AT1 receptor blockade with losartan prevents maladaptive hypertrophy in pressure overload by inhibiting ROS release

OSCAR H. CINGOLANI; NÉSTOR G. PÉREZ; SUSANA M. MOSCA; GUILLERMO R. SCHINELLA; GLORIA CÓNSOLE; IRENE L. ENNIS; EDUARDO M. ESCUDERO,; HORACIO E. CINGOLANI

Washington

Congreso; 64th High Blood Pressure Research 2010 Scientific Sessions; 2010

American Heart Association

Pressure overload hypertrophy (POH) has been traditionally viewed as a compensatoryresponse that normalizes left ventricular (LV) wall stress to compensate for increased afterload.This controversial concept implies that blunting POH without changing pressure wouldtherefore 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 micereceived 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. Cardiacfunction 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 preventedPOH (table) and showed increased cardiac contractility when compared to TAC (p<0.05 for LVejection fraction and preload recruitable stroke work) despite less LV hypertrophy. Increased LVcollagen 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 (plasmaTBARS) 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 appearto play an important role. LOS seems to prevent this maladaptive hypertrophy and maintaincontractility in spite of a higher workload. These effects could be mediated, at least in partthrough a redox sensitive effect involving P-90 RSK.