Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca2+-ATPase expression in the sarcoplasmic 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 with 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 of both treatments on sarcoplasmic reticulum Ca2+-ATPase (SERCA 20) gene 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 captopril (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) 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 20 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 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 contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT(1)-RA or by ACEI treatment, might contribute to the improvement in diastolic function.