Hepatic stellate cells (Ito cells) are perisinusoidal cells with features typical of tissue pericytes which have been implicated in the modulation of sinusoidal blood flow. They possess endothelin (ET) receptors and contract in response to ETs. To elucidate the role of ET receptors in stellate cell contraction, a model cell contraction system was used to examine the effect of ET-1, ET-3, sarafotoxin S6C (a pure ETB receptor agonist) and ETA and/or ETB receptor antagonists. ET-1 and sarafotoxin S6C elicited similar contractile responses (EC50 0.18 and 0.21 nM, respectively). BQ-123, an ETA antagonist, minimally inhibited ET-1 induced contraction, while bosentan, a mixed, nonpeptide ETA/ETB antagonist, inhibited ET-1 and sarafotoxin S6C mediated contraction in a similar fashion. In contrast, bosentan had little effect on ET-3 stimulated contraction. The data demonstrate that the ETB receptor is a prominent mediator of stellate cell contraction and raise the possibility of a novel ET receptor subtype.