High salt‐induced hypertension in B 2 knockout mice is corrected by the ET A antagonist, A127722

Background and Purpose The contribution of endothelin‐1 ( ET ‐1) in a B 2 KO mouse model of a high salt‐induced arterial hypertension was investigated. Experimental Approach Wild‐type ( WT ) or B 2 KO mice receiving a normal diet ( ND ) or a high‐salt diet ( HSD ) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ET A antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET ‐1 by RIA . In a separate series of experiments, the ET A antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L‐N G ‐nitroarginine methyl ester ( L‐NAME ) in anaesthetized WT and B 2 KO mice. Key Results In B 2 KO , but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure ( MAP ) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B 2 KO mice under ND . Significant increases in immunoreactive ET ‐1 were detected only in the lungs of B 2 KO mice under HSD . On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B 2 KO compared with WT mice under ND . Finally, BQ123 (2 mg·kg −1 ) reduced by 50% the pressor response to L‐NAME (2 mg·kg −1 ) in B 2 KO , but not WT mice under anaesthesia. Conclusions and Implications Our results support the concept that functional B 2 receptors oppose high salt‐induced increments in MAP , which are corrected by an ET A receptor antagonist in this mouse model of experimental hypertension.