Abstract
Background: Portal pressure (PP) results from the interplay of vasoconstrictors and vasodilators. Recently, we have shown that Kupffer cell (KC) activation increases PP. Aims: The role of the vasodilating compounds nitric oxide (NO) and carbon monoxide (CO) was studied. The hypothesis of the present study was that these vasodilators counteract the PP increase following KC activation. Methods: Livers of rats weighing 180–200 g were isolated and perfused. KCs were activated by zymosan A (cell wall particles from yeast; 150 µg/ml). The effects of NO and guanylate cyclase (GC) were evaluated by the NO synthase inhibitor NG-nitro-<smlcap>L</smlcap>-arginine methylester (<smlcap>L</smlcap>-NAME; 0.3 m<smlcap>M,</smlcap> and the GC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028, 1.0 µ<smlcap>M</smlcap>); the effects of the heme oxygenase (HO) derived compound CO were evaluated by direct administration of CO or inhibition of HO by zinc protoporphyrin IX (ZnPP IX, 1.0 µ<smlcap>M</smlcap>). Results: In isolated perfused rat livers, administration of <smlcap>L</smlcap>-NAME or NS-2028 further raised PP increase following KC activation. This effect could be reduced by the cGMP analogue 8-Br-cGMP. Inhibition of HO caused marked amplification of PP increase in zymosan-treated organs. CO prevented this PP increase cGMP independently. Interestingly, KC activation and simultaneous inhibition of HO augmented the production of prostaglandins D2 and F2α and of thromboxane A2. Accordingly, indomethacin blunted the increase of PP in zymosan/ZnPP-treated livers. Conclusions: NO restricts the initial PP increase after KC activation by GC-mediated cGMP. CO from heme degradation limits the increase of PP after KC activation eicosanoid dependently, but cGMP independently.
Journal Section:
Original Paper
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