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)

1. An isolated, buffer-perfused rabbit ear preparation was used to investigate the influence of NG-nitro-L-arginine methyl ester (L-NAME) on endothelium-dependent vasodiltation and modulation of vasoconstrictor responses and vascular conductance. 2. Acetylcholine (0.55 pmol-1.6 nmol) caused dose-related vasodilatation of preparations constricted by the combination of 5-hydroxytryptamine and histamine (both 1 microM), with an ED50 = 31.1 +/- 7.8 pmol and a maximum dilatation of 69.9 +/- 4.3%. In the presence of 10 microM L-NAME the dose-response for vasodilator effects was shifted significantly (P less than 0.001) to the right (ED50 = 3.07 +/- 1.18 nmol) and there was a significant (P less than 0.01) depression of the maximum response (Rmax = 44.3 +/- 4.0%). The higher concentration of 100 microM L-NAME completely abolished vasodilatation to acetylcholine. L-Arginine (10 mM) did not reverse the inhibitory actions of L-NAME at either concentration. 3. L-NAME 100 microM, augmented vascular tone induced by 1 microM 5-hydroxytryptamine and 1 microM histamine, thus altering the characteristics of both pressure/flow and conductance/flow relationships such that conductance was reduced at all flow rates. The augmentation of constrictor tone was reversed in a concentration-dependent manner by L-arginine (10 microM-10 mM) and the effect of L-NAME on the conductance/flow relationships was similarly reversed by 10 mM L-arginine. The augmentation of tone was endothelium-dependent as it did not occur following functional destruction of the endothelium by perfusion of the vascular bed with the detergent CHAPS (0.3%) for 150s. 4. In conclusion, L-NAME is a potent inhibitor of agonist-induced endothelium-dependent vasodilatation. L-NAME reduces vascular conductance in pharmacologically constricted preparations and this emphasizes the important role of EDRF in vascular regulation. The ability of L-arginine to reverse L-NAME-induced inhibition of basal EDRF activity but not L-NAME-induced inhibition of agonistinduced endothelium-dependent relaxations suggests that there is pharmacological heterogeneity in the mechanisms responsible for the conversion of L-arginine to EDRF.
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PMID:Differential effects of L-arginine on the inhibition by NG-nitro-L-arginine methyl ester of basal and agonist-stimulated EDRF activity. 179 35

Despite continuous exposure to gut-derived endotoxin (lipopolysaccharide) under normal conditions, Kupffer cells (KC) fail to generate detrimental cytokine responses. KC function within a unique microenvironment in which high hepatic arginase activities (25 times greater than those activities in the kidney) result in negligible local L-arginine levels. To evaluate the relevance of this profound arginine deficiency on the physiologic function of KC, the kinetics of tumor necrosis factor (TNF-alpha) production and autoregulatory eicosanoid prostaglandin E2 (PGE2) production were compared in lipopolysaccharide-stimulated KC cultured with (1200 mumol/L) and without (10 mumol/L) L-arginine media. In (+)arginine culture the KC TNF-alpha production peaked early before decreasing as PGE2 production increased. In (-)arginine culture, however, KC TNF-alpha production was significantly (p less than 0.01) reduced, whereas PGE2 production was amplified (p less than 0.01). When cyclooxygenase blockade with indomethacin completely prevented KC production of PGE2 in (-)arginine culture, TNF-alpha production was upregulated (p less than 0.001 vs (-)arginine; p not significant vs (+)arginine). These arginine-specific depression of TNF-alpha responses appeared unique to KC because both TNF-alpha and PGE2 levels increased when peritoneal, pleural, and alveolar macrophages were stimulated by lipopolysaccharide in (-)arginine medium. This PGE2-dependent autoregulation of potentially harmful lipopolysaccharide-induced TNF-alpha responses may reflect an evolutionary adaptation by KC to their local hepatic environment and strategic anatomic position in the portal circuit, which optimally removes endotoxin and naturally protects the host.
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PMID:A biologic basis for limited Kupffer cell reactivity to portal-derived endotoxin. 185 31

NG-monomethyl-L-arginine (NMA) and NG-nitro-L-arginine (NNA), both of which are inhibitors of nitric oxide (endothelium-derived relaxing factor, EDRF) production from L-arginine, have been shown to be pressor agents in vivo. This study compared the cardiac and vascular responses to intraaortic administration of NMA and NNA in anesthetized dogs. NMA at doses of 3, 10, 30 and 100 mg kg-1 i.a. increased systemic vascular resistance and decreased cardiac output; mean arterial pressure increased by 10 mm Hg (at 100 mg kg-1 dose). Heart rate did not change. NNA, administered at doses of 1, 3, 10 and 30 mg kg-1 i.a. produced similar cardiovascular actions and was equipotent to NMA. Pretreatment with indomethacin abolished the pressor response to NMA; however, systemic vasoconstriction and cardiac depression still occurred. Increasing mean arterial pressure by phenylephrine infusion to levels much greater than produced by NMA and NNA caused only small reductions in cardiac output. NMA did not reduce coronary blood flow, but instead caused a transient flow increase. Therefore, systemic administration of NMA and NNA result in pronounced systemic vasoconstriction and cardiac depression with only a small pressor response in anesthetized dogs. The cardiac depression did not result from elevated arterial pressure nor was it due to coronary vasoconstriction and reduced myocardial oxygen supply/demand ratio.
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PMID:Cardiovascular actions of inhibitors of endothelium-derived relaxing factor (nitric oxide) formation/release in anesthetized dogs. 189 27

It was demonstrated in experiments on male Wistar rats that preliminary use of a perfusion liquid containing the synthetic tripeptide Tyr-Pro-Arg facilitates restoration of the indices of the function of isolated perfused hearts (IPH) of rats after stress caused by 30-minute total ischemia (TI) of the myocardium at 37 degrees C. Irreversible damages to the myocardium and total depression of its function were recorded in the controls in this period of TI. The optimal concentration of the preparation in the perfusion fluid providing for restoration of IPH function by 80-100% of the initial level is 3.10(-9) M. The protective effect of the preparation is preserved in preliminary (30 minutes prior to TI) intraintestinal and intragastric administration of 10 micrograms/kg. Administration of Tyr-Pro-Arg separately or together with the beta-blocking agent propranolol as well as with atropine, which blocks the vagus effect, revealed their concurrent relations at the level of the adrenergic receptors. It is concluded that the cardioprotective effect of Tyr-Pro-Arg in TI stress is determined to a great measure by its inhibiting effect on the adrenergic mechanisms of cardiac activity regulation. Experiments in which the Ca2+ concentration in the perfusion fluid was increased threefold before and after TI showed that after using Tyr-Pro-Arg the IPH function after TI was restored and stimulated sharply by the increased Ca2+ concentration, in contrast to the controls in which stimulation of cardiac activity before TI increased the ischemic damage to the myocardium.
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PMID:[The cardioprotective effect of a new Soviet synthetic analog of the endogenous opioids in stress due to total myocardial ischemia and its mechanisms]. 238 41

The anterodorsal part of the third ventricle of conscious ducks was perfused intracerebroventricularly (icv) for 10 min with norepinephrine (NE) or with its agonists phenylephrine (alpha 1, Phe), isoproterenol (beta, Iso), and clonidine (alpha 2, Clo) in artificial CSF (aCSF). Their effects on the plasma level of antidiuretic hormone (AVT, arginine vasotocin in birds), urine excretion, heart rate (HR), and mean arterial pressure (MAP) were investigated in steady-state water diuresis. The correct position of the icv cannula was confirmed by enhanced AVT release and antidiuresis in response to icv perfusion of aCSF made hypertonic (400 mosmol/kgH2O) by adding NaCl. Icv perfusion with hypertonic aCSF and 750 ng/min NE had comparable effects on AVT release and urine excretion, but hypertonic aCSF caused small increases in MAP and HR, whereas NE depressed both MAP and HR. Antidiuresis and circulatory depression caused by NE icv perfusion was dose dependent. Among the adrenergic agonists perfused at similar doses (188 ng/min), only Iso stimulated AVT release. Iso and Phe had small depressive effects on MAP and HR (less than 10%). Clo depressed circulation by greater than 20% for longer than 60 min, and AVT release became significantly reduced 30 min after the start of icv perfusion. The consistent results in ducks contrast with the equivocal data hitherto reported for central stimulations with NE or its agonists in mammals and may be due to the concentric perfusion system used in our study for localized stimulations in the vicinity of the paraventricular nucleus.
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PMID:ADH, renal, and circulatory responses to adrenergic stimulation in anterior third ventricle. 238 40

Tuftsin (Thr-Lys-Pro-Arg) is part of the Fc fragment of a leukophilic IgG and is a stimulator of the phagocytic activity of macrophages and polymorphonuclear cells (PMN) when cleaved from its carrier molecule. Tuftsin was shown to stimulate in vitro all PMN and macrophage functions examined through binding to specific cell surface receptors. In the present work, we provide further evidence that synthetic tuftsin administered to mice may act as an immunomodulator and that its effects on immune functions may result from a primary action on macrophages. After i.v. injection at a dosage of 25 micrograms/mouse, tuftsin stimulated effector (phagocytosis) and regulatory (IL1 production) functions of macrophages and potentiated DTH reaction. Lymphocyte functions (proliferative response to mitogens, T cell-mediated cytotoxicity, IL2 and gamma IFN production) were depressed at times at which macrophage activities were maximally enhanced, suggesting that negative regulatory functions of these latter cells were also stimulated. Tuftsin analogues were synthetized representing substitution or derivatization of the threonyl residue. The relative potencies of these analogues in augmenting phagocytosis-induced chemiluminescence of macrophages were tuftsin greater than or equal to (Gly1)-tuftsin greater than for-tuftsin greater than (for-Met1)-tuftsin greater than (Met1)-tuftsin. Concerning potentiation of DTH reaction the order was (Gly1)-tuftsin greater than or equal to (for-Met1)tuftsin greater than tuftsin greater than (Met1)-tuftsin greater than for-tuftsin. In contrast to tuftsin, none of the analogues induced depression of spleen cell reactivity to mitogens. In addition, (for Met1)-tuftsin administration resulted in an increased production of IL2 and IFN by ConA-stimulated spleen cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo immunopharmacological properties of tuftsin (Thr-Lys-Pro-Arg) and some analogues. 242 22

Concentrations of several large neutral amino acids (LNAA) were earlier shown to be low, especially in brain, in rats fed a low protein diet containing a mixture of LNAA analogues. The purpose of this study was to learn if individual analogues would induce similar effects. Four hours after first feeding one meal containing norleucine, norvaline, alpha-aminophenylacetic acid, or alpha-aminooctanoic acid, concentrations of branched-chain amino acids were low in plasma, brain, liver and muscle; tyrosine and phenylalanine were more effectively reduced in brain than in other tissues. Lysine and arginine concentrations were low in brains of rats fed the basic amino acid analogue, homoarginine; concentrations of large and small neutral amino acids were unchanged. Dopamine was not low in brains having low tyrosine levels; serotonin was low in rats receiving alpha-aminooctanoate, the only analogue associated with a significant depression in brain tryptophan. The results suggest that the analogues have differing abilities to alter concentrations of tissue components. Decreases, especially in brain amino acid concentrations, may result from selective competition by analogues of a given transport class with natural amino acids transported from blood into brain by the same system.
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PMID:Tissue amino acids in rats fed norleucine, norvaline, homoarginine or other amino acid analogues. 242 57

1. Actions of the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2) and its derivative YGG-FMRFamide (Tyr-Gly-Gly-Phe-Met-Arg-Phe-NH2) on Ca2+ current were examined in identified, voltage-clamped neurones in the abdominal ganglion of Aplysia californica. 2. 'Puffed' application of either peptide at concentrations of 1-50 microM was followed by a transient partial suppression of pharmacologically isolated inward Ca2+ current elicited by a depolarizing step. At 20 degrees C, suppression was maximal 10-25 s following the brief puff of peptide, and lasted up to 90 s. Bath application of peptide had a steady suppressing effect, showing little if any desensitization. 3. Alternative sources of inward current suppression were ruled out, indicating that application of FMRFamide or YGG-FMRFamide produces a true decrease in Ca2+ current, rather than enhancement of possible contaminating outward (K+, H+ or Cl-) currents. 4. FMRFamide and YGG-FMRFamide were equally effective in suppressing Ca2+ current (apparent dissociation constant, KD* approximately 10 microM). However, only 30-50% of the total Ca2+ current elicited by voltage steps to above +10 mV appeared to be susceptible to suppression by even saturating concentrations of peptide. This, as well as a reduced effect of the peptides on Ca2+ current which was observed at potentials below +10 mV, may perhaps result from the presence of more than one class of Ca2+ channels, only one of which is sensitive to FMRFamide. 5. FMRFamide eliminated a constant fraction of Ca2+ current at all potentials above +10 mV, and had no direct effect on activation or inactivation of the remaining current. This behaviour is consistent with reduction in the number of functional Ca2+ channels by the peptide. 6. Suppression of Ca2+ current produced a concomitant depression of Ca2+-dependent K+ current, which was shown previously to be insensitive to FMRFamide when activated by direct ionophoretic injection of Ca2+ into the cell. 7. The effect of FMRFamide on Ca2+ current was normal following interference with or activation of known second-messenger systems, those involving adenosine 3',5'-cyclic monophosphate (cyclic AMP), cyclic GMP, Ca2+, inositol trisphosphate and protein kinase C. 8. Suppression of Ca2+ current by FMRFamide appeared to be mediated by the same receptor as enhancement by the peptide of K+ current resembling IK(S) (K+ current suppressed by serotonin), an effect seen in most of the same cells. Both effects of FMRFamide were mimicked by injection of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) into the cell, suggesting that the peptide may exert its effects by activating a guanosine 5'-triphosphate (GTP)-binding protein
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PMID:Suppression of calcium current by an endogenous neuropeptide in neurones of Aplysia californica. 244 95

Using isolated polypeptides of the F0 sector of bovine heart mitochondrial H+-ATPase, antisera were developed detecting specifically two components of F0. These two components were identified as F0I and oligomycin-sensitivity-conferring protein (OSCP) respectively. Both F0I and OSCP were digested by mild trypsin treatment of submitochondrial particles depleted of the catalytic part of H+-ATPase (USMP). Proteolysis was largely prevented by binding of F1 to F0. Proteolysis of F0I resulted in the formation of three immunoreactive, membrane-bound fragments of apparently 26 kDa, 25.5 kDa and 18 kDa, respectively, indicating that F0I contains trypsin-accessible Arg or Lys residues located close to the end and the middle part of the protein, respectively, which are in intimate contact with F1. Digestion of USMP with trypsin resulted in depression of passive H+ conduction through F0 which could be ascribed to proteolysis of F0I.
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PMID:Topological and functional characterization of the F0I subunit of the membrane moiety of the mitochondrial H+-ATP synthase. 289 6

We have examined the sites phosphorylated on acetyl-CoA carboxylase by three protein kinases which have been shown to inactivate the enzyme, i.e. cyclic-AMP-dependent protein kinase, acetyl-CoA carboxylase kinase-2 (ACK2, purified from rat mammary gland) and the AMP-activated protein kinase (formerly called acetyl-CoA carboxylase kinase-3, purified from rat liver). Each protein kinase phosphorylates two out of three sites (termed 1-3) which have been established by amino acid sequencing. The two sites phosphorylated by each kinase can be recovered on separate peptides, TC1 and TC2, derived by combined digestion of the native enzyme by trypsin and chymotrypsin: TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site. ACK2 phosphorylates site 1 and, more slowly, an unidentified site(s) within TC1. We have also established the structures of the single major phosphopeptides (T1 and C1 respectively) which are recovered by HPLC after acetyl-CoA carboxylase phosphorylated by cyclic-AMP-dependent protein kinase is digested with trypsin or chymotrypsin alone. T1 is related to TC1, and has the structure: Ser-Ser(P)-Met-Ser-Gly-Leu-His-Leu-Val-Lys. C1 is identical with TC2. We have carried out studies on the correlation of the activity of acetyl-CoA carboxylase with the occupancy of sites 1, 2 and 3 during phosphorylation by each of the three protein kinases. The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2. Our results emphasize that amino acid sequence information is essential in the unequivocal interpretation of data from phosphopeptide mapping experiments and allow a more complete interpretation of previous data on phosphorylation of acetyl-CoA carboxylase in intact cells. They also open the way to experiments which could establish the physiological roles of these protein kinases in the control of fatty acid synthesis.
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PMID:Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. 290 Jan 38


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