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

Exogenously administered endothelin (ET) elicits both presser and depressor responses through the ETA and/or the ETB receptor on vascular smooth muscl e cells and ETB on endothelial cells. To test whether ETB has presser or de pressor effects under basal physiological conditions, we determined arteria l blood pressure (BP) in ETB-deficient mice obtained by crossing inbred mic e heterozygous for targeted disruption of the ETB gene with mice homozygous for the piebald (s) mutation of the ETB gene (ETBs/s). F-1 ETB-/s and ETB/s progeny share an identical genetic background but have ETB levels that a re similar to 1/8 and 5/8, respectively, of wild-type mice (ETB+/+). BP in ETB-/s mice was significantly higher, by similar to 20 mmHg, than that in E TB+/s or ETB+/+ mice. Immunoreactive ET-1 concentration in plasma as well a s respiratory parameters was not different between ETB-/s and ETB+/s mice. A selective ETB antagonist, BQ-788, increased BP in ETB+/s and ETB+/+ but n ot in ETB-/s mice. Pretreatment with indomethacin, but not with N-G-monomet hyl-L-arginine, can attenuate the observed presser response to BQ-788. The selective ETA antagonist BQ-123 did not ameliorate the increased BP in ETB- /s mice. Moreover, BP in mice heterozygous for targeted disruption of the E TA gene was not different from that in wild-type controls. These results su ggest that endogenous ET elicits a depressor effect through ETB under basal conditions, in part through tonic production of prostaglandins, and not th rough secondary mechanisms involving respiratory control or clearance of ci rculating ET.