Huang Bing S, Ahmad Monir, Tan Junhui, Leenen Frans H H
Hypertension Unit, University of Ottawa Heart Institute, H360, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7.
J Mol Cell Cardiol. 2007 Oct;43(4):479-86. doi: 10.1016/j.yjmcc.2007.07.047. Epub 2007 Jul 21.
In rats, blockade of the brain renin-angiotensin-aldosterone system prevents sympathetic hyperactivity and markedly attenuates LV dysfunction post-MI. We evaluated whether peripheral administration of an AT(1) receptor blocker has similar effects. In the first experiment, Wistar rats were injected subcutaneously (sc) daily with losartan at a regular or high dose (15 or 100 mg/kg/day) starting 2 days post-MI. At 4 weeks, sympathetic reactivity to air stress was enhanced, baroreflex function was impaired and cardiac function clearly decreased. Increased AT(1) receptor binding densities post-MI were decreased by losartan towards (regular dose) or well below (high dose) levels of sham rats. Losartan at the high dose prevented sympathetic hyperactivity and baroreflex impairment, and lowered LVEDP but further decreased LVPSP and dP/dt(max). In the second experiment, as of 2 days post-MI, losartan (1 mg/kg/day), spironolactone (10 microg/kg/day) or vehicle was infused intracerebroventricularly (i.c.v), or losartan (100 mg/kg/day) was injected sc for 4 weeks. LV dysfunction and increased fibrosis and cardiomyocyte diameter were clearly present at 4 weeks. Icv losartan or spironolactone improved or normalized LV diastolic and systolic function, LV dimensions, fibrosis and myocyte diameter. In contrast, although sc losartan similarly improved fibrosis and LVEDP, again it did not improve LV systolic function. These data indicate that specific central and general AT(1) receptor blockade can similarly improve sympathetic hyperactivity, cardiac fibrosis and LVEDP, but only central blockade improves LV systolic function, possibly due to differences in the extent of blockade of AT(1) receptors in cardiac myocytes and/or peripheral sympathetic nerves.
在大鼠中，阻断脑肾素 - 血管紧张素 - 醛固酮系统可预防交感神经过度活跃，并显著减轻心肌梗死后的左心室功能障碍。我们评估了外周给予AT(1)受体阻滞剂是否有类似作用。在第一个实验中，从心肌梗死后2天开始，Wistar大鼠每天皮下注射常规剂量或高剂量（15或100 mg/kg/天）的氯沙坦。4周时，对空气应激的交感反应性增强，压力反射功能受损，心脏功能明显下降。氯沙坦使心肌梗死后增加的AT(1)受体结合密度朝着（常规剂量）或远低于（高剂量）假手术大鼠的水平降低。高剂量氯沙坦可预防交感神经过度活跃和压力反射损害，并降低左心室舒张末期压力（LVEDP），但进一步降低左心室峰值收缩压（LVPSP）和最大dp/dt。在第二个实验中，从心肌梗死后2天开始，将氯沙坦（1 mg/kg/天）、螺内酯（10 μg/kg/天）或赋形剂经脑室内注射（i.c.v），或皮下注射氯沙坦（100 mg/kg/天），持续4周。4周时明显出现左心室功能障碍、纤维化增加和心肌细胞直径增大。脑室内注射氯沙坦或螺内酯可改善或使左心室舒张和收缩功能、左心室尺寸、纤维化和心肌细胞直径恢复正常。相比之下，尽管皮下注射氯沙坦同样改善了纤维化和左心室舒张末期压力，但它并未改善左心室收缩功能。这些数据表明，特异性的中枢和全身AT(1)受体阻断均可类似地改善交感神经过度活跃、心脏纤维化和左心室舒张末期压力，但只有中枢阻断可改善左心室收缩功能，这可能是由于心肌细胞和/或外周交感神经中AT(1)受体阻断程度不同所致。
