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PubMed2006

Adenosine A1 receptor-mediated inhibition of in vitro prolactin secretion from the rat anterior pituitary.

In previous studies, we demonstrated biphasic purinergic effects on prolactin (PRL) secretion stimulated by an adenosine A2 agonist. In the present study, we investigated the role of the activation of adenosine A1 receptors by (R)-N6-(2-phenylisopropyl)adenosine (R-PIA) at the pituitary level in in vitro PRL secretion. Hemipituitaries (one per cuvette in five replicates) from adult male rats were incubated. Administration of R-PIA (0.001, 0.01, 0.1, 1, and 10 microM) induced a reduction of PRL secretion into the medium in a U-shaped dose-response curve. The maximal reduction was obtained with 0.1 microM R-PIA (mean +/- SEM, 36.01 +/- 5.53 ng/mg tissue weight (t.w.)) treatment compared to control (264.56 +/- 15.46 ng/mg t.w.). R-PIA inhibition (0.01 microM = 141.97 +/- 15.79 vs control = 244.77 +/- 13.79 ng/mg t.w.) of PRL release was blocked by 1 microM cyclopentyltheophylline, a specific A1 receptor antagonist (1 microM = 212.360 +/- 26.560 ng/mg t.w.), whereas cyclopentyltheophylline alone (0.01, 0.1, 1 microM) had no effect. R-PIA (0.001, 0.01, 0.1, 1 microM) produced inhibition of PRL secretion stimulated by both phospholipase C (0.5 IU/mL; 977.44 +/- 76.17 ng/mg t.w.) and dibutyryl cAMP (1 mM; 415.93 +/- 37.66 ng/mg t.w.) with nadir established at the dose of 0.1 microM (225.55 +/- 71.42 and 201.9 +/- 19.08 ng/mg t.w., respectively). Similarly, R-PIA (0.01 microM) decreased (242.00 +/- 24.00 ng/mg t.w.) the PRL secretion stimulated by cholera toxin (0.5 mg/mL; 1050.00 +/- 70.00 ng/mg t.w.). In contrast, R-PIA had no effect (468.00 +/- 34.00 ng/mg t.w.) on PRL secretion stimulation by pertussis toxin (0.5 mg/mL; 430.00 +/- 26.00 ng/mg t.w.). These results suggest that inhibition of PRL secretion after A1 receptor activation by R-PIA is mediated by a Gi protein-dependent mechanism.

Adenosine↗
PubMed2006

The role of adrenergic agonists on glycogenolysis in rat hepatocyte cultures and possible involvement of NO.

Certain liver metabolic diseases point to the presence of disturbances in glycogen deposition. Epinephrine raises the cAMP level that activates protein kinase A leading to the activation of phosphorylase and glycogen breakdown. In the present report, we sought to investigate whether NO is produced during adrenoceptor agonist-induced glycogenolysis in rat hepatocytes in cultures. Isolated glycogen rich rat hepatocytes in cultures were used. NO production (NO(2)(-)) was assessed under the effect of adrenergic agonists and adrenergic agonist/antagonist pairs, dibutyryl cyclic AMP sodium-potassium salt (db-cAMP), NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). The inducible NO synthase (iNOS) mRNA was examined by the reverse transcription-polymerase chain reaction (RT-PCR). Glycogenolysis was quantified by glucose levels released into medium. The amount of glucose and NO(2)(-) released by hepatocytes was increased as a result of epinephrine, phenylephrine or db-cAMP treatments. The increase in glucose and NO(2)(-) released by epinephrine or phenylephrine was blocked or reduced by prazosin pretreatment and by NOS inhibitors aminoguanidine and L-NAME. iNOS gene expression was up-regulated by epinephrine. It can be concluded that glycogenolysis occurs through -adrenoceptor stimulation and a signaling cascade may involve NO production.

Adrenergic alpha-Agonists↗
PubMed1999

Suppression of hypoxia-associated vascular endothelial growth factor gene expression by nitric oxide via cGMP.

PURPOSE: To investigate the suppressive effect of nitric oxide (NO) on vascular endothelial growth factor (VEGF) gene expression and to elucidate its mechanism of action. METHODS: Immortalized human retinal epithelial (RPE) cells, H-ras-transfected murine capillary endothelial cells, and nuclear factor-kappaB (NF-kappaB) RelA knockout 3T3 fibroblasts had VEGF gene expression stimulated by hypoxia, TPA (phorbol ester 12-O-tetradecanoylphorbol-13 acetate), and ras-transfection. The dose response and time course of inhibition of VEGF gene expression by NO were characterized by northern blot analysis, ribonuclease protection assay, and enzyme-linked immunosorbent assay. The effects of NF-kappaB and cGMP in the NO-induced suppression of VEGF gene expression were quantitated. cGMP production was inhibited by LY 83583 (6-anilino-5,8-quinolinedione), a specific inhibitor of guanylate cyclase production, and cGMP accumulation was quantitated by immunoassay. RelA knockout 3T3 fibroblasts were used to assess the contribution of NF-kappaB to the downregulation of VEGF by NO. RESULTS: The NO donor sodium nitroprusside (SNP) decreased hypoxia-induced VEGF gene expression in a dose- and time-dependent manner. One hundred fifty micromolar SNP completely suppressed hypoxia-induced VEGF mRNA levels for at least 24 hours. Constitutive VEGF expression was not altered by SNP. The SNP-mediated decreases in VEGF expression were associated with increases in intracellular cGMP and were blocked by LY 83583. Sodium nitroprusside was able to decrease hypoxia-induced VEGF mRNA increases in fibroblasts deficient in the RelA subunit of NF-kappaB. Nitric oxide was also effective at suppressing increased VEGF expression secondan, to mutant ras and TPA. CONCLUSIONS: These data indicate that NO decreases hypoxia-induced VEGF via a cGMP-dependent mechanism and suggest that NO may serve as an endogenous inhibitor of both hypoxia- and non- hypoxia-enhanced VEGF expression in vivo.

3T3 Cells↗
PubMed1999

[Evidence for involvement of NO/NOS-cGMP signal system in morphine dependence].

The present study was undertaken to observe changes in cGMP contents, calcium-dependent and non-calcium-dependent NOS activities in brain regions isolated from morphine-dependent mice as well as the effect of NOS inhibitor (L-NMMA) on the development of this dependence. It was found that (1) cGMP contents in cerebellum, striatum, hippocampus and cerebral cortex were significantly decreased. (2) Calcium-dependent NOS activity was noticeably increased in striatum and cerebral cortex, which was inhibited by PKA inhibitor. No similar changes were found in cerebellum and hippocampus. Changes of non-calcium-dependent NOS activity did not occur in morphine-dependent mice brain. (3) In the striatum and cerebral cortex of morphine-dependent mice, the level of 150 kD protein phosphorylation in vitro was noticeably decreased, which was inhibited by IP20 (PKA inhibitor). (4) NOS inhibitor injected (icv) 15 min prior to daily morphine injection could prevent the development of morphine dependence. (5) All the changes above were not observed in mice treated with naloxone 30 min prior to daily morphine injection. Our data suggest that the reduction of cGMP contents and the increase of calcium-dependent NOS activity in striatum and cerebral cortex isolated from morphine-dependent mice may be mediated by opioid receptors and involved in the development of morphine-dependence. Why the increase of NOS activity was in association with the reduction of cGMP contents remains to be answered and it implies that the effect of NO/NOS involved in morphine-dependence may be produced through other mechanisms other than those producing cGMP signal. NOS phosphorylation in some other brain regions, which may be regulated by PKA, probably contributes to the increase of NOS activity in morphine-dependent mice.

Animals↗
PubMedDate not supplied

A three base pair gene variation within the distal 5'-flanking region of the interleukin-10 (IL-10) gene is related to the in vitro IL-10 production capacity of lipopolysaccharide-stimulated peripheral blood mononuclear cells.

Interleukin-10 (IL-10) is an important multifunctional immunmodulator. There is evidence that IL-10 secretion is associated with certain genetic elements of the proximal IL-10 gene 5'-flanking region. The allelic and genotypic comparison of IL-10 expression by lipopolysaccharide (LPS)- stimulated leukocytes (PBMC) with a recently discovered distal "indel" DNA-sequence variation at - 7400 bp revealed significant inter-individual differences in the IL-10 in vitro production capacity. Homozygotes lacking the three base pairs "GGA" (- 7400del) at this gene locus are characterised by high expression of IL-10 with a median of 1690pg/ml (P <or=0.009). The allelic comparison supports this finding (P <or=0.002). Further analysis of the haplotype -7400/- 1087 showed that homozygotes for - 7400del/- 1087G may be classified as very strong IL-10 responders with a median IL-10 secretion of 2378 pg/ml (P <or=0.025). When leukocytes were stimulated in vitro by dibutyryl-cAMP or infected with Epstein-Barr virus no significant inter-individual differences between the - 7400indel alleles or genotypes and the IL-10 in vitro production capacity were observed. Our findings further the understanding of the complexity of IL-10 gene regulation in relation to defined regulatory gene variations.

5' Flanking Region↗
PubMed1987

[Ultrastructure of adenohypophyseal cells of white rats subjected to the effect of a benzodiazepine in chronic form].

The ultrastructure of the pars anterior (adenohypophysis), treated with diazepam (2.5 mg/Kg) has been studied by thin sections and electron microscopy. The structure of Thyrotrophs, Corticotrophs, Gonadotrophs, and Mammotrophs cells were described. Ultrastructural modifications were not observed. It is concluded that the chronic treatment with diazepam did not produce any visible ultrastructural effects in the secretory cells of the adeno hypophysis; maybe because the diazepam has a short life time and due to the small effect of the diazepam metabolites in this species.

Animals↗
PubMed1981

Hydrolysis of ribonucleoside 2',3'-cyclic phosphates by influenza and Newcastle disease viruses.

Two enzymatic activities hydrolysing ribonucleoside 2', 3'-cyclic phosphates (2', 3'-cNMP) to 2'- or 3'- nucleoside monophosphate were found associated with influenza and Newcastle disease viruses. The two enzymatic activities differed from each other by temperature optima and thermoresistance. 2', 3'-Cyclic nucleotide 3'-phosphohydrolase was responsible for splitting of the substrate to 2'-NMP. Splitting of the substrate to 3'-NMP was due either to ribonuclease or to 2', 3'-cyclic nucleotide 2'-phosphohydrolase.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1996

Crystal structures of some acyclonucleosides with antiviral activity and related compounds.

The crystal structure of the acyclonucleoside, 9-[4-hydroxy-2-(hydroxymethyl)-butyl]guanine (2HM-HBG), has been compared with related acyclonucleosides, and that of the acyclonucleotide, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine-3',5'-cyclic phosphate (DHPG-cMP), also with its parent second messenger cGMP and cyclic monophosphate nucleotides. There is considerable conformational flexibility in the acyclic chain of these compounds with several conformations coexisting in the solid state. This flexibility together with the narrow range of the glycosidic torsion angles (from 69 degrees to 94 degrees, with an average of 83(3) degrees for 11 molecules when the aglycon is guanine, and from 92 degrees to 108 degrees with an average of 103(3) degrees for 4 molecules when the aglycon is adenine) may be essential for the antiviral activity of these compounds and their ability to act as substrates. The mechanism of antiviral activity of, 9-[(1,3-dihydroxy-2-propoxy)methyl] guanine-3',5'-cyclic phosphate is different from that of the acyclonucleosides, and is discussed in the light of it being a close structural analogue to the second messenger cGMP.

Animals↗
PubMed1975

Mechanism of nucleotide inhibition of gonadotropin binding to cell membranes of bovine corpus luteum.

ATP, CTP, ADP, AMP, cyclic 3',5'-AMP (cAMP) and cyclic 3',5'-CMP (cCMP) effectively inhibited the specific binding of 125I-labelled human chorionic gonadotropin ([125I]HCG) to bovine corpus luteum cell membranes. This inhibition was observed with 2.5 X 10(-4) M to 1.0 X 10(-3) M nucleotide concentrations, regardless of the presence of a nucleotide regenerating system. Submaximal concentrations of combinations of the nucleotides were additive in inhibiting binding. The inhibition of [125I]HCG binding was observed when the nucleotides were added at the beginning of or during incubation or preincubation of the membranes with nucleotides. Preincubation of membranes with CTP and cAMP, subsequent washing and reincubation with hormone, showed time-dependent inhibition of [125I]HCG binding when the preincubation temperature was 38 degrees C but not at 4 degrees C. The concentrated supernates from nucleotides preincubated with membranes had no inhibitory effect on [125I]HCG binding to fresh membranes. In the absence of added nucleotides, [125I]HCG-membrane interaction had the following apparent binding constants: a Kd of 1.5 X 10(-10) M, 46.3 fmoles of binding sites per mg membrane protein, and rate constants for association and dissociation 4.0 X 10(6) M-1 sec-1 and 1.0 X 10(-3) sec-1, respectively. At steady state conditions of [125I]HCG binding, CTP inhibited [125I]HCG at lower concentrations of added hormone (less than 3 X 10(-9) M) whereas at higher concentrations, this nucleotide enhanced [125I]HCG binding. Scatchard analysis of the data revealed that inhibition and enhancement of [125I]HCG binding in the presence of CTP were due to lowered affinity of gonadotropin receptors (32-37) fold) and to exposure of new low-affinity binding sites for [125I]HCG, respectively. At non-steady-state conditions, nucleotides increased dissociation rates (80 to 100%) and decreased association rates (30 to 38%). The data appear to be compatible with the suggestion that the nucleotides may bind to sites in the membranes and subsequently induce conformational changes in membrane components, resulting in a decreased affinity of gonadotropin receptors. The physiological significance of these findings needs to be determined.

Adenosine Diphosphate↗
PubMed1989

Converging evidence for identification of recurrent relationship themes: comparison of two methods.

The therapeutic process is complex, and researchers and clinicians alike search for organizing principles or underlying structures that will reduce this complexity and thereby augment the efficacy of their respective endeavors. As other papers in this issue indicate, one such organizing principle is the concept of a recurring relationship theme that can be identified in the patient's descriptions of current and past relationships, as well as observed in the patient's interaction with the therapist. This concept has its origins in Freud's discovery of the transference phenomenon (1912), wherein the patient reenacts early relationships with significant others in the relationship with the analyst, and in Sullivan's interpersonal theory of psychiatry, with its central tenet that "personality is the relatively enduring pattern of recurrent interpersonal situations which characterize a human life" (1953, pp. 110-11). In the psychoanalytic and interpersonal therapies, these recurrent interpersonal themes, associated with the patient's difficulty in living and characterized as self-defeating and self-perpetuating, can potentially serve three main purposes: diagnosing and describing patients' difficulties, focusing therapeutic interventions, and measuring change on an individual basis. However, until recently, research on transference and rigidity of interpersonal style has been hampered by the lack of objective and clinically relevant measures for quantifying this clinical phenomenon (Kiesler 1986; Luborsky and Spence 1978). Luborsky (1977) developed the first reliable method for operationalizing the transference concept. Since then, as the companion papers in this issue point out, several different methods have been developed (e.g., Gill and Hoffman 1982; Horowitz 1979; Schacht et al. 1984). Although these methods differ in the postulated structural composition or components of the transference theme or recurrent relationship theme, they operate from similar methods of assessment. This paper presents the results of an initial investigation into convergent validity (Cronbach and Meehl 1955) of two of the major relationship theme methods--the Core Conflictual Relationship Theme (CCRT) of Luborsky and colleagues (Luborsky 1977), and the Cyclical Maladaptive Pattern (CMP: formerly called the "dynamic focus") of the Vanderbilt group (Schacht et al. 1984; Schacht and Henry, in press). In our investigation, developers of the approaches independently applied their methods to the same interview with a depressed patient. It was hypothesized that aside from differences due to the structural composition, the two methods would identify a similar relationship theme.

Adult↗
PubMed2003

Ribonuclease inhibitors in Malus x domestica (common apple): isolation and partial characterization.

A ribonuclease inhibitory activity was detected in the fruits of common apple, Malus x domestica, cv. Fuji, and purified by affinity chromatography on ribonuclease A-Sepharose. It inhibited hydrolysis of cyclic-2':3'-CMP by bovine pancreatic ribonuclease A with an apparent inhibition constant of about 5 x 10(-8) M. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of the purified protein gave two peaks corresponding to the mass numbers of 55,658 and 62,839, while three bands of 43-, 34-, and 21-kDa were detected by SDS-PAGE. These results suggested that the inhibitor preparation was a mixture of two proteins comprised of 43- and 21-kDa subunits or of 34- and 21-kDa subunits. Attempts to separate these two proteins were unsuccessful. Amino acid composition and N-terminal amino acid sequence of these subunits were also identified and N-terminal sequences showed some similarity to that of cottonseed storage globulin. The significance of the presence of ribonuclease inhibitors in apple fruits is not clear, but it might allow some speculation about their possible involvement in the control of the self-incompatibility ribonuclease of Rosaceae plants.

Amino Acid Sequence↗
PubMed1994

[Relation between research and practice in analytic psychotherapy].

The technique of psychoanalytic treatment as an objective, operative-technological theory inevitably experiences a subjective refraction on analyst's personality and his or her own cognitive and interactional styles influencing therapeutic efficiency. Systematic clinical trials of treatment data integrating motions from psychoanalytic, social and cognitive science, reconcile the gap between research and practice, between basic science and application. It will be discussed how empirical research can delineate therapists' cognitive and perceptual skills and the process of transformation from declarative to procedural knowledge, further elaborated in reciprocal connection with practice. The models of Structural Analysis of Social Behavior (SASB) and Cyclic Maladaptive Pattern (CMP) are especially considered. We will also discuss the consequences for training in psychoanalysis.

Countertransference↗
PubMed1999

[The Dusseldorf short-term dynamic psychotherapy project (DKZP)].

Time-limited psychodynamic therapies in the outpatient setting are offered for a broad spectrum of psychogenic disorders. Meta-analyses prove their effectiveness mainly for neurotic disorders. We are interested in the suitability of the here applied CMP/SASB model (Tress et al. 1996) of psychodynamic short-term therapy for patients with psychosomatic and severe personality disorders. We extensively present the concept of Cyclic Mal-adaptive Pattern (CMP) in its clinically relevant parts as the core of psychogenic pathological developments. Particularly the introject, as the patient's attitude towards him- or herself, is of great importance for therapeutic change and its follow-up development. Within the DKZP (Duesseldorf Short-Term Psychotherapy Project), 36 male and female therapists, mostly interns at the local university clinic, treated 82 patients (m: 23/f: 59) with personality disorders (n = 26) and psychosomatic disorders (n = 31) as research groups and, in comparison, neurotic patients (n = 25) in a naturalistic design. 68 treatments have been completed so far, 11 patients have dropped out, the remaining 3 are still in therapy. Relevant research instruments are the Beeinträchtigungsschwere Score (BSS, an impairment score), Global Assessment of Functioning Scale (GAF), Cyclic Maladaptive Pattern (CMP), Symptom Check List (SCL-90-R), and Structural Analysis of Social Behavior (SASB) including process and content ratings, as well as the Intrex questionnaire. The treatments last 25 sessions. We carried out follow-up examinations after 6 months, 1 year, 2, and 5 years. Effect sizes for the whole sample by BSS and GAF are remarkably high, with further increase at follow-up interviews. Psychosomatic patients came off best, but personality disorders in comparison to neurotic patients profited surprisingly well. Effect sizes in self-rating (SCL and Intrex) were less high. However, in self-rating the changes of social functions are not sufficiently addressed. As a result, our form of focal therapy is well suited not only for neuroses, but also for psychosomatic disorders and personality disorders. An enlargement of the indication spectrum for this form of psychodynamic therapy to include these disorders is well founded and promising.

Adult↗
PubMed1983

Purification and properties of an endoribonuclease existing as a complex with inhibitor in rat liver cytosol.

An endoribonuclease existing as a complex with inhibitor in the cytosol of rat liver has been purified about 128,000-fold after inactivation of the inhibitor with CdCl2. The enzyme had a molecular weight of 16,000 and produced 3'-CMP via 2',3'-cyclic phosphate of cytidine from poly(C). The breakdown of poly(U) by the enzyme was less than 5% of poly(C) breakdown. Poly(A) was not hydrolyzed by the enzyme. The enzyme had a pH optimum of 7.5-8, was heat-stable and had a Km of 952 micrograms yeast RNA and a Km of 198 micrograms poly(C) per ml. The maximal velocities for yeast RNA and poly(C) degradation were 3,970 A260/min/mg protein and 1,890 A260/min/mg protein, respectively. The enzyme was slightly stimulated by polyamines or monovalent and divalent cations except Mn2+, but was inhibited by nucleoside triphosphate, poly(G) and rat liver RNase inhibitor. Inhibition of the enzyme by rat liver RNase inhibitor was not prevented by monovalent and divalent cations or polyamines, although inhibition by poly(G) was prevented by these ions.

Ammonium Sulfate↗