Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of combined administration of ethanol (4 g/kg) and chlordiazepoxide (CDP, 12.5 mg/kg) on mouse brain c-AMP and c-GMP levels were investigated in order to test the hypothesis that the supra-additive effect of CDP on ethanol sleep time may be related to a supra-additive alteration in brain cyclic nucleotide levels induced by the combined drugs. Ethanol alone or CDP by itself did not cause any change in brain c-AMP levels, except for a transient decrease in the cerebral cortex and midbrain at 0.5 hr after ethanol injection, as well as a transient increase in the cerebellum at 0.5 hr after CDP injection. The combined drug treatment did not result in a supra-additive effect on c-AMP levels. On the other hand, c-GMP levels were depressed significantly for 4 hr after ethanol injection especially in the cerebellum. The mice regained the righting reflex when the c-GMP levels were still about 30 per cent of control values. Ethanol and CDP together induced a supra-additive decrease of c-GMP concentrations in the cerebellum at 2 and 4 hr. This resulted in a lengthened period (about 2.5 hr) during which the cerebellar c-GMP levels were below 30 per cent of control values, and this interval coincided with the increase in sleep time, suggesting a possible relationship between these two factors. Injection of ethanol and N-demethyl-chlordiazepoxide (NDCDP) simultaneously (the latter being a metabolite of CDP) also elicited a more than additive depression of cerebellar c-GMP levels at 4 hr. These data suggest that NDCDP or its metabolite could be responsible for the supra-additive effect of CDP on the ethanol-induced decrease in cerebellar c-GMP levels.
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PMID:Relationship of brain cyclic nucleotide levels and the interaction of ethanol with chlordiazepoxide. 627 37

All anesthetic agents studied, general and local, that controlled pain sufficiently to permit surgery, produced sharp and prolonged reductions in the output of small and blast lymphocytes into efferent lymph from levels encountered in unanesthetized animals. The depth and duration of the depression in lymphocyte traffic were related to the doses of anesthetic agents and had no relation to the surgical trauma involved. Inflammation from previous recent drainage area surgery, extensive intraoperative manipulation of edematous inflammatory tissue, and postoperative manipulation of inflammatory tissue by distention manipulation with injected fluid were found to exert a strong modulating effect on the anesthesia-associated depression in lymphocyte traffic with the capability of rather quick action in elevating lymphocyte traffic. Rapid infusion of bradykinin and 8-bromo cyclic guanosine monophosphate, both traffic enhancing agents, into cannulated afferent lymphatic vessels of the study nodes during anesthesia-associated depression in traffic also were found to exert a modulating effect with prompt increases in lymphocyte output into the efferent lymph.
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PMID:Anesthesia-associated depression in lymphocyte traffic and its modulation. 632 13

Polymorphonuclear granulocytes play an important role in the immediate unspecific host response, and a depression of their functions can be found in many patients with severe or recurrent infections. Therefore administration of drugs causing such impairment in PMN function may be regarded as an additional risk for negative side effects to the patient. In our report the influence of 13 antibiotics--amphotericin B, ampicillin, tauglicolcillin, amoxicillin, cloxacillin, dicloxacillin, cephaloridine, cefalexin, cefuroxime, chloramphenicol, gentamicin, rifamycin, fosfomycin--on the granulocyte spontaneous and induced migration is investigated under in vitro experimental conditions. Human PMN preincubated with the antibiotics appropriately brought to the desired concentrations (therapeutic dose, 1/10 and 10X) in Hepes-Medium 199-water solution pH 7.2, were washed three times and tested for spontaneous and induced migration under agarose. Our experiments demonstrate that amphotericin B, cefalexin, cephaloridine, cefuroxime, chloramphenicol, dicloxacillin, gentamicin and rifamycin can inhibit in vitro human PMN chemotaxis and/or random migration. Inhibition of intracellular respiratory enzyme synthesis, presence of inactive metabolites of the drug, alterations of cyclic AMP and GMP or of the membrane bound divalent cations can be responsible of the phenomenon.
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PMID:[Influence of antibiotics on leukocyte migration]. 723 61

Nitric oxide (NO), produced by either constitutive or inducible isoforms of NO synthase (cNOS or iNOS), influences myocardial inotropic and chronotropic responses. This pathway has been studied using NO donors or NOS inhibitors or by immune-mediated stimulation of iNOS. Although inhibition of constitutive NO activity in the heart does not influence indices of myocardial contractility, NO donors, in some species and preparations, may exert a negative inotropic effect as well as an enhancement of diastolic relaxation. The best documented cardiac action of NO is inhibition of the positive inotropic and chronotropic responses to beta-adrenergic receptor stimulation. Basal NO production, presumable via cNOS, appears to exert a mild tonic inhibition of beta-adrenergic responses. On the other hand, excessive NO production mediated by iNOS may contribute to the myocardial depression and beta-adrenergic hyporesponsiveness associated with conditions such as sepsis, myocarditis, cardiac transplant rejection, and dilated cardiomyopathy. Muscarinic cholinergic stimulation of the heart appears to stimulate NO production that mediates, at least partially, parasympathetic slowing of heart rate and inhibition of beta-adrenergic contractility. NO-stimulated production of 3',5'-cyclic guanosine monophosphate via guanylyl cyclase accounts for many of the observed physiological actions of NO. 3',5'-Cyclic guanosine monophosphate inhibits the beta-adrenergic-stimulated increase in the slow-inward calcium current and reduces the calcium affinity of the contractile apparatus, actions that could contribute to a negative inotropic effect, an abbreviation of contraction, and an enhancement of diastolic relaxation. Biochemical, immunocytochemical, and molecular biological techniques have been used to show the presence of both cNOS and iNOS within the myocardium. cNOS is expressed in myocytes, endothelial cells, and neurons in the myocardium, and there is evidence for iNOS in myocytes, small vessel endothelium, vascular smooth muscle cells, and immune cells that infiltrate the heart. Taken together, these observations suggest that NO influences normal cardiac physiology and may play an important role in the pathophysiology of certain disease states associated with cardiac dysfunction.
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PMID:Role of nitric oxide in the regulation of myocardial function. 756 4

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returned to the range of untreated animals. The decrease of IMP DH activity (t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1/2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0, 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
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PMID:Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. 790 99

The characteristics of adenosine and inosine outflow evoked by 5 min of ischemia-like conditions in vitro (superfusion with glucose-free Krebs solution gassed with 95% N2/5% CO2) were investigated on rat hippocampal slices. The viability of the slices after "ischemia" was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The evoked dendritic field potentials were abolished after 5 min of superfusion under "ischemia" but a complete recovery occurred after 5 min of reperfusion with normal oxygenated Krebs solution. No recovery took place after 10 min of "ischemia." The addition of the adenosine A1 receptor antagonist 8-phenyltheophylline to the superfusate antagonized the depression of the evoked field potentials caused by 5 min of "ischemia." Five minutes of "ischemia" brought about a six- and fivefold increase in adenosine and inosine outflow, respectively, within 10 min. Tetrodotoxin reduced the outflow of adenosine and inosine by 42 and 33%, respectively, whereas the removal of Ca2+ caused a further increase. The NMDA receptor antagonist D(-)-2-amino-7-phosphonoheptanoic acid and the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione brought about small, not statistically significant decreases of adenosine and inosine outflow. The glutamate uptake inhibitor dihydrokainate did not affect the outflow of adenosine and inosine. Inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP and GMP did not affect basal adenosine outflow but potentiated "ischemia"-evoked adenosine outflow. It is concluded that ischemia-like conditions in vitro evoke a Ca(2+)-independent adenosine and inosine outflow, through a mechanism that partly depends on propagated nervous activity but does not involve excitatory amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Investigations into the adenosine outflow from hippocampal slices evoked by ischemia-like conditions. 851 75

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L-NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis.
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PMID:Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats. 855 31

The probable role of two second messengers, nitrogen oxide (NO) and cyclic guanosine monophosphate (cGMP) in the short- and long-latency effects of the acyclic eicosanoid 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE) on the plasticity of somatic cholinoreceptors of identified RPa3 and LPa3 neurons of Helix lucorum, was investigated using the two-electrode voltage clamp technique on the membrane. It was demonstrated that N omega-methyl-L-arginine (an inhibitor of NO synthase), LY-83,583 [sic], and the dye methylene blue (inhibitors of soluble guanylate cyclase), when applied extracellularly, disrupt the short- and long-latency modulatory influences of 15-HETE on the depression of the inward current induced by acetylcholine during its rhythmic application to the soma. The participation of NO and cGMP in the modulatory effects of 15-HETE on the plasticity of cholinoreceptors is hypothesized.
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PMID:NO synthase and guanylate cyclase inhibitors block modulation of the plasticity of common snail cholinoreceptors by 15-hydroxy-eicosatetraenoic acid. 900 Feb 14

The consequences of becoming tolerant to the analgesic effects of morphine include increased risk of unwanted side effects, such as respiratory depression, because the patient is required to take larger doses of the opioid to get the same relief from pain. Many studies suggest that phosphorylation plays a role in the neuroplasticity associated with opioid tolerance. This study examines the effect of inhibiting cyclic nucleotide-dependent protein kinase activity in the brain or spinal cord of morphine-tolerant mice. KT5720, a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor, or KT5823, a cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor, was centrally administered in morphine-tolerant and placebo-treated mice prior to a systemically administered challenge dose of morphine. KT5720 completely reversed morphine tolerance in the tail-flick assay when the pretreatment was administered intracerebroventricularly (i.c.v.); KT5823 had no effect on morphine via this route. When either of these drugs was administered intrathecally (i.t.), the activity of morphine was greatly diminished in the tolerant animals, with no effect on morphine antinociception in the placebo group. These data suggest that cAMP-dependent protein kinase activity may be upregulated in the brain with morphine tolerance, and that this upregulation is critical to the expression of tolerance to the antinociceptive effects of morphine. In the spinal cord, however, the activity of cyclic nucleotide dependent protein kinases, and possibly their substrate proteins, may be affected by chronic morphine exposure such that inhibition of these kinases produces hyperalgesia.
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PMID:Effects of spinal versus supraspinal administration of cyclic nucleotide-dependent protein kinase inhibitors on morphine tolerance in mice. 903 19

This study examined the effect of N-ethylmaleimide (NEM, 10(-7) M) on agonist-induced contraction and the relaxation following drug-washout, of vascular smooth muscle (VSM) segments derived from hypertensive rabbits. Mean blood pressure increase was produced either by renal constriction plus contralateral nephrectomy, or by cadmium acetate ingestion. Freely-ionized calcium (45Ca)flux, cyclic 3':5'-guanosine monophosphate (cGMP), and cyclic 3':5' adenosine monophosphate (cAMP), were analyzed. NEM was used as a stereoselective probe to clarify the role of sulfhydryl (SH) groups in hypertension. Contractile response to norepinephrine (NE, 5.9 x 10(-7) M), angiotensin II (AT, 9.8 x 10(-8) M), and potassium chloride (KCl, 2.2 x 10(-2) M) were significantly depressed in hypertensive tissue. Exposure to NEM, before agonist challenge, caused an even greater depression in contractile response. As for the normotensive group, an inhibition of relaxation occurred when NEM was added after the development of a maximal contractile response to NE, AT or KCl. Changes in contractile ability and in relaxation were attributed to specific alterations in calcium distribution. These alterations were examined by 45Ca washout components and were related to cAMP and cGMP metabolism. These results suggest a regulatory role of SH groups in contraction and relaxation and a modification of this role in hypertension.
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PMID:Vascular chemical sulfhydryl alkylation in vitro: alterations in intracellular calcium and cAMP and cGMP metabolism. 915 Dec 87


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