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 influence of diabetes on the function of vascular endothelium was examined with respect to the role of nitric oxide (NO) in the regulation of blood pressure (BP) in vivo, the vascular relaxation, and levels of cAMP and cGMP in the effluent of the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. An intravenous injection of 100 mg/kg N omega-nitro-L-arginine methylester (L-NAME) caused hypertension in both diabetic rats and controls. However, the degree of hypertension in the diabetic rats was significantly lower than that in the controls. Acetylcholine (ACh)-induced vasorelaxation of the perfused mesenteric arterial bed decreased in diabetic rats. At the same time, the levels of cAMP and cGMP in the effluent of the diabetic rats were also lower than in the controls. These data indicate that NO formation is involved in the regulation of BP in rats, and is decreased in diabetic rats, due to an impairment of the vascular endothelium, including the endothelium of resistance vessels.
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PMID:Changes in endothelium-dependent relaxation and levels of cyclic nucleotides in the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. 839 May 94

Endothelium-derived nitric oxide (EDNO) is an important vasodilator substance produced by the vascular endothelium. The present in vivo and in vitro study is aimed at evaluating its role in vascular regulation and its interactions with norepinephrine (NE), endothelin-1 (ET) and superoxide anion. In male anesthetized wistar rats, inhibition of the in vivo EDNO pathway with L-NAME (an established specific inhibitor of EDNO synthesis, 1-4 (mg/kg, iv bolus) provoked sustained, dose-dependent hypertensive responses (mean arterial pressure increased 45 +/- 1.5% over baseline for more than 60 minutes at a dose of 4 mg/kg, mean +/- Sx, which was completely reversed by L-arginine, the normal substrate for EDNO synthesis). In the in vitro study on rat aortic rings, blocking the endothelial production of EDNO with L-NAME (10(-4) M), caused the most prominent enhancement of the contractile responses to NE (increased maximal responses and lowered EC50), a smaller enhancement of contraction to ET and minimal modification of the vasoconstrictive effects of superoxide anion. L-arginine (10(-4) M), on the contrary, slightly attenuated the contraction to NE and ET but without the contraction to superoxide anion. The present study confirms that EDNO system represents one of the most important physiological depressor mechanisms in vivo, and indicates that EDNO is an important, differential antagonistic mechanism against the vasoconstrictors. It is also demonstrated that L-arginine availability is generally not the rate-limiting step in the in vivo generation of EDNO. The implications of the results were discussed.
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PMID:Endothelium-derived nitric oxide: role in vascular regulation and interaction with norepinephrine, endothelin and superoxide anion. 839 68

Ephedrine is the preferred vasoconstrictor for the treatment of hypotension after epidural and spinal anesthesia in obstetrics because it preserves uterine perfusion better than pure alpha-adrenergic agonists. Previous studies of uterine vascular rings in vitro suggested that direct uterine vasoconstriction from ephedrine is reduced during pregnancy. This study examined the hypothesis that nitric oxide synthase (NOS) is up-regulated in uterine arteries during pregnancy, and that ephedrine stimulates NOS to release nitric oxide (NO) and diminish direct vasoconstriction. Uterine arterial vessels were obtained from 12 pregnant and 9 nonpregnant ewes, and vessel tension was monitored in vitro in response to escalating concentrations of ephedrine or metaraminol. In some experiments, vascular endothelium was mechanically removed, while in others antagonists of NO synthesis (N omega-nitro-L-arginine methyl ester [L-NAME], NO diffusion (hemoglobin [Hgb]), or guanylate cyclase (methylene blue [MB]) were included. In other experiments, solutions containing ephedrine were superfused over uterine arteries from pregnant ewes onto uterine arteries from nonpregnant ewes. Finally, NOS activity, determined by 14C-citrulline generation, was determined in uterine arteries from pregnant and nonpregnant ewes. Both ephedrine and metaraminol caused concentration-dependent constriction of uterine arterial rings from pregnant and nonpregnant animals. Pregnancy reduced maximum constriction from ephedrine more than metaraminol. Similarly, ephedrine-induced constriction was increased more than that of metaraminol in uterine arteries from pregnant animals treated to diminish the effects of nitric oxide (L-NAME, Hgb, MB, endothelium removal). Ephedrine's constriction of uterine arteries from nonpregnant animals was reduced when it was superfused over uterine arteries from pregnant animals. NOS activity was increased in uterine arteries from pregnant compared to nonpregnant animals. These studies confirm decreased direct uterine arterial vasoconstriction during pregnancy from ephedrine and support the hypothesis of increased release of an endogenous vasodilator (NO), either from the vascular endothelium or the vessel wall, as the cause for this decreased vasoconstriction.
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PMID:Pregnancy and ephedrine increase the release of nitric oxide in ovine uterine arteries. 856 28

Vasoconstrictor responses to endothelin-1 (ET-1) and the ETB receptor agonist sarafotoxin S6c (SXS6c) were investigated in the main pulmonary artery and pulmonary artery branch removed from rats previously exposed to 10% O2 [chronic hypoxic (CH) rats] or room air (control rats) for 2 weeks. The effects of nitric oxide synthase (NOS) inhibition with L-Nomega-nitroarginine methyl ester (L-NAME) (100 microM) on ET receptor-induced responses in these arteries were also investigated. In control rats, in rings of main pulmonary arteries and pulmonary artery branches. ET-1 induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were antagonized by the ETA receptor antagonist FR 139317 whereas SXS6c did not vasoconstrict. Chronic hypoxia had no effect on the sensitivity of the main pulmonary arteries to ET-1, whereas small vasoconstrictor responses to SCS6c were evident. ET-1 was more potent in the CH rat pulmonary artery branches than in controls. SXS6c also caused vasoconstriction with a maximum response 30% of that to ET-1 in both endothelium-intact and endothelium-denuded vessels. L-NAME increased the sensitivity to ET-1 in the CH rat main pulmonary arteries and increased the responses to low concentrations of ET-1 in the control rat main pulmonary arteries but did not affect any ET-1 responses in any other vessels. It did disclose responses to SXS6c in control rat main pulmonary arteries. L-NAME itself increased vascular tone to a greater extent in CH rat pulmonary arteries than in controls. In preconstricted pulmonary arteries, however, relaxations to acetylcholine (ACh) were diminished in the CH rats as compared with their controls. All pulmonary artery branches, denuded of their vascular endothelium, relaxed to sodium nitroprusside (SNP) and therefore exhibited endogenous vascular tone. This effect was greatest in the pulmonary artery branches from the CH rats. The results suggest that rat large pulmonary artery responses to ET-1 are normally mediated by ETA receptors. Pulmonary hypertension can potentiate ETA receptor-mediated vasoconstriction and facilitate ETB receptor-mediated vasoconstriction. Endogenous NO may normally suppress ETA receptor-mediated responses in rat main pulmonary arteries. Rat pulmonary arteries exhibit endogenous tone, which is increased by exposure to chronic hypoxia.
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PMID:Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries. 863 98

1. Prostaglandin F2 alpha (PGF2 alpha) and its synthetic analogue, fluprostenol, potently relaxed the precontracted isolated jugular vein of the rabbit (RJuV). The vasorelaxant activity of PGF2 alpha and fluprostenol was dependent upon an intact vascular endothelium. Although removal of the vascular endothelium abolished activity associated with PGF2 alpha-like agonists, it did not significantly alter the relaxant effects of prostaglandin E2 (PGE2). 2. The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at 100 microM significantly inhibited the endothelium-dependent relaxations induced by PGF2 alpha. Lower doses (1 microM, 10 microM) of L-NAME had little or no effect. The relaxant effects of PGE2 were not affected by L-NAME (1-100 microM). D-NAME at 100 microM was without effect on the vasorelaxant responses to either PGF2 alpha or PGE2. 3. The potassium (K)-channel blockers tetraethylammonium (TEA, 1 mM), barium (1 mM) and quinine (100 microM), each tested in the presence of the inactive enantiomer D-NAME (100 microM) did not significantly affect the response to PGF2 alpha. Unexpectedly, both TEA and barium significantly and partially reversed the inhibitory effects of 100 microM L-NAME, whereas quinine had no effect. In similar studies, none of the three potassium channel blockers had any effect on relaxations elicited by PGE2 when given with D-NAME or L-NAME. 4. These results indicate that the PGF2 alpha-sensitive prostanoid receptors found in the vascular endothelium of the rabbit jugular vein are of the FP-receptor subtype. Nitric oxide (NO) appears to be the predominant messenger involved in PGF2 alpha-induced relaxation of the rabbit jugular vein. Potassium channels may have a minor role in mediating the vasorelaxation response to PGF2 alpha. When both NO synthesis and K-channels are simultaneously blocked, inhibition of PGF2 alpha-induced vasorelaxation by L-NAME is opposed by K-channel blockers. This diminution of the inhibitory effect of L-NAME by TEA and barium suggests that K-channels may possibly serve a compensatory role via the NO pathway.
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PMID:Identification of a prostanoid FP receptor population producing endothelium-dependent vasorelaxation in the rabbit jugular vein. 868 Jul 40

1. The L-arginine derivatives NG-nitro-L-arginine (L-NOARG) and NG-nitro-L-arginine methyl ester (L-NAME) have been widely used to inhibit constitutive NO synthase (NOS) in different biological systems. This work was carried out to investigate whether L-NAME is a direct inhibitor of NOS or requires preceding hydrolytic bioactivation to L-NOARG for inhibition of the enzyme. 2. A bolus of L-NAME and L-NOARG (0.25 micromol) increased coronary perfusion pressure of rat isolated hearts to the same extent (21 +/- 0.8 mmHg; n = 5), but the effect developed more rapidly following addition of L-NOARG than L-NAME (mean half-time: 0.7 vs 4.2 min). The time-dependent onset of the inhibitory effect of L-NAME was paralleled by the appearance of L-NOARG in the coronary effluent. 3. Freshly dissolved L-NAME was a 50 fold less potent inhibitor of purified brain NOS (mean IC50 = 70 microM) than L-NOARG (IC50 = 1.4 microM), but the apparent inhibitory potency of L-NAME approached that of L-NOARG upon prolonged incubation at neutral or alkaline pH. H.p.l.c. analyses revealed that NOS inhibition by L-NAME closely correlated with hydrolysis of the drug to L-NOARG. 4. Freshly dissolved L-NAME contained 2% of L-NOARG and was hydrolyzed with a half-life of 365 +/- 11.2 min in buffer (pH 7.4), 207 +/- 1.7 min in human plasma, and 29 +/- 2.2 min in whole blood (n = 3 in each case). When L-NAME was preincubated in plasma or buffer, inhibition of NOS was proportional to formation of L-NOARG, but in blood the inhibition was much less than expected from the rates of L-NAME hydrolysis. This was explained by accumulation of L-NOARG in blood cells. 5. These results suggest that L-NAME represents a prodrug lacking NOS inhibitory activity unless it is hydrolyzed to L-NOARG. Bioactivation of L-NAME proceeds at moderate rates in physiological buffers, but is markedly accelerated in tissues such as blood or vascular endothelium.
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PMID:Inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME): requirement for bioactivation to the free acid, NG-nitro-L-arginine. 883 69

The present study was designed to define the role of nitric oxide (NO) in tumor microcirculation, through the direct intravital microcirculatory observations after administration of NO synthase (NOS) inhibitor and NO donor both regionally and systemically. More specifically, we tested the following hypotheses: 1) endogenous NO derived from tumor vascular endothelium and/or tumor cells increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability, 2) exogenous NO can increase tumor blood flow via vessel dilatation and decrease leukocyte-endothelial interactions, and 3) NO production and tissue responses to NO are tumor dependent. To this end, a murine mammary adenocarcinoma (MCaIV) and a human colon adenocarcinoma (LS174T) were implanted in the dorsal skinfold chamber in C3H and severe combined immunodeficient mice, respectively, and observed by means of intravital fluorescence microscopy. Both regional and systemic inhibition of endogenous NO by N omega-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L superfusion or 10 mg/kg intravenously) significantly decreased vessel diameter and local blood flow rate. The diameter change was dominant on the arteriolar side. Superfusion of NO donor (spermine NO, 100 mumol/L) increased tumor vessel diameter and flow rate, whereas systemic injection of spermine NO (2.62 mg/kg) had no significant effect on these parameters. Rolling and stable adhesion of leukocytes were significantly increased by intravenous injection of L-NAME. In untreated animals, both MCaIV and LS174T tumor vessels were leaky to albumin. Systemic NO inhibition significantly attenuated tumor vascular permeability of MCaIV but not of LS174T tumor. Immunohistochemical studies, using polyclonal antibodies to endothelial NOS and inducible NOS, revealed a diffuse pattern of positive labeling in both MCaIV and LS174T tumors. Nitrite and nitrate levels in tumor interstitial fluid of MCaIV but not of LS174T were significantly higher than that in normal subcutaneous interstitial fluid. These results support our hypotheses regarding the microcirculatory response to NO in tumors. Modulation of NO level in tumors is a potential strategy for altering tumor hemodynamics and thus improving oxygen, drug, gene vector, and effector cell delivery to solid tumors.
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PMID:Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. 903 84

Nitric oxide (NO) plays an important role in the maintenance of a constant vasodilator tone in the vasculature and confers anti-adhesive properties to the normal functioning endothelium. Whether endogenous NO release influences platelet thrombus formation and neutrophil-endothelium interactions under arterial blood flow conditions was investigated in ex vivo bioassay experiments using superfusion flow chambers. Surfaces of intact or deeply injured porcine arterial segments were exposed to flowing porcine arterial blood under shear conditions typical to patent (424 sec-1) and stenosed (3397 sec-1) arteries, at baseline and after administration of the specific inhibitor of NO synthesis N omega-nitro-L-arginine methyl ester (L-NAME, 3 mg/kg + 3 mg/kg/h; i.v.). L-NAME induced a rapid and significant rise in arterial blood pressure, with a moderate reduction in heart rate. 51Cr platelet deposition on the exposed arterial media, which averaged 15.9 +/- 2.9 x 10(6)/cm2 at a shear rate of 424 sec-1, was increased by L-NAME, to 20.4 +/- 2.8 x 10(6)/cm2 (p < 0.05). At 3397 sec-1 of shear rate, platelet deposition was higher (71.4 +/- 11.9 x 10(6)/cm2) (p < 0.001), and was enhanced by 34%, to 95.8 +/- 12.5 x 10(6)/cm2 (p < 0.05), after L-NAME treatment. 111In neutrophil adhesion to the vascular endothelium was also increased by L-NAME by 83%, from 10.6 +/- 2.5 to 19.4 +/- 5.7 x 10(3)/cm2 (p < 0.05) at 424 sec-1, and by 110%, from 14.1 +/- 4.3 to 29.7 +/- 10.0 x 10(3)/cm2 (p < 0.05) at 3397 sec-1 of shear rate. These results suggest that endogenous NO may be an important modulator of thrombotic and inflammatory processes in patent as well as in stenosed arteries.
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PMID:Endogenous nitric oxide release modulates mural platelet thrombosis and neutrophil-endothelium interactions under low and high shear conditions. 906 55

The effects of defibrotide on leukocyte-endothelial cell interaction and P-selectin surface expression on the microvascular endothelium were investigated. Intravital microscopy was performed in the rat mesenteric microcirculation. The rat mesentery was superfused either with Krebs-Henseleit solution (i.e., control) or 50 microM NG nitro-L-arginine methyl ester (L-NAME). Defibrotide (40 mg/kg) was intravenously infused to control rats and to L-NAME superfused rats. P-selectin expression on mesenteric venules was also investigated by immunohistochemistry. L-NAME caused a significant, time-dependent increase in leukocyte rolling (13 +/- 5 to 101 +/- 18 cells/ min; p < 0.001) and adherence (1.6 +/- 0.7 to 12 +/- 2.5 cells/100 microns length of venule; p < 0.01) compared to control superfused rats. However, intravenous infusion of defibrotide (40 mg/kg) consistently decreased the L-NAME-induced leukocyte rolling (101 +/- 18 to 9.3 +/- 1.3 cells/min; p < 0.001) and adherence (12 +/- 2.5 to 1.9 +/- 1.1 cells/100 microns length of venule; p < 0.01). Exposure of rat mesentery to L-NAME consistently increased P-selectin surface expression (p < 0.01) on the vascular endothelium which was significantly attenuated by defibrotide (p < 0.05). In vivo administration of defibrotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. Since P-selectin was upregulated by the specific nitric oxide synthase inhibitor L-NAME, the present study also confirms the crucial role exerted by nitric oxide in attenuating leukocyte-endothelial cell interaction during various pathophysiological conditions.
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PMID:Effects of defibrotide on leukocyte-endothelial cell interaction in the rat mesenteric vascular bed: role of P-selectin. 912 Dec 23

The effect of diatrizoate (Urografin325) on the cumulative dose-response curve of the vasodilatory response to acetylcholine was studied in the isolated perfused rat kidney (IPRK). The effect of 1-nitroarginine methyl ester (L-NAME) (10 mumol l-1) on the cumulative concentration-response curve of the vasodilatory response to acetylcholine and sodium nitroprusside was also studied. Acetylcholine is a vasodilator dependent on nitric oxide (NO) synthesis by the endothelium; sodium nitroprusside is a vasodilator not dependent on endogenous NO synthesis and L-NAME is an inhibitor of endogenous NO synthesis. The effect of L-NAME (10 mumol l-1) on the vasodilatory effect of diatrizoate which is observed in the presence of endothelin A receptor antagonist (BQ123, 10 mumol l-1) was also studied. In all experiments an infusion of angiotensin II (5 ng min-1) was maintained to increase the vascular tone of the preparation. Acetylcholine induced vasodilatation and the maximum increase in renal perfusate flow (RPF) was 17.0 +/- 1.7%, (p < 0.05). Diatrizoate (20 mgl ml-1 perfusate concentration) which induced a sustained fall in the RPF (-31.0 +/- 1.7%, p < 0.05) had no effect on the vasodilatory response to acetylcholine, and a similar increase in the RPF (17.8 +/- 2.2%, p < 0.05) was observed. In contrast, L-NAME (10 mumol l-1) completely abolished the vasodilatory effect of acetylcholine and produced instead a modest decrease in RPF by -5.0 +/- 1.7% (p < 0.05). The vasodilatory effect of sodium nitroprusside was not affected by L-NAME, confirming its selectivity as an inhibitor of endogenous NO synthesis in the IPRK. The maximum increase in the RPF induced by sodium nitroprusside was 23.1 +/- 2.0% (p < 0.05) in the absence of L-NAME and 21.2 +/- 2.2% (p < 0.05) in its presence. L-NAME did not interfere with the vasodilatation induced by diatrizoate in the presence of BQ123. In the presence of BQ123 alone the RPF increased from 23.3 +/- 1.4 ml min-1 g-1 to 26.5 +/- 1.0 ml min-1 g-1 (p < 0.05). In the presence of L-NAME and BQ123 the RPF increased from 24.4 +/- 3.0 ml min-1 g-1 to 27.2 +/- 2.7 ml min-1 g-1 (p < 0.05). There was no difference between the two groups (p > 0.05). In conclusion, diatrizoate did not interfere with endothelium derived NO-dependent vasodilatation in the kidney. A reduced production of NO in the vascular endothelium induced by contrast media is unlikely to play any role in the pathophysiology of the increase in renal vascular resistance produced by these agents. The renal vasodilatation induced by diatrizoate is not dependent on endogenous production of NO.
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PMID:Effect of radiographic contrast media on endothelium derived nitric oxide-dependent renal vasodilatation. 913 41

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