Portal Pressure Regulation following Kupffer Cell Activation: Control of Prostaglandin Production by Heme Oxygenases

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.