Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways

Abstract

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase –NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase –PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.

Beneficial Effect of a Multistrain Synbiotic Prodefen® Plus on the Systemic and Vascular Alterations Associated with Metabolic Syndrome in Rats: The Role of the Neuronal Nitric Oxide Synthase and Protein Kinase A

“…Previous works from our group have demonstrated that the mesenteric vasculature, especially superior mesenteric artery, plays a pivotal role in the maintenance of peripheral resistance through the release of vasodilators, such as NO [8]. Although alterations in blood pressure have been linked with modifications in smooth muscle sensitivity to NO [6,47], we found no differences in the vasodilator response to NO donor DEA-NO among our experimental groups, allowing us to rule out this possibility.…”

Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function

“…Animals were randomly divided into two groups: Shamoperated (SO; n = 17), in which the common bile duct was dissected; and MHC (n = 17), in which the extrahepatic biliary tract was resected (García-Moreno et al, 2005;Sastre et al, 2016b;Gilsanz et al, 2017;Caracuel et al, 2019). Surgery was performed under aseptic but not sterile conditions.…”

“…Systolic blood pressure (SBP) was measured using the tail-cuff method 8 weeks after the surgery was performed (Xavier et al, 2010;Sastre et al, 2016b;Caracuel et al, 2019).…”

“…After an overnight fasting, splenic pulp pressure, an indirect measurement of portal pressure (PP) was measured in four animals from each group, by inserting a fluid filled 20-gauge needle into the splenic parenchyma (Sastre et al, 2016b;Caracuel et al, 2019). The needle was joined to a PE-50 tube, and then connected to a pressure recorder (PowerLab 200 ML 201) and to a transducer (Sensonor SN-844) with a Chart V 4.0 computer program (ADI Instruments), that was calibrated before each experiment.…”

“…Different experimental models of liver cholestasis have shown a decompensation after six postoperative weeks, together with hepatic encephalopathy (HE) and ascites, leading to an acute-on-chronic liver failure (ACLF; García-Moreno et al, 2005;Gilsanz et al, 2017). This decompensation can aggravate these cardiovascular disturbances, causing hypotension, decreased effective blood volume, and increased cardiac output (Møller et al, 2001;Sastre et al, 2016b;Caracuel et al, 2019), eventually leading to patient death.…”