Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1546-55. doi: 10.1152/ajpheart.01006.2009. Epub 2010 Feb 19.
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.
运动训练可使心力衰竭（HF）大鼠的室旁核（PVN）中增强的谷氨酸能机制正常化，并使血浆 ANG II 水平升高正常化。我们使用 Losartan（Los；50 mg·kg-1·d-1，连续 3 周饮水）进行慢性 AT1 受体阻断，以测试 ANG II 型 1（AT1）受体是否参与了 PVN 谷氨酸能机制的正常化。与假手术动物（Sham 组）相比，左心室舒张末期压在 HF + Veh 组和 HF + Los 组均升高，尽管在 HF + Los 组与 HF + Veh 组相比明显降低。Los 对心脏功能的影响与运动训练相似。在 PVN 中注入最高剂量的 N-甲基-D-天冬氨酸（NMDA；200 pmol）时，HF + Veh 组的肾交感神经活动增加 93 +/- 13%，明显高于 Sham + Veh（45 +/- 2%）和 HF + Los（47 +/- 2%）组的增加。与 Sham + Veh 组相比，HF + Veh 组的 PVN 中 NMDA 受体亚单位 NR1 mRNA 表达增加了 120%（P < 0.05），但与 HF + Veh 组相比，HF + Los 组的 NR1 表达明显降低（P < 0.05）。与 Sham + Veh 组相比，HF + Veh 组的 NR1 蛋白表达增加了 87%，但与 HF + Veh 组相比，HF + Los 组的 NR1 蛋白表达明显降低（P < 0.05）。此外，在体外使用神经元 NG-108 细胞的实验中，我们发现 ANG II 处理可刺激 NR1 蛋白表达，而 Los 可显著改善 ANG II 诱导的 NR1 表达。这些数据与我们的假设一致，即慢性 AT1 受体阻断可使 HF 大鼠的 PVN 中的谷氨酸能机制正常化。
