title: Regulation of intrarenal and circulating renin-angiotensin systems in severe heart failure in the rat.
abstract: OBJECTIVE
  Activation of the intrarenal renin-angiotensin system may contribute to the pathophysiology of heart failure by accelerating the generation of angiotensin II at local sites within the kidneys. Activation of the local intrarenal renin-angiotensin system occurs in rats and with mild heart failure. The aim of the present study was to examine components of the circulating as well as the intrarenal renin-angiotensin system in rats with severe heart failure.
  
  
  METHODS
  Six weeks after experimental myocardial infarction (heart failure, HF; n = 8) or sham operation (control, C; n = 6), haemodynamics and the circulating and intrarenal components of the renin-angiotensin system were studied.
  
  
  RESULTS
  HF rats were characterised by large infarctions (scar tissue > 40% of the left ventricular circumference). In comparison to sham operated controls, large myocardial infarctions resulted in severe heart failure with decreased systolic [108(SEM 3) mm Hg v 132(3) in C; p < 0.001] and diastolic arterial blood pressure [83(3) mm Hg v 95(2) in C; p < 0.05], decreased left ventricular systolic pressure [109(3) mm Hg v 132(3) in C; p < 0.005] and increased left ventricular end diastolic pressure [27(2) mm Hg v 5(1) in C; p < 0.0001]. In rats with severe heart failure, the circulating renin-angiotensin system was activated, with an increase in plasma renin activity (3.5-fold, p < 0.05) and plasma angiotensin II concentration (threefold, p < 0.01). In parallel, the intrarenal renin-angiotensin system was activated in severe heart failure. Increases occurred in renal renin mRNA level (1.7-fold, p < 0.01), renal angiotensinogen mRNA level (1.8-fold, p < 0.05), and renal angiotensin II concentration (twofold, p < 0.05) compared to C. Intrarenal angiotensin II concentrations exceeded plasma levels by a factor of 50 and were positively correlated with renal angiotensinogen mRNA levels (r = 0.874, p < 0.001), suggesting that local synthesis is the major source of angiotensin II found in the kidney.
  
  
  CONCLUSIONS
  The intrarenal renin-angiotensin system may be selectively activated in mild heart failure, while both circulating and intrarenal renin-angiotensin systems are induced as the extent of left ventricular function worsens.
authors.affiliation: Department of Internal Medicine II, University of Regensburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schunkert
authors.forename: S S
authors.initials: SS
authors.lastname: Tang
authors.forename: S E
authors.initials: SE
authors.lastname: Litwin
authors.forename: D
authors.initials: D
authors.lastname: Diamant
authors.forename: G
authors.initials: G
authors.lastname: Riegger
authors.forename: V J
authors.initials: VJ
authors.lastname: Dzau
authors.forename: J R
authors.initials: JR
authors.lastname: Ingelfinger
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis / Q000097:blood; D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D015152:Blotting, Northern; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000096:biosynthesis / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin