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PubMed2000

Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures.

Experimental data indicate that NMDA receptor activation is strongly implicated in the pathogenesis of cerebral ischaemia. However, the results from in vivo studies are equivocal, with NMDA antagonists being active in only some models. It has recently been demonstrated that competitive and non-competitive NMDA antagonists behave differently under normal and ischaemic conditions. These studies have used organotypic hippocampal slice cultures to investigate whether this disparity is due to redox-modulation of the NMDA receptor which occurs in ischaemia. NMDA-mediated toxicity was concentration dependent with little damage occurring with less than 10 microM NMDA and maximal damage produced by 30 microM. NMDA toxicity was significantly enhanced by pre-treatment with 1 mM dithiothreitol, a reducing agent, such that damage occurred at 1 nM NMDA, and maximal damage was produced by 10 microM. The efficacy of MK-801 was not altered by reducing conditions, but the EC50 of the competitive antagonist APV was increased by 20-fold. These data strongly suggest that the neuroprotective efficacy of NMDA antagonists is significantly altered under ischaemic conditions, and that more beneficial effects will be obtained with antagonists having a higher affinity for the receptor in the reduced configuration.

Animals↗
PubMed1992

Competitive and non-competitive NMDA receptor antagonists in spatial learning tasks.

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP37849 (3 or 6 mg/kg i.p.) and its ethyl ester CGP39551 (5 or 15 mg/kg i.p.) and of the non-competitive NMDA receptor antagonist, dizocilpine (0.16 mg/kg; i.p.) on acquisition by rats of different spatial orientation tasks in an 8-arm radial maze were evaluated. Neither of the CGP compounds influenced locomotor activity during spontaneous alternation, only dizocilpine increased the number of arm entries (locomotion). Preferred angles between consecutive arm entries were changed by the high doses of CGP37849 (6 mg/kg), CGP39551 (15 mg/kg) and dizocilpine (0.16 mg/kg). The high doses of both CGP compounds as well as dizocilpine produced impairments in the acquisition of an egocentric orientation task and an allocentric reversal task indicated by an increased number of arm entries and re-entries. Such amnesic effects did not occur after administration of low doses of CGP37849 (3 mg/kg) and CGP39551 (5 mg/kg), doses which are sufficient to produce anticonvulsant and anticataleptic effects. In contrast, the non-competitive NMDA receptor antagonist, dizocilpine, produced amnesic effects over the entire behaviourally effective dose range.

2-Amino-5-phosphonovalerate↗
PubMed2003

Local mate competition with lethal male combat: effects of competitive asymmetry and information availability on a sex ratio game.

We constructed a sex allocation model for local mate competition considering the asymmetry of competitive abilities among sons. This model assumes two females of a parasitoid wasp oviposit on the same host in sequential order. The evolutionarily stable strategy will be in either Stackelberg or Nash equilibrium, depending on whether the females can recognize their opponent's sex ratio or not, respectively. The Nash equilibrium predicts the second female produce more males than the first. If the second female is able to know and respond to the strategy of the first (a Stackelberg equilibrium), the first will decide an optimal sex ratio assuming that the second reply to it. Under such an assumption, our model predicts that not producing sons is adaptive for the second female when the sons she produces have low competitive ability. Males of parasitoid wasps Melittobia spp. are engaged in lethal male-male combat, indicating large asymmetry in mating success among sons. If females have the ability to recognize their opponent's sex ratio, our model suggests that the severe lethal male-male combat may be one factor explaining their extremely female-biased sex ratio that is unexplainable by pre-existent models.

Aggression↗
PubMed1975

Switching from competition to sharing or cooperation at large response requirements: competition requires more responding.

Two pairs of high-school students matched-to-sample for money. On each trial, a subject could either respond on one lever to take the matching-to-sample problem himself (taking response) or respond on a second lever to give the problem to his coactor (giving response). The first subject to complete the response requirement determined the distribution of the problem. Competition maximizes the amount of responding over trials, i.e., both subjects make taking responses on each trial. Sharing and cooperation minimize responding: only one subject makes a taking response (sharing) or a giving response (cooperation) on each trial, and the subjects alternate responding such that there is an equitable distribution of responses and reinforcers over trials. Large increases in the fixed-ratio response requirement to distribute problems produced: (1) a switch from competition to sharing or cooperation, (2) the expected concomitant change from inequitable to equitable distributions of reinforcers, and (3) a reduction in the amount of responding for three of the four subjects. Previous animal research has shown that large response requirements may have aversive properties. Switching from competition to sharing or cooperation at large response requirements allows a reduction in responding and, at the same time, a moderate number of reinforcers for each subject.

Journal Article↗
PubMed1990

Direct observation of sexual competition in Drosophila melanogaster: the mutant white in competition with other genotypes.

When two types of Drosophila are in competition, the frequency dependence of mating success routinely is measured in our laboratory by direct observation of mating pairs in "Elens-Wattiaux" observation chambers. The present experiments concern white mutants (used here as a reference standard) in competition with three other genotypes: wild-type Canton S, "giant" gt wa, and "giant" gt13z/w+ Y/C(1)Dx, y f. From the present observations, the frequency dependence of mating success seems a very common phenomenon: a rare-type sexual advantage exists for females and for males. Sexual activity of male and female white mutants is significantly higher when food is present in the mating chamber. Males of the other strains also are more active in the presence of food. Homogamic matings are more frequent among gt13z/w+ Y/C(1)Dx, y f flies.

Animals↗
PubMed2001

Clinical relevance of cardiac natriuretic peptides measured by means of competitive and non-competitive immunoassay methods in patients with renal failure on chronic hemodialysis.

Increased levels of cardiac natriuretic peptides in patients undergoing hemodialysis may be a marker of cardiomyopathy and in consequence may be suitable prognostic indicators for the risk of development of cardiac disease. We measured plasma levels of ANP, BNP, proANP(1-98) and proBNP(1-76)-related peptides with some competitive and non-competitive immunoassay methods in patients with renal failure on chronic hemodialysis in order to compare the analytical performances of these methods and to evaluate the clinical usefulness of each assay for patients with chronic renal failure. ANP and BNP values significantly decreased after hemodialysis (on average, ANP by 36% and BNP by 16%); while all proANP and proBNP values tended to increase, but only proANP(1-30) (by 14.4%) and Nt-proBNP (by 9.5%) significantly. Although significant correlations were found among all the circulating levels of cardiac peptides studied, N-terminal pro-peptides correlated better among themselves than with ANP and BNP; ANP was only slightly correlated with all the other peptides, the only exception being BNP. Only BNP levels significantly increased according to the degree of ventricular hypertrophy and/or ventricular function in patients with chronic renal failure. The ANP assay is preferable in physiological and clinical studies for the rapid changes in atrial pre-load. BNP would be more useful in the follow-up of cardiac complications in patients with end-stage renal disease on regular hemodialysis. The assays of N-terminal proANP(1-98)-and proBNP(1-76)-related peptides proved to be of limited use, because they were not able to detect acute changes in pre-load during hemodialysis and were less useful than BNP levels as markers of ventricular hypertrophy and/or functional cardiac impairment.

Adult↗
PubMed1990

Competitive inhibition of lipolytic enzymes. III. Some acylamino analogues of phospholipids are potent competitive inhibitors of porcine pancreatic phospholipase A2.

Competitive inhibition of porcine pancreatic phospholipase A2 was studied in mixed-micellar systems composed of long- and medium-chain substrates, potential inhibitors and detergents. A number of positional and stereoisomeric monoacylamino, acyloxyglycerophospholipids were investigated for their inhibitory properties, using as substrates the corresponding diacyl-sn-glycero-3-phospholipids possessing the same polar headgroup and identical acyl chain lengths. Based on a kinetic model applicable to water-insoluble inhibitors (see accompanying paper I), which allows a quantitative comparison of the inhibitory power (Z) of the various phospholipid analogues, the following results were obtained: Substitution of a single acylester bond in a diacylglycerophospholipid by an acylamino group can transform the substrate molecule in a potent competitive inhibitor. This property is acquired only when this substitution occurs on the phospholipase-susceptible ester bond of the substrate. If the acylamino group replaces an ester bond which cannot be attacked by the highly positional and stereospecific phospholipase, the resulting molecule binds with similar affinity to the active site of the enzyme as the parent substrate molecule. Because of its positional and stereospecificity, this so-called inhibitory 'amide effect' suggests that these inhibitors behave as substrate-derived analogues. The inhibitory 'amide-effect' observed with several medium- and long-chain monoacyloxy-, monoacylamino-deoxyglycerophosphatides is completely lost upon specific alkaline hydrolysis of the single acylester bond. Reesterification of the free glycerol OH group in these lysoacylaminophosphoglycerides, even with an acetyl residue, restores the inhibitory properties. These observations indicate that specific binding of phospholipids to the active site of pancreatic phospholipase A2, requires the presence of two chains in substrate or inhibitor structure and suggest that those results obtained with lysophospholipids and single-chain analogues may be questionable.

Animals↗
PubMed1990

Effects of competitive and non-competitive NMDA receptor antagonists in spinal cord injury.

The potential role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of spinal cord injury was examined in rats by comparing the effects of the non-competitive NMDA antagonist dextrorphan and the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) on the behavioral and anatomical consequences of impact trauma to the spinal cord. Treatment with either dextrorphan or CPP, administered intrathecally 15 min after trauma, significantly improved chronic (4 weeks) behavioral recovery. Treatment with CPP, but not dextrorphan, limited the decline in serotonin below the injury zone, as shown by both immunocytochemistry and high performance liquid chromatography. Beneficial effects of CPP were dose-dependent. Dextrorphan treatment also improved behavioral outcome when the drug was administered intravenously. These studies implicate NMDA receptor-mediated excitotoxins in tissue damage following spinal cord trauma and suggest that NMDA antagonists may be of value in the treatment of acute, clinical spinal cord injury.

Amino Acids↗
PubMed2005

The competitive exclusion principle versus biodiversity through competitive segregation and further adaptation to spatial heterogeneities.

In this work we introduce a general class of spatially heterogeneous competing species models where the species are assumed to disperse in a random way through the inhabiting region in the presence of some refuge patches where they are free from the aggressions of the antagonist species. Our model shows that the competitive exclusion principle fails to be true under these circumstances, as the species can segregate within their respective refuge areas when the intensity of the aggressions from competitors severely increase. Going beyond, segregation mechanisms, as a result from competition, combined with subsequent species differentiation, as a consequence from territorial heterogeneities--after a certain number of generations--might ultimately explain the extraordinary biodiversity of the Earth's biosphere, which seems to be confirmed by fossil registers in zoo-paleontology. Actually, the existence of Lazaro' species strongly support the validity of the predictions made from our prototype model.

Animals↗
PubMed1997

Competitive and non-competitive inhibition of L-3, 4-dihydroxyphenylalanine uptake in Opossum kidney cells.

The present study aimed to determine the kinetics of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in Opossum kidney (OK) cells and to define the type of inhibition produced by L-5-hydroxytryptophan (L-5-HTP), cyanine 863 and 3,3'-diethyloxacarbocyanine (3,3'-DOC). Non-linear analysis of the saturation curves revealed for L-DOPA a Km (in microM) of 129 (114, 145) and a Vmax (in nmol/mg protein per 6 min) of 30.0 +/- 0.4 IC50 values for L-5-HTP (1454 microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were almost 4-fold those obtained when non-saturating (25 microM) concentrations of L-DOPA were used (330). IC50 values for cyanine 863 and 3,3'-DOC (638 and 353 microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were similar to those obtained when non-saturating (25 microM) concentrations of L-DOPA were used (654 and 339 microM). Vmax values (in nmol/mg protein per 6 min) for L-DOPA uptake were identical in the absence (36.4 +/- 0.7) and the presence of L-5-HTP (39.2 +/- 1.3), but Km values (microM) were significantly greater (P < 0.05) when L-DOPA uptake was studied in the presence of L-5-HTP (121 (100, 142) versus 318 (237, 399)). In contrast, the effect of cyanine 863 and 3,3'-DOC was to cause a significant reduction in Vmax values without significant changes in Km values. It is concluded that L-5-HTP exerts a competitive type of inhibition of L-DOPA uptake in cultured OK cells, whereas both cyanine 863, an organic cation transport inhibitor and 3,3'-DOC behave as non-competitive inhibitors.

Animals↗
PubMed1996

Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice.

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (mu) and delta (delta) agonists, however, has not been reported. In these experiments, selective mu and delta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of mu agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a delta agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.

Analgesics, Opioid↗
PubMed1998

Anti-convulsant and adverse effects of the glycineB receptor ligands, D-cycloserine and L-701,324: comparison with competitive and non-competitive N-methyl-D-aspartate receptor antagonists.

In this study, the anticonvulsant and adverse effects of compounds that belong to four different categories of systemically available N-methyl-D-aspartate (NMDA) receptor ligands were compared, namely the competitive antagonist CGP 40116, the noncompetitive antagonist MK-801 (dizocilpine), the glycineB receptor antagonist L-701,324, and the glycineB receptor high-efficacy partial agonist D-cycloserine. The maximal electroshock seizures (MES), which are widely used to detect drug efficacy against generalized tonic-clonic seizures in humans, were produced by transcorneal electrical stimulation. Abolition of tonic hind-limb extension was taken as the end-point. The drug-induced motor and long-term memory deficits were quantified by using the inverted screen test and the step-through passive-avoidance test, respectively. All tested compounds exhibited significant anticonvulsant effect. The rank order of potency for the respective compounds was: MK-801 = CGP 40116 > L-701,324 >> D-cycloserine. All of these compounds induced motor impairment at doses close to those found to be anticonvulsant, however, hyperlocomotion and stereotyped behavior occurred only with MK-801. The highest protective indices [PI = TD50 (inverted screen)/ED50 (MES)] were calculated for CGP 40116 and D-cycloserine (2.4 and 2.2, respectively). When tested for memory impairment at one-half the MES ED50, again only MK-801 induced significant memory disruption in the passive avoidance test. In conclusion, these results suggest that glycineB receptor high-efficacy partial agonists and competitive NMDA receptor antagonists may be advantageous to noncompetitive NMDA antagonists and glycineB receptor antagonists as potential antiepileptic drugs.

2-Amino-5-phosphonovalerate↗
PubMed1998

[Injury risk of competitive, handicapped cross-country skiers in training nd competition].

Injuries caused by cross country skiing have been poorly investigated in handicapped athletes. The dynamic sliding shape of motion makes this sport to a suitable discipline for people with a deficit of locomotion. Visual handicapped people with a guide are able to improve their motoric skills, co-ordination, orientation and body self-consciousness in the track. Since handicapped athletes are performing in international competitions the training intensity to fulfill the requirements, but also the risk of overstrain induced injuries got increased, like in other high-performance sports. Our study examined injuries and overuse syndromes of the German National Team Ski Nordic during the Paralympics in Tignes/ Albertville (1992). Lillehammer (1994) and the training period in preparation for the Paralympics in Nagano (March 1998). The incidence and kind of injuries in the competitive handicapped cross country skier was comparable with non-handicapped athletes, but the injury pattern was different.

Adult↗
PubMed1997

Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase--further experimental evidence for a multisite model.

P-glycoprotein, a plasma membrane protein overexpressed in multidrug-resistant (MDR) cells, exhibits in vitro an ATPase activity and is responsible for the energy-dependent efflux of structurally unrelated cytotoxic drugs (like vinblastine) and various MDR-reversing agents (like verapamil and progesterone) from these MDR cells. To investigate the mechanism of P-glycoprotein interaction with various compounds, we measured the P-glycoprotein ATPase activity on membrane vesicles prepared from the MDR cell line DC-3F/ADX, and we studied the effects of vinblastine, verapamil and progesterone on this ATPase activity. The basal P-glycoprotein ATPase activity is increased by verapamil and progesterone, with respective half-maximal activating concentrations of approximately 1.5 microM and approximately 25 microM, and activation factors of approximately 1.7 and approximately 2.2. Vinblastine inhibits the activation of P-glycoprotein ATPase induced by verapamil or progesterone with an inhibition constant approximately 0.5 microM in both cases. This demonstrates that vinblastine has a specific modulating site on P-glycoprotein. The combined modulation of P-glycoprotein ATPase by vinblastine and verapamil reveals that these two drugs are mutually exclusive. Since these two molecules have different effects both on the basal P-glycoprotein ATPase activity and on the MgATP concentration dependence of P-glycoprotein ATPase activity, they could bind P-glycoprotein either on different and overlapping sites, or on distant but interacting sites. In contrast, the combined modulation of P-glycoprotein ATPase by vinblastine and progesterone reveals a non-competitive relationship between these two drugs, and hence shows that they can independently and simultaneously bind P-glycoprotein on distinct sites. Since verapamil and progesterone are mutual inhibitors of P-glycoprotein ATPase stimulation in a non-competitive manner, these two molecules can also bind independently P-glycoprotein on separated sites. This is confirmed here by the observation of a synergistic effect when mixtures of verapamil and progesterone are tested for the modulation of P-glycoprotein ATPase. Three MDR-related molecules, taken as models for interaction with P-glycoprotein, appear thus to bind on at least two different separated specific sites. These results favor a multisite model rather than a universal site model to describe the broad substrate specificity characterizing P-glycoprotein function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Competitive and non-competitive effects of 5-hydroxyindole on 5-HT3 receptors in N1E-115 neuroblastoma cells.

1. Effects of 5-hydroxyindole (5-OH-indole) (the aromatic moiety of 5-hydroxytryptamine (5-HT)) on 5-HT-evoked ion current and the nature of these effects on 5-HT3 receptors have been investigated in whole-cell voltage clamp and radioligand binding experiments on cultured N1E-115 mouse neuroblastoma cells. 2. The amplitude of 10 microM 5-HT-evoked ion currents was enhanced up to 150% of the control value by increasing concentrations up to 10 mM 5-OH-indole with half maximum effect of 0.8 mM. At concentrations between 10 mM and 50 mM, 5-OH-indole blocked the 5-HT-evoked ion current. Both the enhancement and the block by 5-OH-indole were accompanied by a marked slowing of the kinetics of decay of the 5-HT-evoked inward currents. 3. The blocking effect was surmounted when the 5-HT concentration was raised from 10 microM to 100 microM. Conversely, the increase in amplitude and the slowing of the decay of the 5-HT-evoked ion current induced by 1 mM 5-OH-indole were not reversed by the same increase of 5-HT concentration. 4. The binding of the selective antagonist [3H]-GR65630 to 5-HT3 receptors was displaced by 5-OH-indole in a concentration-dependent manner with a pKi of 1.96. In saturation binding experiments 10 mM 5-OH-indole reduced the affinity of [3H]-GR65630, whereas the total number of binding sites remained unaffected. 5. It is concluded that the blocking effect of high concentrations of 5-OH-indole is due to a competitive interaction with the antagonist recognition sites of 5-HT3 receptors, whereas the potentiating effect of lower concentrations of 5-OH-indole appears to be mediated by a distinct non-competitive interaction.

Animals↗
PubMed1986

Competition in health care and the rural poor: an assessment from Arizona's competitive Medicaid experiment.

Market competition has been advocated as a possible solution to the rapidly increasing costs of Medicaid programs. However, there have been no major assessments of the impact of this approach on the rural poor. Past efforts have been located in urban areas; where existing HMOs were used to enroll the Medicaid population that elected to join the plans. In 1981 the Arizona Health Care Costs Containment System (AHCCCS, pronounced "access"), a statewide Medicaid experiment involving prepayment and enrollment in health plans, was created. Data from two state-wide, cross-sectional telephone surveys indicate that competitive Medicaid programs may be a feasible strategy in rural areas, but without innovative solutions for those ineligible for Medicaid, many of the rural poor will continue to have in adequate access to medical care.

Arizona↗
PubMed2005

Anthropometry and somatotype of competitive female figure skaters 11-22 years. Variation by competitive level and discipline.

AIM: Variation in anthropometric characteristics and somatotype of female figure skaters by level of competition and discipline was examined. METHODS EXPERIMENTAL DESIGN: ANCOVA with age as the covariate was used to compare the anthropometry of skaters by level (test stream, pre-elite, elite) and discipline (free, dance, pair), while MANCOVA was used to compare somatotype. SETTING: purposive sampling reflecting the skating population by level and discipline was used to recruit skaters in 4 American, and 7 Canadian figure skating clubs. PARTICIPANTS: a total of 161 competitive female figure skaters 11-22 years of age (15.7+/-2.4 years) comprised the sample. MEASURES: a battery of 15 anthropometric dimensions was taken on each skater. Several dimensions, ratios and Heath-Carter somatotypes were derived. RESULTS: Test skaters are heavier and generally larger than pre-elite skaters. Test stream skaters also have larger limb circumferences, estimated calf and arm musculature, and a thicker sum of skinfolds, and are more endomorphic than pre-elite skaters. Elite skaters are more mesomorphic than pre-elite skaters. The sitting height/stature (SH/ST) ratio is significantly lower in pre-elite skaters, while elite and test stream skaters do not differ in this indicator of proportions. Free skaters are taller and heavier; have a higher body mass index (BMI), limb circumferences and sum of skinfolds; and proportionally shorter legs than dancers and pair skaters. Free skaters, dancers and pair skaters, however, do not differ in somatotype. CONCLUSIONS: The results suggest that figure skating favors lightness, leanness, higher mesomorphy and lower endomorphy at more elite levels. Shortness, leanness and linearity of physique appear to be selective factors associated with specialization in dance and pair skating.

Adolescent↗