Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa 125 055, India.
Cardiovasc Toxicol. 2013 Mar;13(1):22-32. doi: 10.1007/s12012-012-9182-y.
Considering the reduced ability of cardiac fibroblasts to release adenosine and increased ability of interstitial adenosine uptake during diabetes mellitus, the present study investigated the effect of adenosine preconditioning and the existence of cross-talk with opioid receptor activation in the diabetic rat heart subjected to ischemia-reperfusion (I/R). Langendorff-perfused normal and streptozotocin (65 mg/kg, i.p., once)-administered diabetic (after 8-weeks) rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR) and myocardial oxidative stress were assessed. The diabetic rat heart showed high degree of I/R injury with increased LDH and CK-MB release, high oxidative stress and reduced CFR as compared to the normal rat heart. The adenosine preconditioning (10 μM) afforded cardioprotection against I/R injury in the normal rat heart that was prevented by naloxone (100 μM) pre-treatment. Conversely, adenosine preconditioning-induced cardioprotection was abolished in the diabetic rat heart. However, co-administration of dipyridamole (100 μM), adenosine reuptake inhibitor, markedly restored the cardioprotective effect of adenosine preconditioning in the diabetic rat heart, and this effect was also abolished by naloxone pre-treatment. The reduced myocardial availability of extracellular adenosine might explain the inability of adenosine preconditioning to protect the diabetic myocardium. The pharmacological elevation of extracellular adenosine restores adenosine preconditioning-mediated cardioprotection in the diabetic myocardium by possibly involving opioid receptor activation.
考虑到糖尿病期间心肌成纤维细胞释放腺苷的能力降低和间质腺苷摄取能力增加，本研究探讨了腺苷预处理以及与阿片受体激活的交叉对话在糖尿病大鼠心脏缺血再灌注（I / R）中的作用。用氯化三苯基四氮唑染色评估 Langendorff 灌注的正常和链脲佐菌素（65mg/kg，ip，一次）处理的糖尿病（8 周后）大鼠心脏的心肌梗死面积，乳酸脱氢酶（LDH）和肌酸激酶（CK-MB）释放等心脏损伤标志物，冠状血流率（CFR）和心肌氧化应激。与正常大鼠心脏相比，糖尿病大鼠心脏的 I / R 损伤程度更高，表现为 LDH 和 CK-MB 释放增加，氧化应激增加，CFR 降低。腺苷预处理（10μM）可防止正常大鼠心脏的 I / R 损伤，而纳洛酮（100μM）预处理可预防该作用。相反，腺苷预处理诱导的心脏保护作用在糖尿病大鼠心脏中被取消。然而，二嘧达莫（100μM），腺苷再摄取抑制剂的共同给药显著恢复了腺苷预处理对糖尿病大鼠心脏的保护作用，纳洛酮预处理也消除了这种作用。细胞外腺苷的心肌可用性降低可能解释了腺苷预处理不能保护糖尿病心肌的原因。细胞外腺苷的药理升高通过可能涉及阿片受体激活来恢复糖尿病心肌中腺苷预处理介导的心脏保护作用。
