Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure.Am J Physiol Heart Circ Physiol. 2010 May; 298(5):H1546-55.AJ
Exercise training normalizes enhanced glutamatergic mechanisms within the paraventricular nucleus (PVN) concomitant with the normalization of increased plasma ANG II levels in rats with heart failure (HF). We tested whether ANG II type 1 (AT(1)) receptors are involved in the normalization of PVN glutamatergic mechanisms using chronic AT(1) receptor blockade with losartan (Los; 50 mg.kg(-1).day(-1) in drinking water for 3 wk). Left ventricular end-diastolic pressure was increased in both HF + vehicle (Veh) and HF + Los groups compared with sham-operated animals (Sham group), although it was significantly attenuated in the HF + Los group compared with the HF + Veh group. The effect of Los on cardiac function was similar to exercise training. At the highest dose of N-methyl-d-aspartate (NMDA; 200 pmol) injected into the PVN, the increase in renal sympathetic nerve activity was 93 +/- 13% in the HF + Veh group, which was significantly higher (P < 0.05) than the increase in the Sham + Veh (45 +/- 2%) and HF + Los (47 +/- 2%) groups. Relative NMDA receptor subunit NR(1) mRNA expression within the PVN was increased 120% in the HF + Veh group compared with the Sham + Veh group (P < 0.05) but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). NR(1) protein expression increased 87% in the HF + Veh group compared with the Sham + Veh group but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). Furthermore, in in vitro experiments using neuronal NG-108 cells, we found that ANG II treatment stimulated NR(1) protein expression and that Los significantly ameliorated the NR(1) expression induced by ANG II. These data are consistent with our hypothesis that chronic AT(1) receptor blockade normalizes glutamatergic mechanisms within the PVN in rats with HF.