Elevation of blood pressure by genetic and pharmacological disruption of the ET_Breceptor in mice

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_Bgene with mice homozygous for the piebald (s) mutation of theET_B gene (ET_B^s/s). F₁ET_B^−/sandET_B^+/sprogeny share an identical genetic background but have ET_B levels that are ∼$\frac{1}{8}$ and $\frac{5}{8}$ , respectively, of wild-type mice (ET_B^+/+). BP inET_B^−/smice was significantly higher, by ∼20 mmHg, than that inET_B^+/sorET_B^+/+mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different betweenET_B^−/sandET_B^+/smice. A selective ET_B antagonist, BQ-788, increased BP inET_B^+/sandET_B^+/+but not inET_B^−/smice. 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^−/smice. 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.