Up-regulation of nNOS and associated increase in vasorelaxation in superior mesenteric arteries in portal hypertension

2004 ◽  
Vol 42 (01) ◽  
Author(s):  
L Jurzik ◽  
R Wiest ◽  
RH Straub ◽  
J Schoelmerich
Keyword(s):  
Portal Hypertension ◽  
Mesenteric Arteries

Hepatic venoconstriction is involved in anaphylactic hypotension in rats

2005 ◽  
Vol 289 (4) ◽  
pp. H1436-H1441 ◽  
Author(s):  
Toshishige Shibamoto ◽  
Sen Cui ◽  
Zonghai Ruan ◽  
Wei Liu ◽  
Hiromichi Takano ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Venous Pressure ◽  
Liver Weight ◽  
Systemic Arterial Pressure ◽  
Mesenteric Arteries ◽  
Isolated Perfused Rat Liver ◽  
Circulating Blood Volume ◽  
Anesthetized Rats ◽  
Occlusion Technique ◽  
Vascular Beds

We determined the roles of liver and splanchnic vascular bed in anaphylactic hypotension in anesthetized rats and the effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused rat livers. In anesthetized rats sensitized with ovalbumin (1 mg), an intravenous injection of 0.6 mg ovalbumin caused not only a decrease in systemic arterial pressure from 120 ± 9 to 43 ± 10 mmHg but also an increase in portal venous pressure that persisted for 20 min after the antigen injection (the portal hypertension phase). The elimination of the splanchnic vascular beds, by the occlusions of the celiac and mesenteric arteries, combined with total hepatectomy attenuated anaphylactic hypotension during the portal hypertension phase. For the isolated perfused rat liver experiment, the livers derived from sensitized rats were hemoperfused via the portal vein at a constant flow. Using the double-occlusion technique to estimate the hepatic sinusoidal pressure, presinusoidal ( Rpre) and postsinusoidal ( Rpost) resistances were calculated. An injection of antigen (0.015 mg) caused venoconstriction characterized by an almost selective increase in Rpre rather than Rpost and liver weight loss. Taken together, these results suggest that liver and splanchnic vascular beds are involved in anaphylactic hypotension presumably because of anaphylactic presinusoidal contraction-induced portal hypertension, which induced splanchnic congestion resulting in a decrease in circulating blood volume and thus systemic arterial hypotension.

scholarly journals COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl4-Induced Liver Fibrosis and Portal Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhifeng Zhao ◽  
Chihao Zhang ◽  
Jiayun Lin ◽  
Lei Zheng ◽  
Hongjie Li ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Vascular Remodeling ◽  
Mesenteric Arteries ◽  
Cytokeratin 19 ◽  
Dual Inhibitor ◽  
Bile Duct Proliferation ◽  
Cox 2

Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT).Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis.Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-β (TGF-β).Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-β.

Enhanced Y1-receptor-mediated vasoconstrictive action of neuropeptide Y (NPY) in superior mesenteric arteries in portal hypertension

2006 ◽  
Vol 44 (3) ◽  
pp. 512-519 ◽  
Author(s):  
Reiner Wiest ◽  
Lars Jurzik ◽  
Lukas Moleda ◽  
Matthias Froh ◽  
Bernd Schnabl ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Neuropeptide Y ◽  
Mesenteric Arteries ◽  
Y1 Receptor

Up-regulation of nNOS and associated increase in nitrergic vasodilation in superior mesenteric arteries in pre-hepatic portal hypertension

2005 ◽  
Vol 43 (2) ◽  
pp. 258-265 ◽  
Author(s):  
Lars Jurzik ◽  
Matthias Froh ◽  
Rainer H. Straub ◽  
Jürgen Schölmerich ◽  
Reiner Wiest
Keyword(s):  
Portal Hypertension ◽  
Mesenteric Arteries ◽  
Hepatic Portal

Effects of chronic portal hypertension on small heat-shock proteins in mesenteric arteries

2005 ◽  
Vol 288 (4) ◽  
pp. G616-G620 ◽  
Author(s):  
Xuesong Chen ◽  
Hai-Ying Zhang ◽  
Kristin Pavlish ◽  
Joseph N. Benoit
Keyword(s):  
Portal Hypertension ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Mrna Expression ◽  
Protein Level ◽  
Small Heat Shock Proteins ◽  
Mesenteric Arteries ◽  
Protein Levels ◽  
Small Hsps ◽  
Shock Proteins

Previous studies have shown that impaired vasoconstrictor function in chronic portal hypertension is mediated via cAMP-dependent events. Recent data have implicated two small heat-shock proteins (HSP), namely HSP20 and HSP27, in the regulation of vascular tone. Phosphorylation of HSP20 is associated with vasorelaxation, whereas phosphorylation of HSP27 is associated with vasoconstriction. We hypothesized that alterations in the expression and/or phosphorylation of small HSPs may play a role in impaired vasoconstriction in portal hypertension. A rat model of prehepatic chronic portal hypertension was used. Studies were conducted in small mesenteric arteries isolated from normal and portal hypertensive rats. Protein levels of HSP20 and HSP27 were detected by Western blot analysis. Protein phosphorylation was analyzed by isoelectric focusing. HSP20 mRNA expression was determined by RT-PCR. To examine the role of cAMP in the regulation of small HSP phosphorylation and expression, we treated both normal and portal hypertensive vessels with a PKA inhibitor Rp-cAMPS. We found both an increased HSP20 phosphorylation and a decreased HPS20 protein level in portal hypertension, both of which were restored to normal by PKA inhibition. However, PKA did not change HSP20 mRNA expression. We conclude that decreased HSP20 protein level is mediated by cAMP-dependent pathway and that impaired vasoconstrictor function in portal hypertension may be partially explained by decreased expression of HSP20. We also suggest that the phosphorylation of HSP20 by PKA may alter HSP20 turnover.

Effects of chronic portal hypertension on agonist-induced actin polymerization in small mesenteric arteries

2006 ◽  
Vol 290 (5) ◽  
pp. H1915-H1921 ◽  
Author(s):  
Xuesong Chen ◽  
Kristin Pavlish ◽  
Hai-Ying Zhang ◽  
Joseph N. Benoit
Keyword(s):  
Smooth Muscle ◽  
Portal Hypertension ◽  
Vascular Smooth Muscle ◽  
Actin Polymerization ◽  
Smooth Muscle Contraction ◽  
Isometric Tension ◽  
Mesenteric Arteries ◽  
Dynamic Regulation ◽  
Force Development

The ability of arterial smooth muscle to respond to vasoconstrictor stimuli is reduced in chronic portal hypertension (PHT). Additional evidence supports the existence of a postreceptor defect in vascular smooth muscle excitation contraction coupling. However, the nature of this defect is unclear. Recent studies have shown that vasoconstrictor stimuli induce actin polymerization in smooth muscle and that the associated increase in F-actin is necessary for force development. In the present study we have tested the hypothesis that impaired actin polymerization contributes to reduced vasoconstrictor function in small mesenteric arteries derived from rats with chronic prehepatic PHT. In vitro studies were conducted on small mesenteric artery vessel rings isolated from normal and PHT rats. Isometric tension responses to incremental concentrations of phenylephrine were significantly reduced in PHT arteries. The ability to polymerize actin in portal hypertensive mesenteric arteries stimulated by phenylephrine was attenuated compared with control. Inhibition of cAMP-dependent protein kinase (PKA) restored agonist-induced actin polymerization of arteries from PHT rats to normal levels. Depolymerization of actin in arteries from normal rats reduced maximal contractile force but not myosin phosphorylation, suggesting a key role for the dynamic regulation of actin polymerization in the maintenance of vascular smooth muscle contraction. We conclude that reductions in agonist-induced maximal force development of PHT vascular smooth muscle is due, in part, to impaired actin polymerization, and prolonged PKA activation may underlie these changes.

Neuropeptide Y restores non-receptor-mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension

2015 ◽  
Vol 35 (12) ◽  
pp. 2556-2563 ◽  
Author(s):  
Johannes Hartl ◽  
Peter Dietrich ◽  
Lukas Moleda ◽  
Martina Müller-Schilling ◽  
Reiner Wiest
Keyword(s):  
Portal Hypertension ◽  
Neuropeptide Y ◽  
Mesenteric Arteries

Alterations in mechanical properties of mesenteric resistance arteries in experimental portal hypertension

2009 ◽  
Vol 297 (4) ◽  
pp. G849-G857 ◽  
Author(s):  
Markus Resch ◽  
Reiner Wiest ◽  
Lukas Moleda ◽  
Sabine Fredersdorf ◽  
Benjamin Stoelcker ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Structural Changes ◽  
Cross Sectional Area ◽  
Mesenteric Arteries ◽  
Sectional Area ◽  
Resistance Arteries ◽  
Cross Sectional ◽  
Strain Stress

Splanchnic vasodilation is the pathophysiological hallmark in the development of the hyperdynamic circulatory syndrome in liver cirrhosis and portal hypertension. This has been attributed so far mainly to a marked vascular hyporeactivity to endogenous vasoconstrictors. However, myogenic tone and vessel stiffness have not been addressed in mesenteric arteries in liver cirrhosis. CCl4−-induced ascitic cirrhotic (LC) and age-matched control rats, portal vein-ligated (PVL) rats, and sham-operated rats were investigated. Third-order mesenteric resistance arteries were studied under no-flow conditions using a pressure myograph measuring media thickness and lumen diameter in response to incremental increases in intramural pressure, from which wall mechanics were calculated. Electron microscopy was used for investigation of wall ultrastructure, especially the fenestrae in internal elastic lamina (IEL). In PVL animals, no significant change in passive vessel strain, stress, media-to-lumen ratio, or cross-sectional area was noted. In contrast, in LC rats, vessel strain was markedly elevated compared with healthy control rats, indicating a marked reduction in vessel stiffness. In addition, the strain-stress curve was shifted to the right, and the elastic modulus in dependency on vessel stress decreased, demonstrating predominantly structure-dependent factors to be involved. The media-to-lumen quotient was not significantly altered, but cross-sectional area was highly increased in LC rats, indicating hypertrophic outward remodeling. These findings were paralleled by enlarged fenestrae in the IEL but no change in thickness of IEL or proportion of extracellular matrix or vascular smooth muscle in LC rats. We concluded that, in long-standing severe portal hypertension such as ascitic LC but not in short-term conditions such as PVL, mesenteric resistance arteries exhibit vascular remodeling and markedly less resistant mechanical properties, leading to decreased vessel stiffness accompanied by structural changes in the IEL. This may well contribute to the maintenance and severity of splanchnic arterial vasodilation in LC.

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