[Inhibition of reactive hyperemia by kallikrein inhibitors in canine oral tissue].
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Inhibition and reactivation of Mn-catalase. Implications for valence changes at the active site manganese.
The Mn-catalase of Lactobacillus plantarum was inactivated when exposed to NH2OH plus H2O2, an effect which was not reversed by dialysis. N-Methylhydroxylamine was approximately 1% as effective as was NH2OH, while O-methylhydroxylamine was not detectably active in this regard. Approximately 40% of the lost activity could be restored by dithionite or by O-2, whereas other reductants such as ethanol, ascorbate, or nitrite were without effect. Oxidants such as persulfate and ferricyanide also failed to reactivate the enzyme. The active enzyme was inactivated, to an apparent limit of 50%, by an enzymic or photochemical flux of O-2 and this was entirely prevented by superoxide dismutase. The catalytic cycle of the enzyme is thought to involve the trivalent and pentavalent forms of the active site Mn; while inactivation by H2O2 + NH2OH appears to be due to conversion to the quadrivalent state. Partial bleaching of the enzyme by H2O2 and the nearly complete bleaching caused by NH2OH + H2O2 are in accord with this interpretation. The enzyme was unaffected by 2.0 mM EDTA, thiourea, o-phenanthroline, alpha, alpha'-dipyridyl, 8-hydroxyquinoline, diethyldithiocarbamate, thiourea, hydrazine, phenylhydrazine, isoniazid, semicarbazide, sulfite, nitrite, or sulfide, all at pH 7.0.
Binding Sites↗
The mechanism of cytoprotective action of lazaroids I: Inhibition of reactive oxygen species formation and lethal cell injury during periods of energy depletion.
Tirilazad mesylate and related compounds, known as lazaroids, are recognized as inhibitors of membrane lipid peroxidation that also act as free radical scavengers. These compounds have demonstrated protective activity in animal models of traumatic head injury and cerebral ischemia. In this study we used an in vitro cell model to investigate the mechanism by which tirilazed mesylate and related antioxidants delay or prevent the lethal cell injury provoked by chemically induced energy depletion. When the cultured human astrocytoma cell line UC-11MG was treated with the metabolic inhibitor sodium iodoacetate for 4 hr, the cells exhibited signs of irreversible cell injury, including alterations in plasma membrane morphology, the breakdown of membrane phospholipids (release of arachidonic acid into the extracellular medium) and the loss of viability as indicated by the leakage of cytoplasmic components. A large quantity of reactive oxygen species (ROS) was detected in the injured cells by a dichlorofluorescin assay. Increases in early lipid peroxidation products were detected as elevated hydroxyeicosatetraenoic acids in the membrane phospholipds, which indicated that the membrane lipids were oxidatively damaged. The addition of tirilazad mesylate, a troloxamine derivative or the common phenolic antioxidant nordihydroguaiaretic acid effectively prevented the increases in ROS, attenuated the elevation of hydroxyeicosatetraenoic acids, and delayed irreversible cell injury. We propose that the destruction of crucial cell constituents in the lipophilic compartments by ROS is one of the major causes of lethal cell injury. The cyytoprotective action of the lazaroids in related, as least in part, to their ability to block the formation of ROS and to arrest the secondary cell injury.
Arachidonic Acids↗
P2-purinoceptors of two subtypes in the rabbit mesenteric artery: reactive blue 2 selectively inhibits responses mediated via the P2y-but not the P2x-purinoceptor.
alpha,beta-Methylene ATP and ATP both produced concentration-dependent contractions of the isolated mesenteric artery of the rabbit that were not inhibited by reactive blue 2. In preparations where the tone had been raised with noradrenaline, ATP and 2-methylthio ATP, but not alpha,beta-methylene ATP, produced relaxations of the vessel. These relaxations were inhibited in the presence of reactive blue 2. Reactive blue 2 did not inhibit the contractions to noradrenaline, and only slightly inhibited relaxations to adenosine and acetylcholine. The rank order of potency of purine nucleotide analogues in contracting the vessel was: alpha,beta-methylene ATP greater than beta,gamma-methylene ATP = 2-methylthio ATP greater than ATP, and in relaxing the vessel at raised tone was: 2-methylthio ATP greater than ATP greater than beta,gamma-methylene ATP greater than alpha,beta-methylene ATP. It is concluded from this study that in the isolated mesenteric artery of the rabbit, purine nucleotides act via P2y-purinoceptors to cause the muscle to relax and via P2x-purinoceptors to cause the muscle to contract. The results also suggest that reactive blue 2 selectively inhibits responses mediated via the P2y-purinoceptor, at least within a limited concentration range.
Adenosine Triphosphate↗
Inhibition of acetylcholinesterase by diisocyanates and its spontaneous reactivation.
The inhibition of human acetylcholinesterase (AchE) by 4,4'-diphenylmethane diisocyanate (MDI) is determined and compared with the previously described inhibition of this enzyme by two other industrially used diisocyanates: toluene diisocyanate (TDI) and hexamethylene diisocyanate (HDI). The inhibition potency of these three diisocyanates is found to be in the oder HDI greater than TDI greater than MDI. The spontaneous reactivation of inhibited AchE is reanalysed with the help of a computer program designed to fit the reactivation data to the exponential rate equation Vt = Vinf (1 - e-Kobs X (t - to) ). The enzyme inhibited by HDI and MDI undergoes very slow and limited spontaneous reactivation. The rate of delivery of diisocyanates into the respiratory tract of an exposed worker may be faster than the rate of spontaneous reactivation of the inhibited enzyme. These results are discussed in connection with the obstructive lung disease observed in approximately 5% of the workers employed in the isocyanate industry.
Acetylcholinesterase↗
Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol.
Acetaminophen (500 mg/kg i.p.) induced hepatotoxicity in fasted ICR mice in vivo. Acetaminophen also caused a long-lasting 50% reduction of the hepatic ATP content, an irreversible loss of hepatic xanthine dehydrogenase activity and a transient increase of the xanthine oxidase activity. All effects occurred before parenchymal cell damage, i.e., the release of cellular enzymes. The hepatic content of GSH and GSSG was initially depleted by acetaminophen without affecting the GSSG:GSH ratio (1:200), however, during the recovery phase of the hepatic GSH levels the GSSG content increased faster than GSH, resulting in a GSSG:GSH ratio of 1:18 24 h after acetaminophen administration. The mitochondrial GSSG content increased from 2% in controls to greater than 20% in acetaminophen-treated mice. The extremely elevated tissue GSSG levels were accompanied by a 4-fold increase of the plasma GSSG concentrations but not by an enhanced biliary efflux, although hepatic GSSG formation and biliary excretion were not affected by acetaminophen. Allopurinol protected dose-dependently against acetaminophen-induced cell injury, the loss of ATP and the increase of the GSSG content in the total liver and in the mitochondrial compartment without inhibiting reactive metabolite formation. High, protective as well as low, nonprotective doses of allopurinol almost completely inhibited hepatic xanthine oxidase and dehydrogenase activity, but only high doses prevented the increase of the mitochondrial GSSG content. The data indicate a long-lasting, primarily intracellular oxidant stress during the progression phase of acetaminophen-induced cell necrosis. The protective effect of allopurinol is unlikely to involve the inhibition of reactive oxygen formation by xanthine oxidase but could be the result of its antioxidant property.
Acetaminophen↗
Reactivation of cytoplasmic actomyosin in Physarum plasmodia extracted with glycerol and dimethylsulphoxide.
Thin-spread plasmodia of Physarum were subjected to extraction procedures using 50% glycerol or DMSO (dimethylsulphoxide) followed by labelling of actin with fluorescent phallotoxins. During the reactivation of the actomyosin system by 2 mM-MgATP fluorescent actin fibres contract isotonically, which results in numerous fluorescent 'contraction beads'. After short-term extraction 1 mM-Ca2+ has an inhibitory effect on the reactivation. This calcium sensitivity is abolished after long-term extraction with glycerol. Calcium at 10 mM irreversibly inhibits reactivation, irrespective of the duration of extraction. The inhibitory effect of 10 mM-calcium is prevented by phallotoxin labelling prior to incubation in Ca2+. The DMSO model shows an improvement in structural preservation when compared with the glycerol models. However, reactivation is inhibited by prolonged treatment with DMSO.
Actomyosin↗
Apparent HIV-1 glycoprotein reactivity on western blot in uninfected blood donors.
OBJECTIVES: To investigate samples with 'false-positive' reactivity to HIV-1 glycoproteins on Western blot (WB). DESIGN: Samples from 13 blood donors with glycoprotein reactivity were examined for serological evidence of HIV infection and followed-up where possible. METHODS: Samples were tested for anti-HIV-1, HIV-1 p24 antigen, anti-HIV-2 and anti-HTLV-1. Reactivity to multimeric, monomeric, and deglycosylated gp41 was determined, as was the ability of recombinant gp160 (rgp160) to inhibit reactivity to multimeric gp41. RESULTS: Serology and follow-up failed to confirm HIV infection in any of the donors. All samples reacted to multimeric gp41, and eight out of the 13 reacted to deglycosylated gp41. Reactivity on a commercial WB was inhibited by rgp160. CONCLUSION: Apparent reactivity to HIV-1 glycoprotein may occur in individuals with no other serological evidence of HIV infection. Reactivity to different forms of gp41 and inhibition by rgp160 suggested that the observed WB reactivity may be due to cross-reactivity with gp41 rather than to a co-migrating contaminant.
AIDS Serodiagnosis↗
Reactivation of acetylcholinesterase inhibited by methamidophos and analogous (di)methylphosphoramidates.
Reactivation of electric eel acetylcholinesterase (AChE) inhibited by MeO(NH2)P(O)SMe (methamidophos) and by MeS(NH2)P(O)SMe was studied at pH 7.5 and 25 degrees C. The former inhibited enzyme shows a rather rapid spontaneous reactivation (t1+2 = 3.7 h); this reactivation is accelerated by 1 micrometer of the bispyridinium oximes TMB4 and obidoxine, and, to a lesser extent, by the monopyridinium oximes P2S and its 1-benzyl analogue (benzyl-P2A). The latter inhibited enzyme shows rapid aging (t1+2 = 0.6 h). Reactivation with 1 mM of the bispyridinium oximes is incomplete and reactivation with 1 mM of the monopyridinium oximes proceeds very slowly. These large differences between the properties of the two inhibited enzymes indicate that the methylthio group is the leaving group during inhibition of AChE by methamidophos. Additional support is afforded by the observation of induced aging of the former inhibited enzyme by thiourea. Upon comparison of the reactivation of AChE inhibited by methamidophos with that of AChE inhibited by an N-methyl analogue, crufomate, and an N,N-dimethyl analogue, tabun, it appears that the rate of spontaneous reactivation decreases with increasing alkylation of the P-NH2 group. Whereas benzyl-P2A is somewhat less active than P2S for reactivation of ACHE inhibited by methamidophos, it is superior to P2S for reactivation of ACHE inhibited by crufomate and also superior to P2S and to the bispyridinium oximes for AChE inhibited by tabun.
Acetylcholinesterase↗
Toward a central-peripheralist model of work decrement.
Payne and others, within a Hullian framework, have analytically defined reactive inhibition in terms of a negative drive occurring within the effector system. In strong support, they have demonstrated that the maintenance of work decrement is dependent upon limb, but not task, specificity. However, equally creditable research by Adams allows interpretations of inhibition based on the processing of information. These contrasting arguments are evaluated, and an initial model integrating the two is proposed.
Humans↗
A comparison of the potency of trimedoxime and other currently available oximes to reactivate tabun-inhibited acetylcholinesterase and eliminate acute toxic effects of tabun.
Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The potency of trimedoxime and other commonly used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate tabun-inhibited acetylcholinesterase and to eliminate tabun-induced acute effects was evaluated using in vitro and in vivo methods. In vitro calculated kinetic parameters of reactivation of tabun-inhibited acetylcholinesterase from rat brain homogenate and in vivo determined percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats show that trimedoxime seems to be the most efficacious reactivator in the case of tabun poisonings. Trimedoxime was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in tabun-poisoned rats and mice. The oxime HI-6, so efficacious against soman, does not seem to be sufficiently effective oxime to reactivate tabun-inhibited acetylcholinesterase and to counteract acute lethal effects of tabun.
Acetylcholinesterase↗
Qualitative analysis of the performance of introverts and extraverts on Standard Progressive Matrices.
The present study was designed to bring out the differences between extraverts and introverts on Standard Progressive Matrices. A group of 100 subjects of equal number of sexes were given a qualitative analysis of their performance on SPM. The study brought out the initial superiority of extraverts over introverts. But with passage of time and increase in difficulty level the introverts did significantly better as shown both by the t-ratios and the F-ratios. Personality interacted with sex to yield differences in performance of wrong scores only. These findings were discussed in terms of arousal, cortical excitation and reactive inhibition.
Achievement↗
Effects of hand preference on the sex difference in psychomotor reminiscence.
Psychomotor reminiscence was investigated in 80 young adults as a function of sex, handedness, and hand employed in practice. Women reminisced more than men when practice was conducted with the preferred hand but not when it was conducted with the other hand. Hand preference was not a significant factor in men's reminiscence. Results were discussed within the context of reactive inhibition theory.
Adolescent↗
Extinction revisited: similarities between extinction and reductions in US intensity in classical conditioning of the rabbit's nictitating membrane response.
The mechanisms of extinction were examined by reducing the intensity of the unconditioned stimulus (US) after acquisition training to determine whether such reductions lie on a continuum with CS-alone extinction. The experiments revealed that reductions in US intensity yielded extinction-like effects. Specifically, there were proportional reductions in the daily mean level of responding across sessions. There were also persistent within-session declines and between-session increases of responding analogous to spontaneous recovery. Surprisingly, even when US intensity was held constant, within-session declines and between-session increases were apparent. The results are discussed with respect to possible contributions from unlearning, new learning, generalization decrement, and nonassociative loss, especially CS-specific attentional changes and CR-specific reactive inhibition.
Animals↗
Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase.
The efficacy of various oximes to reactivate acetylcholinesterase phosphorylated by tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) was tested by in vitro and in vivo methods. The oximes commonly used for the treatment of acute poisonings with highly toxic organophosphates appeared to be almost ineffective (HI-6, pralidoxime, methoxime) or just slightly effective (obidoxime) against tabun. On the other hand, trimedoxime seemed to be a significantly more efficacious reactivator than the others in the case of tabun poisonings. In vitro, the concentration of trimedoxime corresponding to 1.0 mmol/l was able to reach 50% reactivation of tabun-inhibited brain acetylcholinesterase. Higher reactivating potency of trimedoxime in comparison with the other commonly used oximes was demonstrated by in vivo method, too. In addition, other structural analogues of trimedoxime were found to be efficacious in counteracting tabun-induced acetylcholinesterase inhibition although not as efficacious as trimedoxime itself. Some effective acetylcholinesterase reactivators were characterised by dissociation constant of enzyme-reactivator complex as well as enzyme-inhibitor-reactivator complex and by rate constant of reactivation.
Acetylcholine↗
Relations between performance on the advance matrices and the EPI in high-intelligence subjects.
This study continues the investigation of the relationship between performance on tests of intelligence, and the personality parameters of the Eysenckian theoretical framework. Candidates for admission to an honours degree course (n = 281) were given the Advanced Progressive Matrices as a screening device. Those admitted to the course were on later occasions given both forms of the Eysenck Personality Inventory (EPI). In view of problems of test-retest on the EPI, scores were analysed in a novel fashion to give three groups: 'introverts', 'extraverts' and 'ambiverts'. The 'introverts' scored significantly highest on the Matrices, but the scores of the 'ambiverts' were lowest. Neuroticism showed little interaction with other variables. These results are discussed in terms of the theory of reactive inhibition. New data on the Advanced Progressive Matrices are given which are significantly higher than the published university norms.
Humans↗
Isoenzyme specific inhibition of the reactivation of in vitro dissociated lactic dehydrogenase isoenzymes by two different peptides isolated from human liver.
The catalytic activity of the LDH-isoenzymes depends on their tetrameric structure. Low pH or other denaturants leads to dissociation into monomers and to the loss of the specific activity. After removal of the denaturing conditions reassociation and reactivation occur spontaneously. Neither NADH nor NAD+ shows a significant effect on the reactivation. We have isolated two different peptides which isoenzyme specifically inhibit the reactivation of dissociated LDH. Inhibition was abolished by treating with proteases. Additionally, NAD+ and NADH were found to be antagonists of the inhibitors. The heart-type enzyme-inhibitor system is especially susceptible for NADH whereas NAD+ affects the inhibition only slightly. The muscle-type system shows the opposite behavior, e.g., the completely inhibited system can be fully reactivated by NAD+ but not by NADH. These findings together with first kinetic studies suggest a possible specific regulatory function of these peptides.
Amino Acids↗
Vascular matrix metalloproteinase-9 mediates the inhibition of myogenic reactivity in small arteries isolated from rats after short-term administration of relaxin.
UNLABELLED: During pregnancy and chronic relaxin administration to nonpregnant rats (for days), vascular MMP (matrix metalloproteinase)-2 is increased and mediates renal vasodilation, hyperfiltration, and inhibition of myogenic reactivity of small renal arteries. However, the renal vasodilatory actions of relaxin also occur after only several hours of hormone administration to nonpregnant rats, and we hypothesized a pivotal role for vascular MMP-2. Accordingly, we used gelatin zymography, which reveals not only vascular MMP-2, but also MMP-9 activity in small renal arteries isolated from rats administered recombinant human relaxin (rhRLX) or vehicle for 4-6 h. Furthermore, we tested whether myogenic reactivity is inhibited, and if so, whether the inhibition is mediated by increased vascular MMP-2. Surprisingly, we detected no significant difference in either pro or active MMP-2 in small renal arteries isolated from rhRLX and vehicle control treatment groups. In contrast, vascular MMP-9 was up-regulated by 70% (P < 0.0005 vs. vehicle). These results were completely unexpected and novel. MMP-9 protein expression was confined to the vascular smooth muscle. MMP-9, but not MMP-2 activity, was also increased in mesenteric arteries after short-term rhRLX administration (P < 0.005 and >0.05 vs. vehicle, respectively). Myogenic reactivity was inhibited in small renal arteries isolated from nonpregnant rats treated with rhRLX for 4-6 h (P < 0.01 vs. vehicle) and was completely restored by incubation with MMP-9, but not MMP-2 neutralizing antibodies in vitro. CONCLUSION: In contrast to chronic rhRLX administration, MMP-9 rather than MMP-2 plays a central role in the vasodilatory effect of short-term relaxin administration.
Animals↗