title: Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy.
abstract: BACKGROUND
  Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.
  
  
  OBJECTIVE
  To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.
  
  
  RESULTS
  Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.
  
  
  CONCLUSIONS
  In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.
authors.affiliation: Klinik III für Innere Medizin der Universität zu Köln, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: F
authors.initials: F
authors.lastname: Schiffer
authors.forename: O
authors.initials: O
authors.lastname: Zolk
authors.forename: Y
authors.initials: Y
authors.lastname: Pinto
authors.forename: J P
authors.initials: JP
authors.lastname: Stasch
authors.forename: A
authors.initials: A
authors.lastname: Knorr
authors.forename: S
authors.initials: S
authors.lastname: Ettelbrück
authors.forename: M
authors.initials: M
authors.lastname: Böhm
mesh_terms: D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000032:analysis; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D003971:Diastole / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004095:Dihydropyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; C109119:embusartan; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D002216:Captopril; D012083:Renin; D000252:Calcium-Transporting ATPases