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Penicillin stimulates the formation of ribonuclease in embryoless rice (Oryza sativa L.) endosperm and enhances gibberelin-induced response. Penicillin-induced RNase production is completely inhibited by abscisic acid.
Canaline and gabaculine, inhibitors of gamma-aminotransferases and thus of ornithine aminotransferase (E.C. 2.6.1.13), decreased the flow through ornithine carbamoyl transferase (E.C. 2.1.3.3) in isolated rat hepatocytes incubated with 10 mM NH4Cl and ornithine. The levels of acetylglutamate, an essential activator of carbamoyl phosphate synthetase (ammonia) (E.C. 6.3.4.16), were also decreased, suggesting that the inhibitors had also caused a decrease in the rate of carbamoyl phosphate synthesis. Under these conditions, ornithine appears to be a precursor of acetylglutamate, via ornithine aminotransferase, possibly as a consequence of glutamate synthesis. The influence of aminooxyacetate, an aminotransferase inhibitor, has also been examined.
The aim of this work was to study the neurochemical effects in the brain of GABA-transaminase inhibition by systemic administration of gabaculine (100 mg/kg, i.a.) in the rat. In order to investigate neurotransmitter and related amino-acid compartmentation and metabolism, we have developed an original tool: the coupling, in vivo, on the same animal, of 2D COSY 1H-NMR spectroscopy with intracerebral microdialysis. The main result is a continuous increase in GABA levels, both in the intracellular compartment (up to 3000+/-450%; P<0.001) and extracellular compartment (up to 808+/-82%; P<0.01) at the sixth hour. The intracellular increase in GABA level became significant at the first hour following gabaculine administration, whereas the extracellular level increased as of the second hour, probably indicating that accumulation of GABA in nerve endings precedes its release in synaptic clefts. Moreover, the levels of the excitatory amino acids, glutamate and aspartate, were decreased both in the intra- and extracellular compartments, thus enhancing sedative effects of the drug. We also observed a decrease in the global energetic creatine-phosphocreatine pool, which also could be related to the sedative properties of gabaculine, measurable by the diminution of cortical electrical activity and mean arterial blood pressure. Finally, the coupling between 2D 1H-NMR spectroscopy and intracerebral microdialysis appears to be an original tool for investigating the cerebral metabolic effects induced by pharmacological agents, in situ, in living animals.
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Crude aurintricarboxylic acid synthesized by the conventional method was fractionated into 8 components (A1-A8) by silica gel thin layer chromatography. Some of the components were isolated and their effects were tested on nuclear swelling and on in vitro RNA synthesis and DNA synthesis using isolated polymerases. Only two components with low RF (A7 and A8) induced strong nuclear swelling. The other components were almost inactive. Formaurin-dicarboxylic acid, a contaminating polyanion of crude aurintricarboxylic acid, was synthesized separately. It was as effective as the two active components in nuclear swelling and inhibited RNA and DNA polymerases on naked DNA template. However, it stimulated RNA synthesis on chromatin template probably by dissociating histones from DNA. Unfractionated aurintricarboxylic acid showed the same effects at higher concentrations. A preliminary analysis indicated one of the inactive components (A4) is genuine aurintricarboxylic acid. The results suggest that the observed activity of crude aurintricarboxylic acid is due to some contaminating substances, one of which is formaurindicarboxylic acid.
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Analogs of chemotactic peptides (Formyl-Met-X-Phe-OMe) containing the stereochemically constrained residues alpha-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Acc5) and 1-aminocyclohexanecarboxylic acid (Acc6) at position 2 are compared with the parent sequence (X = Leu) for their ability to induce lysozyme release in rabbit neutrophils. The Acc6 analog is about 78 times more active than the parent peptide, For-Met-Leu-Phe-OH, whereas Aib and Acc5 analogs are approximately 3 and 2 times, respectively, less active than the parent peptide. NMR and model building studies clearly favour a Met-Acc6 beta-turn solution conformation in the Acc6 analog, suggesting that the neutrophil receptor is capable of recognizing a folded peptide structure. The significant differences in the activities of the Acc5 and Acc6 analogs suggest an important role for the residue 2 sidechain in receptor interactions.
The binding of 1,25-dihydroxyvitamin D3-receptor complexes from chicken intestine to DNA-cellulose and isolated intestinal nuclei is inhibited in a dose-dependent manner by aurintricarboxylic acid and rifamycin AF/013. Since both nuclear- and cytoplasmic-associated receptors have been identified, some experiments were carried out on both populations of receptors. Concentrations resulting in 50% displacement of cytoplasmic receptor complexes were 3.2 X 10(-6) M and 1.2 X 10(-4) M for aurintricarboxylic acid and rifamycin AF/013 respectively. Moreover, rifamycin AF/013 was approximately nine times more potent at inhibiting nuclear receptor binding to DNA-cellulose compared to cytoplasmic receptors. Contrary to these findings, rifampicin, which does not inhibit eukaryotic RNA or DNA polymerases, did not cause a loss of receptor complex binding to DNA-cellulose at the doses tested. Neither aurintricarboxylic acid, rifampicin, nor rifamycin AF/013 resulted in any significant loss of sterol binding. Inhibition of receptor binding to DNA-cellulose by these polymerase inhibitors was not due to alteration of the DNA and was reversed by dialysis. Incubation of receptor complexes with aurintricarboxylic acid or rifamycin AF/013 inhibited binding to Cibacron blue-agarose and phosphocellulose. Furthermore, these polymerase inhibitors were utilized specifically to desorb receptor complexes from Cibacron blue-agarose columns. Sucrose density gradient analysis of inhibitor treated and untreated receptor revealed that rifamycin AF/013 treatment resulted in the appearance of a broadened 3.7 S sedimenting receptor in addition to specific bound 1,25-dihydroxyvitamin D3 in the 6.0 S region and in the pellet of the gradient.
Previous studies have implicated a decreased efficacy of GABA as an important defect subserving the audiogenic seizures of the genetically epilepsy-prone rat (GEPR-9). The inferior colliculus (IC) is a critical site for audiogenic seizure (AGS) initiation, and the pontine reticular formation (PRF) is implicated in the propagation of AGS and in other generalized seizure models. The present study observed that microinjection of baclofen, a GABA-B receptor agonist, into IC protects against AGS, and blockade of the breakdown of endogenous GABA by gabaculine, a GABA transaminase inhibitor, increased GABA levels and blocked AGS susceptibility in the GEPR-9. Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less. Uptake of [3H]GABA into GEPR-9 synaptosomes from the IC is significantly increased as compared to normal, which could contribute to the diminished effectiveness of GABA in the GEPR-9. Previous studies indicate that GABA-A receptor agonists block AGS with IC microinjection, and recent data indicate that blockade of GABA uptake in this nucleus significantly reduced AGS severity. These data taken together strongly support the critical importance of the defect in GABA function in the IC in modulating susceptibility to audiogenic seizure initiation in the GEPR-9.
The accumulation of total RNA transcripts of 18 late embryo-abundant (Lea) gene families, each encoding two closely related Lea mRNAs, was measured in cotyledon total RNA during embryogenesis and germination of Gossypium hirsutum L. by RNA dot hybridization. Transcript abundance of the three storage protein families was also followed. The Lea mRNAs belong to only two related groups of commonly regulated mRNAs. The transcript level of each of the 6 members of Class I has two transient maxima during early maturation and a maximum level at 3 days prior to desiccation. The transcript level of each of the 12 members of Class II increases abruptly in late maturation with a maximum concentration at 3 days before desiccation (Class IIA) or at desiccation (Class IIB). Several patterns of early accumulation also exist within Class II, some overlapping with those of storage protein or Lea Class I mRNAs. The concentrations of Lea mRNAs increase at least 10- to 1700-fold during embryogenesis and decline 15- to 220-fold during the first day of germination. Earlier studies indicated that most Lea mRNAs, but no storage protein mRNAs, are induced in excised embryos exposed to abscisic acid (ABA). Free (+)ABA was measured during embryogenesis using a monoclonal antibody-based ELISA. The ABA concentration shows maxima correlating with the maxima in early Class I Lea mRNA abundance. However, ABA declines during the accumulation of Class I and Class II Lea mRNAs in late embryogenesis. Consequently, ABA could be an endogenous regulator of Class I Lea mRNAs during early maturation but is not the primary regulator of Lea mRNAs during late maturation. In contrast, cotyledon water potential exhibits a decrease that correlates with the late induction of Lea mRNAs. These findings are consistent with the hypothesis that low water potential is the endogenous regulator of some ABA-inducible mRNAs. The cessation of vascular flow to the embryo may also be involved in the disappearance of storage protein mRNAs and the late induction of Lea mRNAs.
Ethanol's intoxicating effects may result from ethanol-induced changes in central gamma-aminobutyric acid (GABA) mechanisms. To further test this hypothesis, mice were pretreated with bicuculline (1 mg/kg s.c.), aminooxyacetic acid (15, 20, 25 or 30 mg/kg i.p.) or gabaculine (20 or 40 mg/kg i.p.). Following pretreatment, 20% ethanol (2.25 g/kg i.p.) was administered and rolling roller performance evaluated. All ethanol-treated control animals showed lack of rolling roller performance at 5 min post ethanol but regained rolling roller performance by 35 min. Only 42% of the bicuculline pretreated mice demonstrated lack of rolling roller performance at 5 min post ethanol and all regained rolling roller performance by 15 min. Impairment of rolling roller performance by ethanol was potentiated by aminooxyacetic acid in a dose-dependent manner. Aminooxyacetic acid (25 and 30 mg/kg doses) slowed blood ethanol disappearance although analysis of blood ethanol disappearance and motor impairment curves indicated that aminooxyacetic acid potentiation of ethanol-induced rolling roller performance impairment cannot be attributed solely to aminooxyacetic acid's effect on blood ethanol levels. Gabaculine also potentiated ethanol's impairment of rolling roller performance but was more effective than aminooxyacetic acid in slowing ethanol disappearance, suggesting that in comparison to aminooxyacetic acid, alteration of ethanol metabolism plays a greater role in gabaculine's potentiation of ethanol-induced motor impairment.
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The presence of 50-200 microM aurintricarboxylic acid (ATA) blocked the uptake of [3H]-triamcinolone acetonide (3H-TA)-receptor complex from rat liver cytosol by isolated nuclei. The half-maximal inhibition (I.D.50) in the nuclear uptake of [3H]-TA-receptor complex was observed at 70- and 80 microM ATA depending upon whether the inhibitor was added prior to or following receptor activation. In addition, the nuclear-bound [3H]-TA-receptor complex from control samples could be completely extracted by an incubation with 20-100 microM ATA. The amount of [3H]-TA-receptor complex remained unchanged under these conditions. The effects of ATA may result due to its interaction with the glucocorticoid receptor at/near the sites that are involved in its nuclear uptake. ATA, therefore is a potentially useful chemical probe for analysis of glucocorticoid receptor.
Aurintricarboxylic acid (ATA) was immobilized on Sepharose 4B via a carbodiimide coupling mechanism. A majority of the chick oviduct progesterone receptor was retained on the affinity resin and could be recovered upon washing the column with buffer containing free ligand or 3 M guanidine-HCl. The [3H]progesterone-receptor complex retained its integrity following the chromatography on ATA-Sepharose as judged by sedimentation analysis. The procedure allowed significant purification of progesterone receptor: SDS-polyacrylamide gel electrophoresis of the purified preparation revealed elimination of many peptide bands present in the cytosol prior to ATA-Sepharose chromatography. The technique thus has a clear potential in characterization and purification of progesterone receptor.
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