To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ET_A receptor agonist ET-1 and of the selective ET_B receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 × 10⁹ M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 × 10⁹ M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ET_B receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.