INFLUENCE OF ACE INHIBITORS ON FRAILTY AND CARDIAC FUNCTION IN MIDDLE-AGED FEMALE C57BL/6 MICE

Abstract

AbstractACE inhibitors improve exercise capacity in older adults without cardiovascular disease and in aged rodents. We hypothesised that chronic ACE inhibitor treatment may attenuate frailty through changes in cardiac function. Female C57BL/6 mice (12 months) were given enalapril (40 mg/kg/day; n=10) or control (n=10) for 3 months. Frailty was quantified with the mouse clinical frailty index (FI). Blood pressure (BP) was measured with a tail-cuff and in vivo cardiac function was measured using echocardiography. Cardiomyocytes were isolated for field-stimulation and voltage clamp experiments (2 Hz). FI scores were significantly lower in the enalapril group when compared to control mice (0.14 ± 0.01 vs 0.21 ± 0.03, p<0.05) after 3 months. BP, heart structure and contractile function were not significantly different between the enalapril and control groups. Field stimulation experiments showed that enalapril treatment increased cell shortening (1.6 ± 0.2 vs 3.0 ± 0.5 %, p<0.001), velocity-to-peak contraction (0.068 ± 0.005 vs 0.133 ± 0.016 µm/ms, p<0.001) and ½ relaxation (0.044 ± 0.005 vs 0.100 ± 0.016 µm/ms, p<0.001), with no change in underlying calcium transients. Under voltage clamp conditions both calcium transients (37.6 ± 3.2 vs 49.0 ± 3.9 nM, p<0.05) and contractions (5.7 ± 0.7 vs 8.9 ± 0.9 %, p<0.05) were increased by enalapril treatment. Calcium current and sarcoplasmic reticulum (SR) calcium content were unchanged. These results show that enalapril attenuates frailty in middle-aged animals, even in the absence of cardiovascular disease, and suggest that ACE inhibitor treatment may increase calcium release from the SR.