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At least 19 recordsLinked to original sources
PubMed1976

The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics.

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.

Adenosine↗
PubMed1977

The actions of cyclic AMP, its butyryl derivatives and Na butyrate on the proliferation of malignant trophoblast cells in vitro.

Cyclic AMP, and its derivatives N6-monobutyryl cyclic AMP and dibutyryl cyclic AMP, have been found to inhibit the proliferation of trophoblast cells of the BeWo cell line in vitro. Sodium butyrate (1 mM), a possible degradation product of the butyrate derivatives, also inhibited cell proliferation, giving similar growth rates to equimolar dibutyryl cyclic AMP. The inhibition by butyrate was however, not sufficient to account for the action of 1 mM N6-monobutyryl cycli AMP, which, like cyclic AMP, completely inhibited cell proliferation. The potency, specificity and toxicity of the substances were compared. The results suggest different modes of action for cyclic AMP and dibutyryl cyclic AMP.

Bucladesine↗
PubMed1977

Positive dromotropic effect of dibutyryl cyclic adenosine 3',5'-monophosphate on the atrioventricular node.

The effect of atrioventricular (A-V) conduction of N6-2'-0-dibutyryl cyclic 3',5'-adenosine monophosphate (dibutyryl cyclic AMP) was investigated in comparison with those of norepinephrine, cyclic 3',5'-adenosine monophosphate (cyclic AMP), adenosine-5'-monophosphate (5'-AMP), and adenosine by the use of the isolated, blood-perfused A-V node preparation of the dog. Single injections of dibutyryl cyclic AMP (3-300 micronmol) and norepinephrine (0.1-1 nmol) into the posterior septal artery of the preparation (the upper part of the A-V node is mainly perfused through this artery) produced a dose-dependent decrease in the A-V conduction time. The time to the peak effect and the duration of the effect of dibutyryl cyclic AMP were much longer than with norepinephrine. The positive dromotropic effect of dibutyryl cyclic AMP was resistant to the beta-adrenoceptor blocking action of propranolol. Unlike dibutyryl cyclic AMP, cyclic AMP (above 30 nmol), 5'-AMP and adenosine (above 1 nmol) injected into the posterior septal artery prolonged the A-V conduction time in a dose-dependent manner. The results indicate that dibutyryl cyclic AMP has a mode of action on A-V nodal cells which differs distinctly from that of either norepinephrine or cyclic AMP, 5'-AMP, and adenosine.

Adenosine↗
PubMed1975

Cyclic AMP binding proteins in early embryos of Drosophila melanogaster.

A variety of effects of cyclic AMP on cellular and subcellular phenomena suggest that there may be other modes of action of cyclic AMP then activation of protein kinase. It is also known that developing embryos contain cyclic AMP and its related enzymes. In order to explore the role of cyclic AMP in embryogenesis, a survey of proteins capable of binding cyclic AMP in the embryonic supernatant of Drosophila melanogaster was carried out. As the result, two cyclic AMP-binding proteins were found and characterized. The one (L) is, as expected, associated with protein kinase and has a dissociation constant of about 10(-9) M. Its molecular weight of 21 000 daltons is extremely small when compared with similar proteins in other organisms. The other (H), whose function is yet to be found, has a molecular weight of about 200 000 daltons and has a dissociation constant of about 10-7 M. Some laxity in binding specificity of the latter protein among adenosine nucleotides was observed, but cyclic AMP is the strongest ligand among them.

Adenine Nucleotides↗
PubMed1978

Cyclic AMP-induced enhancement of calcium accumulation by the sarcoplasmic reticulum with no modification of the sensitivity of the myofilaments to calcium in skinned fibres from a yeast skeletal muscle.

In the presence of low concentrations of total EGTA (5 . 10(-4) M) and free Mg2+ (3.16 . 10(-5) M) and in the presence of caffeine (8 . 10(-3) M), cyclic AMP (5 . 10(-6) M) produces a relaxation of the tension developed by skinned fibres from cat caudo-femoralis. The relaxation can be attributed to an enhancement of the Ca2+ accumulation by the sarcoplasmic reticulum, since cyclic AMP does not modify the sensitivity of the myofilaments of Ca2+. These results are similar to those previously reported for the effect of cyclic AMP on skinned cardiac cells in the presence of a higher free Mg2+ concentration and in the absence of caffeine. This similarity suggests that the mode of action of cyclic AMP on the sarcoplasmic reticulum is not fundamentally different in cardiac and fast skeletal muscles.

Animals↗
PubMed2025

Marine-Inspired Antimicrobial Peptides Disrupt Gene Expression at the DNA Level.

Genome mining of Streptomyces sp. H-KF8 combined with sequence engineering yielded two serum-stable, noncytotoxic, nonlytic antimicrobial peptides, L3 and L3-K. Initial studies in uropathogenic Escherichia coli suggested membrane effects and nucleoid relaxation, prompting a comprehensive investigation of their mode of action. In this study tandem mass tag (TMT)-based quantitative proteomics revealed extensive proteome remodeling, with 175 and 120 differentially expressed proteins (DEPs) after treatment with L3 and L3-K, respectively. L3 induced predominantly upregulated responses linked to metabolism, RNA processing, transport, and homeostasis, whereas L3-K mainly caused the downregulation of proteins involved in metabolism, transport, and cell structure. Both peptides disrupted ABC transporter-mediated nutrient uptake and elicited stress responses, while L3 specifically perturbed the mal regulon, indicative of broader transcriptional dysregulation. Complementary fluorescent dye displacement and in vitro transcription/translation assays demonstrated nonspecific DNA binding, stronger for L3 than L3-K, and potent inhibition of transcriptional and translational processes. Strikingly, inhibitory concentrations paralleled their minimum inhibitory concentrations, directly linking DNA binding and interference with central information processing to antimicrobial activity. These findings reveal that L3 and L3-K primarily act by targeting DNA and interfering with the transcription-translation machinery. Beyond offering mechanistic insights, this study underscores peptides' potential to act as scaffolds for next-generation antimicrobial peptides with DNA-binding and nonmembrane-lytic activity.

Antimicrobial Peptides↗
PubMed1976

Comparison of prostaglandin E1 and TSH stimulation of cyclic AMP synthesis in thyroid tissues from euthyroid subjects and thyrotoxic patients.

Possible differences of the mode of action of TSH and prostaglandin E1 (PGE) on the synthesis of cyclic AMP were studied in normal human thyroids (normal thyroid) and thyroids from thyrotoxic patients (toxic thyroid). TSH was less effective in toxic thyroids than in normal thyroids; whereas PGE1 was equally effective in normal thyroids and toxic thyroids. Since the basal level of cyclic AMP was the same in normal and toxic thyroids, this lower sensitivity of toxic thyroids to TSH was not due to the fact that toxic thyroids were already overactive in terms of cyclic AMP synthesis. The measurement of adenylate cyclase and phosphodiesterase activities in the plasma membranes or homogenates failed to explain this lower sensitivity of toxic thyroids to TSH. Small and large doses of T4 and T3 failed to suppress an increase of cyclic AMP produced by PGE1, in the slices and plasma membranes of normal and toxic thyroids; whereas large doses of T3 depressed an increase of cyclic AMP in response to TSH in the thyroid plasma membrane of toxic thyroids. When both TSH and PGE1 were administered simultaneously, an additive increase of cyclic AMP was found in normal thyroids and in toxic thyroids. From the data accumulated, we suggest that, although TSH and PGE1 stimulate cyclic AMP synthesis in normal and toxic thyroids, the site of action and/or mode of action of these two stimulators may possibly be different, at least in human thyroids.

Adenylyl Cyclases↗
PubMed1975

Mode of action of antirheumatic drugs on the cyclic 3',5'-AMP regulated glycosaminoglycan secretion in fibroblasts.

The effect non-steroidal anti-inflammatory drugs on formation and release of glycosaminoglycans (GAG) and cyclic 3',5'-AMP levels was studied in embryonic mouse fibroblasts. The results were compared and correlated with the action of these drugs on cyclic 3',5'-AMP-dependent as well as independent protein kinase obtained from bovine diaphragm. 1. Phenylbutazone dose-dependently decreased cyclic 3',5'-AMP levels and GAG secretion both in unstimulated and PGE1 stimulated cells. 2. Indometacin decreased cyclic 3',5'-AMP levels and GAG secretion only in cells with elevated cyclic 3',5'-AMP levels after stimulation by PGE1. 3. Sodium salicylate decreased cyclic 3',5'-AMP levels in the presence and absence of PGE1. However, GAG secretion was reduced only in cells with elevated cyclic 3',5'-AMP levels, since the drug activated cyclic 3',5'-AMP-independent protein kinase activity, thus presumably precluding changes in GAG formation at low levels of cyclic 3',5'-AMP. 4. Mefenamic acid decreased cyclic 3',5'-AMP levels in cells stimulated by PGE1, whereas GAG secretion was increased both in the absence and presence of PGE1. This increase in GAG secretion was closely correlated to an enhanced cyclic 3',5'-AMP-dependent and independent protein kinase activity. The results indicate that non-steroidal anti-inflammatory drugs may exert their effects on GAG formation by interfering with cyclic 3',-5'-AMP formation or function.

Animals↗
PubMed1979

Effects of [N-(2-oxo-3,5,7-cycloheptatrien-1-yl)] aminooxoacetic acid ethyl ester (AY-25,674) on cyclic 3',5'-nucleotide formation and phosphodiesterase activity.

The orally-effective antiallergic compound [N-(2-oxo-3,5,7-cycloheptatrien-1-yl)] aminooxoacetic acid ethyl ester (AY-25,674) exhibited a potency equivalent to or 3 times less than theophylline in inhibiting guinea-pig lung and beef heart PDE, respectively, AY-25,674 did not affect the basal activity of guinea-pig lung adenyl cyclase. Although part of the antiallergic activity of AY-25,674 may be due to the ability to elevate cyclic AMP levels by PDE inhibition, other modes of action appear to be of greater relevance.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

Papaverine, cyclic AMP and the dependence of the rat aorta on extracellular calcium.

The spasmolytic effects of papaverine and dibutyryl cyclic AMP (db-cAMP) were compared on isometric contractile responses induced by addition of increasing amounts of external calcium to K+-depolarized or noradrenaline-stimulated rat aorta strips. Papaverine at a concentration active on depolarized strips (3 times 10(-5) moles/1) reduced the maximal contraction (Emax) elicited by Ca2+ in these preparations, while db-cAMP did not. Contrary to what was observed on depolarized aortae, the degree of inhibition of noradrenaline-stimulated strips did not decrease with increasing extracellular calcium concentration (Ca)e. Both db-cAMP and papaverine at a concentration which did not depress Emax (5 times 10(-6) moles/1) potentiated the relaxing effect of high (Ca)e on contractions elicited by noradrenaline. In conclusion, cyclic AMP is probably implicated in the mode of action of papaverine on the noradrenaline-stimulated rat aorta. At a concentration active on depolarized strips, papaverine is also able to impair contractility directly.

Animals↗
PubMed1979

Theophylline: biochemical pharmacology and pharmacokinetics.

Theophylline and its derivatives, such as aminophylline, have an established role as bronchodilators, although their mode of action in man is not clear. There is circumstantial evidence that therapeutic doses of theophylline may have a phosphodiesterase inhibiting effect, thus potentiating the effects of cyclic AMP. However, it remains to be established whether this is the primary mode of action of theophylline at the biochemical level. The pathways of theophylline metabolism have been clarified, although most of the enzymes involved have not been characterized. Hepatic microsomal enzyme induction by polycyclic hydrocarbons will increase the rate of theophylline elimination. There are a number of factors which influence theophylline clearance in adults, which is known to be highly variable. These factors include obesity, smoking habit, diet and the presence of such diseases as hepatic cirrhosis, acute pulmonary oedema, cor pulmonale and viral respiratory infection. There is a good correlation between plasma theophylline level and bronchodilator effect. This can be demonstrated at plasma levels as low as 5 microgram/ml, although optimal levels are usually greater than 10 microgram/ml. Unacceptable toxicity usually occurs in association with plasma levels greater than 20 microgram/ml. The maintenance of adequate plasma theophylline levels by the use of a sustained-release aminophylline tablet is discussed.

Aminophylline↗
PubMed1977

Influence of phenylephrine on levels of cyclic 3',5'-AMP in the heart of rats in vivo.

In the course of an investigation into the mode of action of phenylephrine using the radioimmunoisotope method, its influence on levels of cyclic 3'5'-AMP in the heart of rats was studied. Phenylephrine in the dose of 1 microgram/kg/min after five minutes lowered levels of this nucleotide by about 20%. Phenylephrine also inhibited the influence of theophyline, an inhibitor of phosphodiesterase which raises levels of c-AMP. The results suggest that the drop in c-AMP after phenylephrine is connected with lowered activity of adenyl cyclase, but do not exclude the possiblity of an interaction between theophylline and phenylephrine acting on phosphodiesterase, which could be referred to the observed effect.

Animals↗
PubMed1978

Physiological roles of adenosine derivatives which are released during neurotransmission in mammalian brain.

1. Experiments using synaptosome beds suggested that ATP was released from presynaptic sites and degraded to adenosine in the synaptic cleft and that the resulting adenosine was taken up again into nerve endings where it was re-phosphorylated to ATP. 2. Adenosine derivatives in the synaptic cleft inhibited the postsynaptic potentials in olfactory cortex slices in vitro, presumably by the inhibition of Ca2+ influx into nerve endings which resulted in the reduction of transmitter release. 3. The adenosine derivatives also increased the level of cyclic AMP in the slices under the same conditions as above. 4. Although the nature of the "adenosine receptors" for both functions was remarkably similar, the increase of cyclic AMP did not mediate the inhibitory action, but the presynaptic increase of cyclic AMP induced by adenosine derivatives might mediate the facilitation observed in the olfactory cortex. 5. Possible physiological roles of extracellular adenosine derivatives in mammalian brain were classified, at different sites of action around the synapses, with different time courses and modes of action, directly or via the increase of intracellular cyclic AMP.

Adenine Nucleotides↗
PubMed1976

Mode of action of Vibrio cholerae enterotoxin in cultured adrenal tumor cells.

The effects of Vibrio cholerae enterotoxin on steroidogenesis and on formation of adenosine 3':5'-cyclic phosphate (cyclic AMP) in two adrenal tumor cell lines were compared. Steroidogenesis was half-maximal at concentrations of 1 ng of cholera toxin/ml in the mutant OS-3 cells and 3 ng of cholera toxin/ml in the parent Y-1 cells. At the end of an 8-hr incubation, toxin-induced formation of cyclic AMP in the mutant cell line was reduced by 90%. A molar ratio of GM1 ganglioside (galactosyl-N-acetylgalactosaminyl [sialosyl] lactosyl ceramide; GGnSLC) to cholera toxin of 3:1 caused half-maximal inhibition of steroidogenesis in both cell lines. When equine antiserum to choleragenoid was added to adrenal cells 15 min after cholera toxin, there was marked inhibition of cyclic AMP formation and of steroidogenesis. Pretreatment of Y-1 cells with adrenocorticotropin rendered them unresponsive to hormonal induction of cyclic AMP formation, but these cells had an unimpaired response to cholera toxin. These studies, utilizing two adrenal cell lines, suggest important differences between the mode of action of cholera toxin and that of adrenocorticotropin in cultured adrenal tumor cells.

Adenosine↗
PubMed1979

Induction of alkaline phosphatase in cultured human fibroblasts. Comparison of normal cells and those from patients with cystic fibrosis.

The membrane glycoprotein enzyme, alkaline phosphatase was induced in cultured human fibroblasts by dibutyryl cyclic AMP, sodium butyrate, the serum glycoprotein fetuin, the Tamm-Horsfall urinary glycoprotein, and by a number of inhibitors of DNA synthesis. The uninduced basal enzyme activity increased at later stages of growth when the cells became confluent. Induction by dibutyryl cyclic AMP or fetuin was most effective when the agents were added after the cells had reached stationary phase and was maximal after at least two days of exposure. The levels of induction resulting from the addition of pairs of the agents, dibutyryl cyclic AMP, n-butyrate and fetuin were additive indicating that these have different modes of action. The inhibitors of DNA synthesis, cytosine arabinoside, hydroxyurea, and methothrexate were less effective inducers. Bromodeoxyuridine which also has non-DNA mediated effects induced to the same extent as dibutyryl cyclic AMP. Similar experiments with sex- and age-matched cell strains derived from patients with cystic fibrosis failed to detect differences in the levels of induction from those observed in normal cells. In addition, the combined inductive effects of Tamm-Horsfall glycoprotein, isoproterenol and theophylline, were similar with normal and cystic fibrosis cells.

Alkaline Phosphatase↗
PubMed1976

Maintainance of specificity, information, and thermostability in thermophilic Bacillus sp. glutamine synthetase.

Glutamine synthetase has been purified to homogeneity from B. subtilis (37 degrees) B. stearothermophilus (55 degrees), and B. caldolyticus (75 degrees). Those characteristics compared include size (6.0 +/- 0.3 X 10(5) daltons), quaternary structure (12 SU) amino acid content, substrate Km's and specificity for structural analogs, metal ion activation, number and kind of separate feedback modifier sites, and the complexity of modifier-substrate and modifier-modifier site interactions. Although the 37 degrees and 55 degrees systems are quite similar, the 75 degrees system shows important alterations in substrate specificity and modes of modifier action. Whereas at 37 degrees and 55 degrees AMP inhibits synergistically with amino acids (glycine, glutamine, histidine), the 75 degrees enzyme is inhibited directly by the products ADP, (which assumes the role of AMP) and glutamine, plus other ligands. Ligand binding domains are compared and found to be very different. Thermostabilization occurs by (a) protection by bound L-glutamate, (b) protein aggregation, (c) trends in the content of total polar residues, total Asx + Flx residues, the average hydrophobicity, and (d) disulfide bond cross-linking. Such studies provide insights to molecular evolution occurring with changes in environmental stress.

Adenine Nucleotides↗
PubMed1978

Attempt to demonstrate an in vivo effect of mianserin hydrochloride on erythrocyte Na+-K+-ATPase activity and cyclic AMP concentration.

1. There is evidence that erythrocyte Na+-K+-ATPase activity and erythrocyte cyclic AMP change on recovery from a depressive illness. Mianserin is a recently introduced antidepressant but its mode of action is unknown. The present study was therefore designed to investigate in vivo the effect of mianserin on erythrocyte Na+-K+-ATPase and cyclic AMP. 2. Biochemical estimations were made on blood from depressed patients before beginning either mianserin or matched placebo treatment, after 1 week, and again after 2 weeks' treatment. 3. Neither the erythrocyte Na+-K+-ATPase, nor the erythrocyte cyclic AMP concentration, changed significantly in either the mianserin- or the placebo-treated group. 4. The study sheds no light on the possible mechanism of action of mianserin.

Adenosine Triphosphatases↗
PubMed1977

Elevation of adenosine 3',5'-monophosphate in the perfusate of rat kidney after addition of dopamine.

Dopamine (10-4 M) and vasopressin (1 mU/ml) were found to increase the level of cyclic AMP in the perfusate of rat kidney. There were some differences in the mode of action of these two drugs. Firstly, the effect of dopamine, but not of vasopressin, was completely antagonized by spiroperidol. Secondly, the maximal response was attained within 1 min after dopamine perfusion, but 8 min after vasopressin perfusion. These results suggest that a specific dopamine receptor which acts to increase the concentration of cyclic AMP is located in the vascular tissue of rat kidney.

Animals↗