Khaliulin Igor, Halestrap Andrew P, Bryant Simon M, Dudley Declan J, James Andrew F, Suleiman M-Saadeh
School of Clinical Sciences and Bristol Cardiovascular, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK.
J Transl Med. 2014 May 21;12:139. doi: 10.1186/1479-5876-12-139.
Consecutive treatment of normal heart with a high dose of isoproterenol and adenosine (Iso/Ade treatment), confers strong protection against ischaemia/reperfusion injury. In preparation for translation of this cardioprotective strategy into clinical practice during heart surgery, we further optimised conditions for this intervention using a clinically-relevant dose of Iso and determined its cardioprotective efficacy in hearts isolated from a model of surgically-induced heart failure.
Isolated Langendorff-perfused rat hearts were treated sequentially with 5 nM Iso and 30 μM Ade followed by different durations of washout prior to 30 min global ischaemia and 2 hrs reperfusion. Reperfusion injury was assessed by measuring haemodynamic function, lactate dehydrogenase (LDH) release and infarct size. Protein kinase C (PKC) activity and glycogen content were measured in hearts after the treatment. In a separate group of hearts, Cyclosporine A (CsA), a mitochondria permeability transition pore (MPTP) inhibitor, was added with Iso/Ade. Failing hearts extracted after 16 weeks of ligation of left coronary artery in 2 months old rats were also subjected to Iso/Ade treatment followed by ischaemia/reperfusion.
Recovery of the rate pressure product (RPP) in Iso/Ade-treated hearts was significantly higher than in controls. Thus in Iso/Ade treated hearts with 5 nM Iso and no washout period, RPP recovery was 76.3±6.9% of initial value vs. 28.5±5.2% in controls. This was associated with a 3 fold reduction in LDH release irrespective to the duration of the washout period. Hearts with no washout of the drugs (Ade) had least infarct size, highest PKC activity and also showed reduced glycogen content. Cardioprotection with CsA was not additive to the effect of Iso/Ade treatment. Iso/Ade treatment conferred significant protection to failing hearts. Thus, RPP recovery in failing hearts subjected to the treatment was 69.0±16.3% while in Control hearts 19.7±4.0%. LDH release in these hearts was also 3 fold lower compared to Control.
Consecutive Iso/Ade treatment of normal heart can be effective at clinically-relevant doses and this effect appears to be mediated by glycogen depletion and inhibition of MPTP. This intervention protects clinically relevant failing heart model making it a promising candidate for clinical use.
用高剂量的异丙肾上腺素和腺苷连续处理正常心脏（异丙肾上腺素/腺苷处理），可对缺血/再灌注损伤产生强大的保护作用。为了将这种心脏保护策略转化为心脏手术中的临床实践，我们使用临床相关剂量的异丙肾上腺素进一步优化了该干预的条件，并确定了其在从手术诱导的心力衰竭模型分离出的心脏中的心脏保护效果。
将离体的Langendorff灌注大鼠心脏先用5 nM异丙肾上腺素和30 μM腺苷依次处理，然后在进行30分钟全心缺血和2小时再灌注之前进行不同时长的洗脱。通过测量血流动力学功能、乳酸脱氢酶（LDH）释放和梗死面积来评估再灌注损伤。在处理后的心脏中测量蛋白激酶C（PKC）活性和糖原含量。在另一组心脏中，加入线粒体通透性转换孔（MPTP）抑制剂环孢素A（CsA）与异丙肾上腺素/腺苷一起处理。对2月龄大鼠左冠状动脉结扎16周后取出的衰竭心脏也进行异丙肾上腺素/腺苷处理，然后进行缺血/再灌注。
异丙肾上腺素/腺苷处理的心脏中速率压力乘积（RPP）的恢复显著高于对照组。因此，在未进行洗脱期处理的用5 nM异丙肾上腺素处理的心脏中，RPP恢复为初始值的76.3±6.9%，而对照组为28.5±5.2%。这与LDH释放减少3倍相关，且与洗脱期时长无关。未洗脱药物（腺苷）的心脏梗死面积最小，PKC活性最高，糖原含量也降低。CsA的心脏保护作用与异丙肾上腺素/腺苷处理的效果无相加作用。异丙肾上腺素/腺苷处理对衰竭心脏有显著保护作用。因此，接受该处理的衰竭心脏中RPP恢复为69.0±16.3%，而对照心脏为19.7±4.0%。这些心脏中的LDH释放也比对照组低3倍。
用临床相关剂量连续进行异丙肾上腺素/腺苷处理对正常心脏有效，这种作用似乎是由糖原耗竭和MPTP抑制介导的。这种干预对临床相关的衰竭心脏模型有保护作用使其成为临床应用的有希望的候选者。
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