title: High salt-induced hypertension in B2 knockout mice is corrected by the ETA antagonist, A127722.
abstract: OBJECTIVE
  The contribution of endothelin-1 (ET-1) in a B2KO mouse model of a high salt-induced arterial hypertension was investigated.
  
  
  METHODS
  Wild-type (WT) or B2KO 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 ETA 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 ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) in anaesthetized WT and B2KO mice.
  
  
  RESULTS
  In B2KO, 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 B2KO mice under ND. Significant increases in immunoreactive ET-1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO 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 B2KO, but not WT mice under anaesthesia.
  
  
  CONCLUSIONS
  Our results support the concept that functional B2 receptors oppose high salt-induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.
authors.affiliation: Department of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Brochu
authors.forename: M
authors.initials: M
authors.lastname: Houde
authors.forename: L
authors.initials: L
authors.lastname: Desbiens
authors.forename: E
authors.initials: E
authors.lastname: Simard
authors.forename: F
authors.initials: F
authors.lastname: Gobeil
authors.forename: W
authors.initials: W
authors.lastname: Semaan
authors.forename: G
authors.initials: G
authors.lastname: Bkaily
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects; D000077868:Atrasentan; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D043782:Receptor, Bradykinin B2 / Q000235:genetics*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D013686:Telemetry
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D011759:Pyrrolidines; D043782:Receptor, Bradykinin B2; D017673:Sodium Chloride, Dietary; D012964:Sodium; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D019331:NG-Nitroarginine Methyl Ester; D000077868:Atrasentan
keywords: A127722; ET-1; RIA; bradykinin; high-salt diet; knockout mice; radiotelemetry