Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin

2000 ◽  
Vol 99 (6) ◽  
pp. 475-482 ◽  
Author(s):  
Chi-Jen CHU ◽  
Shwu-Ling WU ◽  
Fa-Yauh LEE ◽  
Sun-Sang WANG ◽  
Full-Young CHANG ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Rat Model ◽  
Portal Pressure ◽  
Specific Inhibitor ◽  
Portal Vein Ligation ◽  
Relative Contribution ◽  
Hoe 140 ◽  
Long Acting

Hyposensitivity to vasopressin is a well documented phenomenon in animals with portal hypertension and patients with cirrhosis subject to haemorrhage. Haemorrhage is associated with the endogenous release of bradykinin, which may subsequently stimulate the formation of nitric oxide (NO). The present study investigated the relative contribution of NO synthase (NOS) isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivity to a long-acting vasopressin analogue, glypressin, in rats with portal hypertension induced by partial portal vein ligation (PVL). At 14 days after the operation, systemic and portal haemodynamics were measured in stable or bleeding PVL rats receiving an intravenous infusion of glypressin (0.07 mg/kg). In the treatment groups, NG-nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor), L-canavanine (a specific inhibitor of inducible NOS) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 min before the infusion of glypressin. In rats with a hypotensive haemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was re-infused before the administration of glypressin or various inhibitors. Splanchnic hyposensitivity to glypressin was demonstrated in the haemorrhage/transfused PVL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding PVL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. It is concluded that constitutive NOS and bradykinin are responsible, at least partly, for the splanchnic hyposensitivity to glypressin observed in the early stages of the haemorrhage/transfused rat model of portal hypertension.

Aminoguanidine ameliorates splanchnic hyposensitivity to glypressin in a haemorrhage-transfused rat model of portal hypertension

1998 ◽  
Vol 95 (5) ◽  
pp. 629-636 ◽  
Author(s):  
Chi-Jen CHU ◽  
Fa-Yauh LEE ◽  
Sun-Sang WANG ◽  
Full-Young CHANG ◽  
Han-Chieh LIN ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Portal Vein ◽  
Rat Model ◽  
Portal Pressure ◽  
Hypotensive Effect ◽  
Portal Vein Ligation ◽  
Nitric Oxide Synthase Inhibitor

1.Hyposensitivity to vasopressin is a well-documented phenomenon in animals with portal hypertension and patients with cirrhosis subjected to haemorrhage. Excessive formation of nitric oxide is at least partly responsible for the vascular hyporesponsiveness to vasoconstrictors observed in experimental portal hypertension or in rats with haemorrhagic shock. This study investigated whether addition of aminoguanidine, a preferential inducible nitric oxide synthase inhibitor, to glypressin (a long-acting vasopressin analogue) could enhance its portal hypotensive effect in portal-hypertensive rats with bleeding. 2.Portal hypertension was induced by partial portal vein ligation. Fourteen days after operation, systemic and portal haemodynamics were measured in stable or bleeding portal vein-ligated rats receiving intravenous glypressin (0.07 ;mg/kg) or aminoguanidine (70 ;mg/kg) followed by glypressin infusion. In rats with a hypotensive haemorrhage, 4.5 ;ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or aminoguanidine. 3.Glypressin resulted in a significantly greater decrease in portal pressure in portal vein-ligated rats without bleeding than in those with bleeding (P< 0.001). In contrast, glypressin induced similar changes in mean arterial pressure between the two groups (P> 0.05). The addition of aminoguanidine significantly potentiated the portal-hypotensive effect of glypressin in bleeding portal vein-ligated rats (P< 0.005) without an effect on the changes in mean arterial pressure induced by glypressin infusion (P> 0.05). 4.Splanchnic hyposensitivity to glypressin exists in a haemorrhage-transfused rat model of portal hypertension. This hyposensitivity can be ameliorated by the administration of aminoguanidine.

Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension

1999 ◽  
Vol 277 (2) ◽  
pp. G463-G468 ◽  
Author(s):  
Vijay Shah ◽  
Reiner Wiest ◽  
Guillermo Garcia-Cardena ◽  
Greg Cadelina ◽  
Roberto J. Groszmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Specific Inhibitor ◽  
No Production ◽  
Portal Vein Ligation ◽  
Rat Mesentery ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The molecular chaperone, heat shock protein 90 (Hsp90), acts as an intermediate in the signaling cascades leading to activation of endothelial nitric oxide synthase (eNOS). In this study, we examine the participation of this pathway in nitric oxide (NO)-dependent vasodilation in the rat mesentery in vitro. In normal animals, immunoprecipitation of eNOS from intact mesentery coimmunoprecipitates Hsp90 and, additionally, both eNOS and Hsp90 colocalize to the endothelial lining of mesenteric vessels. In the perfused mesenteric vasculature of normal animals, geldanamycin (GA), a specific inhibitor of Hsp90 signaling, attenuates ACh-dependent vasodilation but does not affect vasodilation in response to sodium nitroprusside. Next, studies were performed in animals with experimental portal hypertension induced by portal vein ligation (PVL). In PVL animals, NOS catalytic activity is markedly enhanced in mesenteric tissue and the perfused mesentery is hyporesponsive to the vasoconstrictor methoxamine (MTX). GA significantly potentiates MTX-induced vasoconstriction after PVL, thereby partially reversing the hyporeactivity to this agent exhibited in the mesenteric vasculature after PVL. These studies suggest that Hsp90 can act as a signaling mediator of NO-dependent responses in the mesenteric circulation and indicate that the excessive NO production observed in portal hypertension is mediated in part through Hsp90 signaling.

Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state

2006 ◽  
Vol 290 (5) ◽  
pp. G980-G987 ◽  
Author(s):  
Juan G. Abraldes ◽  
Yasuko Iwakiri ◽  
Mauricio Loureiro-Silva ◽  
Omar Haq ◽  
William C. Sessa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Portal Pressure ◽  
No Production ◽  
Portal Vein Ligation ◽  
Vegf Expression ◽  
Enos Expression ◽  
Hyperdynamic Circulation ◽  
Intestinal Microcirculation ◽  
Hypertension Portal

Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation.

Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin

2000 ◽  
Vol 99 (6) ◽  
pp. 475 ◽  
Author(s):  
Chi-Jen CHU ◽  
Shwu-Ling WU ◽  
Fa-Yauh LEE ◽  
Sun-Sang WANG ◽  
Full-Young CHANG ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Rat Model

scholarly journals Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

2008 ◽  
Vol 295 (5) ◽  
pp. G953-G964 ◽  
Author(s):  
N. J. Skill ◽  
N. G. Theodorakis ◽  
Y. N. Wang ◽  
J. M. Wu ◽  
E. M. Redmond ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
The United States ◽  
Portal Vein Ligation ◽  
Wild Type ◽  
Sham Surgery ◽  
Cox 2 ◽  
Hemodynamic Measurements ◽  
Cyclooxygenase Isoforms ◽  
Cox 1

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI2), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI2 biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1−/−, and COX-2−/− mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI2 biosynthesis were determined 1–7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI2 biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1−/− mice with NS398 or COX-2−/− mice with SC560 restricted PGI2 biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI2 biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI2 rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.

Induction of Vasoactive Substances Differs in LPS-Induced and TF-Induced DIC Models in Rats

2002 ◽  
Vol 88 (10) ◽  
pp. 663-667 ◽  
Author(s):  
Mariko Okudaira ◽  
Tomotaka Yoshida ◽  
Yasuo Ontachi ◽  
Masahide Yamazaki ◽  
Eriko Morishita ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Organ Dysfunction ◽  
Disseminated Intravascular Coagulation ◽  
Rat Model ◽  
Plasma Levels ◽  
Fibrinolytic Activity ◽  
Tail Vein ◽  
Vasoactive Substances ◽  
Rat Tail

SummaryWe have investigated the role of two vasoactive substances, nitric oxide (NO) and endothelin (ET), in the pathophysiology of disseminated intravascular coagulation (DIC), using two types of DIC models. Experimental DIC was induced by sustained infusion of 0.1, 1, 10, or 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin (TF), for 4 h via the rat tail vein. Plasma levels of both NOX (metabolites of NO) and ET were significantly increased following infusion of 0.1 mg/kg or greater of LPS in the LPS-induced DIC rat model. In contrast, although a marked increase in the plasma levels of NOX was observed, only a slight increase in plasma ET levels was seen in the TF-induced DIC rat model. No significant differences in the plasma levels of platelets or thrombin-ATIII complex were observed among the TF-induced and LPS (50 mg/dl)-induced DIC models. However, plasma NOX levels rose significantly higher in the TF-induced model, relative to the LPS-induced model (p <0.01). Conversely, plasma ET levels were significantly greater after LPS-induction, compared to TF-induction, of DIC (p <0.01). Vasoconstriction, as well as depressed fibrinolytic activity, may be additional factors leading to severe organ dysfunction in the LPS-induced DIC rat model. Moreover, vasodilatation, as well as enhanced fibrinolytic activity, may help to prevent rats from severe organ dysfunction in the TF-induced DIC model. Our results suggest that modulator of vasoactive substances should be examined in the treatment of DIC.

Basal release of nitric oxide in the mesenteric artery in portal hypertension and cirrhosis: Role of dimethylarginine dimethylaminohydrolase

2013 ◽  
Vol 28 (5) ◽  
pp. 880-886 ◽  
Author(s):  
Eva Serna ◽  
María Dolores Mauricio ◽  
Paloma Lluch ◽  
Gloria Segarra ◽  
Belén Cortina ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Portal Hypertension ◽  
Mesenteric Artery ◽  
Dimethylarginine Dimethylaminohydrolase ◽  
Basal Release

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.

Role of Endoscopic Ultrasound to Assess and Manage Portal Hypertension

2020 ◽  
Vol 04 (02) ◽  
pp. 103-109
Author(s):  
Sidhant Singh ◽  
Saurabh Mukewar
Keyword(s):  
Portal Hypertension ◽  
Gastrointestinal Tract ◽  
Endoscopic Ultrasound ◽  
Portal Pressure ◽  
Pressure Measurements ◽  
Vascular Changes ◽  
Ectopic Varices ◽  
Portal Venography ◽  
Intrahepatic Shunt

AbstractPortal hypertension leads to the development of varices along the gastrointestinal tract. Endoscopy plays an important role in the diagnosis and management of varices. Endosonography (EUS) enables visualization and permits access to varices and veins outside the gastrointestinal tract. EUS has emerged as an important tool, with the ability to identify vascular changes, treat gastric and ectopic varices, perform portal pressure measurements, portal venography, and intrahepatic shunt placement. This review discusses the role of endoscopy and the emerging role of EUS in evaluation and management of portal hypertension.

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