title: Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats.
abstract: BACKGROUND
  We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II.
  
  
  METHODS
  mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin-angiotensin system (RAS) were measured at the completion of the experiments.
  
  
  RESULTS
  Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration.
  
  
  CONCLUSIONS
  Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang-(1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade.
authors: Hypertension and Vascular Research Center, Wake Forest University, Winston-Salem, NC, USA. jvaragic@wfubmc.edu
authors: Jasmina
authors: J
authors: Varagic
authors: Sarfaraz
authors: S
authors: Ahmad
authors: Jessica L
authors: JL
authors: VonCannon
authors: Norihito
authors: N
authors: Moniwa
authors: K Bridget
authors: KB
authors: Brosnihan
authors: Jan
authors: J
authors: Wysocki
authors: Daniel
authors: D
authors: Batlle
authors: Carlos M
authors: CM
authors: Ferrario
mesh_terms: D000450:Aldosterone / Q000097:blood; D000803:Angiotensin I / Q000097:blood / Q000502:physiology*; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006973:Hypertension / Q000097:blood / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000068557:Olmesartan Medoxomil; D010446:Peptide Fragments / Q000097:blood / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D000068557:Olmesartan Medoxomil; D000803:Angiotensin I; D012083:Renin; C118790:angiotensin I (1-7)