Agent Competition Research Articles

Quantitative examination of the interaction of competitive neuromuscular blocking agents on the indirectly elicited muscle twitch.

Gallamine, metocurine, pancuronium, and d-tubocurarine were compared when given alone and in combination with isolated guinea pig nerve-lumbrical preparations stimulated via the nerve. The experimental design was set up to control the effects of variation among preparations, order of administration, and time of administration (i.e., fresh vs. older preparation). The result was an assay able to measure potentiation with a coefficient of variation of 3%. A format for a graphic presentation to summarize such results is presented and discussed. Two combinations, gallamine plus d-tubocurarine and gallamine plus pancuronium, showed no sign of an interaction beyond that to be expected from a simple competitive interaction. Two others, metocurine plus pancuronium and gallamine plus metocurine, showed about a twofold greater potency when combined than would have been expected. The last two sets, pancuronium plus d-tubocurarine and metocurine plus d-tubocurarine, showed a slight degree of potentiation. These studies demonstrate that the deviation from simple additivity seen in vivo persists when examined in a system free from artifacts associated with uptake and distribution in the whole organism.

Study of the electrooxidative behaviour of 5-hydroxyindole-3-acetic acid, 5-hydroxytryptophan and serotonine in the presence of sodium ethylenediaminetetraacetic acid

The great instability of the indole derivatives 5-hydroxytryptophan (5-HTP), serotonine (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) in strong acid medium and the protective role of sodium ethylenediaminetetracetate (EDTA H 2Na 2) could be explained by their electrooxidative behaviour on a carbon paste electrode. Voltamperometric curves obtained in a 1–8 pH range show that oxidation occurs in two irreversible steps; the mechanism is more complex than a simple electron transfer. For the three molecules, new redox couples have been detected on cyclic voltammograms at lower potentials than the parent compound, indicating that more easily oxidized derivatives are formed. On the other hand, the anodic oxidation of EDTA H 2Na 2 has been investigated and in the present case the molecule is not acting by complexing metal traces but should actually be considered a competitive agent preventing the second oxidation step of the indole derivatives.

Histamine H-1 binding site on human polymorphonuclear leukocytes.

Neutrophilic polymorphonuclear leukocytes (PMN) infiltrate the sites of allergic reactions and may respond to histamine, one of the major mediators of allergy. In order to characterize histamine interactions with PMN, the binding of [3H]pyrilamine was studied. Human PMNs bind [3H]pyrilamine in a specific, saturable, and reversible fashion and demonstrate specificity (H-1 antagonists greater than histamine greater than H-2 antagonists) for the competitive binding agents studied. Human PMNs have a homogeneous population of H-1 receptors of moderate affinity (Kd = 52 nM) in large number (265 X 10(3)/cell) which do not demonstrate cooperativity. Thus PMNs attracted to sites of allergic inflammation have H-1 binding sites which may respond to histamine stimulation.

Banking, recession, depression, and government expenditure

We examine public good expenditure given a stylized business cycle. This cycle exhibits three characteristics, (a) a full employment path, (b) occasional drops from that path followed by reconvergence and (c) sustained underemployment following a large drop. A banking system, modeled using Samuelson's overlapping generations approach, propagates shocks. Two sources of shocks are treated, anticipated future shocks to technology and inherent instability of the banking system, both of which precipitate shocks to demand. We conclude that under gross substitutes the government acting as competitive purchasing agent follows countercyclical policy.

Heparin binding sites in the human spermatozoa membrane.

The existence in the human spermatozoa membrane of receptorlike functional group for heparin was studied. Incubation of whole spermatozoa with tritiated heparin induced the specific binding of 745 +/- 112 pmol of heparin per 5 x 10(7) sperm cells with an intrinsic association constant KD = 3.6 x 10(-6) M. The specificity of binding was shown by the lack of competence in the binding process of some other glycosaminoglycans used at concentrations 20 x higher than heparin. However, dextran sulfate was a very efficient competitive agent. Autoradiography experiments showed that labeling was almost completely restricted to sperm cells in the process of nuclear decondensation. This technique showed the presence of a high amount of radioactive heparin in the isolated sperm membranes even after several washings. Heparin may participate both in the final part of the capacitation process (acrosome reaction) and in the decondensation of sperm nuclei.

A preliminary assessment of atracurium, a new competitive neuromuscular blocking agent.

Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl 1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate is a potent non-depolarising (competitive) neuromuscular blocking agent in the cat, monkey, dog and anaesthetized man. In man, it caused complete paralysis of the tetanic response of the adductor pollicis muscles at doses of 0.2 mg/kg. Blockade was of medium duration with rapid spontaneous recovery, and was readily reversed by neostigmine. The electrocardiogram, heart rate, arterial blood pressure and central venous pressure were virtually unchanged following doses of 0.2-0.4 mg/kg. Intubation was readily accomplished in 1.5-2 min after administration of 0.25-0.3 mg/kg.

Rational rationing and increasing returns an example

The paper gives an example of an economy where it is rational for a monopolist to control a competitive agent by setting both prices and quantities supplied. There are increasing returns in production, and the competitive agent has a discontinuous offer curve. The monopolist reaches points in the discontinuity by rationing.

Adsorption of bacteria on soils: Experiments, thermodynamic rationale, and application

A model for the adsorption of bacteria to soil particles is described using the physical-chemical Langmuir isotherm and the van't Hoff equation. An example of the use of the model for assessing bacterial movement through soil is provided.Staphylococcus aureus was the sorbate with sorbents of activated charcoal, kaolinite clay, Mendon silt loam, and silica sand. Competitive agents sodium lauryl sulfate, sodium chloride, and peptone were also studied. Peptone was the most successful competitor with the bacteria for sites on the sorbent.

Toward a Functional Interpretation of Synchronous Flashing by Fireflies

In certain firefly species of tropical Southeast Asia the males habitually congregate in trees in huge numbers and flash in rhythmic synchrony all night, each night. Though females do not synchronize, they are attracted to the trees and mate there. Many fireflies remain in the trees by day. We believe that each display tree approximates a steady-state population in which a constant number of males, stabilized by a balance of inflying and eventual death, is interacting with a constant flux of females, stabilized by a balance of in- and out-migration. There are some very tenuous indications that different tree populations may be partially isolated and somewhat inbred. The mass-display fireflies are unique in possessing a neural mechanism that automatically synchronizes the rhythmic flashing of conspecific males. Mass congregation and mass synchrony are therefore inseparable. All evidence agrees in indicating that the mass synchronized assemblies are exclusively reproductive. In the Thai Pteroptyx malaccae and the Melanesian Pteroptyx cribellata and Luciola pupilla we believe that courtship and mating involve two successive photic interactions. Distant males and females are being attracted indiscriminately into the tree by the massed rhythmic luminescence of the in-tree males. The range and species-specificity of this attraction are enhanced by the flash synchronization. Simultaneously males established individually in the tree and flashing rhythmically in small, defended territories compete for in-tree females. In extension of Lloyd's analysis, we postulate mutual recognition via one or more sexual differences in light emission and surmise that the female probably does most of the short-range moving connected with pair formation. We postulate that the female selects her mate on the basis of the intensity of his signal relative to those of other males visible to her simultaneously. As in Lloyd's model the selection must depend on a genetic predilection of females for males that are flashing synchronously. Poststimulus refractoriness is suggested as the mechanism for the predilection. The synchronized tree congregation thus performs a long-range attraction of both males and females to the tree and simultaneously operates as a huge permanent lek. In the various in-tree interactions, flash synchronization is thought to improve mating opportunity for all participants and to exclude possible conspecific cheaters. The orthodox view that large-scale synchrony must be only the incidental or statistical consequence of a small-scale adaptive synchrony is questioned on the following bases: 1. From natural selection theory, flash synchronization per se, being a group behavior, cannot serve as the competitive agent for promoting the reproductive fitness of an individual participating male, no matter how small the synchronizing group. 2. Flash synchronization is, for physiological reasons, obligatory between two or more close-together males. Mass synchrony depends on mass congregation. 3. Because most fireflies court by continuous line-of-sight photic contact, environmental obstacles such as abound in the jungly vegetation of Southeast Asia could be a major obstacle to dialogue-type communication. Conversely, the formation by males of a large, concentrated communal light beacon, visible through vegetation for long distances in all directions, might attract more females per unit time than a given male would meet in solo search through a population dispersed in dense vegetation. 4. Such a congregation, it is argued, would benefit all participating males, penalize none, and be safeguarded against nonflashing or nonsynchronizing cheaters by the female's requirement for flash coincidence during comparison of male flash intensities. Mass congregation could thus, we suggest, be a group adaptation, made possible by unique physiological and ecological circumstances. The observed evolutionary perpetuation of the behavior is made possible by the fact that flashing-the act that, when synchronized, permits nonspecific sexual gain at two levels (increased mate accessibility for both sexes and eligibility for individual competition between males)-can also be modulated to serve as the competitive instrument between conspecific males vying for selection by females. Any synchronizing male in the congregation who mates will therefore transmit the genetic basis for the flash synchronization as well as that controlling competitive use of flash intensity, and the female will gain by having selected a competitive mate.

COMPETITIVE PHOTOSENSITIZED OXIDATION AT TiO2 PHOTOANODE

Abstract The rotating ring-disk electrode (RRDE) technique has been applied to the study of photosensitized oxidation of various redox agents in competition with the oxidation of water on a TiO2 photoanode. The results are discussed referring to the standard redox potentials of the reducing agents.

Drug antagonism and reversibility of the binding of indoleamines in brain

The specificity of the binding of serotonin to brain preparations was investigated with various competitive agents. A probable relationship between their structure and their capability of displacement was suggested. Bufotenine and morphine displaced serotonin (0.5 × 10 −5 M) binding to synaptic membranes 87 and 49% respectively. Dissociation constants of the binding of 5-HT and tryptamine to synaptic membranes, and displacement constants of certain drugs were determined. The binding of 5-HT and tryptamine to calf brain preparations was also investigated by equilibrium dialysis, in order to determine affinity constants and reversibility of the binding. Differences were noted in the specificity of binding sites for serotonin and tryptamine, suggesting a different binding site for tryptamine. Extrapolations of Scatchard plots were used for determination of the constants. A characteristic low dissociation constant was found for 5-HT in synaptic membranes (K ∼ 1 × 10 −6 M). Probably, the binding macromolecule (receptor?) is a proteolipid.

Pharmacological properties of the adrenergic receptors regulating systemic vascular resistance in the rainbow trout

1. The adrenergic receptors in the systemic vasculature of the rainbow trout have been pharmacologically characterized using an isolated trunk preparation perfused at constant flow. 2. The dominant α-constrictory receptors in the trunk are similar to those of mammals in their adrenaline/noradrenaline potency ratio (3.2/1.0), and in the natures of their blockade by phenoxybenzamine and yohimbine. However they are more selective than mammalian α-receptors, responding directly to only adrenaline and noradrenaline, and not to phenylephrine, methoxamine, dopamine, or isoprenaline. 3. Tyramine and dopamine cause weak α-adrenergic constriction, apparently indirectly through the release of catecholamine stores. 4. The α-adrenergic response is susceptible to inhibition by competitive β-blocking agents, but this effect is due to non-competitive antagonism with a point of action beyond the adrenergic receptor. 5. β-dilatory receptors of the β2, as in the homologous systemic vasculature of mammals, also apparently occur, but their dilatory actions cn only be demonstrated against a background of α-adrenergic vasoconstriction. 6. The racemate d,l-isoprenaline is a more potent vasodilator than the pure isomer l-isoprenaline during α-adrenergic tone because of the competitive α-blocking activity of the d-isomer.

AN ELECTROMYOGRAPHIC STUDY OF MUSCLE RELAXANTS IN MAN

Supramaximal paired stimuli were applied to the ulnar nerve, and the amplitude of the muscle action potential evoked in the abductor digiti minimi by the second member of the stimulus pair (test response) was compared with that evoked by the first component (conditioning response). The interval between the two components of the stimulus pair (the pair interval) was increased stepwise from 7 to 100 msec and a curve (recovery curve) was obtained by relating the changes in pair interval to the difference in amplitude of the test and conditioning responses. Alterations of the recovery curve (RC) during partial paralysis by muscle relaxants were investigated in healthy adult patients under the lightest plane of general anaesthesia. The control curve obtained in 32 subjects before the administration of a muscle relaxant drug was characterized by slight depressions at very short intervals of paired stimuli, followed by a slight potentiation at 20-100 msec. With non-depolarizing relaxants, RC altered to the characteristic pattern of potentiation at very short intervals of stimuli, followed by a notable depression at longer intervals. In depolarizing blocks with small doses of suxamethonium, the depression of RC at short intervals in the control was enhanced and the pattern of RC was different from that of non-depolarizing agents. When desensitization blocks were instigated by the i.v. administration of suxamethonium, the RC patterns were similar to those of competitive agents.

Competition between different scrapie agents in mice.

STRAINS of scrapie agent differ in a number of their biological properties, one of which is average incubation period1,2. Incubation period is inversely proportional to dose for all known strains of scrapie and some differ so markedly that there is no overlap in their dose-incubation period curves. A large dose of one agent takes longer to produce the disease than the LD50 dose of another agent3. Two such scrapie agents are 22A and 22C when compared by intracerebral injection of VM mice. Agent 22A has a much shorter incubation period than 22C in VM mice because they carry the p7 allele of the sine gene that controls scrapie incubation. It should therefore be possible to produce mixed infections in VM mice, but to ensure that the clinical disease is produced by the 22A agent. It can be checked that 22A causes the disease, rather than 22C, by examining the distribution of brain lesions2. Interaction during pathogenesis between the two agents—competition or synergism—would be seen as a difference in the incubation period of 22A. We achieved mixed infection by injecting 22C first and 22A on a later occasion.

RECOVERY FROM NEUROMUSCULAR BLOCKADE DURING SINGLE SHOCK AND TETANIC NERVE STIMULATION IN CATS

SUMMARY Indirectly stimulated gastrocnemius muscles of anaesthetized cats were more sensitive to paralysis by non-depolarizing or competitive agents when tetanic bursts rather than single shocks were employed. This action may be mainly attributable to a reduction in the output of acetylcholine during tetanic stimulation. Recovery from paralysis of equal intensities was similar. Although the twitch response of the gastrocnemius had recovered, respiration was not adequately restored until the tetanus was fully sustained. Hence it is advisable to apply tetanic stimulation when monitoring recovery from neuromuscular paralysis. If reversal of competitive blockade is inadequate, the consequent rapid shallow breathing may lead to apnoea due to recurarization of the muscles concerned. The course of action of depolarizing agents was shorter when tetanic stimulation rather than single shocks were applied to the sciatic nerves. The slower recovery of muscles stimulated by single shocks could be mainly the result of their lower temperature, as recovery was similar when both muscles were maintained at body temperature.

Action of lipid-soluble quaternary ammonium ions on the resting potential of myelinated nerve fibers of the frog

1. 1. This paper presents an approach to the mechanism of action of lipid-soluble quaternary ammonium ions (PAD, PDI, noracetylcholine 12) by analyzing their effect on the resting potential of nerve fibers. 2. 2. The degree of depolarization depends on the concentration of the compounds. The time course is slower than with 2·10 −2 M KCl. PAD is the most effective of the 3 compounds investigated. 3. 3. Washing with Ringer's solution brings the potential back to the initial value after 30 min (10 −4 M PAD, 5·10 −4 M noracetylcholine). When smaller concentrations of PAD are used, the depolarization is reversed in a shorter time. 4. 4. The depolarization must be the result of a change in the relative permeability of the various active ions. 5. 5. Physostigmine-Ringer's solution scarcely alters the resting potential. Physostigmine (7·10 −3 M) inhibits the depolarization of 10 −4 M PAD. Lower concentrations of physostigmine counteract the effect of PAD, but do not abolish it, while higher concentrations of PAD overcome the protective action. 6. 6. The antagonism between PAD and physostigmine is typical for competitive agents. 7. 7. It is suggested that the lipid-soluble quaternary ammonium ions act with a receptor and that this reaction effects a change in permeability.