In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade

1992 ◽  
Vol 262 (6) ◽  
pp. G996-G1001 ◽  
Author(s):  
C. C. Sieber ◽  
R. J. Groszmann
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Muscle Tone ◽  
Portal Vein Ligation ◽  
Alpha Adrenoceptor ◽  
No Formation ◽  
Adrenoceptor Agonist ◽  
Mesenteric Arterial Bed ◽  
Vascular Smooth Muscle Tone

The endothelial cell plays an important role in the local control of vascular smooth muscle tone. Portal hypertension is accompanied by systemic vasodilatation and a decreased response to vasoconstrictors, changes especially evident in the superior mesenteric arterial bed. To evaluate a possible effect of the locally released endothelium-derived relaxing factor nitric oxide (NO), we tested the effect of NO blockade in in vitro perfused superior mesenteric arterial beds of normal (sham) and portal hypertensive (PVL) rats, induced by partial portal vein ligation. A significant (n = 7/group; P = 0.02) hyporeactivity to the vasoconstrictive properties of the alpha-adrenoceptor agonist methoxamine (3 x 10(-6) to 3 x 10(-4) M) was prevented by blocking NO formation in PVL compared with sham rats, using the stereospecific biosynthesis antagonist N omega-nitro-L-arginine (10(-4) M, n = 7/group; NS for all methoxamine concentrations tested). This effect was reversed by the NO precursor L-arginine (10(-3) M, n = 5/group). In conclusion, these in vitro results in mesenteric vessels demonstrate that 1) portal hypertension is accompanied by a hyporeactivity to the vasopressor methoxamine and 2) locally released NO in this preparation is responsible for the decreased vasoconstrictive response.

Modulation of cerebral arterial tone by endothelium-derived relaxing factor

1993 ◽  
Vol 264 (4) ◽  
pp. H1245-H1250 ◽  
Author(s):  
J. E. Brian ◽  
R. H. Kennedy
Keyword(s):  
Nitric Oxide ◽  
Muscle Tone ◽  
Cerebral Arteries ◽  
Maximum Tension ◽  
Relaxing Factor ◽  
Middle Cerebral Arteries ◽  
Endothelium Derived Relaxing Factor ◽  
Vascular Smooth Muscle Tone ◽  
Dose Dependent ◽  
Arterial Tone

This study was designed to further elucidate the role of the endothelium in regulation of cerebral vascular smooth muscle tone. Dose-dependent vasoconstrictive effects of serotonin (5-HT) were examined in endothelium-intact and endothelium-denuded ring segments prepared from canine basilar and middle cerebral arteries. Some preparations were pretreated with 10(-5) M N omega-nitro-L-arginine (L-NNA), an agent that inhibits the production of L-arginine-derived nitric oxide, one of the compounds proposed to be endothelium-derived relaxing factor. L-NNA alone elicited marked dose-dependent increases in tension in endothelium-intact preparations; a significantly smaller response was seen in endothelium-denuded preparations. The effects of L-NNA on endothelium-intact preparations were partially reversed by washing and treatment with L-arginine. The maximum tension induced by 5-HT was approximately doubled by removal of the endothelium as well as by L-NNA treatment of endothelium-intact preparations; a slight increase in maximum tension occurred in endothelium-denuded preparations treated with L-NNA. The concentration of 5-HT producing half-maximal contraction (ED50) was not affected by L-NNA. These data suggest that L-arginine-derived nitric oxide modulates canine cerebral arterial tone in both the resting state and during contraction with 5-HT.

scholarly journals Nitric oxide interactions with cobalamins: biochemical and functional consequences

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1857-1864 ◽  
Author(s):  
M Brouwer ◽  
W Chamulitrat ◽  
G Ferruzzi ◽  
DL Sauls ◽  
JB Weinberg
Keyword(s):  
Nitric Oxide ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Paramagnetic Resonance ◽  
No Formation ◽  
Iron Nitrosyl ◽  
Wide Range ◽  
Functional Consequences

Abstract Nitric oxide (NO) is a paramagnetic gas that has been implicated in a wide range of biologic functions. The common pathway to evoke the functional response frequently involves the formation of an iron- nitrosyl complex in a target (heme) protein. In this study, we report on the interactions between NO and cobalt-containing vitamin B12 derivatives. Absorption spectroscopy showed that of the four Co(III) derivatives (cyanocobalamin [CN-Cbl], aquocobalamin [H2O-Cbl], adenosylcobalamin [Ado-Cbl], and methylcobalamin [MeCbl]), only the H2O- Cbl combined with NO. In addition, electron paramagnetic resonance spectroscopy of H2O-Cbl preparations showed the presence of a small amount of Cob-(II)alamin that was capable of combining with NO. The Co(III)-NO complex was very stable, but could transfer its NO moiety to hemoglobin (Hb). The transfer was accompanied by a reduction of the Co(III) to Co(II), indicating that NO+ (nitrosonium) was the leaving group. In accordance with this, the NO did not combine with the Hb Fe(II)-heme, but most likely with the Hb cysteine-thiolate. Similarly, the Co(III)-NO complex was capable of transferring its NO to glutathione. Ado-Cbl and Me-Cbl were susceptible to photolysis, but CN- Cbl and H2O-Cbl were not. The homolytic cleavage of the Co(III)-Ado or Co(III)-Me bond resulted in the reduction of the metal. When photolysis was performed in the presence of NO, formation of NO-Co(II) was observed. Co(II)-nitrosyl oxidized slowly to form Co(III)-nitrosyl. The capability of aquocobalamin to combine with NO had functional consequences. We found that nitrosylcobalamin had diminished ability to serve as a cofactor for the enzyme methionine synthase, and that aquocobalamin could quench NO-mediated inhibition of cell proliferation. Our in vitro studies therefore suggest that interactions between NO and cobalamins may have important consequences in vivo.

ET-1 and TNF-α in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats

2004 ◽  
Vol 286 (2) ◽  
pp. G294-G303 ◽  
Author(s):  
Bao Luo ◽  
Lichuan Liu ◽  
Liping Tang ◽  
Junlan Zhang ◽  
Yiqun Ling ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Nitric Oxide Synthase ◽  
Receptor Expression ◽  
Heme Oxygenase 1 ◽  
Portal Vein Ligation ◽  
Biliary Cirrhosis ◽  
Duct Ligation ◽  
Tnf Α ◽  
Oxide Synthase

Common bile duct ligation (CBDL) triggers a molecular cascade resulting in the hepatopulmonary syndrome (HPS). Both increased hepatic endothelin-1 (ET-1) production and pulmonary vascular ETB receptor expression with stimulation of endothelial nitric oxide synthase and TNF-α mediated inducible nitric oxide synthase and heme oxygenase-1 expression in pulmonary intravascular macrophages occur. Whether biliary cirrhosis is unique in triggering ET-1 and TNF-α alterations and HPS is unknown. We evaluated for HPS in rat prehepatic portal hypertension [partial portal vein ligation (PVL)], biliary (CBDL) and nonbiliary [thioacetamide treatment (TAA)] cirrhosis, and assessed ET-1 infusion in normal and PVL animals. Control, PVL, CBDL, TAA-treated, and ET-1-infused PVL animals had ET-1 and TNF-α levels measured and underwent molecular and physiological evaluation for HPS. HPS developed only in biliary cirrhosis in association with increased plasma ET-1 and TNF-α levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF-α levels and TAA treatment increased TNF-α levels alone, and neither resulted in the full development of molecular or physiological changes of HPS despite portal pressure increases similar to those after CBDL. Exogenous ET-1 increased TNF-α levels and triggered HPS after PVL. Combination of ET-1 and TNF-α overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF-α levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF-α interact to trigger pulmonary microvascular changes in experimental HPS.

Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension

2002 ◽  
Vol 282 (6) ◽  
pp. H2084-H2090 ◽  
Author(s):  
Yasuko Iwakiri ◽  
Ming-Hung Tsai ◽  
Timothy J. McCabe ◽  
Jean-Philippe Gratton ◽  
David Fulton ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Specific Activity ◽  
Ex Vivo ◽  
Active Form ◽  
Initial Increase ◽  
No Production ◽  
Portal Vein Ligation ◽  
Sprague Dawley ◽  
Perfusion Studies

Akt, also known as protein kinase B, is a serine/threonine kinase. Akt becomes active when phosphorylated by the activation of receptor tyrosine kinases, G protein-coupled receptors, and mechanical forces such as shear stress. Studies in vitro have shown that Akt can directly phosphorylate endothelial nitric oxide (NO) synthase (eNOS) and activate the enzyme, leading to NO production. The aim of this study was to test the hypothesis that the phosphorylation of eNOS plays a role in the enhanced NO production observed in early portal hypertension. Male Sprague-Dawley rats were subjected to either sham or portal vein ligation (PVL), and mesenteric arterial beds were used for ex vivo perfusion studies. Mesenteric arterial beds from PVL rats had an approximately 60–70% decrease in response to methoxamine (an α1-agonist and vasoconstrictor) compared with the sham group ( P < 0.01). When N G-monomethyl-l-arginine (a NOS inhibitor) was added to the perfusion, the difference in perfusion pressure between the two groups was abolished, suggesting that enhanced NO production in the PVL group blunted the response to the vasoconstrictor. The reduced responsiveness in PVL was not due to changes in eNOS expression but was due to an increase in enzyme-specific activity, suggesting posttranslational modification of eNOS. The phosphorylation of eNOS at Ser1176 was significantly increased by twofold ( P < 0.05) in the PVL group. Furthermore, PVL significantly increased Akt phosphorylation (an active form of Akt) by threefold ( P< 0.05). When vessels were treated with wortmannin (10 nM) to block the phosphatidylinositol-3-OH-kinase/Akt pathway, NO-induced vasodilatation was significantly reduced. These results suggest that the phosphorylation of eNOS by Akt activates the enzyme and may be the first step leading to an initial increase in NO production in portal hypertension.

scholarly journals Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice

2009 ◽  
Vol 297 (2) ◽  
pp. G306-G311 ◽  
Author(s):  
Xiaofeng Sun ◽  
Andrés Cárdenas ◽  
Yan Wu ◽  
Keichi Enjyoji ◽  
Simon C. Robson
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Portal Vein ◽  
Vascular Permeability ◽  
Extracellular Nucleotides ◽  
Intestinal Bleeding ◽  
Portal Vein Ligation ◽  
Dependent Manner ◽  
Wild Type ◽  
Intestinal Hemorrhage

Vasoactive factors that regulate splanchnic hemodynamics include nitric oxide, catecholamines, and possibly extracellular nucleosides/nucleotides (adenosine, ATP). CD39/ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1) is the major vascular ectonucleotidase that hydrolyzes extracellular nucleotides. CD39 activity may be modulated by vascular injury, inflammation, and altered oxygen tension. Altered Cd39 expression by the murine hepatosplanchnic vasculature may impact hemodynamics and portal hypertension (PHT) in vivo. We noted that basal portal pressures (PPs) were comparable in wild-type and Cd39-null mice ( n = 9). ATP infusions resulted in increments in PP in wild-type mice, but, in contrast, this significantly decreased in Cd39-null mice ( n = 9) post-ATP in a nitric oxide-dependent manner. We then studied Cd39/NTPDase1 deletion in the regulation of portal hemodynamics, vascular integrity, and intestinal permeability in a murine model of PHT. Partial portal vein ligation (PPVL) was performed in Cd39-null ( n = 44) and wild-type ( n = 23) mice. Sequential measurements obtained after PPVL were indicative of comparable levels of PHT (ranges 14–29 mmHg) in both groups. There was one death in the wild-type group and eight in the Cd39-null group from intestinal bleeding ( P = 0.024). Circulatory stasis in the absence of overt portal vein thrombosis, portal congestion, intestinal hemorrhage, and increased permeability were evident in all surviving Cd39-null mice. Deletion of Cd39 results in deleterious outcomes post-PPVL that are associated with significant microcirculatory derangements and major intestinal congestion with hemorrhage mimicking acute mesenteric occlusion. Absent Cd39/NTPDase1 and decreased generation of adenosine in the splanchnic circulation cause heightened vascular permeability and gastrointestinal hemorrhage in PPVL.

scholarly journals Arginine Therapy for Lung Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeremy A. Scott ◽  
Harm Maarsingh ◽  
Fernando Holguin ◽  
Hartmut Grasemann
Keyword(s):  
Nitric Oxide ◽  
Lung Development ◽  
Lung Diseases ◽  
Muscle Tone ◽  
Therapeutic Strategies ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Nos Inhibitors ◽  
Inflammatory Processes ◽  
Vascular Smooth Muscle Tone

Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.

scholarly journals Effects of chronic nitric oxide synthase inhibition on responses to acute exercise in swine

2008 ◽  
Vol 104 (1) ◽  
pp. 186-197 ◽  
Author(s):  
Richard M. McAllister ◽  
Sean C. Newcomer ◽  
Eric R. Pope ◽  
James R. Turk ◽  
M. Harold Laughlin
Keyword(s):  
Nitric Oxide ◽  
Acute Exercise ◽  
Maximal Exercise ◽  
Tap Water ◽  
Treadmill Running ◽  
Blood Flows ◽  
No Formation ◽  
Exercise Induced ◽  
Oxide Synthase

Nitric oxide (NO) is potentially involved in several responses to acute exercise. We tested the hypotheses that inhibition of NO formation reduces maximal O2 delivery to muscle, but does not affect O2 utilization by muscle, therefore lowering maximal O2 consumption. To test these hypotheses, swine (∼30 kg) drank either tap water (Con, n = 25) or water with NG-nitro-l-arginine methyl ester (8.0 ± 0.4 mg·kg−1·day−1 for ≥4 wk; LN, n = 24). Treatment efficacy was reflected by higher mean arterial pressure and lower plasma NO metabolite concentration in LN than Con (both P < 0.05). Swine completed two graded treadmill running tests to maximum. In the first test, O2 consumption was determined at rest through maximal exercise intensity. O2 consumption did not differ between groups at rest or at most exercise intensities, including maximum (Con, 40.8 ± 1.8 ml·min−1·kg−1; LN, 40.4 ± 2.9; not significant). In the second test, tissue-specific blood flows were determined using the radiolabeled-microsphere technique. At rest, blood flows were lower ( P < 0.05) in LN compared with Con for a number of tissues, including kidney, adrenal, lung, and several skeletal muscles. During both submaximal and maximal exercise, however, blood flows were similar between Con and LN for all 16 muscles examined; only blood flows to kidney (Con, 99 ± 16 ml·min−1·100 g; LN, 55 ± 15; P < 0.05) and pancreas (Con, 25 ± 7; LN, 6 ± 2; P < 0.05) were lower in LN at maximum. Endothelium-dependent, but not -independent, relaxation of renal arterial segments was reduced ( P < 0.05) in vitro. These data indicate that exercise-induced increases in muscle blood flows are maintained with chronic inhibition of NO formation and that maximal O2 consumption is therefore preserved. Redundant vasodilatory pathways and/or upregulation of these pathways may underlie these findings.

Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats

1992 ◽  
Vol 262 (2) ◽  
pp. G274-G277 ◽  
Author(s):  
C. C. Sieber ◽  
P. G. Mosca ◽  
R. J. Groszmann
Keyword(s):  
Muscle Tone ◽  
Clinical Settings ◽  
Hypertensive Rats ◽  
Resistance Vessels ◽  
Vessel Resistance ◽  
Vascular Smooth Muscle Tone ◽  
Mesenteric Vascular Resistance ◽  
Analogue Octreotide

Vasoactive effects of natural somatostatin (SRIF-14) and its analogue octreotide were studied in in vitro perfused superior mesenteric arterial beds of normal (Sham) and portal hypertensive (PVL) rats. Tested concentrations covered the whole range used in clinical settings (10(-10) to 10(-5) M for SRIF-14 and 10(-11) to 10(-6) M for octreotide, respectively). Vessel resistances only minimally changed to infusions of SRIF-14 (from 3.5 +/- 0.4 to 3.7 +/- 0.5 mmHg.ml-1.min and 3.8 +/- 0.3 to 3.9 +/- 0.4 mmHg.ml-1.min for PVL and Sham) and octreotide (from 3.3 +/- 0.2 to 3.4 +/- 0.4 mmHg.ml-1.min and 3.8 +/- 0.4 to 4.0 42- 0.4 mmHg.ml-1.min for PVL and Sham). The same was true for bolus injections. In contrast, norepinephrine induced significant increases in vessel resistance (up to 110.6 +/- 20.1 mmHg.ml-1.min). In conclusion, SRIF-14 and octreotide exert no direct effect on vascular smooth muscle tone in splanchnic resistance vessels of Sham and PVL rats. The vasoconstriction reported in vivo seems therefore probably mediated by the ability of these peptides to inhibit the secretion of vasodilatatory substances.

Nonadrenergic noncholinergic neurotransmitter of feline trachealis: VIP or nitric oxide?

1993 ◽  
Vol 74 (1) ◽  
pp. 31-39 ◽  
Author(s):  
J. T. Fisher ◽  
J. W. Anderson ◽  
M. A. Waldron
Keyword(s):  
Nitric Oxide ◽  
Muscle Tone ◽  
Passive Immunization ◽  
Electrical Field Stimulation ◽  
Isometric Tension ◽  
Normal Serum ◽  
Rabbit Serum ◽  
Normal Rabbit Serum ◽  
Response Curves

We tested the hypothesis that vasoactive intestinal peptide (VIP) or nitric oxide (NO) is the nonadrenergic noncholinergic (NANC) neurotransmitter in feline trachealis. Isometric tension was measured in trachealis (open or closed tracheal rings) in vitro. Propranolol (10 microM) and atropine (1 microM) were present throughout the experiment, and smooth muscle tone was increased to 60–90% maximal with 5-hydroxytryptamine. We used three methodologies to reduce the relaxation function of VIP, which in turn should reduce NANC-mediated relaxation. 1) The putative VIP antagonist peptide T (10 microM) did not affect VIP concentration-response curves or electrical field stimulation- (EFS) induced NANC responses. 2) Incubation of tissue in specific VIP antiserum (16 h at 4 degrees C) did not reduce EFS-induced NANC relaxations relative to tissue incubated in normal rabbit serum (P > 0.05). On the basis of our passive immunization techniques, it is not possible to absolutely reject VIP as the NANC transmitter. We speculate that nonspecific peptidases present in normal serum and VIP antiserum reduce EFS-induced responses similarly. 3) VIP desensitization, confirmed by a significant rightward shift (P < 0.01) in the VIP concentration-response curve, was achieved by exposing tissues (n = 11) to 1.0 microM VIP for 30 min. Desensitization did not reduce the EFS-induced NANC relaxatory response (P < 0.05) compared with control tissues, suggesting that VIP is not the NANC mediator.(ABSTRACT TRUNCATED AT 250 WORDS)

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