Endotoxin pretreatment enhances portal venous contractile response to endothelin-1

To test whether endotoxin pretreatment modulates the portal hemodynamic response to endothelin (ET)-1 and phenylephrine (PE), two potent vasoconstrictors in the portal circulation of the normal liver, rats received intraperitoneal injections of Escherichia coli lipopolysaccharide (LPS; 1 mg/kg body wt) or saline. Livers were isolated after 6 or 24 h and perfused with Krebs buffer containing 5% autologous erythrocytes. Analyses of portal pressure-flow (P-Q) relationships and epifluorescence video microscopy were performed before and after ET-1 (10(-9) M) or PE (10(-5) M) administration. LPS pretreatment increased total portal resistances (R-t), zero-flow pressures (P-Q=0), and linear regression slopes of P-Q relationships, and decreased the sinusoidal diameters (D-s) and sinusoidal volumetric flow (Q(v)). The response to ET-1 was enhanced 6 and 24 h after LPS administration, leading to greater increases in R-t, P-Q=0, and slope and more pronounced decreases in D-s, red blood cell velocity (V-RBC), and Q(v). In contrast, PE effects were similar (P-Q=C, slope, D-s) or even attenuated (R-t, V-RBC, Q(v)) in livers from LPS-treated compared with control animals. Thus endotoxin pretreatment increased the portal contractile response to ET-1 but not to PE. This enhanced ET-1 response appeared to occur at sinusoidal and presinusoidal levels and may contribute to endotoxin-induced hepatic microcirculatory failure.