction phase but did not increase contractions produced by TMA.6. Iso-OMPA, in concentrations which preferentially inhibit butyrylcholinesterase, had no effect on responses to acetylcholine, nicotine, transmural stimulation or TMA.7. HC-3 inhibited contractions produced by TMA in the presence of anticholinesterases but had little effect on contractions produced by acetylcholine.8. These results suggest that TMA produces contractions by acting directly on receptors of the smooth muscle. An analysis of possible reasons for HC-3 (in the concentrations used) acting as an antagonist of TMA but not of acetylcholine indicates that the findings do not necessarily contradict the interpretation that both agonists act on the same receptor.
Acetylcholine↗
The actions of some cholinomimetic drugs on the isolated taenia of the guinea-pig caecum.
1. The actions on the taenia of 4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride (McN-A-343), N-benzyl-3-pyrrolidyl acetate methobromide (AHR-602), tetramethylammonium (TMA) and choline phenyl ether have been examined and compared with the actions of acetylcholine, nicotine and 1,1-dimethyl-4-phenylpiperazinium (DMPP).2. Responses of the taenia to these agonists are quantitatively and often qualitatively dependent on the tone of the preparation. A method is described which makes allowance for the effect of tone on heights of contractions.3. Acetylcholine, McN-A-343 and AHR-602 produced only contractions; TMA produced contractions or biphasic responses; and choline phenyl ether, nicotine and DMPP produced contractions, relaxations or biphasic responses.4. The mode of action of these compounds has been analysed by means of hyoscine, ganglion-blocking drugs, tetrodotoxin and local anaesthetics.5. It is concluded that acetylcholine, McN-A-343, AHR-602, TMA and choline phenyl ether act on muscarinic receptors in the smooth muscle. Choline phenyl ether has an additional action on nicotinic receptors of cholinergic neurones. Nicotine and DMPP act on nicotinic receptors of cholinergic neurones and of inhibitory neurones. An action on the latter is sometimes also seen with TMA and choline phenyl ether.6. With nicotine or DMPP, and TMA or choline phenyl ether in the presence of hyoscine, part of the contraction phase of biphasic responses (in which a contraction follows relaxation) is best explained as being triggered by the initial relaxation-that is, as a "rebound contraction".7. None of the compounds tested appeared to exert an atropine-sensitive action on neurones.8. In the presence of hyoscine high concentrations of agonists can act on sites not involved with lower concentrations.
Acetylcholine↗
The action of protriptyline on peripheral autonomic function.
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Animals↗
Antimuscarinic action of an alkane-bis-ammonium compound alone and in combination with (+)-benzetimide.
Heptane-1,7-bis-(dimethyl-3'-phthalimidopropylammonium bromide) ('C7/3-phthalimido-propyl') in concentrations of 10(-7) to 0.5 X 10(-3) inhibited negative inotropic responses to carbachol or acetylcholine to a similar extent in the electrically stimulated isolated guinea-pig left atrium. However, the degree of antagonism of responses to carbachol was less than expected for a competitive antagonist when the higher concentrations of 'C7/3-phthalimido-propyl' were employed. When 'C7/3-phthalimido-propyl' was combined with competitive antagonists such as (+)-benzetimide, atropine or homatropine the degree of antagonism was greater than expected for combination of 2 competitive antagonists. Qualitatively similar results were obtained in the presence of practolol (1.5 X 10(-5) M). The results obtained with 'C7/3-phthalimido-propyl' are shown to agree with theoretical predictions for a metaffinoid antagonist which influences the affinities of both agonists and competitive antagonists by combining with a regulatory site distinct from, but interdependent with the binding sites for agonists and competitive antagonists. Further, it is shown that the alkane-bis-ammonium compound produces a much greater reduction in the affinity of carbachol than that of the competitive antagonists and as a consequence causes 'supra-additive' effects when combined with a competitive antagonist. The reduction in the affinity of (+)-benzetimide produced by 'C7/3-phthalimido-propyl' did not differ significantly from the reduction in the affinities of atropine or homatropine.
Acetylcholine↗
Sensitivity changes in guinea-pig atria and ileum following subacute administration of dyflos.
1. Subacute administration of dyflos to guinea-pigs (1.2 mg/kg, s.c., daily for 10 days) led to the development of subsensitivity to carbachol in the ileum but not in the electrically stimulated left atrium. 2. Atria from dyflos-pretreated animals became supersensitive to acetylcholine but the ileum became subsensitive to this agonist despite marked inhibition of cholinesterases. The degree of subsensitivity was less than that for carbachol. 3. Subsensitivity also developed to histamine and was of a similar order to that observed for carbachol supporting the suggestion that subsensitivity is a nonspecific post-receptor mechanism. 4. Other changes which occurred in the ileum, together with the increase in the EC50 value to agonists were an increase in tissue mass, an increase in the slope of the concentration-response curve to agonists and an increase in the maximal response to agonists.
Animals↗
The influence of subacute dyflos administration on the sensitivity to agonists of longitudinal and circular muscle preparations of the guinea-pig ileum.
1. Changes in the EC50 values to various agonists in longitudinal and circular muscle preparations of guinea-pig ileum were investigated following daily pretreatment of the animals for 10 days with dyflos (1.2 mg/kg, s.c.). 2. In the longitudinal muscle no significant change in sensitivity to acetylcholine and potassium chloride was noted following dyflos treatment. Marked subsensitivity to carbachol and histamine was observed. 3. In circular muscle a marked supersensitivity to acetylcholine occurred and there was no change in sensitivity to carbachol. 4. Dyflos treatment induced an increase in the slope of the log concentration-response curve and the maximal contractile response obtained to agonists in both longitudinal and circular muscle preparations. An increase in tissue mass was also associated with dyflos pretreatment. 5. Subsensitivity development was not attributable to changes in affinity for agonists at the receptor site but rather to changes at the post-receptor level leading to a nonspecific subsensitivity.
Acetylcholine↗
Muscarinic receptor inhibition and other effects of pancuronium in the rabbit ear artery preparation.
The effect of pancuronium in the rabbit ear artery was investigated in order to measure the inhibition it produces at the prejunctional muscarinic receptor on sympathetic nerve endings in this tissue. Pancuronium (0.1-0.2 mmol/l) produced an enhancement of responses to transmural electrical stimulation but this effect was absent in experiments conducted in the presence of cocaine (10 mumol/l) suggesting that an inhibition of the uptake1 mechanism occurs with pancuronium in this tissue. Pancuronium (10 mumol/l) in the presence of cocaine (10 mumol/l) and yohimbine (1 mumol/l) caused a small transient increase in resting output of tritium from arteries preincubated with 3H-noradrenaline but did not affect stimulated output of tritium nor the perfusion pressure in perfused preparations. Pancuronium in the presence of cocaine or cocaine plus yohimbine caused a parallel shift of the concentration-response curve for the inhibitory effect of carbachol (CCh) on the increase in perfusion pressure induced by nervous stimulation. An Arunlakshana-Schild plot of the data was linear but the slopes of 0.92 and 0.95 respectively, were significantly different from unity (P less than 0.05). The calculated pKB value suggests that pancuronium has a different affinity for prejunctional muscarinic receptors on sympathetic nerve endings in this tissue compared to that previously reported in cardiac or ileal smooth muscle.
Animals↗
Comparison of the affinity of secoverine for some muscarinic receptors.
The selective muscarinic receptor antagonist secoverine was found to have a similar affinity for muscarinic receptors in the guinea-pig left atrium and ileal longitudinal muscle as well as in the rat urinary bladder and ileum.
Animals↗
Allosteric interactions at muscarinic cholinoceptors.
1. An allosteric interaction occurs when the binding of a ligand to its site on a receptor is able to modify the binding of another ligand to a topographically distinct site on the same receptor and vice versa. The muscarinic cholinoceptors represent the best-studied examples of allosteric phenomena among the G-protein-coupled receptor superfamily. 2. The simplest model describing allosteric interactions at muscarinic cholinoceptors is the ternary complex model, which allows for a three-way interaction between the receptor, a classical (orthosteric) ligand and an allosteric modulator. The interaction may be quantified using the dissociation constant of each ligand for its respective binding site on the free receptor and the 'co-operativity factor' alpha. This latter term is the ratio of affinities of a ligand for the occupied versus the unoccupied receptor and is a measure of the magnitude of the cooperativity between two concomitantly bound ligands. 3. Identification of allosteric phenomena requires the utilization of both radioligand binding and functional approaches. Manifestations of allosterism include: (i) a limited ability to influence radioligand binding as the concentration of the latter is increased; (ii) alterations in the dissociation rate of orthosteric ligands; (iii) curvilinear Schild regressions; and (iv) nonadditivity of agonist/orthosteric antagonist/allosteric modulator combination concentration ratios. 4. Allosteric modulators of muscarinic cholinoceptors represent a diverse range of compounds. Some of the most studied agents include gallamine, alcuronium and the bis-ammonium compounds, C7/3'-phth and W84. Alcuronium has proven a most useful pharmacological tool, as it has been shown to display both positive and negative co-operativity, depending on the receptor subtype and orthosteric ligand involved in the interaction. 5. Evidence has accumulated pointing to the existence of a common allosteric binding site on the muscarinic cholinoceptors, located close to the orthosteric site, but at a more extracellular level. However, the possibility of more than one accessory binding site on various receptor subtypes cannot be excluded. 6. Allosteric modulators offer a number of potential therapeutic advantages, including a ceiling level to their effects and the possibility of 'absolute selectivity' of action, based on the degree of co-operativity rather than the affinity of the modulator for any one receptor subtype.
Alcuronium↗