Increase by anaphylatoxin C5a of glucose output in perfused rat liver via prostanoids derived from nonparenchymal cells: Direct action of prostaglandins and indirect action of thromboxane A(2) on hepatocytes

In the perfused rat liver the anaphylatoxin C5a enhanced glucose output, re duced flow, and elevated prostanoid overflow Because hepatocytes (HCs) do n ot express C5a receptors, the metabolic C5a actions must be indirect, media ted by e.g, prostanoids from Kupffer cells (KCs) and hepatic stellate cells (HSCs), which possess C5a receptors. Surprisingly, the metabolic C5a effec ts were not only impaired by the prostanoid synthesis inhibitor, indomethac in, but also by the thromboxane A(2) (TXA(2)) receptor antagonist, daltroba n, even though HCs do not express TXA(2) receptors. TXA(2) did not induce p rostaglandin (PG) or an unknown factor release from KCs or sinusoidal endot helial cells (SECs), which express TXA(2) receptors, because (1) daltroban did neither influence the C5a-induced release of prostanoids from cultured KCs nor the C5a-dependent activation of glycogen phosphorylase in KC/HC coc ultures and because (2) the TXA(2) analog, U46619, failed to stimulate pros tanoid release from cultured KCs or SECs or to activate glycogen phosphoryl ase in KC/HC or SEC/HC cocultures, In the perfused liver, Ca2+-deprivation inhibited not only flow reduction but also glucose output elicited by C5a t o similar extents as daltroban. Similarly, in the absence of extracellular Ca2+, flow reduction and glucose output induced by U46619 were almost compl etely prevented, whereas glucose output induced by the directly acting PGF( 2 alpha) was only slightly lowered. Thus, in the perfused rat liver PGs rel eased after C5a-stimulation from KCs and HSCs directly activated glycogen p hosphorylase in HCs, and TXA(2) enhanced glucose output indirectly mainly b y causing hypoxia as a result of flow reduction.