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PubMed1970

Entry of decamethonium in rat muscle studied by autoradiography.

1. When a steady plasma level of decamethonium was maintained by infusion in rats, the labelled compound became concentrated in the region of the end-plate of skeletal muscle, as shown by scintillation counting.2. The distribution of tritium-labelled decamethonium in single muscle fibres was studied by autoradiography of frozen sections, with resolution less than 1 mu.3. After intravenous injection of a dose of decamethonium which produced partial paralysis it was shown that the labelled compound had entered muscle fibres in the region of the end-plate, and for several hundred microns on either side of the end-plate.4. Entry of decamethonium could be demonstrated as early as 30 sec after intra-arterial injection. There was no evidence of any redistribution of labelled drug for a period of 2 hr after the initial entry.5. Previous administration of tubocurarine markedly reduced the entry of labelled decamethonium.

Animals↗
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↗
PubMed1990

A maxi calcium-activated potassium channel from chick lens epithelium.

The apical membrane of embryonic chick lens epithelium contains at high density, a large conductance K+ channel whose open probability is increased by Ca++ at the inner surface of the membrane and by depolarization. The conductance of the channel when it is fully open in symmetrical 150 mM K+ solutions is 214 +/- 3 pS (mean +/- std. error). The current through the channel is a function of the K+ concentration. Gating (open probability) at positive transmembrane voltages increases as the internal [Ca++] is raised above 10(-7) M. The open probability decreases monotonically as the transmembrane voltage is made more negative. The channel is at least 87 times more permeable to K+ than to Na+ or Li+ and shows appreciable permeability to Rb+ and NH4+. It has at least three subconductance levels amounting to approximately 3/4, 1/2, and 1/4 the fully open unitary conductance. The occurrence of these subconductance levels is highly variable from one patch to another. The channel is blocked by physiological levels of internal Na+ but not over a physiological voltage range. This block is partially overcome by elevated external K+. This K+ channel from chick lens epithelium is blocked by a number of compounds known to block BK channels in other tissues. Here we show that decamethonium and Ba++ are effective blockers when added to the inner bathing solution at concentrations greater than .1 mM. Tetraethylammonium, Cs+, quinine, quinidine and Ba++ are all effective blockers when applied to the outer side of the channel in the .1 mM - 5 mM range. With the exception of internal Ba++, all of these compounds produce a fast flicker-type blockade. We use a one-site model to quantify the blockade caused by these flicker producing agents. The voltage dependence of the blockade by Cs+ suggests that this channel probably allows multiple occupancy.

Animals↗
PubMed1960

Reciprocal potentiating action of depolarizing drugs on the isolated frog rectus abdominis muscle.

Subthreshold concentrations of the depolarizing agents, acetylcholine and decamethonium, potentiated isotonic contractures of the isolated frog rectus abdominis muscle elicited by effective doses of either of these drugs or by choline in the absence of the anticholinesterases, sarin, or dyflos. Comparable potentiation of the contracture produced by decamethonium or choline could be obtained by alternate stimulation with acetylcholine in the absence of dyflos or sarin. Furthermore, dyflos alone did not effect potentiation in the absence of alternate stimulation with acetylcholine. Finally, the inhibitory action of tubocurarine, as measured by depression of the contracture elicited by decamethonium and acetylcholine, was not antagonized by sarin. It was concluded that the enhancement of the response to acetylcholine produced by dyflos and by sarin was brought about exclusively by their action as inhibitors of cholinesterase. The ability of dyflos and of sarin to potentiate contractures elicited by decamethonium or by choline may be attributed to a facilitation of the action of the depolarizing compounds by subthreshold concentrations of acetylcholine available in the presence of these anticholinesterases.

Acetylcholine↗
PubMed1977

Movement of labelled decamethonium in muscle fibres of the rat.

1. Tritium-labelled decamethonium accumulated in diaphragm muscles of the rat in vitro with a peak at the end-plate region and the distributions were fitted by Gaussian curves. 2. Prolonged wash in physiological saline (10 hr) produced some loss in radioactivity but no detectable spread of the labelled compound along the fibres, which indicated that the decamethonium was not in a mobile form. 3. Rats injected with labelled decamethonium showed radioactivity in the diaphragm muscles after 21 days. 4. A slow spread of the labelled compound along the fibres was detected, and from the widening of the Gaussian curves the apparent diffusion coefficient was 1.2 X 10(-8) cm2sec-1, which is less than 1/500 of that in free solution.

Animals↗
PubMed1978

Effects of cholinesterase inhibitors on the spasmogenic action of acetate esters on rat uterus.

Acetate esters, such as phenyl acetate and aspirin, induced atropine-sensitive contractions of isolated uterus only when choline was present. These contractions were selectively and reversibly inhibited by carbamate-type cholinesterase inhibitors, such as neostigmine and eserine, and quaternary ammonium compounds, such as tetraethylammonium and decamethonium. After treatment with organophosphorus cholinesterase inhibitors, such as di-isopropyl fluorophosphate and tetraethyl pyrophosphate, the uterus failed to respond to the acetate esters, even when high concentrations of choline were present. The inhibition of the response of the uterus by organophosphates was effectively removed by pyridine-2-aldoxime methiodide. Pretreatment of the uterus with neostigmine or simultaneous addition of high concentrations of quaternary ammonium compounds prevented the inhibition by organophosphates. The inhibition produced by neostigmine was also reduced by simultaneous addition of quaternary ammonium compounds. These findings suggest that some esterase having an anionic site and an esteratic site, probably cholinesterase, may mediate in the uterine contractions induced by acetate esters in the presence of choline, and that inhibition by organophosphates, carbamates and quaternary ammonium compounds of cholinesterase activity in the preparation may impede the initiation of contractions by the acetate esters in the presence of choline.

Acetates↗
PubMed1973

Biliary excretion of some diquaternary ammonium cations in the rat, guinea pig and rabbit.

1. The extent of the excretion in the bile and urine of the (14)C-labelled dications, diquat, paraquat, morfamquat, decamethonium and dimethyltubocurarine in bile-duct-cannulated rats, guinea pigs and rabbits was examined. 2. These compounds were excreted unchanged in bile and urine, except diquat, which was metabolized to a significant extent (18% of the dose) in the rabbit only. 3. The extent of the biliary excretion of diquat (mol wt. of ion 184), paraquat (186), decamethonium (258) and morfamquat (469) was less than 10% of the dose in the three species, whereas that of dimethlytubocurarine (653) was greater than 10% in the rat and rabbit but not in the guinea pig. 4. These results together with data from the literature suggest that the molecular weight at which the excretion of dications in the bile exceeds 10% of the dose is in the region of 500-600, which differs from the values for monocations (Hughes et al., 1973) and anions (Millburn et al., 1967; Hirom et al., 1972).

Animals↗
PubMed1989

In vitro time course studies on train-of-four fade induced by hexamethonium, pancuronium and decamethonium in the rat hemidiaphragm.

1. In vitro time course studies on the effects of hexamethonium (7 mmol/L), pancuronium (5 mumol/L) and decamethonium (220 mumol/L) on nerve-evoked (2 Hz for 2 s every 20 s) maximal twitches (T1, T2, T3, T4) of the rat hemidiaphragm were conducted. All three drugs progressively depressed all four twitches in a given train but at different rates (T4 greater than T3 greater than T2 much greater than T1). 2. The response-time profiles for T1 and T4 varied widely for the three drugs such that, for the same degree of T1-block, each drug produced a different magnitude of T4-block during the onset of and recovery from neuromuscular blockade. 3. Analysis of the T1 versus T4/T1 plot showed that, at 50% T1-block, the corresponding T4/T1 (i.e. train-of-four ratios) during the onset (and recovery) phase were 0.16 (0.29), 0.46 (0.40) and 0.66 (0.53) for hexamethonium, pancuronium and decamethonium, respectively. Thus, for the same degree (i.e. 50%) of twitch (T1) tension depression, the three drugs differed widely in their ability (hexamethonium much greater than pancuronium greater than decamethonium) to produce fade as reflected in the respective train-of-four ratio. 4. Our results therefore show that the train-of-four ratio (T4/T1) at 50% T1-block obtained from such in vitro time course studies is a useful quantitative index of the potential of various drugs to cause train-of-four fade. Based on this index a classification of various compounds already studied is proposed as follows: hexamethonium much greater than pancuronium approximately (+)-tubocurarine greater than decamethonium approximately succinylcholine much greater than alpha-bungarotoxin.

Animals↗
PubMed1997

Differences in active site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase.

Amino acid sequence alignments of cholinesterases revealed that 6 of 14 aromatic amino acid residues lining the active center gorge of acetylcholinesterase are replaced by aliphatic amino acid residues in butyrylcholinesterase. The Y337 (F330) in mammalian acetylcholinesterase, which is replaced by A328 in human butyrylcholinesterase, is implicated in the binding of ligands such as huperzine A, edrophonium, and acridines and one end of bisquaternary compounds such as BW284C51 and decamethonium. Y337 may sterically hinder the binding of phenothiazines such as ethopropazine, which contains a bulky exocyclic substitution. Inhibition studies of (-)-huperzine A with human butyrylcholinesterase mutants, where A328 (KI = 194.6 microM) was modified to either F (KI = 0.6 microM, as in Torpedo acetylcholinesterase) or Y (KI = 0.032 microM, as in mammalian acetylcholinesterase), confirmed previous observations made with acetylcholinesterase mutants that this residue is important for binding huperzine A. Inhibition studies of ethopropazine with butyrylcholinesterase mutants, where A328 (KI = 0.18 microM) was modified to either F (KI = 0.82 microM) or Y (KI = 0.28 microM), suggested that A328 was not solely responsible for the selectivity of ethopropazine. Volume calculations for the active site gorge showed that the poor inhibitory activity of ethopropazine toward acetylcholinesterase was due to the smaller dimension of the active site gorge which was unable to accommodate the bulky inhibitor molecule. The volume of the butyrylcholinesterase active site gorge is approximately 200 A3 larger than that of the acetylcholinesterase gorge, which allows the accommodation of ethopropazine in two different orientations as demonstrated by rigid-body refinement and molecular dynamics calculations.

Animals↗
PubMed1989

Ligand stabilization of cholinesterases.

Stabilization of fetal bovine serum (FBS) acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) (AChE) and human butyrylcholinesterase (acylcholine acylhydrolase, EC 3.1.1.8) (BuChE) by ligands and inhibitors was studied as a function of physical and chemical perturbation. Denaturation of AChE occurred as a binary exponential function in the temperature range studied (50-56 degrees C); the slower fraction progressively diminished as the temperature was increased. Inclusion of ligands or inhibitors stabilized AChE as a function of temperature, ligand concentration and time. The rank order in which ligands stabilized AChE was: edrophonium greater than decamethonium greater than pralidoxime chloride much greater than procainamide. BuChE denaturation was retarded by ligands in the order: decamethonium greater than procainamide greater than edrophonium greater than pralidoxime. A plot of the quotient of the fast/slow ratio against the log of the 50% inhibitory concentration (I50) for ligands providing substantial protection yielded a linear relation, suggesting that these compounds stabilized AChE by a common mechanism involving the anionic site of the active center. Urea-induced cholinesterase denaturation was also retarded by these ligands.

Acetylcholinesterase↗
PubMed1999

Role of polyamine structure in inhibition of K+-Cl- cotransport in human red cell ghosts.

1. K+-Cl- cotransport in human red cell ghosts is inhibited by divalent inorganic cations, soluble polycations and amphipathic organic cations. These findings suggest a common mechanism of inhibition, namely, binding of the cations to negative charges at the surface of a hydrophobic structure. 2. We have characterized the inhibitory capacity of a number of polyamines in order to obtain information about the nature of the charges with which they interact. Neomycin inhibited swelling-stimulated cotransport. The diquaternary amines dimethonium and decamethonium were relatively ineffective inhibitors. These compounds are thought to shield negative charges, but not bind to them. 3. Comparison of a homologous series of polyamines indicated that primary amines were better inhibitors than secondary amines, that inhibition increased with the charge of the polyamine, and that inhibition increased as the distance separating the amines increased. 4. The results indicate that the negative charges to which polycations bind are multiple and mobile. Since they must be associated with a hydrophobic environment, it is likely that they are negatively charged phospholipids located in the inner leaflet of the bilayer membrane. 5. Heating red cells or ghosts to 49 C denatures spectrin. Heating markedly increased K+ uptake in swollen ghosts but not in shrunken ghosts. The increase in uptake was reversed when swollen ghosts were shrunk even though denaturation of spectrin was not reversed. Polyamines, which inhibited swelling-activated K+ uptake in control ghosts, similarly inhibited the increased uptake in heated ghosts. 6. We speculate that spectrin, which is closely associated with the inner bilayer leaflet, shields negative charges in a volume-dependent manner and so regulates volume-sensitive K+ transport.

Amines↗
PubMed1979

Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells.

The mode of action of ACh antagonists on the parasympathetic neurones of the submandibular ganglion of the rat was studied by means of a two-micro-electrode voltage-clamp technique. The currents produced by various agonists (carbachol, ACh, suberylcholine) were studied in steady state and after voltage steps, before and after perfusion of various antagonists. 2. For three antagonists (tubocurarine, hexamethonium, decamethonium) the blocking action increases with hyperpolarization. For three other antagonists (surugatoxin, trimetaphan, mecamylamine) the effects observed at low concentrations appear to be independent of membrane potential, although in some cases voltage dependence of the block was observed for mecamylamine. 3. The blocks the 'open' channel-reception complex. The block produced by tubocurarine, hexamethonium and decamethonium increases with the agonist concentration, an observation which supports a 'sequential' scheme in which the antagonist blocks the 'open' channel-receptor complex. The block produced by trimetaphan and mecamylamine decreases slightly with increased agonist concentration, which in turn suggests that these two compounds are competitive antagonists, preventing binding of the agonists to the closed channel-receptor complex. 4. In the cases where the block is voltage dependent, voltage jumps trigger slow relaxations which are not present in control conditions. In the case of tubocurarine and hexamethonium, the relaxation following a hyperpolarizing voltage jump corresponds to a decrease in conductance. In the case of decamethonium, the slow relaxation is in the opposite direction. 5. The slow relaxations observed with tubocurarine and hexamethonium are speeded by an increase of the antagonist concentration; the slow relaxations observed with decamethonium are slowed by an increase of the decamethonium concentration. 6. The steady-state observations and the relaxations can be interpreted in terms of a scheme in which tubocurarine, hexamethonium and decamethonium act mainly by blocking the channels opened by the cholinergic agonists. 7. The two types of slow relaxation are those predicted if tubocurarine and hexamethonium dissociate slowly from the channel, and decamethonium rapidly. 8. An additional effect of tubocurarine is described, which consists of a potentiation of the rising phase of the response to an ionophoretic pulse. Possible mechanisms of this effect are discussed.

Acetylcholine↗
PubMed1985

Assays for, and cross-reactivities of, IgE antibodies to the muscle relaxants gallamine, decamethonium and succinylcholine (suxamethonium).

Two radioimmunoassays have been developed to detect IgE antibodies to succinylcholine, decamethonium and gallamine in the sera of patients who have experienced life-threatening anaphylactoid reactions following administration of a muscle relaxant drug. They involve the coupling of choline and its ethyl analogue, triethylcholine to activated Sepharose. A high degree of cross-reactivity was shown to occur between drug-reactive IgE antibodies and 6 muscle relaxants as well as choline and triethylcholine. Results suggest that the specificities of the IgE antibodies are directed towards quaternary or tertiary ammonium ions on the drugs that bind the antibodies. Molecular models of these compounds support the structure-activity relationships determined in the inhibition studies.

Antibody Specificity↗
PubMed1975

Influence of extracellular calcium and a water-soluble carboxyl group reagent on cholinergic drug-receptor interactions in skeletal muscle.

Contractions of frog rectus abdominus muscles induced by suxamethonium or decamethonium, and to a lesser extent by carbamylcholine, were decreased as the extracellular calcium concentration was increased. The inhibition of all three agonist responses by 1.1 mM calcium was competitive. The contractions induced by bis-onium compounds, but not carbamylcholine, were further antagonized at higher calcium concentrations (4.4 mM) in a noncompetitive manner. This latter effect of calcium may be due to antagonism of bis-onium compounds at a peripheral anionic site. Carboxyl group carbodiimide reagents inhibited muscle contractions, and this inhibition was slowly reversible. The extent of the inhibition was increased, and its recovery delayed, by prior exposure of the muscle to an agonist. The results support suggestions that receptor activation initially involves displacement of membrane calcium. The study provides further evidence that interaction of agonists iwth nicotinic receptors results in structural changes, possibly related to increased ion flow.

Animals↗
PubMed1975

Synthesis and biological activity of spin-labeled analogs of biotin, hexamethonium, decamethonium, dichlorisoproterenol, and propranolol.

Spin-labeled analogs of biotin (vitamin H), hexamethonium, decamethonium, dichlorisoproterenol, propranolol, and primaquine containing the nitroxide free radical have been synthesized and tested for biological activity. The four spin-labeled analogs of biotin, 4-biotinamido-2,2,6,6-tetramethyl-1-piperidinyloxy (IV), 3-biotinamido-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (V), 3-biotinamidomethyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (VI), and 4-(biotinylglycyl)amino-2,2,6,6-tetramethyl-1-piperidinyloxy (VII), all interacted with avidin, a specific biotin binding protein found in raw egg white, at the same sites as did biotin itself. An unsymmetrical decamethonium spin label (XVIII) in which one of the quaternary methyl groups had been replaced by the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) moiety was 13 times more potent as an inhibitor of Torpedo californica acetylcholinesterase than the parent drug. The symmetrical decamethonium (XVI) and hexamethonium (XIV) spin labels were 18 and 1.8 times as active as decamethonium in the same assay system. The substitution of the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) group for the isopropyl groups of beta-adrenergic blocking drugs dichlorisoproterenol and propranolol, to give spin labels XXI and XXII, caused a 45 and 54% reduction, respectively, in the ability of these compounds to inhibit the isoproterenol-stimulated activity of rat fat cell membranes. Finally, modification of primaquine by the introduction of the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) substituent into the amino group of the butyl side chain completely abolished the ability of the drug to bind to nuclei acids. These results suggest that the incorporation of the nitroxide group into drug molecules may be a useful approach to the synthesis of more specific spin labels for biological systems, such as egg white avidin, acetylcholinesterase, and the beta-adrenergic receptor.

Adenylyl Cyclase Inhibitors↗
PubMed1959

A comparison between the effects of edrophonium and choline in the skeletal muscles of the cat.

The effects of edrophonium and choline have been compared with those of the depolarizing substances acetylcholine, decamethonium, and suxamethonium, in both innervated and chronically denervated tibialis anterior muscles of cats under chloralose anaesthesia. Both edrophonium and choline were more potent antagonists to paralysis by tubocurarine than could be accounted for by their ability to stimulate the motor end-plates directly. It appeared likely that direct depolarization of the end-plate played no part in the anti-curare action of edrophonium and only some part in the anti-curare action of choline. A paralysis produced by the neuromuscular blocking agent, benzoquinonium, was more readily antagonized by a tetanus or by acetylcholine, suxamethonium, and decamethonium than a similar paralysis produced by tubocurarine. The tetraethyl ammonium ion was also slightly more effective against a paralysis by benzoquinonium. On the other hand, edrophonium was about 300 times and choline about five times less potent as an antagonist to benzoquinonium than to tubocurarine. Furthermore, the previous administration of benzoquinonium abolished the antagonistic action to tubocurarine of normally effective doses of edrophonium and reduced that of choline. These results were similar to those previously obtained with neostigmine, physostigmine and ethyl pyrophosphate and suggested that there was some similarity in the mechanism of action of all of these substances. Benzoquinonium, therefore, showed promise as a useful pharmacological tool for distinguishing compounds with this particular type of action. These anti-curare compounds did not appear to act by cholinesterase inhibition, not by an increase in the sensitivity of the motor end-plates. In common with other workers, we suggest that there is a pre-synaptic mechanism of action.

Acetylcholine↗
PubMed1977

Allosteric interactions between the membrane-bound acetylcholine receptor and chemical mediators. Kinetic studies.

The kinetics of the specific irreversible reaction of a snake neurotoxin, alpha-bungarotoxin, with the acetylcholine receptor of electroplax membrane preparations have been investigated. The effects of activators (decamethonium, carbamylcholine) and inhibitors (alpha-bungarotoxin, d-tubocurarine) of neural transmission on this reaction have been measured and the following new information obtained. (1) The irreversible reaction is preceded by the reversible formation of toxin-receptor complexes. (2) Two types of receptor binding site exist. d-Tubocurarine directly competes with the toxin for one type of binding site. Decamethonium and carbamylcholine are noncompetitive inhibitors of the toxin reaction. (3) The data are inconsistent with binding sites on separate and distinct molecules or with preexisting nonequivalent binding sites. A simple model is proposed to explain both the kinetic data and equilibrium measurements which indicated that activators and inhibitors of neural transmission compete for only one-half of the receptor sites available to them. The model proposes that for the compounds investigated the binding sites of activators do not overlap with those of inhibitors and the ligand-induced conformational changes of the receptor result in changes in the affinities of the binding sites. The model is simple and is based on mechanisms which have been found to be valid for many well-characterized regulatory enzymes.

Acetylcholine↗
PubMed2004

Decamethonium bromide-mediated inhibition of embryonic muscle development.

This study determined the effect of decamethonium bromide (DMBr), a non-competitive blocker of the neuromuscular junction, on skeletal muscle development during chick embryogenesis. Decamethonium bromide caused generalized edema and high mortality with treated embryos rarely surviving beyond day 16 of incubation. Muscle degeneration was grossly evident on the muscles of abdomen, pectoral girdle, and leg. Semi-thin sections showed a high infiltration of macrophages in treated embryos and a massive degenerative process. Electron microscopy showed that both fast and slow fibers formed in the control and treated embryos, but those of the treated embryos failed to form myofibrils. Other organ systems, such as the heart and the gut, appeared histologically normal throughout the course of treatment. To investigate possible nerve independent action of DMBr on muscle development we determined the effect of this compound on the growth and differentiation of the C2C12 skeletal muscle cell line. DMBr treatment of C2C12 cell cultures did not affect the growth or survival of the cells, even at a tenfold higher concentration than that used in ovo, but myosin heavy chain expression was dramatically inhibited. We conclude that DMBr has a nerve independent blocking inhibition effect on myosin heavy chain synthesis in the developing avian embryo besides the recognized role as a non-competitive post-synaptic blocker of the neuromuscular junction.

Animals↗