Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO-synthase blockade

2002 ◽  
Vol 80 (11) ◽  
pp. 1106-1118 ◽  
Author(s):  
Jodan D Ratz ◽  
Michael A Adams ◽  
Brian M Bennett
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Nitrate Tolerance ◽  
Metabolite Formation ◽  
No Donor ◽  
No Donors ◽  
Nos Inhibitors ◽  
Pressure Lowering ◽  
Oxide Synthase

Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide (NO) donors. We used this model as a sensitive index to evaluate the relative importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the development of nitrate tolerance. NOS-blockade hypertension using NG-nitro-L-arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or tolerant NOS-blockade hypertensive animals, indicating that NO-dependent vasodilatory mechanisms remain intact despite the development of GTN tolerance. The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were restored 48 h after cessation of chronic GTN exposure. These alterations in the pharmacodynamic response to GTN during tolerance development and reversal were associated with parallel changes in the pattern of GTN metabolite formation, suggesting that the activity of one or more enzymes involved in nitrate metabolism was altered as a consequence of chronic GTN exposure. These findings suggest that the vasodilation resulting from the vascular biotransformation of GTN to NO (or a closely related species) is severely compromised in nitrate-tolerant animals, and that although other mechanisms may contribute to the vascular changes observed following the development of GTN tolerance, decreased GTN bioactivation is likely the most important.Key words: biotransformation, glyceryl trinitrate, hypertension, nitric oxide, tolerance.

Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

2008 ◽  
Vol 294 (4) ◽  
pp. E768-E777 ◽  
Author(s):  
Mary Courtney Moore ◽  
Catherine A. DiCostanzo ◽  
Marta S. Smith ◽  
Ben Farmer ◽  
Tiffany D. Rodewald ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
No Donor ◽  
Nitric Oxide Synthase Inhibitor ◽  
Significant Difference ◽  
Nos Inhibitors ◽  
Hepatic Glucose ◽  
Hepatic Portal ◽  
Oxide Synthase ◽  
Arterial Glucose

Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal) hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: control (receiving intraportal saline infusion; n = 8) and LN [receiving NG-nitro-l-arginine methyl ester (l-NAME), a nonspecific NOS inhibitor; n = 11] intraportally at 0.3 mg·kg−1·min−1 for 90 min (P2). During the final 60 min of study (P3), l-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 μg·kg−1·min−1 while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional glucose extraction (NHFE) in control dogs was 0.034 ± 0.016, 0.039 ± 0.015, and 0.056 ± 0.019 during P1, P2, and P3, respectively. NHFE in LN was 0.045 ± 0.009 and 0.111 ± 0.007 during P1 and P2, respectively ( P < 0.05 vs. control during P2), and 0.087 ± 0.009 and 0.122 ± 0.016 ( P < 0.05) during P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204 ± 5 vs. 138 ± 11 mg/dl ( P < 0.05) in LN vs. control to compensate for l-NAME's effect on blood flow. Therefore, another group (LNlow; n = 4) was studied in the same manner as LN/SAL, except that arterial glucose was clamped at the same concentrations as in control. NHFE in LNlow was 0.052 ± 0.008, 0.093 ± 0.023, and 0.122 ± 0.021 during P1, P2, and P3, respectively ( P < 0.05 vs. control during P2 and P3), with no significant difference in glucose infusion rates. Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.

scholarly journals Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-κB binding to DNA

1997 ◽  
Vol 322 (2) ◽  
pp. 609-613 ◽  
Author(s):  
Song Kyu PARK ◽  
Hsin Lee LIN ◽  
Sean MURPHY
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Interferon Γ ◽  
No Production ◽  
No Donor ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase ◽  
Spermine Nonoate ◽  
Dna Complex

Treatment of astroglial cells with interleukin 1β and interferon γ transcriptionally activates the nitric oxide synthase (NOS)-2 gene. The duration of mRNA expression is brief because of transcript instability. In addition, NO donors reduce the expression of NOS-2 mRNA dramatically by reducing the rate of transcription. In this study we observed that the NO donor, spermine NONOate did not inhibit the activation and translocation of NF-κB, a key transcription factor in the induction of NOS-2, but inhibited formation of the NF-κB–DNA complex. This effect was reversed by methaemoglobin (acting as an NO trap) and by the reducing agent dithiothreitol. Formation of the interferon-regulatory factor–DNA complex was unaffected by NO. These results suggest that NO can modulate its own production by interfering with NF-κB interaction with the promoter region of the NOS gene, a negative feedback effect that may be important for limiting NO production in vivo.

Nitric oxide mediates human chorionic gonadotrophin-induced prostaglandin E generation in rat oocyte - cumulus complexes

1997 ◽  
Vol 9 (4) ◽  
pp. 391 ◽  
Author(s):  
Alicia Jawerbaum ◽  
Elida T. Gonzalez ◽  
Alicia Faletti ◽  
Virginia Novaro ◽  
Martha A. F. Gimeno
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
No Synthase ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Prostaglandin E ◽  
No Donors ◽  
Nos Inhibitors ◽  
Preovulatory Follicles

To determine whether nitric oxide (NO) generation mediates human chorionic gonadotrophin (hCG)-induced prostaglandin E (PGE) secretion by oocyte–cumulus complexes (OCC), the secretion of PGE by cultured rat OCC in the presence of NO donors and NO synthase (NOS) inhibitors was characterized. NO donors (sodium nitroprusside and 3-morpholino-sydnonimine- hydrochloride) increased PGE accumulation in OCC to values similar to those obtained in the presence of hCG. The three NOS inhibitors tested (N G -nitro-L-arginine methyl ester, NG -monomethyl-L-arginine and aminoguanidine) prevented the hCG-induced PGE accumulation in cultured OCC. This effect appears to be specific since D-enantiomers NG -nitro-D-arginine methyl ester and NG -monomethyl-D-arginine had no effect. The present results suggest that NO mediates the hCG-induced accumulation of PGE in rat OCC, a process which may occur in vivo in preovulatory follicles prior to ovulation.

The distribution of NADPH-diaphorase-labelled interneurons and the role of nitric oxide in the swimming system of Xenopus laevis larvae

2000 ◽  
Vol 203 (4) ◽  
pp. 705-713 ◽  
Author(s):  
D.L. McLean ◽  
K.T. Sillar
Keyword(s):  
Nitric Oxide ◽  
Xenopus Laevis ◽  
Swimming Activity ◽  
Nadph Diaphorase ◽  
Membrane Properties ◽  
Neuronal Membrane ◽  
Cycle Period ◽  
No Donor ◽  
Nos Inhibitors

The possible involvement of the free radical gas nitric oxide (NO) in the modulation of spinal rhythm-generating networks has been studied using Xenopus laevis larvae. Using NADPH-diaphorase histochemistry, three putative populations of nitric oxide synthase (NOS)-containing cells were identified in the brainstem. The position and morphology of the largest and most caudal population suggested that a proportion of these neurons is reticulospinal. The possible contribution of nitrergic neurons to the control of swimming activity was examined by manipulating exogenous and endogenous NO concentrations in vivo with an NO donor (SNAP, 100–500 micromol l(−)(1)) and NOS inhibitors (l-NAME and l-NNA, 0.5-5 mmol l(−)(1)), respectively. In the presence of SNAP, swim episode duration decreased and cycle period increased, whereas the NOS inhibitors had the opposite effects. We conclude from these data that the endogenous release of NO from brainstem neurons extrinsic to the spinal cord of Xenopus laevis larvae exerts a continuous modulatory influence on swimming activity, functioning like a ‘brake’. Although the exact level at which NO impinges upon the swimming rhythm generator has yet to be determined, the predominantly inhibitory effect of NO suggests that the underlying mechanisms of NO action could involve modulation of synaptic transmission and/or direct effects on neuronal membrane properties.

Nitric oxide modulates cGMP levels in neurons of the inner and outer retina in opposite ways

1998 ◽  
Vol 15 (5) ◽  
pp. 945-955 ◽  
Author(s):  
SEBASTIAN GOTZES ◽  
JAN de VENTE ◽  
FRANK MÜLLER
Keyword(s):  
Nitric Oxide ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Outer Retina ◽  
Inner Retina ◽  
No Donors ◽  
Nos Inhibitors ◽  
No Release ◽  
Oxide Synthase

In the mammalian retina, neuronal nitric oxide synthase (NOS) is mainly localized in subpopulations of amacrine cells. One function of nitric oxide (NO) is to stimulate soluble guanylate cyclases which in turn synthesize cGMP. We used an antibody specific for cGMP to demonstrate cGMP-like immunoreactivity (cG-IR) in bovine, rat, and rabbit retinae and investigated the effects on cGMP levels of both exogenously applied NO and of endogenously released NO. We found that cGMP levels in inner and outer retina were controlled in opposite ways. In the presence of the NO-donors SNP, SIN-1 or SNAP, cG-IR was prominent in neurons of the inner retina, mainly in cone bipolar cells, some amacrine and ganglion cells. Retinae incubated in IBMX showed weak cG-IR in bipolar cells. Glutamate increased cG-IR in the inner retina, presumably by stimulating endogenous NO release, whereas NOS inhibitors or GABA and glycine decreased cG-IR in bipolar cells by reducing NO release. In somata, inner segments and spherules of rod photoreceptors the situation was reversed. cG-IR was undetectable in the presence of NO-donors or glutamate, was moderate in IBMX-treated retinae, but increased strongly in the presence of NOS inhibitors or GABA/glycine. We conclude that NO is released endogenously in the retina. In the presence of NO, cGMP levels are increased in neurons of the inner retina, but are decreased in rods.

Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II

2002 ◽  
Vol 282 (6) ◽  
pp. H2377-H2385 ◽  
Author(s):  
Mary D. Frame ◽  
Randall J. Fox ◽  
Dongsoo Kim ◽  
Amy Mohan ◽  
Bradford C. Berk ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitrate Tolerance ◽  
Oxygen Species ◽  
Continuous Administration ◽  
Adult Rats ◽  
No Donors ◽  
Vascular Responses ◽  
Left Flank

Our purpose was to evaluate hyporesponsivity to nitric oxide (NO)-induced dilation in small arterioles during nitrate tolerance. An Alza osmotic pump was implanted in the left flank of adult rats ( n = 56) for continuous administration of nitroglycerin (140 μg/h) or vehicle (propylene glycol). On postoperative day 3, arcade (∼50-μm diameter) and terminal (∼20 μm) arterioles were observed in the cremaster preparation with in vivo video microscopy. Local vascular responses were obtained with micropipette-applied NO donors, with and without superoxide dismutase (SOD), Mn(III) tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP), or losartan. On day 3, NO-mediated dilation was significantly attenuated in nitroglycerin-treated rats. Attenuation was greater in the terminal arterioles compared with the arcades. Control responses were restored by SOD, MnTBAP, or losartan, suggesting a role for elevated angiotensin II and reactive oxygen species (ROS) as mediators of the attenuated NO dilation (nitrate tolerance). Addition of losartan to the drinking water likewise prevented nitrate tolerance. In summary, terminal arterioles are affected by nitrates to a greater extent than the arcade arterioles that feed them, in a process dependent on angiotensin II and ROS.

In vivo pharmacological evaluation off two novel type II (inducible) nitric oxide synthase inhibitors

1995 ◽  
Vol 73 (5) ◽  
pp. 665-669 ◽  
Author(s):  
W. Ross Tracey ◽  
Masaki Nakane ◽  
Fatima Basha ◽  
George Carter
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
No Production ◽  
Type Ii ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Inducible Nitric Oxide

Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and >95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.Key words: nitric oxide, nitrite, nitrate, sepsis, lipopolysaccharide.

scholarly journals CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress

2010 ◽  
Vol 298 (3) ◽  
pp. C665-C678 ◽  
Author(s):  
Yixin Tang ◽  
Elizabeth A. Scheef ◽  
Zafer Gurel ◽  
Christine M. Sorenson ◽  
Colin R. Jefcoate ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Wild Type ◽  
Enos Expression ◽  
No Donor ◽  
Enos Activity ◽  
Oxide Synthase

We have recently shown that deletion of constitutively expressed CYP1B1 is associated with attenuation of retinal endothelial cell (EC) capillary morphogenesis (CM) in vitro and angiogenesis in vivo. This was largely caused by increased intracellular oxidative stress and increased production of thrombospondin-2, an endogenous inhibitor of angiogenesis. Here, we demonstrate that endothelium nitric oxide synthase (eNOS) expression is dramatically decreased in the ECs prepared from retina, lung, heart, and aorta of CYP1B1-deficient (CYP1B1−/−) mice compared with wild-type (CYP1B1+/+) mice. The eNOS expression was also decreased in retinal vasculature of CYP1B1−/− mice. Inhibition of eNOS activity in cultured CYP1B1+/+ retinal ECs blocked CM and was concomitant with increased oxidative stress, like in CYP1B1−/− retinal ECs. In addition, expression of eNOS in CYP1B1−/− retinal ECs or their incubation with a nitric oxide (NO) donor enhanced NO levels, lowered oxidative stress, and improved cell migration and CM. Inhibition of CYP1B1 activity in the CYP1B1+/+ retinal ECs resulted in reduced NO levels and attenuation of CM. In contrast, expression of CYP1B1 increased NO levels and enhanced CM of CYP1B1−/− retinal ECs. Furthermore, attenuation of CYP1B1 expression with small interfering RNA proportionally lowered eNOS expression and NO levels in wild-type cells. Together, our results link CYP1B1 metabolism in retinal ECs with sustained eNOS activity and NO synthesis and/or bioavailability and low oxidative stress and thrombospondin-2 expression. Thus CYP1B1 and eNOS cooperate in different ways to lower oxidative stress and thereby to promote CM in vitro and angiogenesis in vivo.

Increased prostaglandin E generation and enhanced nitric oxide synthase activity in the non-insulin-dependent diabetic embryo during organogenesis

1998 ◽  
Vol 10 (2) ◽  
pp. 191 ◽  
Author(s):  
Alicia Jawerbaum ◽  
Elida T. Gonzalez ◽  
Virginia Novaro ◽  
Alicia Faletti ◽  
Debora Sinner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Congenital Abnormalities ◽  
Prostaglandin E ◽  
No Donor ◽  
Insulin Dependent ◽  
Nos Inhibitor ◽  
Insulin Dependent Diabetic ◽  
Oxide Synthase

Embryonic development, prostaglandin E (PGE) generation and nitric oxide synthase (NOS) activity during organogenesis were evaluated in an experimental rat model of non-insulin- dependent diabetes (NIDD) generated by neonatal administration of streptozotocin. Gross malformations were detected in 5% of NIDD embryos and these embryos were all non-viable; in the other 95%, growth was retarded but no congenital abnormalities were found. Control embryos were all alive and not malformed. The NIDD 11-day embryos secreted more PGE into the incubation medium than did controls. The NO donor SIN–1 increased PGE production in both control and NIDD embryos. A NOS inhibitor (L-NMMA) reduced PGE generation in both experimental groups, suggesting a modulatory role of NO on embryonic PGE production. Activity of NOS was higher in NIDD 11-day embryos than in controls. Treatment in vivo of control and NIDD rats (Days 7–11 of gestation) with a NOS inhibitor (L-NAME; 5 mg kg-1 i.p.) reduced embryonic PGE production and induced a higher resorption rate and an increase in neural-tube defects. The results suggest that NO modulates PGE generation in the organogenetic embryo. In the NIDD model, overproduction of NO is observed, this NO probably enhancing embryonic PGE production. The relationship between PGE generation and the appearance of congenital abnormalities is discussed.

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