Brain Ang III inhibition attenuates sympathetic hyperactivity and LV dysfunction in rat post myocardial infarction (MI)

In rats post‐MI, angiotensinergic pathways in the CNS contribute to sympathetic hyperactivity and progressive LV dysfunction. The present study examined whether Ang III in the brain is the main effector peptide. After coronary artery ligation (MI size ~25%), rats were infused icv for 4 weeks with aCSF, losartan at 0.25mg/day, or RB150 at 0.3mg/day (n=8–11/group). RB150 is a prodrug of the specific aminopeptidase A inhibitor, EC33 which, when centrally injected, blocks the conversion of Ang II to Ang III. Echocardiography was performed, BP, HR and RSNA in response to air‐stress and acute changes in BP were measured in conscious rats, and LV hemodynamics by Millar catheter.sham MI+veh MI+los MI+RB150air‐stress Δ RSNA (%) 17±2 34±2 * 23±2 † 20±2 † Baroreflex control of RSNA Max Gain (%/mmHg) 3.5±0.3 2.2±0.1 * 2.6±0.1 * † 2.9±0.2 † EF (%) 92±2 66±3 * 63±3 * 76±2 * † LVPSP (mmHg) 126±2 120±1 * 118±3 * 124±2 LVEDP (mmHg) 3±1 16±2 * 9±1 * † 9±1 * † dP/dt max (mmHg/s) 8076±145 6116±141 * 6740±63 * † 7259±293 * †Data are means±SEM. * p<0.05 vs sham; † p<0.05 vs MI+vehInhibition of brain APA activity blocking the brain RAS showed similar or more attenuation of sympathetic hyperactivity and LV dysfunction than blockade of central AT 1 receptors by losartan. These results indicate that Ang III plays a pivotal role in the CNS. RB150 may be a potential candidate for CNS targeted therapy post‐MI. Supported by Canadian Inst of Health Research grant #FRN:MOP‐13182