Elevation of blood pressure by genetic and pharmacological disruption of the ET B receptor in mice. Am. J. Physiol. 276 (Regulatory Integrative Comp. Physiol. 45): R1071-R1077, 1999.-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

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... ure (BP) in ET B -deficient mice obtained by crossing inbred mice heterozygous for targeted disruption of the ET B gene with mice homozygous for the piebald (s) mutation of the ET B gene (ET B s/s ). F 1 ET B Ϫ/s and ET B ϩ/s progeny share an identical genetic background but have ET B levels that are ϳ 1 ⁄8 and 5 ⁄8, respectively, of wild-type mice (ET B ϩ/ϩ ). BP in ET B Ϫ/s mice was significantly higher, by ϳ20 mmHg, than that in ET B ϩ/s or ET B ϩ/ϩ mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different between ET B Ϫ/s and ET B ϩ/s mice. A selective ET B antagonist, BQ-788, increased BP in ET B ϩ/s and ET B ϩ/ϩ but not in ET B Ϫ/s mice. Pretreatment with indomethacin, but not with N 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 in ET B Ϫ/s mice. Moreover, BP in mice heterozygous for targeted disruption of the ET 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.