Pisarenko O I, Tskitishvily O V, Studneva I M, Serebryakova L I, Timoshin A A, Ruuge E K
Cardiology Research Centre, Institute of Experimental Cardiology, Moscow, Russia.
Biochim Biophys Acta. 1997 Oct 24;1361(3):295-303. doi: 10.1016/s0925-4439(97)00042-2.
Recent studies have indicated that activation of A1/A2-receptors may mediate metabolic adaptation of the heart to ischemia/reperfusion stress. This study tests whether pretreatment with A1-selective agonist R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA) might mimic effects of a brief period of coronary occlusion (ischemic preconditioning, IP) on energy metabolism and hydroxyl radical (OH.) formation in canine myocardium following subsequent prolonged ischemia and reperfusion. Anaesthetized dogs were randomized to a control group subjected to 40-min occlusion of a diagonal branch of left anterior descending coronary artery (LAD) followed by 1-h reperfusion, or a preconditioned group (PC) in which the same period of sustained ischemia and reperfusion was preceded by a single cycle of IP (5-min occlusion of the same LAD branch and 10-min reperfusion), or to PIA group in which R-PIA infusion into the same branch of LAD (0.4 microg/kg per min during 5 min) was followed by 10 min of perfusion prior to sustained ischemia-reperfusion. Pretreatment with R-PIA similarly to IP reduced lactate (Lac), creatine (Cr) and inorganic phosphate (Pi) release from myocytes into the interstitial fluid during sustained ischemia compared to these indices in control. By the end of reperfusion, both IP and R-PIA infusion enhanced recovery of myocardial ATP and phosphocreatine (PCr) and attenuated the total creatine (sigmaCr = PCr + Cr) loss, an index of cell membrane damage. A1-receptor activation by R-PIA, as IP, led to a significant reduction in OH. radical generation following reperfusion assessed by a spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) using cardiac microdialysis. R-PIA pretreatment did not affect systemic and cardiac hemodynamic parameters. We conclude that (1) adaptive mechanisms of IP involve A1-receptor activation that contributes to the overall metabolic response and (2) R-PIA acts as a useful preconditioning-mimetic and anti-ischemic agent in dogs.
近期研究表明，A1/A2受体的激活可能介导心脏对缺血/再灌注应激的代谢适应。本研究旨在测试用A1选择性激动剂R(-)-N6-(2-苯异丙基)腺苷（R-PIA）预处理是否可模拟短暂冠状动脉闭塞（缺血预处理，IP）对犬心肌在随后长时间缺血和再灌注后的能量代谢及羟自由基（OH·）形成的影响。将麻醉的犬随机分为对照组，接受左前降支冠状动脉（LAD）对角支40分钟闭塞，随后1小时再灌注；预处理组（PC），在相同的持续缺血和再灌注期之前先进行一个IP周期（同一LAD分支5分钟闭塞和10分钟再灌注）；或PIA组，在持续缺血-再灌注之前，先向LAD同一分支输注R-PIA（5分钟内0.4微克/千克每分钟），随后灌注10分钟。与对照组相比，R-PIA预处理与IP相似，在持续缺血期间减少了心肌细胞向间质液中释放乳酸（Lac）、肌酸（Cr）和无机磷酸盐（Pi）。再灌注结束时，IP和R-PIA输注均增强了心肌三磷酸腺苷（ATP）和磷酸肌酸（PCr）的恢复，并减轻了总肌酸（σCr = PCr + Cr）的损失，这是细胞膜损伤的一个指标。R-PIA激活A1受体，与IP一样，通过使用心脏微透析的自旋捕获剂5,5'-二甲基-1-吡咯啉-N-氧化物（DMPO）评估，导致再灌注后OH·自由基生成显著减少。R-PIA预处理不影响全身和心脏血流动力学参数。我们得出结论：（1）IP的适应性机制涉及A1受体激活，这有助于整体代谢反应；（2）R-PIA在犬中作为一种有用的预处理模拟物和抗缺血剂发挥作用。
