—Homozygous knock-out of ET_A or ET_B receptor genes results in lethal developmental phenotypes in the mouse. Such deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially defective in ET_A or ET_B receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ET_B (+/−) knock-out mice showed a significantly higher mean arterial blood pressure than the ET_A (+/−) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ET_B agonist, IRL-1620, was significantly reduced in the ET_A (+/−) knock-out mice. In ET_B (+/−) knock-out mice, the pressor effect of IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ET_A and ET_B receptors were found to be involved in the pressor effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123 (ET_A antagonist) or BQ-788 (ET_B antagonist). Also, ET_A-selective or mixed ET_A/ET_B- but not ET_B-selective antagonists reversed the hypertensive state of the ET_B (+/−) knock-out mice to the level of wild-type littermates. Finally, radiolabeled ET-1 plasmatic clearance was altered in ET_B (+/−) but not ET_A (+/−) knock-out mice when compared with wild-type animals. Thus, heterozygous knock-out of ET_B receptors results in a hypertensive state, suggesting an important physiological role for that particular receptorial entity in opposing the endogenous ET-1–dependent pressor effects in the mouse.