Mauricio R. Loureiro-Silva

The role of hepatic arterial flow on portal venous and hepatic venous wedged pressure in the isolated perfused CCl4-cirrhotic liver

In cirrhosis, hepatic venous pressure gradient is used to measure portal venous and sinusoidal pressures, as well as drug-induced decreases of elevated pressures. The aim of this study was to investigate the influence of hepatic arterial flow (HAF) changes on portal venous perfusion (PVPP) and wedged hepatic venous pressure (WHVP). Normal and CCl4-cirrhotic rats were subjected to a bivascular liver perfusion with continuous measurements of PVPP, WHVP, and hepatic arterial perfusion pressure. Flow-pressure curves were performed with the use of different flows either through the portal vein (PVF: 20-32 ml/min) or HAF (5-15 ml/min). Increases in HAF lead to significant absolute and relative increases in PVPP (P = 0.002) and WHVP (P < 0.001). Absolute changes in HAF correlated to absolute changes in PVPP (cirrhosis: r = 0.64, P < 0.001; control: r = 0.67, P < 0.001) and WHVP (cirrhosis: r = 0.71, P < 0.001; control: r = 0.82, P < 0.001). Changes in PVPP correlated to changes in WHVP due to changes in PVF only in cirrhosis (r = 0.75, P < 0.001), whereas changes in HAF correlated in both cirrhosis (r = 0.92, P < 0.001) and control (r = 0.77, P < 0.001). In conclusion, increases and decreases in HAF lead to respective changes in PVPP and WHVP. This suggests a direct influence of HAF on PVPP and WHVP most likely due to changes in sinusoidal perfusion.

Nitric oxide and vascular remodeling modulate hepatic arterial vascular resistance in the isolated perfused cirrhotic rat liver.

BACKGROUND/AIMS Hepatic arterial resistance is modulated by the hepatic arterioles but the role of NO and vascular remodeling in hepatic arterial resistance in cirrhosis is unknown. METHODS Cirrhosis was induced by CCl(4) or BDL. Using a bivascular liver perfusion dose-responses curves to methoxamine were obtained from the hepatic artery in absence and presence of L-NMMA. Lumen-diameter, wall thickness and number of smooth muscle nuclei were quantitated in the arteries using image analysis. RESULTS Hepatic arterial resistance and the response to methoxamine were lower in cirrhosis compared to controls (p< or = 0.04) and lower in BDL compared to CCl(4) (p< or = 0.01). L-NMMA increased the response to methoxamine in CCl(4) (p=0.002) and BDL (p=0.05) but corrected the response only in CCl(4) (p=n.s. vs. control). Wall thickness and the number of smooth muscle nuclei were significantly smaller in cirrhosis compared to controls (p<0.05) and the number of nuclei was also lower in BDL compared to CCl(4) (p=0.005). CONCLUSIONS NO is the main modulator of hepatic arterial resistance in CCl(4) but not in BDL. Intrahepatic arterial remodeling is present in both cirrhotic models but is greater in BDL. This indicates a larger role of structural changes in the control of hepatic arterial resistance in BDL.

Decreased intrahepatic response to α1-adrenergic agonists in lipopolysaccharide-treated rats is located in the sinusoidal area and depends on Kupffer cell function

Background and Aim:  Livers from lipopolysaccharide‐treated rats have a decreased vascular response to α1‐adrenergic agonists due to an increased production of nitric oxide. Kupffer cells play a central role in the development of intrahepatic microvascular abnormalities during endotoxemia. We investigated the role of Kupffer cells in the intrahepatic vascular tone control in normal and endotoxemic rats.

Nitric oxide modulates both pre-sinusoidal and sinusoidal responses to phenylephrine in normal rat liver

Methods• Animals were studied 4 weeks after sham surgery or bile duct ligation (BDL). NOS activity was assessed by measuring L-NAME inhibited L-citrulline generation from liver lysates in the presence of a standard concentration ot calmodutin {0.1 /~M) or alternatively lO-fold excess in calmodulin (1.0 /~M). eNOS/iNOS protein levels were assessed by quantitative immunoprecipitation/Western blot analysis. Results, NOS activity was significantly reduced in liver lysates from BDL rat livers in the presence of 0.1 /~M calmodulin, the concentration routinely used in this assay [see Figure (white bars); *P<O.05; sham vs 6DL at 0.1 /~M calmodulin; n = 6]. Western blot analysis demonstrated no reduction in eNOS protein levels or iNOS protein expression in BDL liver lysates. Importantly, supplementation of lO-fold excess calmodulin (1.0/~M) did not affect NOS activity from sham animals, but significantly increased NOS catalytic activity in BDL lysates, thereby correcting deficient hepatic NOS activity (see Figure, **P<O.O5; 0.1 /LM VS. 1.0 ~M calmodulin in BDL; n=6). Conclusion. Provision of excess calmodulin corrects deficient NOS catalytic activity detected from BDL liver lysates in an experimental cell-free assay.

Impaired vasodilation in cirrhotic livers

Similarly to other vascular systems, the intrahepatic circulation has an intrinsic mechanism of vascular tone control. In addition to humoral and neural factors intrahepatic vascular tone is modulated by local production of vasoactive substances with autocrine and paracrine effects. Although different liver cells are able to produce vasoactive substances that can modulate intrahepatic vascular tone, endothelial cells playa central role in this function. Interposed between the lumen and the contractile elements of the vessel wall, endothelial cells react to different intraluminal stimuli releasing vasoconstrictor and vasodilator substances to adjust vascular tone to a particular situation1.