Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Eur J Pharmacol. 2009 Oct 25;621(1-3):71-7. doi: 10.1016/j.ejphar.2009.08.033. Epub 2009 Sep 6.
Previously, we showed that oral allopurinol increased survival in mice with post-ischemic cardiomyopathy and attributed this outcome to an improvement of excitation-contraction coupling that boosted contractility. In this study, we tested the sustainability of this enhanced contraction associated with decreased oxidative damage over an extended time. Mice were divided into three groups: sham-operated control, myocardial infarction-heart failure (MI-HF), and oxypurinol-treated heart failure (Oxy-HF). After 9-11 months, echocardiography showed that mice treated with oxypurinol (1mM in drinking water) had significantly higher left ventricle fractional contraction and fractional wall thickening during systole than did mice in the MI-HF group (left ventricle fractional contraction: 28.4+/-2.2% vs. 19.9+/-2.3%, P<0.05; left ventricle fractional wall thickening: 45.0+/-4.0% vs. 23.5+/-2.0%, P<0.05). Left ventricular diastolic dimension, however, remained enlarged (0.50+/-0.04 vs. 0.54+/-0.05 cm, not significant). Twitch force was significantly higher at any given external Ca(2+) concentration in the Oxy-HF group than in the MI-HF group (P<0.01); amplitudes of intracellular Ca(2+) transients were also higher in the Oxy-HF group but were not statistically different from those of the MI-HF group. Force-frequency relation was improved in the Oxy-HF group. Muscle in the Oxy-HF group exhibited increases in myofilament Ca(2+) responsiveness, as evidenced by significantly higher maximal Ca(2+)-activated force (77.8+/-12.7 vs. 36.4+/-4.4 mN/mm(2), P<0.01). Finally, lipid peroxidation and myofilament oxidation were suppressed in the Oxy-HF group. These results indicate that the beneficial effects of antioxidation can be sustained by long-term treatment with oxypurinol after ischemic heart failure, with significantly improved cardiac contractility.
先前，我们发现口服别嘌醇可提高缺血性心肌病小鼠的存活率，并将此结果归因于兴奋-收缩偶联的改善，从而增强收缩力。在这项研究中，我们测试了在延长时间内，与氧化损伤减少相关的这种增强收缩的可持续性。将小鼠分为三组：假手术对照组、心肌梗死心力衰竭组（MI-HF）和别嘌呤醇治疗心力衰竭组（Oxy-HF）。9-11 个月后，超声心动图显示，用别嘌呤醇（1mM 饮用水）治疗的小鼠在收缩期的左心室分数收缩和分数壁增厚明显高于 MI-HF 组（左心室分数收缩：28.4+/-2.2% vs. 19.9+/-2.3%，P<0.05；左心室分数壁增厚：45.0+/-4.0% vs. 23.5+/-2.0%，P<0.05）。然而，左心室舒张尺寸仍保持增大（0.50+/-0.04 vs. 0.54+/-0.05cm，无统计学意义）。在任何给定的外部 Ca（2+）浓度下，Oxy-HF 组的抽搐力均明显高于 MI-HF 组（P<0.01）；Oxy-HF 组的细胞内 Ca（2+）瞬变幅度也较高，但与 MI-HF 组无统计学差异。Oxy-HF 组的力频率关系得到改善。Oxy-HF 组的肌纤维 Ca（2+）反应性增加，表现为最大 Ca（2+）激活力显著升高（77.8+/-12.7 与 36.4+/-4.4mN/mm（2），P<0.01）。最后，Oxy-HF 组的脂质过氧化和肌丝氧化受到抑制。这些结果表明，缺血性心力衰竭后长期用别嘌呤醇治疗可维持抗氧化的有益作用，显著改善心肌收缩力。
