Factors mediating the hemodynamic effects of tumor necrosis factor-α in portal hypertensive rats

Abstract

Nitric oxide, prostacyclin, and glucagon have been implicated in promoting the hyperdynamic circulatory state of portal hypertension. Recent evidence also indicates that increased tumor necrosis factor-α (TNF-α) production is involved in the pathogenesis of this hemodynamic abnormality. This study was aimed at investigating in rats with portal vein stenosis (PVS) the effects on splanchnic hemodynamics of blocking circulating TNF-α and the factors mediating the vascular action of this cytokine in this setting. Anti-TNF-α polyclonal antibodies or placebo was injected into rats ( n = 96) before and 4 days after PVS (short-term inhibition) and at 24 h and 4, 7, 10 days after PVS (long-term inhibition). Short-term TNF-α inhibition reduced portal venous inflow and cardiac index and increased splanchnic and systemic resistance. Portal pressure was unchanged, but portal-systemic shunting was decreased. After long-term TNF-α inhibition, portal venous inflow and portal pressure were unchanged, but arterial pressure and systemic resistance rose significantly. Anti-TNF-α PVS rats exhibited lower increments of systemic resistance after N ω-nitro-l-arginine methyl ester and indomethacin administration and lower serum levels of TNF-α, nitrates-nitrites, and 6-keto-PGF1α, both over the short and the long term. Serum glucagon levels rose after long-term inhibition. In conclusion, the specific role played by TNF-α in the development of the hyperdynamic state of portal hypertension appears to be mainly mediated through an increased release of nitric oxide and prostacyclin. Maintenance of the splanchnic hyperemia after long-term TNF-α inhibition could be due to a compensatory release of glucagon.

Biology of Intracranial Aneurysms: Role of Inflammation

“…In addition, TNFa is known to activate MMP (Polavarapu et al, 2005;Thomson et al, 2012), which is critical in aneurysm pathology. Risk factors associated with aneurysm development have been associated with TNFa induction (Jayaraman et al, 2008), including hypertension (Munoz et al, 1999) Sun et al, 2007;Wright et al, 2007). In a study by Jayaraman et al (2005), the expression of TNFa and its proapoptotic downstream target FAS were increased in IA, indicating that TNFa has a proapoptotic and pro-inflammatory action in the wall of aneurysms.…”

Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

“…Patients and animal models with portal hypertension had an elevated TNF-α level which stimulated release of nitric oxide (NO) and prostacyclin, important mediators of a hyperdynamic circulation [148] . For example, in one study, 96 healthy rats were injected with either anti-TNF-α polyclonal antibodies or placebo before surgically creating portal vein stenosis (PVS) to induce portal hypertension and 4 d after in the short-term inhibition group and 1, 4, 7 and 10 d after PVS in the long term-inhibition group.…”

“…In another study, iNOS and cNOS levels were also higher in gastric mucosa of patients with PHG than in controls [153] , and were significantly higher in patients with severe PHG as compared to patients with mild or no PHG [154] . Nitrous oxide may underlie the gastric vascular dilation [152] , and hyperdynamic circulation in PHG [148] . However, Lee et al [155] reported administration of aminoguanidine, an iNOS inhibitor, successfully corrected the hyperdynamic circulation without affecting PHG, suggesting that iNOS and NO are important in the hyperdynamic circulation in portal hypertension, but play a limited role in PHG development.…”

“…Serum glucagon levels were significantly correlated with high systemic vascular resistance index (r = -0.523; P = 0) and HVPG (r = 0.34; P = 0.019). Glucagon significantly increases portal pressure [157][158][159] , and causes splanchnic vasodilation [148] . Geraghty et al [158] found a strong correlation between portal pressure and glucagon levels (r = 0.85).…”

Profilaxis preprimaria de la hemorragia por varices

“…Hecho que no hace sino enfatizar la relevancia del aumento de flujo esplácnico en el desarrollo de la colateralización portosistémica. Consecuencias similares se logran inhibiendo el TNF-alfa circulante, citoquina proinflamatoria cuya concentración sérica está aumentada en la hipertensión portal, y que estimula la actividad de la eONS (29). Más recientemente, se ha demostrado que el bloqueo de mediadores específicos de la angiogé-nesis, como el VEGF, también atenúa la colateralización portosistémica (44,51).…”