Enhancement of anaphylatoxin C5a-stimulated prostaglandin-dependent glucose release in the perfused rat liver by thromboxane-induced flow reduction and fenestral contraction of sinusoidal endothelial cells

In perfused rat liver, the anaphylatoxin C5a enhanced glucose output and re duced flow. Both effects were inhibited not only by the prostanoid synthesi s inhibitor indomethacin but also by the thromboxane receptor antagonist da ltroban. Since hepatocytes express prostaglandin bur not thromboxane recept ors, thromboxane in contrast to prostaglandins cannot directly activate hep atocellular glycogen phosphorylase but must act indirectly either i) by ind ucing the release of a soluble factor from the thromboxane receptor-bearing sinusoidal endothelial cells or Kupffer cells or ii) by inducing physical changes within the liver tissue. The thromboxane analog U46619 failed to ac tivate glycogen phosphorylase in cocultures of sinusoidal endothelial cells or Kupffer cells with hepatocytes, arguing against the involvement of a so luble factor. In Ca2+-free media both the U46619-and PGF(2 alpha)-elicited flow reduction of the perfused liver were almost completely prevented, wher eas glucose output induced by U46619 was strongly but glucose output induce d by PGF(2 alpha), which can directly activate hepatocellular glycogen phos phorylase, was only slightly reduced. Moreover, U46619 rapidly decreased bo th the number and the diameters of sinusoidal endothelial cell fenestrae. T hus, most likely thromboxane supports prostaglandin-mediated glucose output from hepatocytes induced by rrC5a i) by causing hypoxia as a result of flo w reduction and ii) by retaining prostaglandins and thus increasing prostag landin concentrations in the Space of Disse due to narrowing of the fenestr ae in sinusoidal endothelial cells.