Department of Pharmacology, National Institute of Health, Rome, Italy.
Blood Transfus. 2013 Jan;11(1):88-93. doi: 10.2450/2012.0176-11. Epub 2012 Jun 28.
Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart.
Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods.
As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1 ± 0.1 mm to 3.5 ± 0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group.
These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.
慢性输血治疗会导致渐进性铁过载，从而损害包括心脏在内的许多器官。最近的证据表明，在铁过载的情况下，L 型钙通道在心肌细胞中铁摄取中起重要作用。鉴于β肾上腺素能刺激显著增强 L 型钙电流，我们假设β肾上腺素能阻断药物可以减少铁过载对心脏的有害影响。
雄性 C57BL/6 小鼠每周腹腔注射右旋糖酐铁（1g/kg）一次，共 8 周，以产生铁过载，同时在饮用水中给予普萘洛尔（40mg/kg/天）。通过超声心动图和组织学方法评估心功能和心室重构。
与安慰剂相比，铁注射导致心脏铁沉积。令人惊讶的是，尽管铁过载，但与安慰剂治疗的小鼠相比，铁处理的小鼠的心肌功能和心室几何形状没有变化。普萘洛尔的给药增加了铁过载小鼠的心脏功能。具体而言，与铁过载组相比，在接受普萘洛尔治疗的铁过载动物中，左心室短轴缩短率增加（从 31.6%增加到 44.2%，P=0.01），而左心室舒张末期直径减小（从 4.1±0.1mm 减少到 3.5±0.1mm，P=0.03）。普萘洛尔对安慰剂组的心脏收缩功能或左心室大小没有影响。
这些结果表明，C57BL/6 小鼠对铁过载诱导的心肌损伤具有抗性，并且普萘洛尔的治疗能够增加铁过载小鼠的心脏功能。然而，由于 C57BL/6 小鼠对铁诱导的损伤具有抗性，因此仍需要进一步评估普萘洛尔是否可以预防铁过载性心肌病。
