Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease
Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease
复制标题
DOI：
10.1152/ajpregu.00727.2009
复制
发表时间：
2010-03-01
影响因子：
2.8
通讯作者：
Joles, J. A.
中科院分区：
文献类型：
--
作者：
Bongartz, L. G.;Braam, B.;Joles, J. A.
Bongartz LG，Braam B，Verhaar MC，Cramer MJ，Goldschmeding R，Gaillard CA，Doevendans PA，Joles JA.一过性一氧化氮还原导致慢性肾脏疾病大鼠心脏永久性收缩功能障碍，加重肾脏损害。Am J Physiol Regul Integr Comp Physiol 298：R815-R823,2010.首次发表于2009年12月23日；DOI：10.1152/ajpregu.00727.2009。-慢性肾脏疾病患者的左心室收缩功能障碍与较差的预后有关。由于慢性肾脏病患者通常表现为一氧化氮(NO)可获得性进行性降低，并且抑制NO的产生可减少心输出量，因此我们假设CKD患者NO可获得性的丧失与LVSD的发病有关。对肾大部切除(SNX)大鼠给予小剂量一氧化氮合酶抑制剂N-omega-硝基-L-精氨酸(L-NNA；20 mg/L水；SNX+L-NNA)治疗，并与相应对照组进行比较。为了研究永久性变化和血流动力学的影响，SNX+L-NNA组和SNX组在8周后停用L-NNA，并随访到15周，直到血压接近。为了单独研究NO耗竭的影响，对照组给予大剂量L-NNA(L-NNA-High：100 mg/L)。SNX后13周出现轻度收缩功能障碍。SNX+L-NNA组从第4周开始收缩功能下降近50%，同时全身NO生成明显减少，死亡率高。L-NNA-High组LVSD较SNX+L-NNA组轻，且对肾功能无明显影响。停用L-NNA后，L-NNA-High组的LVSD和NO均可逆，SNx+L-NNA组的LVESD和NO均持续低。与SNX组相比，大鼠尿蛋白增多，肾小球硬化和心肌纤维化加重。我们的结论是，SNX+L-NNA可诱导出功能和结构上不同于CKD的加速性和永久性的LVSD，或不单独耗竭。NO的可获得性似乎在CKD患者维持心功能方面起着关键作用。
Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Doevendans PA, Joles JA. Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease. Am J Physiol Regul Integr Comp Physiol 298: R815-R823, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00727.2009.-Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor N-omega-nitro-L-arginine (L-NNA; 20 mg/l water; SNX + L-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, L-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX + L-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose L-NNA (L-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX + L-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In L-NNA-High, LVSD was not as severe as in SNX + L-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in L-NNA-High after L-NNA was stopped, but both were persistently low in SNX + L-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX + L-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.