UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hemodynamic, anti-ischemic, metabolic, and neurohumoral effects of the phosphodiesterase inhibitor enoximone were investigated in 17 patients (mean age 58 +/- 2 years) with coronary heart disease as established by coronary angiography and positive exercise tests after i.v. application of 0.75 mg/kg body weight. Whereas administration of enoximone resulted in a significant increase in heart rate from 75 +/- 17 to 83 +/- 14 per minute (p less than 0.01), exercise heart rate, blood pressure and myocardial oxygen consumption did not change significantly (p greater than 0.05). At rest, enoximone led to a significant decrease of mean right atrial pressure from 5.7 +/- 2.3 to 3.8 +/- 1.2 mm Hg (p less than 0.01). During exercise there was a significant fall in pulmonary pressure (PAm from 40 +/- 7 to 24 +/- 7 mm Hg, p less than 0.001; PCm from 24 +/- 7 to 14 +/- 6 mm Hg, p less than 0.001) caused by preload reduction and concomitant inotropic increase; there was also a significant rise in cardiac output from 12.7 +/- 5 to 13.8 +/- 5 mm Hg (p less than 0.01) and a decrease of ST-segment depression from 1.97 +/- 0.76 to 0.53 +/- 0.51 mm (p less than 0.001). With improved peripheral and probably coronary blood flow, a concomitant decrease of the metabolic ischemic markers was detected during exercise (potassium 4.44 +/- 0.29 vs. 4.31 +/- 0.30 mval, p less than 0.05; lactate 19 +/- 9 vs. 18 +/- 7 mg/dl; pH 7.28 +/- 0.27 vs. 7.36 +/- 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hemodynamic, anti-ischemic, metabolic and neurohumoral effects of enoximone (MDL 17,043) in patients with coronary disease]. 297 29

This study evaluated the effect of prostaglandin I2 (PGI2) on fibronectin-mediated macrophage phagocytosis in vivo and in vitro. Phagocytosis measured in vivo in rats by the vascular clearance rate and hepatic localization gelatinized sheep erythrocytes was inhibited in a dose-dependent manner after intravenous administration of PGI2. Phagocytosis was assessed in vitro in terms of uptake of fibronectin-dependent gelatinized sheep erythrocytes by monolayers of casein-elicited rat peritoneal macrophages. Concentrations of 1 ng/ml PGI2 or greater resulted in inhibition of particle internalization but not attachment to macrophages. This inhibitory effect was enhanced by aminophylline, a phosphodiesterase inhibitor. PGI2 increased cAMP levels and these were further increased in the presence of aminophylline. These data indicate that PGI2 inhibits macrophage uptake of gelatinized particles and support the idea that this is mediated by increased intracellular levels of cyclic AMP. PGI2 should thus be considered a potential etiologic factor in the phagocytic depression observed in association with thrombosis.
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PMID:Influence of prostaglandin I2 on fibronectin-mediated phagocytosis in vivo and in vitro. 298 44

We have investigated the type of purine receptor in the guinea-pig olfactory cortex, using pial surfaces slices maintained in vitro. Adenosine (0.1 to 100 mumol/l) bath applied in the presence of the uptake inhibitor nitrobenzylthioinosine, depressed the evoked potentials in a dose related fashion. Synthetic and uptake resistant adenosine analogues had the same effect as adenosine and the order of potency of these was: 5'-N-ethylcarboxamide adenosine greater than L-N6-phenylisopropyl adenosine (L-PIA) = N6-cyclohexyladenosine = 2-chloroadenosine greater than adenosine greater than D-N6-phenylisopropyladenosine (D-PIA). The D-stereoisomer of PIA was 45 times less potent than L-PIA. The methylxanthine compounds 8-phenyltheophylline (3 mumol/l) and 3-isobutyl-1-methylxanthine (50 mumol/l) antagonised the depression produced by L-PIA. Rolipram, a phosphodiesterase inhibitor, in concentrations up to 100 mumol/l had no effect on the evoked potentials or on adenosine action. Forskolin, a cAMP stimulant, slightly increased the amplitude of the evoked potential, and partly reversed the depressant effect of adenosine. Noradrenaline had no effect either alone or in the presence of adenosine. The results of these experiments indicate the existence of A1 subtype adenosine receptors in the guinea pig olfactory cortex probably linked to a depression of intracellular cAMP.
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PMID:Adenosine-induced depression of synaptic transmission in the isolated olfactory cortex: receptor identification. 298 40

With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. 298 81

Continued exposure of many beta-adrenoceptor-coupled adenylate cyclase systems to high doses of agonist causes diminished responsiveness, a phenomenon called desensitization. After exposure of isolated guinea pig tracheae to a high concentration of isoproterenol for 30 min, relaxation produced by subsequent challenge by a lower concentration was attenuated, as expected. However, potentiation of isoproterenol-induced relaxation by aminophylline was greater after desensitization as compared to that prior to desensitization. This observation was further investigated using a graphical method that allows quantitative and statistical evaluation of combinations of synergistically acting drugs. Concentration-relaxation curves (CRC) for isoproterenol alone and in the presence of a fixed concentration of aminophylline were determined in isolated rat trachea. A theoretical additive curve was constructed from the data obtained, and the displacement of the isoproterenol CRC from the theoretical additive curve caused by aminophylline in tracheae desensitized by 2.5 hr of exposure to 2 X 10(-5) M isoproterenol (DESN) was compared to that in tracheae equilibrated for a similar period in physiologic salt solution (CON). Desensitization had no significant effect on aminophylline-induced relaxation but caused a marked depression and right-shift of the isoproterenol CRC. In the CON group aminophylline shifted the isoproterenol CRC upward and to the left indicating that the synergistic interaction between the two agents was greater than additive. The left-shift and elevation of the ceiling effect of the isoproterenol CRC caused by aminophylline were significantly greater in the DESN group vs the CON group. These observations from intact tissue are compared with published data from biochemical and broken cell studies. The possibility of increased phosphodiesterase activity as an explanation for the observations reported is discussed.
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PMID:Potentiation of isoproterenol-induced relaxation of isolated trachea by aminophylline: modulation by desensitization. 361 5

The metabolism of adenosine 3',5'-monophosphate (cyclic AMP) was studied in specific pathogen-free mice exposed to neonatal infection with mouse enterovirus or to malnutrition during early life. Metabolic activity was determined by measuring the turnover of cyclic AMP-8-(14)C to respiratory (14)CO(2), its incorporation into various organs and plasma, and the binding activity of synaptosome for cyclic AMP. Early malnutrition increased the catabolism of cyclic AMP as measured by expiration in respiratory CO(2). The level of cyclic AMP was lower in plasma and its incorporation into various tissues was decreased in infected and malnourished animals. Metabolic products of cyclic AMP were isolated from plasma by ion exchange chromatography. Cyclic AMP-8-(14)C had completely disappeared 9 hr after injection. Fewer metabolites of cyclic AMP were detected in infected or malnourished groups than in controls and the metabolic reaction from 5'-AMP to adenosine seemed to be slow in these animals. The ability to incorporate cyclic AMP to synaptosome was also impaired in the experimental groups. The concentrations of brain cyclic AMP were lower in infected or malnourished animals than in controls. Depression of accumulation of cyclic AMP probably resulted from excessive activity of phosphodiesterase, rather than from impairment of adenyl cyclase. Intraperitoneal administration of theophylline brought the activity level of phosphodiesterase to normal in infected or malnourished mice; this fact probably accounted for enhanced accumulation of brain cyclic AMP.
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PMID:Lasting biological effects of early environmental influences. VII. Metabolism of adenosine in mice exposed to early environmental stress. 433 97

A variety of chemical and electrophysiological evidence indicates that the onset of afterdischarge and the subsequent profound enhancement of spike broadening that occur in the bag cell neurons of Aplysia are related to an increase in adenosine 3',5'-monophosphate-(cAMP) dependent protein phosphorylation. We have now used a two-electrode voltage clamp to study the properties of isolated bag cell neurons in cell culture and their response to 8 benzylthio-cAMP (8BTcAMP) and N6-n-butyl 8BTcAMP. These membrane-permeant and phosphodiesterase-resistant cAMP analogs induce spontaneous discharge and spike broadening in both the intact bag cell cluster and isolated bag cell neurons in cell culture. The dominant inward current in these cultured cells was found to be the calcium current, Ica, which was abolished by Co2+ (20 mM) or Ni2+ (10 mM) and could be observed in Na+-free media. In a minority of cells (2 of 12), in normal ionic media, a transient inward current was observed that was unaffected by Co2+ and Ni2+ and probably represents a sodium current. The three characterized potassium currents, the delayed rectifying current IK, the calcium-dependent current IC, and the early transient current IA, distinguished by their differing pharmacological and voltage-activation properties, were present in all healthy cells. Three effects of the cyclic AMP analogs (0.5 mM) on the electrical properties of these cells were 1) the emergence of a region of negative slope resistance in the steady-state I-V relations, 2) a depression of the net sustained outward currents due to depolarizing commands, and 3) a marked reduction in IA. When outward currents had been largely suppressed using high concentrations of tetraethylammonium (TEA) ions (100-460 mM) no effects of the cyclic AMP analogs could be observed on peak inward currents using NA+ and Ca2+ or Ba2+ as carriers of inward current. At least part of these electrical effects of the cyclic AMP analogs could be accounted for by a depression of a delayed potassium current and the A current.
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PMID:A voltage-clamp analysis of currents underlying cyclic AMP-induced membrane modulation in isolated peptidergic neurons of Aplysia. 609 Jun 5

The acetylcholine (ACh) stores of cholinergic neurons of the myenteric plexus of guinea-pig ileum were labelled by preincubation with 3H-(methyl)-choline. The secretion of labelled transmitter evoked by electrical field stimulation at 1 Hz in the presence of eserine increased by 55% after addition of 0.5 mM 8-Br adenosine 3', 5'-cyclic monophosphate (8-Br cAMP). Atropine further enhanced the secretory response, but not more than in the absence of 8-Br cAMP. 8-Br guanosine 3', 5'-cyclic monophosphate (8-Br cGMP, 0.5 mM) did not change the secretory response to 0.5 or 1 Hz stimulation, either at 1.8 mM or at 0.6 mM calcium, in the absence of eserine. Nor did 1 mM 8-Br cGMP alter the effects of atropine or of oxotremorine. Activation of guanylate cyclase by 0.1 mM N-methyl-N'-nit-ro-N-nitroso guanidine failed to alter the secretory response to 0.5 Hz stimulation in the absence of eserine, or to influence the depression of the secretion caused by oxotremorine. The phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (a mM) neither altered the secretory response in the presence of eserine, nor the enhancing effect of atropine. The results suggest that cyclic nucleotides are probably not critically involved as "second messengers" in the muscarinic "autoinhibition" of ACh secretion from cholinergic myenteric neurons of guinea-pig ileum.
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PMID:Secretion of 3H-acetylcholine from guinea-pig ileum myenteric plexus is enhanced by 8-Br adenosine 3', 5'-cyclic monophosphate but not changed by 8-Br guanosine 3', 5'-cyclic monophosphate. 618 55

1 Excitatory junction potentials (e.j.ps) were recorded with intracellular microelectrodes from smooth muscle cells of the mouse isolated vas deferens. The amplitude of the e.j.p. was used as a measure of transmitter release evoked by applying single pulse stimuli to the intramural nerves. 2 Cyclic adenosine 3',5'-monophosphate (cyclic AMP) and dibutyryl cyclic AMP (db cyclic AMP, up to 1 mM) depressed the amplitude of e.j.ps, probably by interacting with extracellular sites on the nerve terminals, similar to those responsive to adenosine. 3 The phosphodiesterase inhibitors, 1-methyl-3-isobutyl xanthine (IBMX) and 1-ethyl-4-hydrazino-1H-pyrazolo(3,4-b)pyridine-5-carboxylic acid, ethylester, hydrochloride (SQ20,006) increased e.j.p. amplitude; this increase was much greater when the phosphodiesterase inhibitor was applied together with db cyclic AMP. 4 Neither the cyclic nucleotides nor the phosphodiesterase inhibitors altered the resting membrane potential of smooth muscle cells. 5 The amplitude of the e.j.p. was depressed by normorphine, D-Ala2-Met5-enkephalinamide (DAEA) and D-Ala2-D-Leu5-enkephalin (DADL) with respective EC50s of 560 nM, 49 nM and 510 pM. 6 There was no change in the EC50 for normorphine in the presence of cyclic AMP (1 mM) or in the presence of a combination of IBMX (50 microM) and db cyclic AMP (500 microM). Similarly, the depression of the e.j.p. by DAEA or DADL was not affected by the combination IBMX (500 microM) and db cyclic AMP (250 microM). 7 These findings provide evidence against the hypothesis that a reduction in cyclic AMP levels in nerve terminals is an essential step in the inhibition by opiates and opioid peptides of transmitter release.
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PMID:A study of the role of cyclic adenosine 3',5'-monophosphate in the depression by opiates and opioid peptides of excitatory junction potentials in the mouse vas deferens. 625 91

1. Cyclic AMP levels have been determined in the soleus muscles of anaesthetized cats in the absence of drugs, and during depression of incomplete tetanic contractions produced by (-)-isoprenaline, ICI 63,197 (a phosphodiesterase inhibitor) or levodopa. 2. Cyclic AMP levels were elevated at the peak of tension depression produced by isoprenaline. Effects of isoprenaline on cyclic AMP and on contractions were dose dependent and statistically significantly related one to the other. Both effects were blocked by propranolol. 3. ICI 63,197 and levodopa produced isoprenaline-like effects on contractions but times to peak effect and recovery were longer. Cyclic AMP levels estimated during the depressant action were elevated. 4. The results support the involvement of cyclic AMP in the depressant effect of beta-adrenoreceptor agonists on slow-contracting mammalian skeletal muscle.
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PMID:Effects of isoprenaline, levodopa and a phosphodiesterase inhibitor (ICI 63,197) on cyclic AMP levels and contractions of soleus muscles in anesthetized cats. 625 31

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