Steib, Christian J.; Gmelin, Leonore; Bilzer, Manfred; Göke, Burkhard; Gerbes, Alexander L.
Portal Pressure Regulation following Kupffer Cell Activation: Control of Prostaglandin Production by Heme Oxygenases.
In: Digestion, No. 2: pp. 102-109
Background: Portal pressure (PP) results from the interplay ofvasoconstrictors and vasodilators. Recently, we have shown that Kupffercell (KC) activation increases PP. Aims: The role of the vasodilatingcompounds nitric oxide (NO) and carbon monoxide (CO) was studied. Thehypothesis of the present study was that these vasodilators counteractthe PP increase following KC activation. Methods: Livers of ratsweighing 180-200 g were isolated and perfused. KCs were activated byzymosan A (cell wall particles from yeast; 150 mu g/ml). The effects ofNO and guanylate cyclase (GC) were evaluated by the NO synthaseinhibitor N-G-nitro-L-arginine methylester (L-NAME; 0.3 m M, and the GCinhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one(NS-2028, 1.0 mu M); the effects of the heme oxygenase (HO) derivedcompound CO were evaluated by direct administration of CO or inhibitionof HO by zinc protoporphyrin IX (ZnPP IX, 1.0 mu M). Results: Inisolated perfused rat livers, administration of L-NAME or NS-2028further raised PP increase following KC activation. This effect could bereduced by the cGMP analogue 8-Br-cGMP. Inhibition of HO caused markedamplification of PP increase in zymosan-treated organs. CO preventedthis PP increase cGMP independently. Interestingly, KC activation andsimultaneous inhibition of HO augmented the production of prostaglandinsD-2 and F-2 alpha and of thromboxane A(2). Accordingly, indomethacinblunted the increase of PP in zymosan/ZnPP-treated livers. Conclusions:NO restricts the initial PP increase after KC activation by GC-mediatedcGMP. CO from heme degradation limits the increase of PP after KCactivation eicosanoid dependently, but cGMP independently.