ENDOTHELIN-1 INDUCES DIRECT CONSTRICTION OF HEPATIC SINUSOIDS

We studied the hepatic microvascular response to endothelin (ET) and t he possible role of Ito cells (fat-storing cells) acting as pericytes in this response using isolated rat livers under high-power intravital microscopy. Livers were perfused in a modified pressure-controlled sy stem with Krebs buffer plus rat erythrocytes (RBC, 10%), and sinusoids at the site of Ito cells were observed under a x100 objective (total magnification x2,533) before and during infusion of ET-1 (10(-9) M) al one, sodium nitroprusside (NP, 10(-5) M) plus ET-1, or phenylephrine ( PE, 10(-7) M). Both ET-1 and PE decreased portal flow (25 and 51%) and increased inflow pressure (28 and 43%), respectively. PE had no effec t on any sinusoidal parameters except that it decreased measured sinus oidal RBC velocity (P < 0.05); ET-1 decreased sinusoidal diameter by 2 5% and increased the calculated sinusoidal pressure gradient and resis tance by 116 and 350%, respectively, but did not alter RBC velocity. N P significantly inhibited changes induced by ET-1. These results demon strate that ET-1 induces a specific sinusoidal constriction that disru pts normal acinar flow dynamics, and the sinusoidal constriction coloc alizes with Ito cells, suggesting that the constriction may be mediate d at least in part by ET-1 action on Ito cells, which can be inhibited by a nitric oxide donor.