UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of hydroperoxides is rapidly increased and remains at 200-280% of the control 1-24 h after the second daily application of 17 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin in vivo. The levels of hydroperoxides are increased 1.63-, 2.64-, 4.07-, and 4.31-fold 18 h after one, two, three, or four applications of TPA at 24-h intervals, respectively. The hydroperoxide response to TPA observed in whole skin reflects almost entirely the increased hydroperoxide-producing activity of the epidermis. Such hydroperoxide responses are triggered to various degrees by the anthrone derivatives and the phorbol esters and diterpene with complete and/or stage 2 tumor-promoting activities but not by the agents with only inflammatory, hyperplastic or stage 1 tumor-promoting activities. However, the Ca2+ ionophores A23187 and ionomycin are potent inducers of hydroperoxide formation. Several discrepancies are observed between the hydroperoxide response to TPA and the known effects of the tumor promoter on ornithine decarboxylase (ODC) induction. In contrast to the refractory state against ODC induction caused by TPA treatments repeated at intervals of less than 48 h, the time interval required for recovery of the hydroperoxide response to TPA in TPA-pretreated skins is only 5 h. The stimulatory effects of A23187, ionomycin and various diacylglycerols (DAGs) on hydroperoxide production do not correlate with their ODC-inducing activities. The increasing susceptibilities of C57BL/6, CF-1, and SEN-CAR mice to skin tumor promotion correlate with their hydroperoxide responses but not with their ODC responses to TPA. alpha-Difluoromethylornithine (DFMO) and other inhibitors of TPA-induced ODC activity fail to alter hydroperoxide production whereas the compounds that inhibit the hydroperoxide response to TPA, such as fluocinolone acetonide, have no or only minimal inhibitory activity against ODC induction. This would suggest that the hydroperoxide response to TPA does not require ODC induction and may not be essential for ODC induction. The hydroperoxide response to TPA is mimicked, but to a lesser degree, by the activator of protein kinase C, 1,2-dioctanoyl-sn-glycerol, and inhibited by verapamil, trifluoperazine, and palmitoylcarnitine. Populations of TPA-treated keratinocytes, therefore, may be responsible not only for ODC activation but also for hydroperoxide production. However, these two responses, which involve, at least in part, Ca2+ mobilization and protein kinase C activation and play important roles in the mechanism of skin tumor promotion, do not appear to be correlated.
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PMID:Characterization of the hydroperoxide response observed in mouse skin treated with tumor promoters in vivo. 250 65

An inbred strain of SENCAR mice was developed that is more sensitive to two-stage skin carcinogenesis protocols than the outbred parental stock. These mice, registered as SSIN/UTSP, were compared to the SENCAR in initiation-promotion protocols using the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 22 weeks at dose levels of 0.5, 1.0 and 2.0 micrograms. With 0.5 microgram of TPA, the number of papillomas in the SSIN was 3-fold higher than in the SEN-CAR; the tumor incidence was 100 versus 60%, respectively. Similar, although less dramatic, results were found with 1.0 and 2.0 micrograms of TPA. In two-step promotion protocols using TPA twice weekly for 2 weeks and 2 micrograms mezerein twice weekly for 15 weeks the SSIN produced approximately 50% more tumors than the SENCAR at 0.5 microgram of TPA. At 2 micrograms of TPA the tumor response between the two mice was not significantly different. Epidermal hyperplasia was considerably greater in the SSIN at 0.5 microgram of TPA as was ornithine decarboxylase activity. These TPA-sensitive inbred mice should be useful in investigations on the biochemical and genetic factors involved in skin tumor promotion.
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PMID:Characterization of an inbred strain of the SENCAR mouse that is highly sensitive to phorbol esters. 354 26

Cerebral ischemia in the gerbil results in early hippocampal changes, which include transient activation and/or translocation of protein kinase C (PKC), increased enzymatic activity of ornithine decarboxylase (ODC), and elevated DNA binding ability of activator protein-1 (AP1). The time-course of all three of these postischemic responses was found to be almost parallel, peaking at 3 hr after the ischemic insult. The effectiveness of known modulators of postischemic morphological outcome (MK-801, L-NAME, and gingkolides BN 52020 and BN 52021) in counteracting the induction of PKC, ODC, and AP1 formation was tested. These drugs were administrated as followed: MK-801 (a noncompetitive inhibitor of NMDA channel), 0.8 mg/kg i.p., 30 min before ischemia, and 5 min after the insult; L-NAME (competitive inhibitor of NO synthase), 10 mg/kg i.p., 30 min before ischemia, and 5 mg/kg, 5 min after ischemia; BN52020 and BN52021 (inhibitors of platelet-activating factor: PAF receptors) were administered as a suspension in 5% ethanol in water by oral route, 10 mg/kg for 3 days before ischemia. Three of these drugs, MK-801, L-NAME, and BN52021, significantly reduced ischemia-elevated activity of PKC and ODC, whereas AP1 formation was only partially attenuated. Our observations implicate the existence of different mechanism(s) for postischemic PKC and ODC activation, which in turn is engaged in AP1 induction.
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PMID:Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. 774 16

Ammonia (NH4OH) generated by urease from urea in the Helicobacter pylori (Hp)-infected stomach is considered as a one of the major pathogenic factors in the Hp-associated gastritis but the mechanism of the deleterious action of NH4OH on gastric mucosa has not been fully explained. In this study, the gastric mucosa was exposed to topical NH4OH in various concentrations (15-250 mM) (series A) and to NH4OH in a small concentration followed by a high concentration (250 mM) of NH4OH (series B) or to the combination of urea and urease to generate NH4OH (series C) followed by 250 mM NH4OH in order to determine the "mild irritant" and protective properties of this substance on the mucosa. Administration of NH4OH alone resulted in a concentration-dependent mucosal damage starting at 30 mM and reaching at 250 mM the degree similar to that obtained with 100% ethanol. The acute mucosal damage by NH4OH was accompanied by the fall in gastric blood flow reaching nadir at 250 mM NH4OH of about 30% of the normal value. When the mucosa was first exposed to low concentration of NH4OH (15 mM) and then insulted with its larger concentration (250 mM), the lesion area was markedly reduced as compared to that obtained with 250 mM NH4OH alone and this effect was accompanied by a significant rise in the GBF. This adaptive cytoprotection by 15 mM NH4OH was reversed, in part, by the pretreatment with indomethacin to inhibit prostaglandins (PG) or L-NAME to suppress nitric oxide (NO) formation or after capsaicin-induced denervation of sensory nerves. Blockade of endogenous sulfhydryls (SH) by N-ethylmaleimide (NEM) eliminated this adaptive cytoprotection but the suppression of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, by alpha-difluoro methylornithine (DFMO) failed to influence the protection and accompanying hyperemia afforded by NH4OH in low concentration. The combination of urea (2%) and urease (100 U), which raised the gastric luminal NH4OH concentration by about 5-folds, also reduced significantly the lesions provoked by 250 mM NH4OH. This protection and accompanying hyperemia induced was significantly attenuated by the pretreatment with indomethacin or hydroxyurea, a potent urease inhibitor. Hydroxyurea abolished completely the rise in luminal NH4OH produced by the combined treatment of urea plus urease. We conclude that 1) NH4OH in high concentration damages the gastric mucosa but when applied at lower concentration or generated in the stomach by urea-urease system, acts as local mild irritant to induce adaptive cytoprotection that probably involves PG, sensory nerves and arginine-NO-pathaway.
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PMID:Urea-urease system in cytoprotection against acute mucosal damage. 877 94

The goal of the present study was to characterize the activation profile of the growth-related enzyme ornithine decarboxylase (ODC) in cardiovascular tissue during hypertension induced by chronic NO synthase blockade in relation to the development of structurally based changes in the heart and blood vessels. In previously instrumented conscious rats, mean arterial pressure and ODC activation were measured in cardiovascular tissue of rats treated with N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg per day P.O.) for 4 hours and 1, 6, and 12 days. After 12 days of L-NAME treatment alone or in combination with 3% L-ornithine, structurally based hindlimb resistance properties were assessed. A marginal activation of ODC in the left ventricle and aorta was seen at 4 hours but returned to control levels at 1, 6, and 12 days of L-NAME treatment. A slightly prolonged yet transient activation of ODC occurred in the mesenteric vascular bed. Structurally based hindlimb vascular resistance was enhanced by 15% at maximum vasoconstrictor tone, and no change in cardiac mass occurred with L-NAME treatment. L-NAME+3% L-ornithine treatment resulted in a similar level of structural upregulation compared with L-NAME treatment alone. In summary, 12 days of L-NAME treatment resulted in only a modest change in vascular resistance, and only at maximum constriction, and no cardiac hypertrophy despite the presence of marked hypertension. The results of the present study indicate that either (1) pressure alone is not a sufficient stimulus to induce cardiovascular growth processes or (2) L-NAME may be "nonspecifically" inhibiting cardiovascular growth processes.
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PMID:Blunted cardiovascular growth induction during prolonged nitric oxide synthase blockade. 931 26

The question was addressed whether short-term (4 hour) NO deficiency, inducing an increase in blood pressure in anaesthetized dogs, does influence proteosynthesis in the myocardium and coronary arteries. A potentially positive answer was to be followed by the study of the supporting role of ornithine decarboxylase for the polyamines pathway. N(G)-nitro-L-arginine-methyl ester (L-NAME) (50 mg/kg per hour) was administered i.v. to inhibit NO synthase. After the first L-NAME dose diastolic blood pressure increased from 131.8+/-2.0 to 149.4+/-3.9 mm Hg (p<0.001) and was maintained at about this level till the end of the experiment. Systolic blood pressure only increased after the first dose (from 150.8+/-1.1 to 175.0+/-5.8 mm Hg, p<0.01), returning thereafter to the control level. Similarly, the heart rate declined only after the first dose (from 190.4+/-5.3 to 147.6+/-4.5 beats/min, p<0.01). Total RNA concentrations increased in the left cardiac ventricle (LV), the left anterior descending coronary artery (LADCA) and left circumflex coronary artery (LCCA) by 15.9+/-0.7, 29.7+/-1.3 and 17.6+/-1.0%, p<0.05, respectively. The same applied to [14C]leucine incorporation (by 86.5+/-5.0, 33.5+/-2.6, 29.3+/-4.1%, p<0.05, respectively). The above parameters indicated an increase of proteosynthesis in the LV myocardium and both coronary arteries LADCA and LCCA after short-term NO deficiency. Surprisingly, the ornithine decarboxylase activity in the LV myocardium decreased significantly by 40.2+/-1.6% (p<0.01) but the changes were not significant in the coronary arteries. This unexpected finding makes the role of polyamines in increasing proteosynthesis during a pressure overload due to NO deficiency questionable.
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PMID:Early changes of protein synthesis in myocardium and coronary arteries induced by NO synthase inhibition. 1045 47

Nitric oxide (NO) is a short-lived, readily diffusible intracellular messenger molecule associated with multiple organ-specific regulatory functions. Endogenous stimulation or exogenous administration of NO have been shown to inhibit production of reactive oxygen species (ROS) and expression of oxidant-mediated molecular or tissue injury. Potassium bromate (KBrO3) is one such potent renal oxidant that acts through generation of ROS-mediated lipid peroxidation, and causes increased ornithine decarboxylase activity, enhanced rate of DNA synthesis and depletion of the antioxidant armoury of the tissue. In this study, we elucidate the effect of exogenous NO administration, using the NO donor glyceryl trinitrate (GTN), on KBrO3-induced nephrotoxicity, oxidative stress and cell proliferation. KBrO3 administration at a dose of 125 mg/kg body weight results in significant (P < 0.001) depletion in renal glutathione (GSH) content, and glutathione reductase (GR) activity with a concomitant increase in microsomal lipid peroxidation, and blood urea nitrogen (BUN) and creatinine levels. Parallel to these changes, we found significant enhancement in ornithine decarboxylase (ODC) activity and rate of renal DNA synthesis. Subsequent administration of GTN resulted in dose-dependent amelioration of GSH content and GR activity with concomitant inhibition of lipid peroxidation, and BUN and creatinine levels. In addition, GTN administration to KBrO3-intoxicated rats resulted in significant dose-dependent down regulation of enhanced ODC activity and rate of [3H]-thymidine incorporation in renal DNA, providing support for the protective role of NO in attenuation of KBrO3-induced oxidative stress and cell proliferation. Enhancement of oxidative tissue injury and cell proliferation on administration of the NO inhibitor, L-NAME, further demonstrates the protective efficacy of endogenous NO. These data suggest that NO inhibits KBrO3-induced tissue injury, oxidative stress and proliferative response in the rat kidney.
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PMID:Glyceryl trinitrate, a nitric oxide donor, suppresses renal oxidant damage caused by potassium bromate. 1077 65

NO concentration in the femoral artery and femoral vein of anesthetized dogs was found to be 154.2+/-5.6 nM and 90.0+/-12 nM, respectively. Inhibition of NO synthase (NOS) slightly decreased the basal NO concentration in femoral artery from 154.2+/-5.6 to 137.2+/-3.3 nM. Acetylcholine-induced increase in NO concentration was slightly but still significantly attenuated, suggesting that very probably L-NAME did not inhibit all sources of nitric oxide (NO). Local NOS inhibition in the posterior hypothalamus dose-dependently increased systemic blood pressure (BP) in rats. Short-term general NOS inhibition in anesthetized dogs increased diastolic BP but not systolic BP. The heart rate after one-hour down-fluctuation returned to initial values. Proteosynthesis in the myocardium and both branches of the left coronary artery increased, but this was not supported by polyamines, since the activity of ornithine decarboxylase declined. Long-term general NOS inhibition elicited a sustained BP increase, a decrease in heart rate, cardiac hypertrophy and an increase in wall thickness of the coronary and carotid artery. The results indicate that NO deficiency itself plays a role in proteosynthesis and cardiac hypertrophy, in spite of relatively small increase in diastolic blood pressure and no change in systolic blood pressure, at least after an acute L-NAME administration. The hypotension response to acetylcholine and bradykinin studied in anesthetized NO-compromised rats, was unexpectedly enhanced. The elucidation of this paradoxical phenomenon will require further experiments.
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PMID:Nitric oxide-compromised hypertension: facts and enigmas. 1080 2

l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis. Adult male Wistar rats were treated with azoxymethane (AOM, 15 mg/kg ip), a chemical carcinogen, once a week for 2 weeks. One week after the second injection the rats were randomly divided into two groups. One group (n = 8) received l-NAME (10 mg/kg body wt/day) in drinking water. The control group (n = 8) received tap water. After 5 weeks, the rats receiving l-NAME showed enhanced mean basal arterial blood pressure, decreased heart rate, and a significant decrease of the cGMP content in the colonic mucosa. In both groups, AOM induced the formation of colonic aberrant crypt foci (ACF). In l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis.
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PMID:Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats. 1113 66

The question was addressed of how nitric oxide synthase (NO synthase) inhibition-induced hypertension in rat parents would affect the cardiovascular system in their offsprings. Two experimental groups were set up: Group I -- offsprings of parents who had both been administered NO synthase inhibitor L-nitro-arginine methyl ester (L-NAME 40 mg/kg/day) for 5 weeks, the treatment of dams continued till week 12. Group II -- offsprings fed by dams administered L-NAME after delivery only for a period of 4 weeks. Control age-matched offsprings formed the third group. Blood pressure and heart rate in parents and in 3-week-old offsprings were determined noninvasively. In the offsprings, body and heart weight were measured and the heart/body weight ratio (HW/BW) was calculated. The NO synthase activity, and also ornithine decarboxylase activity as a marker of polyamine production, were determined in the heart. The acetylcholine-induced relaxation of aortic rings was also followed. A marked blood pressure increase with a tendency to a decreased heart rate was found in the offsprings of Group I. A significant decrease in heart weight and body weight with a decreased HW/BW ratio indicated cardiac hypotrophy that contrasted with the decrease in NO synthase activity and increase in ornithine decarboxylase activity in the heart. Noteworthy was also the finding of completely preserved relaxation of the aorta to acetylcholine. Offsprings of Group II were similarly characterized by significantly higher blood pressure, a tendency to decreased heart rate, a decrease in heart weight, but not of the HW/BW ratio. The contrasting findings of heart weight decrease on the one hand and NO synthase activity decrease and ornithine decarboxylase increase on the other, were also found in this group. Full relaxation of the aorta to acetylcholine was preserved. It can be concluded that remarkable alterations in the cardiovascular system were found in offsprings of hypertensive NO compromised parents.
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PMID:Cardiovascular system of offsprings of hypertensive rats with defective nitric oxide production. 1247 Jan 99

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