Heterozygous knock-out of ETB receptors induces BQ-123-sensitive hypertension in the mouse

Homozygous knock-out of ETA or ETB 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 ETA or ETB receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ETB (+/-) knock-out mice showed a significantly higher mean arterial blood pressure than the ETA (+/-) knock-out or their wild-type littermates. The presser response to ET-1 but not to a selective ETB agonist, IRL-1620, was significantly reduced in the ETA (+/-) knock-out mice. In ETB (+/-) knock-out mice, the presser effect of IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ETA and ETB receptors were found to be involved in the presser effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123 (ETB antagonist) or BQ-788 (ETB antagonist). Also, ETA-selective or mixed ETA/ETB- but not ETB-selective antagonists reversed the hypertensive state of the ETA (+/-) knock-out mice to the level of wild-type littermates. Finally, radiolabded ET-1 plasmatic clearance was altered in ETB (+/-) but not ETA (+/-) knock-out mice when compared with wild-type animals. Thus, heterozygous I;nock-out of ETB receptors results in a hypertensive state, suggesting an important physiological role for that particular receptorial entity in opposing the endogenous ET-1-dependent presser effects in the mouse.