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)

To elucidate the molecular mechanism underlying the adverse depression of myocardial contractility observed during antiarrhythmic therapy of quinidine, we investigated its action on the phosphatidylethanolamine N-methyltransferase (EC 2.1.1.17) activities of cardiac subcellular membranes. Rat heart sarcolemma, mitochondria, and microsomes (sarcoplasmic reticular fragments) were isolated, and the three catalytic sites for N-methylation activities were examined with 0.055 (site I), 10 (site II), and 150 (site III) microM concentrations of S-adenosyl-L-[methyl-3H]methionine as a methyl donor. Total methyl group incorporation into sarcolemmal phosphatidylethanolamine was depressed by 10(-6)-10(-3) M quinidine at sites II and III. The activity of site I was stimulated at low (10(-9) M) concentrations and inhibited at high concentrations of the drug. A similar behaviour was observed with procainamide, although the inhibitory effect was less pronounced and was not additive with quinidine. Quinidine-induced inhibition was associated with a depression of Vmax, while the apparent affinity for S-adenosyl-L-methionine was unaltered. Analysis of individual methylated phospholipids confirmed inhibition by quinidine at sites II and III in sarcolemma. Microsomal phosphatidylethanolamine N-methylation was affected by 10(-6) M quinidine only at site II, whereas no changes were noted in mitochondria. Quinidine also inhibited both the positive inotropic response and concomitant increase in tissue N-methylated phospholipids observed upon L-methionine perfusion of rat heart. These results suggest that quinidine alters the intramembranal level of N-methylated phospholipids, and this may serve as a biochemical mechanism contributing to its negative inotropic effect.
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PMID:Alterations of phosphatidylethanolamine N-methylation in rat heart by quinidine. 248 Nov 91

Mechanism of methylmercury cytotoxicity was investigated with special reference to its preferential action on microtubules and protein biosynthesis in cultured cells. The tubulin synthesis analyzed by autoradiography of two-dimensional electropherogram using 35S-methionine was inhibited by 50-70% in mouse glioma cells exposed to 5 x 10(-6) M methylmercury for 3 h, which almost completely depolymerized microtubules. Total protein synthesis monitored by incorporation of labeled methionine into acid insoluble fraction was decreased slightly but significantly and the protein bands other than tubulin on gradient urea-PAGE gel appeared to remain unchanged under the experimental condition used. These results suggest that the inhibition of protein synthesis observed on exposure to methylmercury can be ascribed, at least partly, to a possible autoregulatory depression in tubulin synthesis owing to the increase in the pool of tubulin subunits resulted from microtubule depolymerization by methylmercury.
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PMID:Mechanism of cytotoxicity of methylmercury. With special reference to microtubule disruption. 248 6

Two experiments were conducted using corn from clean or aflatoxin B1 (AFB1)-contaminated (182 ppb) sources. Weanling pigs (28 d) were fed one of eight dietary treatments arranged in a 2 x 2 x 2 factorial design. In Exp. 1 (192 pigs), treatments varied in corn source (clean or AFB1-contaminated), CP level (18 or 20%) and added fat (0 or 5%). At the end of the 28-d growth trials, plasma samples were obtained. An AFB1 x CP level interaction was detected (P less than .05) for growth rate (ADG), feed intake (FI) and feed/gain ratio (F/G). Feeding AFB1 reduced (P less than .05) ADG (.30 vs .37 kg/d) and FI (.57 vs .66 kg/d) and increased F/G (1.88 vs 1.78) of pigs fed 18% CP diets. Performance of pigs fed 20% CP diets was not altered by AFB1. Adding 5% fat to diets improved (P less than .05) F/G but did not improve ADG of pigs fed AFB1. There was an AFB1 x CP x fat interaction (P less than .05) for plasma cholesterol. Adding fat or increasing the CP level prevented the depression of plasma cholesterol in pigs fed AFB1. In Exp. 2 (96 pigs), all diets contained 18% CP and the treatments varied in corn source (clean or AFB1-contaminated), added L-lysine HCl (0 or .25%) and added DL-methionine (0 or .15%). Feeding AFB1 reduced (P less than .05) ADG of pigs fed the 18% CP diet (.44 vs .50 kg/d) but not of pigs fed diets supplemented with .25% lysine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of dietary protein, fat or amino acids on the response of weanling swine to aflatoxin B1. 249 62

The effects of methyl-group acceptors such as glycine, guanidinoacetic acid, and nicotinamide on cholesterol metabolism and phosphatidylcholine(PC) biosynthesis were investigated with rats fed a 25% casein diet containing cholesterol with or without methionine supplement. The effect of ethanolamine, an indirect methyl-group acceptor via phosphatidylethanolamine(PE) formation, was also compared with those of methyl-group acceptors. The methyl-group acceptors and ethanolamine decreased or tended to decrease plasma total cholesterol level when added to the 25% casein diet. These compounds also significantly depressed the methionine-induced enhancement of plasma cholesterol level. The activity of PE N-methyltransferase was decreased by the addition of glycine, guanidinoacetic acid, and nicotinamide, but not ethanolamine, to the reaction mixture when assayed using the postmitochondrial fraction of liver homogenate, suggesting that PE N-methyltransferase activity can be depressed by glycine N-methyltransferase, guanidinoacetic acid N-methyltransferase, and nicotinamide N-methyltransferase systems. The PE N-methyltransferase activity in liver microsomes, however, did not decrease in response to the dietary addition of methyl-group acceptors. The in vitro incorporation of [CH3-14C]methionine into PC of liver slices was also significantly inhibited by the addition of glycine and nicotinamide, but not guanidinoacetic acid and ethanolamine, to the incubation medium. It is suggested that methyl-group acceptors can decrease plasma cholesterol level at least in part through the depression of PC biosynthesis via PE N-methylation pathway, and that the mechanism for the plasma cholesterol-lowering effect of ethanolamine is different from that of methyl-group acceptors.
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PMID:Effects of methyl-group acceptors on the regulation of plasma cholesterol level in rats fed high cholesterol diets. 253 19

The endogenous opioids and their receptors are known to play a major role in neoplasia. In the present study, naltrexone (NTX), a potent opioid antagonist, was utilized to explore the interactions of opioids and opioid receptors in mice with transplanted neuroblastoma (S20Y). Tumors from mice subjected to either intermittent (4-6h/day; 0.1 mg/kg NTX) or complete (24 h/day; 10 mg/kg NTX) opioid receptor blockade exhibited an up-regulation of DADLE and Met-enkephalin binding sites, as well as tissue levels of beta-endorphin and Met-enkephalin. Binding affinity to [D-Ala2,D-Leu5]enkephalin (DADLE) or ethylketocyclazocine (EKC), the levels of plasma beta-endorphin, and the anatomical location and quantity of Met- and Leu-enkephalin and cytoskeletal components (i.e. tubulin, actin, brain spectrin (240/235) were similar in NTX and control tumor-bearing animals. Tissue viability of the 0.1 NTX group was increased compared to controls. Both mitotic and labeling indexes were increased during the period of opioid receptor blockade, but decreased in the period subsequent to receptor blockade. NTX treatment produced a 2-fold increased in sensitivity to opioids. Met-enkephalin (10 mg/kg) produced a depression in both mitotic and labeling indexes in tumor-bearing mice that could be reversed by naloxone (10 mg/kg) administration. Thus, the endogenous opioids are trophic agents that inhibit growth by suppressing cell proliferation. The duration of receptor blockade by opioid antagonists modulates these actions, affecting both tumor incidence and survival time. Complete opioid receptor block prevents the interaction of increased levels of putative growth-related peptides with a greater number of opioid receptors, thereby increasing cell proliferation and accelerating tumor growth. With intermittent blockade, an enhanced opioid-receptor interaction occurs during the interval when the opioid antagonist is no longer present, producing an exaggerated inhibitory action on cell proliferation and the repression of tumorigenic events.
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PMID:Opioid antagonist modulation of murine neuroblastoma: a profile of cell proliferation and opioid peptides and receptors. 254 Aug 73

The purpose of this study was to investigate the cardiorespiratory effects of the synthetic Met-enkephalin, D-Ala-2-Me-Phe-4-Met-(0)-ol enkephalin (FK 33-824) after its administration into the anterior hypothalamic area, paraventricular hypothalamic nuclei and third ventricle. Wistar rats, anaesthetised with pentobarbitone and breathing spontaneously, received an injection of FK 33-824, 1 or 2 micrograms into one of these three areas. FK 33-824 produced significant (analysis of variance, p less than 0.05) and sustained hypotension of similar degree following injection into any one of these three sites. Significant (p less than 0.05) reductions in heart rate and respiratory rate were also observed. Hypotension and bradycardia occurred, but to a lesser degree, when respiratory depression was prevented by mechanical ventilation. FK 33-824 produced fatal bradyarrhythmias in spontaneously breathing and mechanically ventilated animals. When respiratory depression was prevented by mechanical ventilation, survival was lowest after third ventricular administration followed by paraventricular and anterior hypothalamic injections. Thus D-Ala-2-Me-Phe-4-Met-(0)-ol enkephalin produced marked vasodepression and respiratory depression in the rat. These effects were interrelated but reductions in heart rate and blood pressure also occurred independently of the respiratory depression.
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PMID:Cardiorespiratory effects of D-Ala-2-Me-Phe-4-Met-(0)-ol enkephalin in the third ventricle, and in anterior hypothalamic and paraventricular areas of the rat brain. 262 Mar 18

The effect of vitamin B12 (B12) deficiency on the levels of S-adenosylmethionine (SAM) in tissues and the activities of hepatic methionine synthase, methionine adenosyltransferase and glycine N-methyltransferase were investigated. The striking depression of methionine synthase activity was observed in all rats fed the B12-deficient diets with or without methionine supplementation for 150 days. The SAM level in liver was decreased by B12 deficiency. However, brain SAM level was not affected. The activities of hepatic methionine adenosyltransferase isozymes, alpha-form and beta-form, were decreased by B12 deficiency. Hepatic glycine N-methyltransferase activity in rats fed the low methionine-B12-deficient diet showed a tendency to lower, although the change the activity was not statistically significant, compared with B12-supplemented rats. It is proposed that the fall in the activity of hepatic methionine adenosyltransferase may be one of the causes of the decreased hepatic SAM level in B12-deficient rats.
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PMID:Effect of vitamin B12 deficiency on S-adenosylmethionine metabolism in rats. 273 12

1. The inhibitory effects of inorganic and organic sulphur-containing compounds, copper and tungsten on nitrate reduction by mixed rumen micro-organisms were investigated in two in vitro studies. 2. Coarsely strained rumen fluid from nitrate-adapted (Expt 1) or non-adapted (Expt 2) Suffolk Down wethers maintained on lucerne (Medicago sativa) cubes was used as an inoculum. In Expt 1, anaerobic incubation was carried out for 24 h for each medium supplemented with 10 mM-sodium nitrate and the following chemicals: 0, 1, 2, 3, 5, 8 and 10 mM-sodium sulphide, 1 and 10 mM-sodium sulphite, 1 and 10 mM-sodium sulphate, 1 and 10 mM-L-cysteine, 1 and 10 mM-DL-methionine, 1 mM-sodium tungstate and 1 mM-copper sulphate. In Expt 2, 1 and 10 mM-Na2S, 1 and 10 mM-L-cysteine, 1 mM-Na2WO4, and 1 mM-CuSO4 were added to incubation media to test for chemical inhibition of microbial reduction of nitrate. 3. In Expt 1, the amount of nitrite formed decreased with increasing concentration of sulphide-S added. The additions of L-cysteine, W and Cu suppressed nitrite formation in media from both nitrate-adapted and non-adapted sheep. 4. In contrast to the effects of sulphide, L-cysteine and W counteracted, to some degree, nitrate-induced reduction of volatile fatty acid (VFA) production. Addition of Cu to the media resulted in a further depression of VFA production.
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PMID:Inhibitory effects of sulphur compounds, copper and tungsten on nitrate reduction by mixed rumen micro-organisms. 275 22

The objective of this study was to predict the prognosis of patients who become symptomatic after having undergone coronary artery bypass grafting (CABG) using clinical and exercise test responses. A retrospective analysis was performed of all veterans referred for clinical indications to a Veterans Administration Medical Center for a treadmill test after having undergone CABG. Of 2,044 patients who were exercise tested from April 1984 to May 1987, 296 had previously undergone CABG. Clinical data considered included age, sex, medication and symptom status, history of myocardial infarction, type of myocardial infarction and time from CABG. The exercise test responses considered were MET level, maximal heart rate, maximal systolic blood pressure, chest pain pattern and ST-segment response. During a 2-year follow-up after exercise testing, there were 15 deaths, 11 nonfatal myocardial infarctions, 6 repeat CABGs and 3 percutaneous transluminal coronary angioplasties. Although MET level and maximal heart rate were significantly related to prognosis and no patient who exceeded 8 METs died, the predictive power of these exercise test responses was low and ST-segment depression was not predictive at all. The inability of the exercise electrocardiogram to predict cardiac events in patients after CABG requires the use of other methods of testing to identify those who need invasive studies and intervention.
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PMID:Use of the exercise test to predict prognosis after coronary artery bypass grafting. 278 26

Cysteine is required for the synthesis of cosubstrates for two pathways of acetaminophen metabolism: 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for sulfation and glutathione (GSH) for detoxification of the reactive metabolite (N-acetyl-p-benzoquinoneimine, NAPQI). Dietary deficiency of cysteine may reduce hepatic production of PAPS and GSH and thereby reduce metabolism of the drug (by sulfation and detoxification of NAPQI) and hence lead to potentiation of acetaminophen liver injury. Conversely, limitation of sulfur-containing amino acids could result in depression of protein synthesis and hepatic cytochrome P450 levels, and hence in decreased reactive metabolite formation and decreased liver injury. To determine whether the potentiating effects exceed the protective effects, rats were fed isocaloric AIN-76 liquid diets containing various levels of methionine as the sole source of sulfur in the diet for 3 weeks prior to administration of acetaminophen. Sulfur deficiency was assessed by measuring urinary inorganic sulfate levels. Sulfur-deficient diets retarded growth but did not affect nitrogen balance. Sulfur-deficient animals had lower basal levels of hepatic GSH. Pharmacokinetic studies revealed that at low doses of acetaminophen (20 mg/kg), animals fed sulfur-deficient diets metabolized the drug more slowly due to a markedly reduced sulfation capacity, whereas at the high dose of acetaminophen (400 mg/kg), rats that were fed sulfur-deficient diets had a higher clearance of the drug than rats that were fed the complete diet. The increase in clearance was due largely to an enhanced glucuronidation capacity and an enhanced P450-dependent oxidation as indicated by mercapturate formation. Histologic studies revealed that rats fed sulfur-deficient diets showed increases in both incidence and severity of acetaminophen hepatic necrosis. Thus, the potentiating effects exceeded the protective effects. These observations raise the possibility that nutritional inadequacy of sulfur-containing amino acids which could occur during protein malnutrition may similarly enhance susceptibility to acetaminophen liver injury in humans.
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PMID:Effects of sulfur-amino acid-deficient diets on acetaminophen metabolism and hepatotoxicity in rats. 281 88


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