Effect of venotropic drugs on the respiratory activity of isolated mitochondria and in endothelial cells.
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Several drugs used in the treatment of chronic peripheral ischaemic and venous diseases, i.e. aescine, Cyclo 3, Ginkor Fort, hydroxyethylrutosides, naftidrofuryl, naphthoquinone and procyanidolic oligomers, were tested on the mitochondrial respiratory activity. The results show that all these drugs protected human endothelial cells against the hypoxia-induced decrease in ATP content. In addition, they all induced a concentration-dependent increase in respiratory control ratio (RCR) of liver mitochondria pre-incubated with the drugs for 60 min. The drugs were divided into two groups according to their effects. The first group (A), comprising aescine, Ginkor Fort, naftidrofuryl and naphthoquinone, increased RCR by decreasing state 4 respiration rate. The second group of drugs (B), comprising hydroxyethylrutosides, procyanidolic oligomers and Cyclo 3, increased RCR by increasing state 3 respiration rate. The drugs of group A were able to prevent the inhibition of complexes I and III respectively by amytal and antimycin A while the first two drugs of group B increased adenine nucleotide translocase activity. Cyclo 3 inhibited the carbonylcyanide m-chlorophenyl hydrazone (mCCP)-induced uncoupling of mitochondrial respiration. None of these seven drugs could protect complexes IV and V, respectively, from inhibition by cyanide and oligomycin. When tested on endothelial cells the drugs of group A, in contrast to group B, prevented the decrease in ATP content induced by amytal or antimycin A. The present results suggest that the protective effects on mitochondrial respiration activity by these venotropic drugs may explain their protective effect on the cellular ATP content in ischaemic conditions and some of their beneficial therapeutic effect in chronic vascular diseases. (+info)
Wada testing in pediatric patients by use of propofol anesthesia.
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BACKGROUND AND PURPOSE: Wada testing may provide important information for surgical planning in pediatric patients with medically refractory epilepsy, but it is often not used because of the difficulties in performing the angiographic portion of the procedure in conscious children. We reviewed our experience using propofol, a short-acting IV administered anesthetic agent, for pediatric patients undergoing Wada testing. METHODS: In a retrospective review of Wada tests performed on patients younger than 18 years, we identified 24 cases in which propofol anesthesia was used. We reviewed the medical records of these patients, with particular reference to dose of propofol, physiological parameters during anesthesia, and adequacy of neuropsychological testing after emergence from anesthesia. RESULTS: Patients ranged in age from 6 to 16 years (mean age, 12.5 years). Propofol induced mild reductions in blood pressure (12.4% for systolic and 13.9% for diastolic blood pressure) and heart rate (mean reduction of 4.7%), which did not require specific treatment in any patient. Recovery from anesthesia was smooth and rapid, allowing initiation of Wada testing within 15 to 25 minutes of cessation of propofol. Wada testing was successfully accomplished in all patients. CONCLUSION: Propofol provided rapid induction of anesthesia, was administered without endotracheal intubation, and did not cause substantial changes in cardiorespiratory parameters. Propofol anesthesia allowed controlled angiography among patients as young as 6 years and did not interfere with neuropsychological testing. (+info)
Comparison of radioimmunoassay with thin-layer chromatographic and gas-liquid chromatographic methods of barbiturate detection in human urine.
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A radioimmunoassay (I) for barbiturates was compared with thin-layer chromatographic (II) and gas-liquid chromatographic (III) methods for barbiturate detection in human urine. Timed urine samples were obtained from volunteers who had ingested 100 mg of a barbiturate. I detected barbiturate in all urines tested up to 76 h after the dose, and III in all up to 52 h and in 90% up to 76 h. II detected barbiturates in 90% of all urine samples for only 30 h, after which is reliability declined. Glutethimide interfered with radioimmunoassay of barbiturate, producing false positives. I is sensitive, reliable, and fast, and lends itself to screening large numbers of urine samples for barbiturates. For routine urine surveillance, however, we found I to be less useful than II, which is still the method of choice. I has, however, proved to be an excellent method for confirming results of II. (+info)
Interaction of barbiturate analogs with the Torpedo californica nicotinic acetylcholine receptor ion channel.
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Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [(14)C]Amobarbital binds to one high-affinity (K(d) = 3.7 microM) and several (approximately 11) low-affinity (K(d) = 930 microM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5'-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5'-(3-methylbutyl) barbituric acid] in inhibiting [(14)C]amobarbital binding. (2) A binding locus within the pore of the nAChR ion channel. Each of the barbiturate analogs inhibited the binding of [(3)H]tetracaine or photoincorporation of 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine in a mutually exclusive manner. (3) Stereoselective binding. The R(+)-enantiomers of isobarbital and pentobarbital are approximately 2-fold more potent in inhibiting 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine photoincorporation than the S(-)-enantiomers. Finally, molecular modeling suggests that within the channel, the pyrimidine ring of the barbiturate is located just above the highly conserved leucine ring (M2--9; e.g., delta Leu-265), whereas the 5' side chain projects downward, and depending upon its conformation, introduces steric hindrance to binding because of the restriction in the lumen of the channel introduced by the leucine side chains. (+info)
Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces.
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The relation between pyruvate utilization and acetylcholine synthesis was investigated in minces of adult rat brain. The flux of pyruvate to acetylcholine was less than 1% of that to CO2; nevertheless, a number of agents which inhibited conversion of [1-14C]-pyruvate or [2-14C]pyruvate into 14CO2 were associated with corresponding decreases in the conversion of [2-14C]pyruvate into acetylcholine. The amount of acetylcholine produced by minces of whole rat brain, measured by g.l.c.-mass spectrometry, decreased similarly. Among the inhibitory compounds tested were 3-bromopyruvate, an irreversible inhibitor of pyruvate dehydrogenase; 2-oxobutyrate, a competitive inhibitor of pyruvate dehydrogenase; other 2-oxo acids; and amobarbital and pentobarbital. Linear-regression equations relating CO2 production to acetylcholine synthesis gave correlation coefficients of 0.89-0.93 for the combined observations. The inhibition of acetylcholine synthesis could not be attributed to inhibition of choline acetyltransferase. Incorporation of [2-14C]pyruvate into lipids, proteins and nucleic acids was effected less than that into acetylcholine. Under these experimental conditions, it was shown that pyruvate utilization can limit acetylcholine synthesis. (+info)
Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat.
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Earlier studies showed that phenobarbital feeding enhanced hepatic tumorigenesis in rats previously fed 2-acetylaminofluorene for a brief period. As part of an investigation of the mechanism of this enhancement, the present study evaluated the relative enhancing abilities of amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane (DDT), agents that resemble phenobarbital to varying degrees in their effects on liver structure and metabolism. A comparison of hepatic tumor yields in rats fed 2-acetylaminofluorene, followed by the test substance (sequential treatment), showed that amobarbital and diphenylhydantoin had no enhancing activity, whereas the enhancing effect of DDT was similar to that of phenobarbital. These results show that the sequential treatment technique readily distinguishes among substances differing in enhancing ability and should prove useful in screening additional substances for this activity. The comparative biochemical effects of these substances in the liver can then be correlated with their relative enhancing abilities to provide information on the molecular events specifically associated with enhancement. Such correlations were initiated in this study by comparing the effects of the four test substances on liver weight and DNA synthesis. The results showed that the enhancers, phenobarbital and DDT, each stimulated liver DNA synthesis and increased liver weight, whereas the nonenhancers, amobarbital and diphenylhydantoin, had neither effect. Phenobarbital and DDT both increased the early tumor incidence rate and maintained an increment in tumor incidence over that in the other treatment groups throughout the experiment, although it is not clear whether this increment would persist indefinitely. In addition, although the spectrum of tumor types observed ranged from highly differentiated to poorly differentiated in all treatment groups, DDT and phenobarbital selectively increased the incidence of highly differentiated tumors throughout most of the experiment. (+info)
Simple, highly selective screening method for barbiturates in urine.
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I present a new, simple colorimetric method for detecting and estimating barbiturates in urine. After the barbiturates are extracted with ether, an aliquot of the washed ether phase is added to the color reagent (a bivalent mercury/dithizone chelate in chloroform). On addition of diluted pyridine and shaking, a pinkish-violet color appears if a barbiturate is present. The overall sensitivity of the above method was evaluated by probit analysis in the case of sodium phenobarbital. The concentration of sodium phenobarbital in urine detectable at least 99% of the time was 6.72 mg/liter, with 95% confidence limits of 5.37 to 10.36 mg/liter. Sodium phenobarbital, 10 mg/liter, can be detected in the presence of phenytoin (50 mg/liter), glutethimide (100 mg/liter), or bemegride (100 mg/liter). The whole procedure requires less than 10 min. An excretion study illustrates application of the procedure. (+info)
Shifts in ATP synthesis during preimplantation stages of mouse embryos.
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The actual and potential activities of the cyochrome system were studied in cleavage-stage mouse embroys. Activities were determined by assaying embroys for total ATP and the rates of [32-P]ATP synthesis both before and after their incubation in medium supplemented either with an energy coupling site inhibitor (antimycin, amytal or cyanide) or with the FADH-linked substrate, succinate. The data indicate that there are three major shifts in the mode of ATP production during preimplantation stages: the first, between the two-cell and late four-cell stages; the second, between the eight-celland late morula stages; and the third, between the late morula and late blastocyst stages. These data are discussed in relation to studies on the energy metabolism of cleavage and blastocyst stage mouse embryos. (+info)