In rats with portal hypertension induced by partial ligation of the portal vein, we have recently demonstrated an increased portal venous inflow that becomes an important factor in the maintenance of portal hypertension. The sequence of events that leads into this circulatory disarray is unknown. We evaluated chronologically the chain of hemodynamic changes that occurred after portal hypertension was induced by partial ligation of the portal vein. In this model it is possible to follow, from the initiation of the portal-hypertensive state, the interaction between blood flow and resistance in the portal system as well as the relation between the development of portal-systemic shunting and the elevated portal venous inflow. The study was performed in 45 portal-hypertensive rats and in 29 sham-operated rats. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. The constriction of the portal vein was immediately followed by a resistance-induced portal hypertension characterized by increased portal resistance (9.78 +/- 0.89 vs. 4.18 +/- 0.71 dyn X s X cm-5 X 10(4), mean +/- SE, P less than 0.01), increased portal pressure (17.7 +/- 0.9 vs. 9.5 +/- 0.6 mmHg, P less than 0.001), and decreased portal venous inflow (3.93 +/- 0.26 vs. 6.82 +/- 0.49 ml X min-1 X 100 g body wt-1, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
A method for determining the extent of portal-systemic shunting (PSS) is described and evaluated in lightly anesthetized (ketamine) rats. This method relies on the intrasplenic injection of 15-micrometers gamma-labeled spheres and the subsequent measurement of liver and lung radioactivities. After the splenic injection of the microspheres, a fraction of microspheres shunting the hepatic sinusoidal bed will be entrapped in the lungs. Thus, the ratio, lung/(lung + liver) radioactivities, will indicate the degree of PSS. The percent of PSS was determined in normal (n = 13; 1.2 +/- 0.3%), in cirrhotic (n = 9; 15.0 +/- 4.5%; P less than 0.01), and in portal vein-ligated animals (n = 14; 95.0 +/- 0.9%; P less than 0.001 for normal and cirrhotic). In addition, PSS was sequentially quantitated (n = 3) before (3.0%) and after (89%) partial portal vein ligation. The variability of PSS found in cirrhotic rats (0.7-41.0%) is in agreement with the reported data for PSS in patients. This technique, which is simple, rapid, and reproducible, allows the quantitation of PSS in small laboratory animals.
This study investigated whether nitric oxide (NO) plays a role in the intrahepatic portal circulation in normal rat livers perfused in situ. N omega-nitro-L-arginine (NNA), a specific NO biosynthesis inhibitor, significantly increased baseline portal pressure compared with controls (P < 0.05). Concentration-effect curves to norepinephrine (NE) were performed. Perfusate flow was maintained as constant, and perfusion pressure was continuously measured. NNA markedly enhanced the responsiveness to NE. This effect was abolished by the addition of L-arginine, a specific NO substrate. Presence of indomethacin did not alter the response to NE. The response to NE in the presence of indomethacin and NNA was significantly more than the response to NE in the presence of NNA alone. In vivo, intraportal infusion of NNA significantly enhanced the portal pressure compared with vehicle. This study demonstrates that NO contributes to the basal vascular tone and attenuates the response to NE in intrahepatic portal vascular bed of normal rats. These results support a functional role of NO in the regulation of the intrahepatic portal circulation in normal rats. This study also suggests a synergistic, albeit limited, role of prostacyclin in the intrahepatic circulation.
The endothelial cell plays an important role in the local control of vascular smooth muscle tone. Portal hypertension is accompanied by systemic vasodilatation and a decreased response to vasoconstrictors, changes especially evident in the superior mesenteric arterial bed. To evaluate a possible effect of the locally released endothelium-derived relaxing factor nitric oxide (NO), we tested the effect of NO blockade in in vitro perfused superior mesenteric arterial beds of normal (sham) and portal hypertensive (PVL) rats, induced by partial portal vein ligation. A significant (n = 7/group; P = 0.02) hyporeactivity to the vasoconstrictive properties of the alpha-adrenoceptor agonist methoxamine (3 x 10(-6) to 3 x 10(-4) M) was prevented by blocking NO formation in PVL compared with sham rats, using the stereospecific biosynthesis antagonist N omega-nitro-L-arginine (10(-4) M, n = 7/group; NS for all methoxamine concentrations tested). This effect was reversed by the NO precursor L-arginine (10(-3) M, n = 5/group). In conclusion, these in vitro results in mesenteric vessels demonstrate that 1) portal hypertension is accompanied by a hyporeactivity to the vasopressor methoxamine and 2) locally released NO in this preparation is responsible for the decreased vasoconstrictive response.
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