ANGIOTENSIN RECEPTOR ANTAGONISM AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IMPROVE DIASTOLIC DYSFUNCTION AND CA2-ATPASE EXPRESSION IN THESARCOPLASMIC-RETICULUM IN HYPERTENSIVE CARDIOMYOPATHY()

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 w ith an angiotensin type 1 receptor antagonist (AT(1)-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects o f both treatments on sarcoplasmic reticulum Ca2+-ATPase (SERCA 20) gen e expression as a major cause of impaired diastolic cardiac relaxation . Methods and results Eight-week-old rats harboring the mouse renin 2( d) gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopri l (Cap) in their food and 100 mg/kg of the AT(1)-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) wer e used as controls. Both treatment regimens normalized the left ventri cular weight, which was increased significantly (P < 0.001) in TG(mREN 2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P< 0.001) higher i n 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]. D ecreased left ventricular SERCA 20 mRNA and protein levels and increas ed atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by N orthern and Western blotting). According to radioimmunoassay and an en zyme assay, respectively, Bay, but not Cap, increased plasma angiotens in I concentrations and the renin activity above normal levels (P < 0. 05), whereas myocardial angiotensin II concentrations (determined by r adioimmunoassay), which were significantly (P< 0.05) increased in TG(m REN2)27, were normalized equally by Bay and Cap. Conclusions In renin- induced hypertensive cardiomyopathy, left ventricular diastolic dysfun ction occurs at the stage of compensated myocardial hypertrophy, The d ecreased left ventricular relaxation velocity might be due to reduced SERCA 20 gene expression. In this model of hypertensive cardiomyopathy , AT(1)-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic co ntractile dysfunction. Normalization of SERCA 2a gene expression, eith er by AT(1)-RA or by ACEI treatment, might contribute to the improveme nt in diastolic function.