Ito Koji, Hirooka Yoshitaka, Sunagawa Kenji
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Circ Res. 2009 Apr 24;104(8):1004-11. doi: 10.1161/CIRCRESAHA.108.188995. Epub 2009 Mar 19.
In animal models of salt-sensitive hypertension, high salt augments sympathetic outflow via central mechanisms. It is not known, however, whether pressure overload affects salt sensitivity, thereby modifying central sympathetic outflow and cardiac function. We induced left ventricular hypertrophy with aortic banding in mice. Four weeks after aortic banding (AB-4), the left ventricle wall thickness was increased without changing the percentage fractional shortening. AB-4 mice were then fed either a high-salt (8%) diet or regular-salt diet for additional 4 weeks. Cardiac dysfunction, wall thickness, and 24-hour urinary catecholamine excretion were increased with high-salt diet compared with regular-salt diet. We then examined brain Na sensitivity. Intracerebroventricular infusion of high-Na (0.2 mol/L) artificial cerebrospinal fluid into AB-4 mice and mice Sham-4 increased urinary catecholamine excretion, arterial pressure, and heart rate more in AB-4 mice than in Sham-4 mice. Intracerebroventricular infusion of an epithelial Na channel blocker (benzamil) into mice with high-salt diet significantly decreased urinary catecholamine excretion and improved cardiac function. Infusion of either an angiotensin II type 1 receptor blocker or a Rho-kinase inhibitor also attenuated the salt-induced sympathetic hyperactivation and cardiac dysfunction in mice with high-salt diet. The levels of angiotensin II type 1 receptor and phosphorylated moesin, a substrate of Rho-kinase, were significantly greater in AB-4 mice than in Sham-4 mice. These results suggest that mice with pressure overload acquire brain Na sensitivity because of the activation of epithelial Na channel via Rho-kinase and angiotensin II, and this mechanism contributes to salt-induced sympathetic hyperactivation, further pressure overload, and cardiac dysfunction.
在盐敏感性高血压动物模型中，高盐通过中枢机制增强交感神经输出。然而，尚不清楚压力超负荷是否会影响盐敏感性，从而改变中枢交感神经输出和心脏功能。我们通过主动脉缩窄在小鼠中诱导左心室肥厚。主动脉缩窄4周后（AB-4），左心室壁厚度增加，而缩短分数百分比未改变。然后，将AB-4小鼠喂食高盐（8%）饮食或常规盐饮食额外4周。与常规盐饮食相比，高盐饮食使心脏功能障碍、壁厚度和24小时尿儿茶酚胺排泄增加。然后，我们检查了脑钠敏感性。向AB-4小鼠和假手术-4小鼠脑室内注入高钠（0.2 mol/L）人工脑脊液，AB-4小鼠的尿儿茶酚胺排泄、动脉压和心率增加幅度比假手术-4小鼠更大。向高盐饮食小鼠脑室内注入上皮钠通道阻滞剂（苄amil）可显著降低尿儿茶酚胺排泄并改善心脏功能。注入血管紧张素II 1型受体阻滞剂或Rho激酶抑制剂也可减轻高盐饮食小鼠的盐诱导交感神经亢进和心脏功能障碍。AB-4小鼠中血管紧张素II 1型受体和Rho激酶底物磷酸化肌动蛋白的水平显著高于假手术-4小鼠。这些结果表明，压力超负荷小鼠由于通过Rho激酶和血管紧张素II激活上皮钠通道而获得脑钠敏感性，并且这种机制导致盐诱导的交感神经亢进、进一步的压力超负荷和心脏功能障碍。
