Abstract 14304: Candesartan Cilexetil Prevents Cardiac Electrical Remodeling and Calcium Handling Abnormalities in Pressure-Overloaded Rats
Background: Left ventricular hypertrophy (LVH) is associated with abnormal ventricular electrophysiology and increased arrhythmia risk. Angiotensin II AT1 receptor blockers were shown to regress the LVH in both experimental and clinical settings. We assessed the effects of candesartan on the electrical and Ca2+ handling alterations of ventricle to arterial pressure overload.
Methods and results: Male SD rats were randomized to one of the following four groups: four weeks of banding of the abdominal aorta (AB) or sham procedure and receiving vehicle or candesartan cilexetil (3.0 mg/kg/day, gastric gavage). Aortic banding was characterized by LV hypertrophy, increased LV systolic and end-diastolic pressure, and prolonged QTc interval. Candesartan administration attenuated the LVH and the hemodynamic and QTc interval abnormalities. In Langendorff-perfused heart paced at 5 Hz, the ventricular repolarization time (VRT) was longer in AB rats (43.6±2.6 ms, n=7 vs. 30.7±2.1 ms Sham, n=7, p<0.01). In LV papillary muscles paced at 1 Hz, an increase in the action potential duration at 90% repolarization (APD90) in AB rats was observed (91.7±5.4 ms, n=6 vs. 54.0±4.6 ms Sham, n=7, p<0.001). Candesartan treatment restored the VRT (31.7±2.2 ms, n=9, p<0.01) and APD90 (73.6±4.6 ms, n=8, p<0.05) in AB rats. Single LV myocytes from AB rats showed increased cell capacitance and decreased both transient outward (Ito) (at +60 mV, 4.5±1.5 pA/pF, n=7 vs. 20.3±2.8 pA/pF Sham, n=6, p<0.01) and inward rectifier (IK1) K+ current densities compared with myocytes from sham controls. However, myocytes from AB rats treated with candesartan had normal cell capacitance and membrane current densities (Ito: 16.5±1.7 pA/pF, n=7, p<0.001). In addition, LV preparations of AB rats had decreased Ca2+ transient amplitude (fura-2 F340/380 ratio: 0.44±0.04, n=19 vs. 0.56±0.03 Sham, n=16, p<0.05), decreased expression of SERCA2a, and increased expression of NCX. Candesartan application improved the Ca2+ handling (F340/380 ratio: 0.63±0.04, n=16, p<0.01) in AB rats.
Conclusions: Candesartan protects the heart from the remodeling induced by pressure overload, and the normalization of the electrical abnormalities seems to be related with the preservation of K+ channel current densities.
- © 2010 by American Heart Association, Inc.