The role of nitric oxide in hemodynamic and metabolic alterations induced by prostaglandin F_(2a) in the perfused rat liver

摘要

In the liver prastuglandin.s have been shown to be potent regulators of portal blood flow, carbohydrate metabolism and bile secretion. It is not known whether these effects represent a direct action of prostaglandins, and it has been suggested that nitric oxide (NO) might be a critical mediator for prostaglandin induced hepatic events. We have studied whether nitric oxide formation or inhibition alters the action of proslagkuulin Is,, (PG F2(I) in a single-pass liver perfusion model. The liver of untreated rats (constitutive NO-synthase) or after prelrealinent with endotoxin (inducible form of NO-synthase) was perfused at a constant pressure via the portal vein. Effluate were collected in l-tnin intervals and bile in 5-min intervals. In both groups the addition of PG F2n (10 /u.M) to the perfusate for 5 min resulted in a significant increase of glucose and lactate production, and in a significant decrease in portal blood flow ( — 0.56 ± 0.04 ml/g per min), in bile flow (—60.7%) and in bile acid release ( — 60.6%). Inhibition of NO synthase by adding A/°-monomethyl-i.-arginine (t.-NMMA, 100 /xM) to the perfusate did not affect any of the alterations induced by PG F,,,. Substitution of the endogenous substrate For the NO synthase i.-arginine (500 /iM) in the perfusate completely prevented the hemodynamic alterations induced by PG F2(, in endotoxin pretreated livers and limited the flow reduction (0.15 ±0.04 ml/g per min) in the untreated group. The substitution of L-arginine in the perfusate of endotoxin pretreated livers raised nitrite (from 1.5 ± 0.3 to 3,6 ± 0.7 nmol/g per min) and urea release (from 65 ± 25 to 294 ± 68 nmol/g per min), but had no effect on any of the other metabolic parameters and bile secretion. We conclude that PG Is,, increases glucose and lactate production in the perfused rat liver and decreases portal flow and bile secretion. The metabolic effects induced by PG F2(, appear to be independent of NO mediation and hemodynamic alterations. Portal flow alone can be influenced by endogenous NO formation.