Exogenously administered endothelin (ET) elicits both pressor and depressor responses through the ET_A and/or the ET_B receptor on vascular smooth muscle cells and ET_B on endothelial cells. To test whether ET_B has pressor or depressor effects under basal physiological conditions, we determined arterial blood pressure (BP) in ET_B-deficient mice obtained by crossing inbred mice heterozygous for targeted disruption of theET_B gene with mice homozygous for the piebald (s) mutation of theET_B gene (ET _B ^s/s ). F₁ ET _B ^−/s andET _B ^+/s progeny share an identical genetic background but have ET_B levels that are ∼and , respectively, of wild-type mice (ET _B ^+/+ ). BP inET _B ^−/s mice was significantly higher, by ∼20 mmHg, than that inET _B ^+/s orET _B ^+/+ mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different betweenET _B ^−/s andET _B ^+/s mice. A selective ET_B antagonist, BQ-788, increased BP inET _B ^+/s andET _B ^+/+ but not inET _B ^−/s mice. Pretreatment with indomethacin, but not withN ^G-monomethyl-l-arginine, can attenuate the observed pressor response to BQ-788. The selective ET_A antagonist BQ-123 did not ameliorate the increased BP inET _B ^−/s mice. Moreover, BP in mice heterozygous for targeted disruption of theET_A gene was not different from that in wild-type controls. These results suggest that endogenous ET elicits a depressor effect through ET_B under basal conditions, in part through tonic production of prostaglandins, and not through secondary mechanisms involving respiratory control or clearance of circulating ET.