Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension

Pizcueta, M. Pilar; Piqué, J.M.; Bosch, Jaume; Whittle, B. J. R.; Moncada, Salvador

doi:10.1111/j.1476-5381.1992.tb14233.x

Cited by 221 publications

(95 citation statements)

References 41 publications

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“…[31][32][33][34][35][36] It has been shown that in PVL rats blockade of NO synthesis increased not only the peripheral and splanchnic vascular resistance but also the portal-collateral resistance. 32,34 In the intrahepatic vasculature, inhibition of NO increased the perfusion pressure of normal rat liver. 33 In addition, the ET-1-mediated intrahepatic vasoconstriction and elevation of portal pressure were markedly reduced by a NO donor.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

et al. 2001

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Cirrhosis of liver leads to portal hypertension and the development of portal-systemic collaterals. 10 The increased hepatic and collateral resistances to an increased portal blood flow maintain portal hypertension. 11 Recently, a possible role of endothelins in the pathophysiology of portal hypertension has been suggested. ET-1 was found to induce hepatic vasoconstriction and subsequently increase portal venous resistance. 4,12 In addition, ET-1 could stimulate contraction of hepatic stellate cells to increase intrahepatic resistance. 13 In vitro experiments also showed that ET-1 produced contraction of rat portal vein. 14 Furthermore, the mesenteric expressions of ET A and ET B receptors and ET-1-induced vasoconstriction were significantly enhanced in partially portal veinligated (PVL) rats. 5 Recently, it has been shown that bosentan, a nonselective endothelin receptor antagonist, significantly reduced the portal pressure of portal hypertensive rats. 15 However, it is not clear if ET-1 could modulate portal pressure by a direct constrictive effect on the collateral vessels of portal hypertensive rats.The aims of this study were to investigate the vascular activity and the receptor-mediated effects of ET-1 on the portalsystemic collaterals of portal hypertensive rats. The regulation of nitric oxide (NO) and prostaglandin on the effects of ET-1 was also evaluated. MATERIALS AND METHODSMale Sprague-Dawley rats weighing 280 to 300 g at the time of surgery were used for experiments. The rats were housed in a plastic cage and allowed free access to food and water. All rats were fasted for 12 hours before operation. In all experiments, the investigators adhered to the American Physiological Society Guiding Principles for the Care and Use of Laboratory Animals.A prehepatic portal hypertensive animal model was created as previously reported. 16 Anesthesia was performed with ketamine HCl (100 mg/kg body weight, intramuscularly). In brief, the portal vein was isolated and a 3-0 silk ligature was tied around both the portal vein and an adjacent 20-gauge blunt-tipped needle. The needle was then removed and the vein allowed to reexpand. A second loose ligature was left around the portal vein with 2 endings of the ligature placed on each side in the abdominal cavity. The abdomen was then closed and the animal was allowed to recover. Perfusion studies were performed in overnight-fasted rats 10 to 13 days after the operation, at which time an extensive collateralization of the portal system was fully established. 17 The body weights of rats were measured on the day of perfusion studies.Abbreviations: ET-1, endothelin-1; PVL, portal vein-ligated; NO, nitric oxide; NNA, n -nitro-L-arginine; INDO, indomethacin.From the Divisions of

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Section: Discussionmentioning

confidence: 99%

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

et al. 2001

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“…Diastolic dysfunction, characterized by an altered pattern of transmitral flow due to impaired diastolic relaxation of left ventricle, can be easily assessed by echocardiography and accordingly can be considered as a marker of this condition. As far as diastolic dysfunction is concerned, many etiological factors have been reliably advocated as potential pathogenic agents: notably substances as NO [18][19][20][21], TNF [22], reactive nitrogen species [23], neurohormones [24][25][26][27][28] may well affect heart structure and function along with circulatory overload [24,29] and overactivity of the SNS [30]. Thickening of heart parietal walls has been reported [12,14,17,31], nevertheless the nature of the structural changes underlying diastolic dysfunction has not been clarified so far.…”

Section: Introductionmentioning

confidence: 99%

Heart Function and Myocardial Tissue Characterization in Patients with HCV Related Cirrhosis: Diastolic Dysfunction and Cardiac Hypertrophy

Pozzi¹,

Pizzala²,

Ratti³

et al. 2007

TOGASJ

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Evidence of diastolic dysfunction in cirrhosis contributed to the definition of cirrhotic cardiomyopathy. In 109 patients with chronic HCV infection with or without cirrhosis E/A ratio, a Doppler marker of diastolic dysfunction, was decreased in cirrhotics (0.89 ± 0.03 vs controls 1.21 ± 0.07, p < 0.01) and to a lesser extent in patients with advanced liver fibrosis (1.17 ± 0.07, p < 0.01). Left ventricular parietal wall thickness was increased. The nature of this abnormality in human cirrhosis has not been clarified, animal studies reporting cardiac hypertrophy. To this aim we employed the echocardiographic integrated backscatter (IBS) technique to obtain an indirect estimate of tissue density (decreased when a higher percentage of muscle fibres is present and increased when fibrosis prevails) to provide myocardial tissue characterization in a subset of patients with compensated HCV cirrhosis. The average IBS signal was reduced in cirrhotics at the level of the posterior wall (21.72 ± 1.46 dB versus 30.85 ± 1.40 dB in controls, p < 0.01). Our results confirm diastolic dysfunction in postviral cirrhosis pointing to cardiac hypertrophy as the anatomopathological background in the compensated stage of disease.

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“…[4][5][6][7][8] Excessive production of nitric oxide (NO) by endothelial NO synthase (eNOS) has been suggested as the basis for the systemic hyperdynamic and abnormal circulation of PHT gastric mucosa. [9][10][11][12] Tumor necrosis factor ␣ (TNF-␣) has been shown indirectly to be a major contributor to the hyperdynamic circulation likely through activation of NO synthase. [13][14][15] However, direct evidence for this has been lacking.…”

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confidence: 99%

Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

et al. 2002

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Activation of endothelial nitric oxide synthase (eNOS) in portal hypertensive (PHT) gastric mucosa leads to hyperdynamic circulation and increased susceptibility to injury. However, the signaling mechanisms for eNOS activation in PHT gastric mucosa and the role of TNF-␣ in this signaling remain unknown. In PHT gastric mucosa we studied (1) eNOS phosphorylation (at serine 1177) required for its activation; (2) association of the phosphatidylinositol 3-kinase (PI 3-kinase), and its downstream effector Akt, with eNOS; and, (3) whether TNF-␣ neutralization affects eNOS phosphorylation and PI 3-kinase-Akt activation. To determine human relevance, we used human microvascular endothelial cells to examine directly whether TNF-␣ stimulates eNOS phosphorylation via PI 3-kinase. PHT gastric mucosa has significantly increased (1) eNOS phosphorylation at serine 1177 by 90% (P < .01); (2) membrane translocation (P < .05) and phosphorylation (P < .05) of p85 (regulatory subunit of PI 3-kinase) by 61% and 85%, respectively; (3) phosphorylation (P < .01) and activity (P < .01) of Akt by 40% and 52%, respectively; and (4) binding of Akt to eNOS by as much as 410% (P < .001). Neutralizing anti-TNF-␣ antibody significantly reduced p85 phosphorylation, phosphorylation and activity of Akt, and eNOS phosphorylation in PHT gastric mucosa to normal levels. Furthermore, TNF-␣ stimulated eNOS phosphorylation in human microvascular endothelial cells. In conclusion, these findings show that in PHT gastric mucosa, TNF-␣ stimulates eNOS phosphorylation at serine 1177 (required for its activation) via the PI 3-kinase-Akt signal transduction pathway. (HEPATOLOGY 2002;35: 393-402.) P ortal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. Gastric hemorrhage-either spontaneous or caused by noxious agents such as alcohol and nonsteroidal anti-inflammatory drugs-occurs in ϳ30% of patients with PHT gastropathy. 1-3 Clinical and experimental data including our own indicate that compared with normal gastric mucosa, the PHT gastric mucosa has increased susceptibility to injury. 1,3-5 The microvascular abnormalities have been implicated in the increased susceptibility of PHT gastric mucosa to damage. [4][5][6][7][8] Excessive production of nitric oxide (NO) by endothelial NO synthase (eNOS) has been suggested as the basis for the systemic hyperdynamic and abnormal circulation of PHT gastric mucosa. [9][10][11][12] Tumor necrosis factor ␣ (TNF-␣) has been shown indirectly to be a major contributor to the hyperdynamic circulation likely through activation of NO synthase. [13][14][15] However, direct evidence for this has been lacking. Our previous study showed that elevated TNF-␣ up-regulates eNOS expression and its enzymatic activity in PHT gastric mucosa and that neutralization of TNF-␣ reverses the hemodynamic abnormalities of PHT gastric mucosa. 13 Although these data clearly indicate that TNF-␣ is involved in the activation of eNOS in PHT gastric mucosa, the molecular mechanisms and signaling pathways of eNOS a...

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Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension

Cited by 221 publications

References 41 publications

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

Heart Function and Myocardial Tissue Characterization in Patients with HCV Related Cirrhosis: Diastolic Dysfunction and Cardiac Hypertrophy

Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-α via the PI 3-kinase-Akt signaling pathway

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