ENDOTHELIN-1 AS A REGULATOR OF HEPATIC MICROCIRCULATION - SUBLOBULAR DISTRIBUTION OF EFFECTS AND IMPACT ON HEPATOCELLULAR SECRETORY FUNCTION

Endothelin-1 is a potent vasoconstrictor in the portal circulation causing sinusoidal constriction as well as presinusoidal resistance changes. Using in vivo videomicroscopy we studied the sublobular differences in dose response characteristics of sinusoid constriction at 10-13 min into continuous infusion of .5, 1.0, 3.0, and 5.0 pmol of endothelin-1 (ET-1)/100 g body weight/min in pentobarbital anesthetized rats. In addition, bile flow was monitored to estimate parenchymal secretory function. ET-1 evoked a profound constrictor effect in both sublobular regions studied. However, the maximal decrease of sinusoidal width in periportal inflow region (zone 1; 1 pmol/100 g/min: 4.8 +/- .1 mum) was reached at slightly lower concentrations of the peptide than in pericentral outflow region (zone 3; 3 pmol/l 00 g/min: 6.2 +/- .3 mum) compared to respective baseline values (zone 1:7.1 +/- .1 mum; zone 3: 10.2 +/- .1 mum), suggesting upstream binding and clearance of the peptide. The constrictor response in zone 1 was biphasic and at higher concentrations of the peptide (5 pmol/100 g/min: 5.5 +/- .2 pm) sinusoidal widths increased again compared to the maximal response with 1 pmol. Secretory function as reflected by the bile flow was maintained or even slightly increased with the lower doses (.5 and 1 pmol) of ET-1 and during the first 10 min into infusion of the higher doses (3 and 5 pmol). Subsequently, an approximately 20-25% decrease in bile flow accompanied the infusion of higher doses of ET-1. These results indicate that the vascular effects occur at lower concentrations than the cholestatic effect and precede the cholestatic effect, suggesting a causal effect of microvascular perturbations on cholestasis that is associated with portal infusion of higher doses of ET-1.