Willems Laura, Reichelt Melissa E, Molina Jose G, Sun Chun-Xiao, Chunn Janci L, Ashton Kevin J, Schnermann Jurgen, Blackburn Michael R, Headrick John P
Heart Foundation Research Center, Griffith University, Southport, QLD 4217, Australia.
Cardiovasc Res. 2006 Jul 1;71(1):79-87. doi: 10.1016/j.cardiores.2006.03.006. Epub 2006 Mar 13.
Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance.
Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs.
Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21+/-4 vs. 38+/-3mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12+/-0.01 vs. 0.21+/-0.02 U/g/min ischaemia), and enhancing pressure development (by 35%; 89+/-6 vs. 66+/-5mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 microM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated.
Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.
腺苷脱氨酶（ADA）可能具有多种功能，可调节腺苷水平和腺苷受体（AR）激动作用，并可能改变AR的功能。在此，我们评估ADA（和A1AR）缺乏对AR介导的反应和缺血耐受性的影响。
研究了野生型小鼠以及ADA和/或A1AR缺乏小鼠离体心脏的常氧功能以及对20或25分钟缺血和45分钟再灌注的反应。
ADA或A1AR缺乏均未显著改变基础收缩力，尽管ADA缺乏会降低静息心率（A1AR缺乏可消除此效应）。ADA缺乏不会改变AR激动剂（2-氯腺苷）引起的心动过缓和血管舒张，而A1AR缺乏会消除心率反应。ADA缺乏时腺苷流出增加10至20倍（以次黄嘌呤为代价）。ADA缺失改善了25分钟缺血后的结果，降低了心室舒张压（降低45%；21±4 vs. 38±3mmHg）和乳酸脱氢酶（LDH）流出（降低40%；0.12±0.01 vs. 0.21±0.02U/g/min缺血），并增强了压力发展（增加35%；89±6 vs. 66±5mmHg）。20分钟缺血后也有类似的保护作用，ADA抑制剂EHNA（5μM）可模拟此作用。ADA缺失还增强了A1AR缺乏心脏的耐受性，尽管对舒张压的影响消失了。
ADA缺乏不会改变心血管A1或A2AR的敏感性（尽管[腺苷]显著升高），但可显著改善缺血耐受性。相反，A1AR缺乏会损害缺血耐受性。ADA缺乏对舒张压的影响似乎仅依赖于A1AR，而其他AR或过程也有助于改善收缩恢复和减少细胞死亡。
