Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) production from exogenous NG-hydroxy-L-arginine (OH-L-Arg) was investigated in rat aortic smooth muscle cells in culture by measuring nitrite accumulation in the culture medium. As well, the interaction between OH-L-Arg and L-arginine uptake via the y+ cationic amino acid transporter was studied. In cells without NO-synthase activity, OH-L-Arg (1-1000 microM) induced a dose-dependent nitrite production with a half-maximal effective concentration (EC50) of 18.0 +/- 1.5 microM (n = 4-7). This nitrite accumulation was not inhibited by the NO-synthase inhibitor NG-nitro-L-arginine methyl ester, L-NAME (300 microM). In contrast, it was abolished by miconazole (100 microM), an inhibitor of cytochrome P450. Incubation of vascular smooth muscle cells with LPS (10 micrograms/ml) induced an L-NAME inhibited nitrite accumulation, but did not enhance the OH-L-Arg induced nitrite production. OH-L-Arg and other cationic amino acids, L-lysine and L-ornithine, competitively inhibited [3H]-L-arginine uptake in rat aortic smooth muscle cells, with inhibition constants of 195 +/- 23 microM (n = 12), 260 +/- 40 microM (n = 5) and 330 +/- 10 microM (n = 5), respectively. These results show that OH-L-Arg is recognized by the cationic L-amino acid carrier present in vascular smooth muscle cells can be oxidized to NO and nitrite in these cells in the absence of NO-synthase, probably by cytochrome P450 or by a reaction involving a cytochrome P450 by-product.
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PMID:Exogenous NG-hydroxyl-L-arginine causes nitrite production in vascular smooth muscle cells in the absence of nitric oxide synthase activity. 751 Nov 14

Proinflammatory cytokines play an important role in the depression of cytochrome P450 (CYP450)-dependent drug metabolism in mammals during inflammation and infection. Although much has been learned concerning the effects and mechanisms of cytokine-mediated suppression of CYP450, there is limited knowledge about how cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present study was to investigate the effects and dose dependency of recombinant human proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities in primary cultures of pig hepatocytes. A possible role of nitric oxide in cytokine-induced suppression of enzyme activities was studied by incubating hepatocytes in the presence of N G-nitro-L-arginine (L-NAME), a competitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) decreased both oxidation and glucuronidation activities dose dependently, in which the effects on glucuronidation activities were even more pronounced. IL-6 differed from IL-1alpha and TNF-alpha by inhibiting CYP450 and UDPFT more effectively after 24 hr of incubation, whereas the inhibition by IL-1alpha and TNF-alpha was more pronounced after 12 hr. Only at a concentration of 500 U/ml did interferon-gamma (IFN-ganna) inhibit CYP450 and UDPGT. The inhibition of CYP450 enzyme activities by cytokines was probably not due to the production of NO, because L-NAME totally blocked NO production but had no effect on the cytokine-induced suppression of CYP450 enzyme activities. However, there might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME slightly though significantly prevented the inhibition of glucuronidation.
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PMID:Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes. 866 49

It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg i.v.) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 microM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.
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PMID:In vivo, ex vivo, and in vitro effects of L-NAME and L-arginine on the metabolism of theophylline in the rabbit. 902 50

1. The nature and cellular mechanisms that are responsible for endothelium-dependent relaxations resistant to indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) were investigated in phenylephrine (PE) precontracted isolated carotid arteries from the rabbit. 2. In the presence of the cyclo-oxygenase inhibitor, indomethacin (10 microM), acetylcholine (ACh) induced a concentration- and endothelium-dependent relaxation of PE-induced tone which was more potent than the calcium ionophore A23187 with pD2 values of 7.03 +/- 0.12 (n = 8) and 6.37 +/- 0.12 (n = 6), respectively. The ACh-induced response was abolished by removal of the endothelium, but was not altered when indomethacin was omitted (pD2 value 7.00 +/- 0.10 and maximal relaxation 99 +/- 3%, n = 6). Bradykinin and histamine (0.01-100 microM) had no effect either upon resting or PE-induced tone (n = 5). 3. In the presence of indomethacin plus the NO synthase inhibitor, L-NAME (30 microM), the response to A23187 was abolished. However, the response to ACh was not abolished, although it was significantly inhibited with the pD2 value and the maximal relaxation decreasing to 6.48 +/- 0.10 and 67 +/- 3%, respectively (for both P < 0.01, n = 8). The L-NAME/indomethacin insensitive vasorelaxation to ACh was completely abolished by preconstriction of the tissues with potassium chloride (40 mM, n = 8). 4. The Ca(2+)-activated K+ (KCa) channel blockers, tetrabutylammonium (TBA, 1 mM, n = 5) and charybdotoxin (CTX, 0.1 microM, n = 5), completely inhibited the nitric oxide (NO) and prostacyclin (PGI2)-independent relaxation response to ACh. However, iberiotoxin (ITX, 0.1 microM, n = 8) or apamin (1-3 microM, n = 6) only partially inhibited the relaxation. 5. Inhibitors of the cytochrome P450 mono-oxygenase, SKF-525A (1-10 microM, n = 6), clotrimazole (1 microM, n = 5) and 17-octadecynoic acid (17-ODYA, 3 microM, n = 7) also reduced the NO/PGI2-independent relaxation response to ACh. 6. In endothelium-denuded rings of rabbit carotid arteries, the relaxation response to exogenous NO was not altered by either KCa channel blockade with apamin (1 microM, n = 5) or CTX (0.1 microM, n = 5), or by the cytochrome P450 mono-oxygenase blockers SKF-525A (10 microM, n = 4) and clotrimazole (10 microM, n = 5). However, the NO-induced response was shifted to the right by LY83583 (10 microM, n = 4), a guanylyl cyclase inhibitor, with the pD2 value decreasing from 6.95 +/- 0.14 to 6.04 +/- 0.09 (P < 0.01). 7. ACh (0.01-100 microM) induced a concentration-dependent relaxation of PE-induced tone in endothelium-denuded arterial segments sandwiched with endothelium-intact donor segments. This relaxation to ACh was largely unaffected by indomathacin (10 microM) plus L-NAME (30 microM), but abolished by the combination of indomethacin, L-NAME and TBA (1 mM, n = 5). 8. These data suggest that in the rabbit carotid artery: (a) ACh can induce the release of both NO and EDHF, whereas A23187 only evokes the release of NO from the endothelium, (b) the diffusible EDHF released by ACh may be a cytochrome P450-derived arachidonic acid metabolite, and (c) EDHF-induced relaxation involves the opening of at least two types of KCa channels, whereas NO mediates vasorelaxation via a guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-mediated pathway, in which a cytochrome P450 pathway and KCa channels do not seem to be involved.
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PMID:NO/PGI2-independent vasorelaxation and the cytochrome P450 pathway in rabbit carotid artery. 905 10

1. We have used the isolated, buffer-perfused, mesenteric arterial bed of the rat (preconstricted with methoxamine or 60 mM K+) to characterize nitric oxide (NO)-independent vasorelaxation which is thought to be mediated by the endothelium-derived hyperpolarizing factor (EDHF). 2. The muscarinic agonists carbachol, acetylcholine (ACh) and methacholine caused dose-related relaxations in preconstricted preparations with ED50 values of 0.18 +/- 0.04 nmol (n = 8), 0.05 +/- 0.02 nmol (n = 6) and 0.26 +/- 0.16 nmol (n = 5), respectively. In the same preparations NG-nitro-L-arginine methyl ester (1-NAME, 100 microM) significantly (P < 0.05) decreased the potency of all the agents (ED50 values in the presence of L-NAME: carbachol, 0.66 +/- 0.11 nmol; ACh, 0.28 +/- 0.10 nmol; methacholine, 1.97 +/- 1.01 nmol). The maximal relaxation to ACh was also significantly (P < 0.05) reduced (from 85.3 +/- 0.9 to 73.2 +/- 3.7%) in the presence of L-NAME. The vasorelaxant effects of carbachol were not significantly altered by the cyclo-oxygenase inhibitor indomethacin (10 microM; n = 4). 3. The K+ channel blocker, tetraethylammonium (TEA, 10 mM) also significantly (P < 0.001) reduced both the potency of carbachol (ED50 = 1.97 +/- 0.14 nmol in presence of TEA) and the maximum relaxation (Rmax = 74.6 +/- 3.2% in presence of TEA, P < 0.05, n = 3). When TEA was added in the presence of L-NAME (n = 4), there was a further significant (P < 0.001) decrease in the potency of carbachol (ED50 = 22.4 +/- 13.5 nmol) relative to that in the presence of L-NAME alone, and Rmax was also significantly (P < 0.05) reduced (74.6 +/- 4.2%). The ATP-sensitive K+ channel inhibitor, glibenclamide (10 microM), had no effect on carbachol-induced relaxation (n = 9). 4. High extracellular K+ (60 mM) significantly (P < 0.01) reduced the potency of carbachol (n = 5) by 5 fold (ED50: control, 0.16 +/- 0.04 nmol; high K+, 0.88 +/- 0.25 nmol) and the Rmax was also significantly (P < 0.01) reduced (control, 83.4 +/- 2.7%; high K+, 40.3 +/- 9.2%). The residual vasorelaxation to carbachol in the presence of high K+ was abolished by L-NAME (100 microM; n = 5). In preparations preconstricted with high K+, the potency of sodium nitroprusside was not significantly different from that in preparations precontracted with methoxamine, though the maximal response was reduced (62.4 +/- 3.4% high K+, n = 7; 83.1 +/- 3.1% control, n = 7). 5. In the presence of the cytochrome P450 inhibitor, clotrimazole (1 microM, n = 5 and 10 microM, n = 4), the dose-response curve to carbachol was significantly shifted to the right 2 fold (P < 0.05) and 4 fold (P < 0.001) respectively, an effect which was further enhanced in the presence of L-NAME. Rmax was significantly (P < 0.01) reduced by the presence of 10 microM clotrimazole alone, being 86.9 +/- 2.5% in its absence and 61.8 +/- 7.8% in its presence (n = 6). 6. In the presence of the cell permeable analogue of cyclic GMP, 8-bromo cyclic GMP (6 microM), the inhibitory effects of L-NAME on carbachol-induced relaxation were substantially enhanced (ED50: L-NAME alone, 0.52 +/- 0.11 nmol, n = 5; L-NAME + 8-bromo cyclic GMP, 1.42 +/- 0.28 nmol, n = 7, Rmax: L-NAME alone, 82.2 +/- 2.4%; L-NAME + 8-bromo cyclic GMP, 59.1 +/- 1.8%. P < 0.001). These results suggest that the magnitude of the NO-independent component of vasorelaxation is reduced when functional cyclic GMP levels are maintained, suggesting that basal NO (via cyclic GMP) may modulate EDHF activity and, therefore, on loss of basal NO production the EDHF component of endothelium-dependent relaxations becomes functionally greater. 7. The present investigation demonstrates that muscaranic receptor-induced vasorelaxation in the rat mesenteric arterial bed is mediated by both NO-dependent and independent mechanisms. The L-NAME-insensitive mechanism, most probably occurs via activation of a K+ conductance and shows the characteristics of EDHF-mediated responses. Finally, the results demonstrate that EDHF activity may become upregulated on inhibition of NO production and this may compensate for the loss of NO.
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PMID:Characterization and modulation of EDHF-mediated relaxations in the rat isolated superior mesenteric arterial bed. 911 62

1. Relaxing factors released by the endothelium and their relative contribution to the endothelium-dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries. 2. BK produced an endothelium-dependent relaxation of arteries pre-contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 microM), produced a parallel shift to the right of the concentration-response curve to BK with a pA2 of 7.75. 3. Neither the cyclo-oxygenase inhibitor, indomethacin (10 microM) alone, the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 300 microM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 microM) alone, nor the combination of L-NAME plus Hb affected the concentration-response curve to BK. Conversely, the combination of indomethacin with either L-NAME or Hb attenuated but did not abolish the BK-induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L-NAME. Also, the presence of indomethacin plus L-NAME produced contraction of arteries with functional endothelium. 4. The indomethacin plus L-NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L-NAME did not affect the nitric oxide donor, S-N-acetylpenicillamine-induced relaxation. 5. The indomethacin plus L-NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 microM), 4-aminopyridine (100 microM), glibenclamide (10 microM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). 6. In the presence of indomethacin plus L-NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 microM) or by the inhibitor of cytochrome P450, SKF 525a (10 microM). Another cytochrome P450 inhibitor, clotrimazole (10 microM) which also inhibits K+ channels, inhibited the relaxation to BK. 7. These results show that BK induces endothelium-dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo-oxygenase derived prostanoid(s) and another factor (probably an endothelium-derived hyperpolarizing factor). They indicate that nitric oxide and cyclo-oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P-450 pathway, in these arteries.
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PMID:Characterization of endothelium-derived relaxing factors released by bradykinin in human resistance arteries. 920 31

The isolated perfused rat mesenteric bed releases endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh) or histamine. I propose that EDHF released in the mesenteric vascular bed is a cytochrome P450 (CYP)-linked, arachidonate metabolite. In the presence of nitro-L-arginine methyl ester (L-NAME) and indomethacin, injections of ACh (0.001 to 10 nmol) or histamine (0.1 to 1,000 nmol) elicited transient, dose-dependent dilation of cirazoline (an alpha1-adrenoceptor selective agonist) preconstricted mesenteric beds. The L-NAME-resistant responses to ACh or histamine were insensitive to tetrodotoxin (1 micromol/L), thus negating its neuronal origin, but were profoundly attenuated by a K+ channel inhibitor tetrabutylammonium (0.5 mmol/L). 7-Ethoxyresorufin (a selective and competitive blocker of CYP 1A isozyme) blunted ACh and histamine mediated EDHF responses but did not alter vasodilation initiated through K+ channel activation by either cromakalim or NS-1619, or through the nitric oxide-cGMP pathway (sodium nitroprusside). Clotrimazole, an imidazole that inhibits CYP by binding to the heme moiety, attenuated ACh, histamine, and cromakalim but not sodium nitroprusside-mediated vasodilator responses. Other CYP isozyme selective inhibitors, such as metyrapone (CYP 2B), 7-pentoxyresorufin (CYP 2B1), sulfaphenazole (CYP 2C/3A), and 17-octadecynoic acid (4A-linked omega-hydroxylase inhibitor), did not alter ACh or histamine-induced EDHF response. The EDHF-mediated dilations initiated by ACh and histamine, as well as K(ATP) activation by cromakalim, were blocked by mepacrine, a nonselective phospholipase A2 inhibitor. Mepacrine did not alter K(Ca) activation by compound NS-1619. I conclude that 1) the isolated perfused rat mesenteric prearteriolar bed releases in response to ACh and histamine, an EDHF that causes vasodilation through K+ channel activation; 2) the EDHF is most likely a CYP-derived arachidonate product; 3) CYP 1A is well suited as the isozyme responsible for EDHF production in this vascular bed; and 4) PLA2 appears to mediate the release of the precursor arachidonic acid.
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PMID:Endothelium-derived hyperpolarizing factor: characterization as a cytochrome P450 1A-linked metabolite of arachidonic acid in perfused rat mesenteric prearteriolar bed. 923 31

The purpose of this study was to determine the involvement of eicosanoids and nitric oxide (NO) in the response to hypoxia in isolated intrapulmonary (third branch) arteries from 10- to 17-day-old piglets. We also compared the response to hypoxia in pulmonary arteries to pulmonary veins, mesenteric arteries and coronary arteries. Hypoxia was generated in vascular rings (under resting force or precontracted with 30 mM KCl) by switching the gas aerating the organ chambers from one composed of 21% O2-5% CO2-balance N2 (pO2 145 +/- 1.27 mm Hg) to a mixture of 5% CO2-balance N2 (pO2 33.87 +/- 0.24 mm Hg). In precontracted rings hypoxia produced a transient vasoconstriction (26 +/- 8% of the precontraction value) reaching a peak in 3-4 min, followed by a relaxation. A similar pattern of response was observed in pulmonary veins, coronary arteries and mesenteric arteries. The contractile phase was not present in endothelium-denuded arteries or after incubation with the NO synthase inhibitor L-NAME (10(-4) M) or the guanylate cyclase inhibitor methylene blue (10(-5) M). No changes in the hypoxia-induced vasoconstriction were observed after preincubation with the NO precursor L-arginine (10(-5) M), the lipoxygenase inhibitor meclofenamate (10(-5) M), the cyclooxygenase inhibitor AA 861 (10(-5) M), or the cytochrome P450 oxidase inhibitor SKF 525A (10(-5) M). These findings demonstrate that the contractile response to hypoxia in the isolated intrapulmonary porcine artery is caused by the loss of the inhibitory effects of endothelium-derived NO on the vascular tone. Eicosanoids do not appear to be involved in this response. Since the response to hypoxia in isolated rings is not specific to pulmonary vessels, any correlation between this response and hypoxic pulmonary vasoconstriction should be avoided.
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PMID:Endothelium-derived nitric oxide-dependent response to hypoxia in piglet intrapulmonary arteries. 931 36

1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel.
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PMID:P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation. 951 92

In cerebellar granule cells, potassium cyanide (KCN) activates the NMDA receptor resulting in generation of nitric oxide and reactive oxygen species (ROS). To study the mechanism by which KCN stimulates ROS generation, the action of cyanide on the enzymatic pathways known to generate ROS were studied. The oxidant-sensitive fluorescent dye, 2,7-dichlorofluorescin was used to measure intracellular levels of nitric oxide and ROS in cerebellar granule cells. Using selective enzyme inhibitors, it was shown that both protein kinase C and phospholipase A2 are involved in KCN-stimulated generation of NO and ROS. In cells treated with indomethacin or nordihydroguairetic acid, inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX) respectively, attenuated (approximately 35%) KCN-induced generation of oxidant species. When L-NAME (LG-nitro-L-arginine methyl ester) (nitric oxide synthase inhibitor, NOS) was combined with either indomethacin or nordihydroguairetic acid, generation of oxidant species was blocked by more than 80%. Pretreatment with NS398 (COX-2 inhibitor) significantly decreased ROS generation indicating the involvement of COX-2 in KCN-induced oxidant generation. Treatment with L-NAME + NS398 blocked oxidant species generation, reflecting involvement of NOS. The participation of cytochrome P450 was not evident because SKF525A did not significantly reduce KCN-induced ROS generation. Furthermore, a correlation was observed between oxidant generation and lipid peroxidation of cellular membranes (as determined by thiobarbituric acid levels). Pretreatment with inhibitors of protein kinase C, phospholipase A2 or COX, LOX, COX-2 partially blocked KCN-induced formation of thiobarbituric acid reactive substance, whereas coincubation of L-NAME with the inhibitors decreased lipid peroxidation by 60 to 90%. In cytotoxicity studies, KCN-induced cell death was partially blocked by the inhibitors and significant protection was observed when L-NAME was combined with these compounds. These findings show that activation of phospholipase A2 and subsequent metabolism of arachidonic acid by the COX-2 and LOX pathways and NOS contribute to cyanide-induced ROS production.
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PMID:Cyanide-induced generation of oxidative species: involvement of nitric oxide synthase and cyclooxygenase-2. 953 16


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