Inhibition of
angiotensin-converting enzyme (ACE) retards the process of myocardial remodeling and contractile dysfunction that leads to
heart failure. However, the intracellular mechanisms by which ACE inhibition preserves myocardial contractility are largely unclear. Using a model of
heart failure induced by
hypertension in Dahl
salt-sensitive (DS) rats, the mechanisms by which
ACE inhibitors (ACEI) exert a beneficial effect on myocardial contractility were studied. Dahl
salt-resistant (DR) rats, DS rats not given
temocapril (DS/T-), and DS rats treated with
temocapril (10 mg/kg per day from 10 to 17 weeks of age, DS/T+) were fed an 8% NaCl diet from 8 to 17 weeks of age (n=8, each group). Echocardiography, hemodynamic measurement, histology, contraction of isolated skinned papillary muscle, and Western blot analysis were carried out. At an elevated final blood pressure similar to that of the DS/T- rats, DS/T+ rats exhibited (1) a decrease in left ventricular (LV) mass associated with decreases in both cardiomyocyte size and interstitial
fibrosis; (2) improvement of both systolic and diastolic LV function; and (3) an increase in
caffeine contraction after constant Ca(2+)-loading with
8-bromo-cAMP into the sarcoplasmic reticulum (SR) associated with an increase in Ser16-phosphorylated
phospholamban, as compared with the DS/T- rats. In addition to inhibition of myocardial remodeling, a restoration of the Ca(2+)-handling ability of the SR by normalized phosphorylated
phospholamban may contribute to the improved LV contractile function achieved by chronic treatment with an ACEI.