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Query: EC:3.1.26.9 (
ribonuclease
)
6,589
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
1 The role of nitric oxide (NO) derived from constitutive and inducible nitric oxide synthase (cNOS and iNOS) and its relationship to oxygen-derived free radicals and prostaglandins (PG) was investigated in a carrageenan-induced model of acute hindpaw inflammation. 2 The intraplantar injection of carrageenan elicited an inflammatory response that was characterized by a time-dependent increase in paw oedema, neutrophil infiltration, and increased levels of nitrite/nitrate (NO2-/NO3-) and prostaglandin E2(PGE2) in the paw exudate. 3 Paw oedema was maximal by 6 h and remained elevated for 10 h following carrageenan administration. The non-selective cNOS/iNOS inhibitors, NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-
NAME
) given intravenously (30-300 mg kg-1) 1 h before or after carrageenan administration, inhibited paw oedema at all time points. 4 The selective iNOS inhibitors, N-iminoethyl-L-lysine (L-NIL) or aminoguanidine (AG), failed to inhibit carrageenan-induced paw oedema during the first 4 h following carrageenan administration, but inhibited paw oedema at subsequent time points (from 5-10 h). iNOS mRNA was detected between 3 to 10 h following carrageenan administration using
ribonuclease
protection assays. iNOS protein was first detected 6 h and was maximal 10 h following carrageenan administration as shown by Western blot analysis. Administration of the iNOS inhibitors 5 h after carrageenan (a time point where iNOS was expressed) inhibited paw oedema at all subsequent time points. Infiltrating neutrophils were not the source of iNOS since pretreatment with colchicine (2 mg kg-1) suppressed neutrophil infiltration, but did not inhibit the iNOS mRNA expression or the elevated NO2-/NO3- levels in the paw exudate. 5 Inhibition of paw oedema by the NOS inhibitors was associated with attenuation of both the NO2-/NO3- and PGE2 levels in the paw exudate. These inhibitors also reduced the neutrophil infiltration at the site of inflammation. 6 Recombinant human Cu/Zn superoxide dismutase coupled to polyethyleneglycol (PEGrhSOD; 12 x 10(3) u kg-1), administered intravenously either 30 min prior to or 1 h after carrageenan injection, inhibited paw oedema and neutrophil infiltration, but had no effect on NO2-/NO3- or PGE2 production in the paw exudate. The administration of catalase (40 x 10(3) u kg-1), given intraperitoneally 30 min before carrageenan administration, had no effect on paw oedema. Treatment with desferrioxamine (300 mg kg-1), given subcutaneously 1 h before carrageenan, inhibited paw oedema during the first 2 h after carrageenan administration, but not at later times. 7 These results suggest that the NO produced by cNOS is involved in the development of inflammation at early time points following carrageenan administration and that NO produced by iNOS is involved in the maintenance of the inflammatory response at later time points. The potential interactions of NO with superoxide anion and PG is discussed.
...
PMID:Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. 879 51
The present study investigated whether or not nitric oxide (NO) synthesis mediates mechanisms regulating activation of renin formation. Studies were performed on afferent arterioles freshly isolated from the rat kidney. We have shown previously that this preparation is a useful model to study regulation of renin synthesis and secretion. The expression of renin mRNA was assessed by
ribonuclease
protection assay, and total renin content and renin secretion by radioimmunoassay. In afferent arterioles isolated from rats treated with the angiotensin-converting enzyme inhibitor ramipril, renin mRNA levels, total renin content and renin secretion were increased threefold compared to untreated controls. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-
NAME
) in the ramipril-treated rats, abolished the increase in renin mRNA levels, total renin content and renin secretion. In other animals furosemide, a diuretic acting on macula densa cells, activated renin synthesis to a level similar to that found in the ramipril-treated group. Addition of L-
NAME
to the furosemide-treated rats suppressed the increases in renin mRNA levels, total renin content and renin secretion, suggesting that NO acts on renin activation by a mechanism independent of angiotensin II. In separate experiments, the inhibitory effect of L-
NAME
on the activation of renin secretion was abolished when afferent arterioles were treated with nicardipine, an L-type Ca2+ channel blocker, suggesting that the suppression of renin activation during NO inhibition is due to increased Ca2+ entry. Since endothelin is a potent mediator of Ca2+ influx and an inhibitor of renin release, we tested whether or not endothelin could be involved in the inhibitory effect of L-
NAME
on renin secretion. Application of the endothelin receptor antagonist, bosentan, in vitro mimicked the effect of nicardipine. In addition, bosentan coadministered with L-
NAME
in vivo blunted the inhibitory effect of L-
NAME
and restored the increases in renin mRNA level, synthesis and secretion. These data indicate that the physiological mechanism(s) regulating activation of renin synthesis and secretion are impaired during NO inhibition, probably because of increased Ca2+ influx. This increase in calcium flux is mediated at least partially by the action of endothelin.
...
PMID:Activation of renin synthesis is dependent on intact nitric oxide production. 918 67
P-selectin translocation to the surface of endothelial cells is increased after exposure to the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-
NAME
), resulting in increased endothelial adhesiveness. L-
NAME
(3 mM) was added to human cultured iliac vein endothelial cells for 1, 2, 4, and 6 h, and P-selectin mRNA expression was quantified by a
ribonuclease
protection assay. In parallel experiments, the NO donor, SPM-5185 (10 microM), was added to human iliac venous endothelial cells, and P-selectin mRNA expression quantified. P-selectin protein synthesis was quantified by Western blot analysis. L-
NAME
caused increased expression of P-selection RNA at 2-4 h, whereas D-
NAME
, the stereoisomer lacking NO synthase-inhibitory activity, had no effect. The stimulatory effect of L-
NAME
was reversed by addition of 3 mM L-arginine. SPM-5185 decreased P-selectin mRNA over the same time period (P < 0.02). The increased P-selectin mRNA expression induced by L-
NAME
was paralleled by an increase in P-selectin protein synthesis. The effects of SPM-5185 and L-arginine were also paralleled by decreases in P-selectin protein synthesis and in decreased adherence of human neutrophils to human iliac venous endothelial cells. The peak effect of inhibition of NO synthesis or addition of exogenous NO occurred at 2-4 h. These results suggest a regulatory effect of NO on endothelial P-selectin expression that modulates early leukocyte-endothelial cell interactions to preserve vascular homeostasis.
...
PMID:Regulation of P-selectin expression in human endothelial cells by nitric oxide. 927 91
Many studies have shown that nitric oxide (NO) production is higher in the systemic vasculature of females than males and is stimulated during pregnancy, a high estrogen state. The present study was performed in rats to determine whether females had a greater expression of endothelial NO synthase (eNOS) in kidneys than did males; whether there were gender differences in the excretion of NO metabolites, nitrate/nitrite; and whether there were gender differences in the renal hemodynamic response to NO synthase inhibition. The renal levels of eNOS mRNA (as measured by
ribonuclease
protection assays) and protein (as measured by Western blot) were 80% higher in kidneys from females than from males (P < .001). Urinary excretion of NO metabolites, nitrate/nitrite, were not different between males and females. To inhibit eNOS, rats were treated with nitro-L-arginine methyl ester (L-
NAME
, 3 to 4 mg/kg/day) for 2 weeks. Although there were no differences in basal renal hemodynamics between males and females, when factored for kidney weight, chronic L-
NAME
increased renal vascular resistance by 130% in males but by only 60% in females, and decreased renal plasma flow by 40% in males but had no effect in females. These data show that although the renal levels of eNOS mRNA and protein are higher in females than in males, the renal vasculature of males is more responsive to NO synthase inhibition. The data suggest that the renal vasculature of males may be more dependent on NO than is the renal vasculature in females.
...
PMID:Gender differences in the renal nitric oxide (NO) system: dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition. 950 56
This study aimed to investigate the role of endogenous nitric oxide (NO) in erythropoietin (EPO) gene expression in mice in vivo. For this purpose EPO mRNA was semiquantitated by
ribonuclease
protection assay in livers and kidneys of three groups of mice: wild-type (wt), endothelial NO-synthase (NOS) knockout mice (eNOS-/-), and wt treated with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (50 mg x kg(-1) x day(-1)) for 4 days (wt+L-
NAME
). EPO gene expression was stimulated by normobaric hypoxia (8% O2) or by 0.1% carbon monoxide (CO) inhalation for 4 h each, or by intraperitoneal injection of 60 mg/kg cobaltous chloride (CoCl2) for 6 h. Renal EPO mRNA in wt increased 12-, 40-, and 13-fold over normoxic levels in response to hypoxia, CO and CoCl2 respectively. EPO mRNA was detectable in the livers only after CO exposure. Renal and hepatic EPO gene expression in wt+L-
NAME
appeared moderately increased relative to wt with a maximal 2.5-fold enhancement after CO exposure. EPO mRNA levels in eNOS-/- mirrored those of wt+L-
NAME
, but the effects were less prominent. Our data suggest that endogenous NO attenuates EPO gene expression in mice. This effect is dependent on the rate of EPO gene induction.
...
PMID:Endogenous nitric oxide attenuates erythropoietin gene expression in vivo. 1067 40
Ranpirnase (Rap) is a cytotoxic ribonuclease (
RNase
) isolated from frog oocytes. Here we describe high antitumor activity of a novel immunotoxin, 2L-Rap-hLL1-gamma4P, composed of 2 Rap molecules, each fused to the N terminus of the light chain of hLL1, an internalizing anti-CD74 humanized antibody. To reduce unwanted side effects, the constant region of hLL1 was changed from gamma1 to gamma4 and further to gamma4P by replacing serine228 to proline to prevent the formation of a half immunoglobulin G (IgG) common for IgG4. In vitro, 2L-Rap-hLL1-gamma4P retained
RNase
activity, specific binding to CD74, and was significantly more potent against CD74+ cell lines (Daudi, Raji, and MC/
CAR
) than naked hLL1. In vivo, the pharmacokinetic profile of 2L-Rap-hLL1-gamma4P was similar to that of naked hLL1. The maximum tolerated dose of 2L-Rap-hLL1-gamma4P in severe combined immunodeficient mice (SCID) or BALB/c mice was 50 microg per mouse. In Raji and Daudi Burkitt lymphoma xenograft models, treatment with a single 5 to 50 microg dose of 2L-Rap-hLL1-gamma4P, given as early or delayed treatment, resulted in cures of most animals. Treatment with 2L-Rap-hLL1-gamma4P was significantly better than all controls, including saline, naked hLL1, and nonspecific immunotoxin. In conclusion, 2L-Rap-hLL1-gamma4P demonstrated excellent in vitro and in vivo efficacy and thus merits further consideration as a therapeutic for CD74+ tumors.
...
PMID:Effective therapy of human lymphoma xenografts with a novel recombinant ribonuclease/anti-CD74 humanized IgG4 antibody immunotoxin. 1610 81
