At1 receptor blockade with Losartan prevents maladaptive hyperthrophy in pressure overload by inhibiting ROS release

CINGOLANI OH; PÉREZ G; MOSCA SM; SCHINELLA GR; CÓNSOLE G; ENNIS IL; ESCUDERO EM; CINGOLANI HE

Congreso; High Blood Pressure Research; 2010

American heart Association

Pressure overload hypertrophy (POH) has been traditionally viewed as a compensatory response that normalizes left ventricular (LV) wall stress to compensate for increased afterload. This controversial concept implies that blunting POH without changing pressure would therefore decrease cardiac function. To challenge this view, transverse aortic constriction (TAC) was performed in mice and maintained for 7 weeks. From the beginning, a group of mice received the AT1 receptor blocker Losartan (TAC_LOS, 40 mg/Kg) in the drinking water, whereas a second group did not (TAC). LV pressure did not change between groups. Cardiac function was assessed at the end by echocardiography and pressure-volume loop analysis. Mice subjected to TAC had an increase in LV mass of _80% compared to sham. LOS prevented POH (table) and showed increased cardiac contractility when compared to TAC (p_0.05 for LV ejection fraction and preload recruitable stroke work) despite less LV hypertrophy. Increased LV collagen volume fraction was observed in the TAC group; and was significantly reduced by LOS (P _0.05). Cardiac levels of p-90RSK, a PKC downstream effector involved in ROS modulation, increased by 39% in TAC and was normalized with LOS (p _0.05). Lipid peroxidation (plasma TBARS) was elevated in TAC, and blunted in TAC_LOS (P _0.05). We conclude that in mice, cardiac POH seems to be a maladaptive phenomenon in which reactive oxygen species appear to play an important role. LOS seems to prevent this maladaptive hypertrophy and maintain contractility in spite of a higher workload. These effects could be mediated, at least in part through a redox sensitive effect involving P-90 RSK.