Hepatocyte heterogeneity in response to icosanoids

The metabolic and hemodynamic effects of prostaglandin F2α, leukotriene C4 and the thromboxane A2 analogue U‐46619 were studied during physiologically antegrade (portal to hepatic vein) and retrograde (hepatic to portal vein) perfusion and in a system of two rat livers perfused in sequence. The stimulatory effects of prostaglandin F2α (3 μM) on hepatic glucose release, perfusion pressure and net Ca2+ release were diminished by 77%, 95% and 64%, respectively, during retrograde perfusion when compared to the antegrade direction, whereas the stimulation of 14CO2 production from [l‐14C]glutamate by prostaglandin F2α (which largely reflects the metabolism of perivenous hepatocytes) was lowered by only 20%. Ca2+ mobilization and glucose release from the liver comparable to that seen during antegrade perfusion could also be observed in retrograde perfusions; however, higher concentrations of the prostaglandin were required. The glucose, Ca2+ and pressure response to leukotriene C4 (20 nM) or the thromboxane A2 analogue U‐46619 (200 nM) of livers perfused in the antegrade direction were diminished by about 90% during retrograde perfusion. Sodium nitroprusside (20 μM) decreased the pressure response to leukotriene C4 (20 nM) and U‐46619 (200 nM) by about 40% and 20% in antegrade perfusions, respectively, but did not affect the maximal increase of glucose output. When two livers were perfused antegradely in series, such that the perfusate leaving the first liver (liver I) entered a second liver (liver II), infusion of U‐46619 at concentrations below 200 nM to the influent perfusate of liver I increased the portal pressure of liver I, but not of liver II. At higher concentrations of U‐46619 there was also an increase of the portal pressure of liver II and with concentrations above 800 nM the pressure responses of both livers were near‐maximal [19.6 ± 0.8 (n = 7) cm H2O and 16.5 ± 1.1 (n= 8) cm H2O for livers I and II, respectively]. There was a similar behaviour of glucose release from livers I and II in response to U‐46619 infusion. When liver I was perfused in the retrograde direction, a significant pressure or glucose response of liver II (antegrade perfusion) could not be observed even with U‐46619 concentrations up to 1000 nM. Similarly, the perfusion pressure increase and glucose release induced by leukotriene C4 (10 nM) observed with liver II was only about 20% of that seen with liver I. However, at leukotriene C4 concentrations of about 70 nM, a response of liver II comparable to that of liver I was seen. Similar experiments with prostaglandin F2α (3 μM) produced only a pressure and glucose response of liver I but not of liver II. The data show (a) that icosanoids are effectively inactivated during a single liver passage and suggest that (b) their inactivation occurs predominantly near the perivenous outflow of the sinusoidal bed. These findings are consistent with the concept of perivenous scavenger cells. (c) Inactivation of the thromboxane A2 analogue U‐46619 and leukotriene C4, but not of prostaglandin F2α, is more efficient in retrograde perfusion than in antegrade perfusions. This could be due to an opening of portal venous‐hepatic venous shunts in antegrade but not in retrograde perfusions. (d) The increase of perfusion pressure in response to icosanoids is due to sphincters near the inflow of the sinusoidal bed. (e) The metabolic and hemodynamic effects of U‐46619 and leukotriene C4 in perfused liver are probably mediated by the action of these compounds on cells near the periportal inflow of the sinusoidal bed, whereas prostaglandins act directly inside the liver acinus.