Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts
Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts
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DOI：
10.1152/ajpheart.00831.2005
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发表时间：
2006-02-01
影响因子：
4.8
通讯作者：
Weiss, RG
中科院分区：
文献类型：
--
作者：
Naumova, AV;Chacko, VP;Weiss, RG
黄嘌呤氧化酶抑制剂改善衰竭小鼠心肌梗死后的能量和功能。美国生理学杂志心脏循环生理学290：H837-H843，2006年。首次发表于2005年9月23日; doi：10.1152/ajpheart.00831.2005。心肌梗死后，心室的几何形状和功能以及能量代谢都发生了明显的变化。在非缺血性心力衰竭中，黄嘌呤氧化酶（XO）的抑制通过改善相对于能量需求减少的收缩性能来改善机械能耦合。然而，XO抑制剂（XOIs）的代谢和收缩作用尚未在梗死后心力衰竭中得到表征。在进行永久性冠状动脉结扎后，小鼠在每日饮用水中接受XOI（别嘌呤醇或羟嘌呤醇）或匹配的安慰剂。四周后，H-1 MRI和P-31磁共振波谱（MRS）被用来量化在体内的功能和代谢的变化，在梗死后重塑小鼠心肌和XOI的影响，该过程。梗死后1个月，与对照心脏（59 +/-8%，P <0.005）相比，收缩末期（ESV）和舒张末期（EDV）容积增加了6倍以上，左心室（LV）质量增加了一倍（P <0.005），左心室射血分数（EF）降低了（14 +/- 9%）。心肌磷酸肌酸（PCr）与ATP的比值（PCr/ATP）在梗死重构心脏中（1.4 +/- 0.6）也显著低于对照动物（2.1 +/- 0.5，P < 0.02），与先前在大型动物中的研究一致。XOI别嘌呤醇和氧嘌呤醇不改变LV质量，但限制了梗死心脏ESV和EDV增加50%，EF增加（23 ± 9%，P = 0.01），心脏PCr/ATP正常化（2.0 ± 0.5，P < 0.04）。我们的结论是，XOIs改善梗死后心室功能，并使心力衰竭患者的高能磷酸盐比率正常化。因此，XOI治疗提供了一种新的和潜在的补充方法，以限制梗死后的不良收缩和代谢后果。
Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts. Am J Physiol Heart Circ Physiol 290: H837-H843, 2006. First published September 23, 2005; doi:10.1152/ajpheart.00831.2005.-After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, H-1 MRI and P-31 magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P < 0.005), and the LV ejection fraction (EF) decreased (14 +/- 9%) compared with control hearts (59 +/- 8%, P < 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 +/- 0.6) compared with control animals (2.1 +/- 0.5, P < 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 +/- 9%, P = 0.01), and normalized cardiac PCr/ATP (2.0 +/- 0.5, P < 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction.