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

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.

Long-term portal hypertension increases the vasodilator response to acetylcholine in rat aorta: role of prostaglandin I2.

In the present study, we have analysed both the effect of long-term portal hypertension on the vasomotor response to acetylcholine in rat aorta and the mechanism involved in this response. For this purpose, sham-operated rats and rats with pre-hepatic PH (portal hypertension; triple partial portal vein ligation) were used at 21 months after surgery. The participation of NO and COX (cyclo-oxygenase) derivatives in the vasodilator response elicited by acetylcholine after incubation with L-NAME (NG-nitro-L-arginine methyl ester), indomethacin, SC-560, NS-398, tranylcypromine and furegrelate, was analysed. NO, TXB2 (thromboxane B2) and 6-keto PGF1alpha (prostaglandin F1alpha) release were measured. In addition, SNP (sodium nitroprusside), U-46619, PGI2 and forskolin vasomotor responses were analysed. COX-1 and COX-2 expression was also determined. The acetylcholine-induced vasodilating response was higher in rats with PH. TXA2 and NO release, and SNP and U-46619 sensitivity were similar in both groups. PGI2 release was not modified by portal hypertension, but vasodilator responses to this prostanoid and to forskolin were higher in rats with PH. COX-1 and COX-2 expression remained unmodified by surgery. In conclusion, increased vasodilation to acetylcholine is maintained in long-term PH. Although the participation of endothelial NO remained unmodified, the COX-2 derivative PGI2 does participate through an increased vasodilator response.