Left ventricular wall stress and sarcoplasmic reticulum Ca2+-ATPase gene expression in renal hypertensive rats: dose-dependent effects of ACE inhibition and AT,-receptor blockade

Background: Cardiac hypertrophy is associated with altered Ca”+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Cazf-ATPase is thought to play a crucial role in the alterations of Cazt handling and LV function. We assessed the dose-dependent effect of chronic ACE inhibition or AT, receptor blockade on cardiac function in relation to the cardiac expression of the SR Ca2+ATPase and ANF. Methods and Results: Renal hypertensive rats (2K-IC) were treated for 12 weeks with three different doses of the ACE inhibitor benazepril, the AT,-receptor antagonist valsartan (each drug 0.3, 3, and 10 mg/kg per day i.p.) or placebo. LV dimensions, hypertrophy and wall stress were determined in vivo by magnetic resonance imaging and the gene expressions of ANF and SR Ca*’ -ATF’ase were quantified by Northern blot. Low doses of both drugs did not affect blood pressure, hypertrophy, systolic wall stress and the ANF and SR Ca2 ’ -ATPase gene expression. High doses of each drug reduced systolic blood pressure, wall stress, and LV hypertrophy to a similar extent and to values comparable to normotensive, age-matched rats. In addition, high dose treatment reduced LV end-systolic and end-diastolic volume as compared to untreated 2K-IC animals and normalized the mRNA levels of both ANF and SR Ca*+-ATPase (as compared to normotensive animals). Conclusions: We conclude that in this model, high doses of ACE inhibition and AT,-receptor blockade are necessary to normalize systolic blood pressure, LV hypertrophy and systolic LV wall stress which, in turn, is associated with restoration of a normal cardiac phenotype with respect to SR Ca *+-ATPase and ANF and normalization of cardiac function.