ENZYME REGULATION IN MYOCARDIAL ADENOSINE PRODUCTION DURING ISCHEMIA & HYPOXIA

为了阐明腺苷酸代谢的生理作用， 探讨AMP与腺苷的关系 离体豚鼠心脏的氧供应是不同的 （95-10% O2）。 净腺苷形成率（AMP -腺苷）和 测定冠状静脉流出液腺苷释放率;游离腺苷释放率 胞浆AMP用~（31）P NMR测定。 从95%切换到40% O2 增加游离AMP和腺苷形成4倍，而游离胞质 腺苷和静脉腺苷释放上升15-20倍。 AMP中 在200 ~ 3000 nmol/L范围内， 游离AMP和腺苷形成;然而，腺苷释放增加 几倍于形成。 而在95%的O2下， 腺苷形成的释放，这部分增加到22%， 表明腺苷抢救减少。 选择性阻断 腺苷脱氨酶和激酶的活性表明， 腺苷激酶从85%减少到35%， 缺氧 数学模型分析表明， 酶活性的降低不是由于饱和，而是由于 腺苷激酶活性抑制至基础水平的6%。 的 数据显示a）腺苷形成与AMP成比例 底物浓度和B）缺氧降低腺苷激酶 活动;从而将心肌腺苷从补救药物中分流 静脉释放途径。 总之，由于正常的高 缺氧诱导的AMP-腺苷代谢循环的周转 腺苷激酶的抑制引起小的 游离AMP的变化转化为腺苷的大幅上升。 这一机制 在心脏的高敏感性中起着重要作用 腺苷系统受损的氧合。

To elucidate the physiological role of the AMP-adenosine metabolic cycle and to investigate the relation between AMP and adenosine formation, oxygen supply of isolated guinea pig hearts was varied (95-10% O2). Net adenosine formation rate (AMP - adenosine) and coronary venous effluent adenosine release rate were measured; free cytosolic AMP was determined by 31P NMR. Switching from 95 to 40% O2 increased free AMP and adenosine formation 4-fold while free cytosolic adenosine and venous adenosine release rose 15-20 fold. In the AMP range from 200 to 3000 nmol/L there was a linear correlation between free AMP and adenosine formation; however, adenosine release increased several-fold more than formation. While at 95% O2 only 6% of adenosine formed were released, this fraction increased to 22% already at 40% O2 demonstrating reduced adenosine salvage. Selective blockade of adenosine deaminase and kinase indicated that flux through adenosine kinase decreased from 85 to 35% of adenosine formation in hypoxia. Mathematical model analysis indicated that this apparent decrease in enzyme activity was not due to saturation but to the inhibition of adenosine kinase activity to 6% of basal levels. The data show a) that adenosine formation is proportional to the AMP substrate concentration and b) that hypoxia decreases adenosine kinase activity; thereby shunting myocardial adenosine from the salvage pathway to venous release. In conclusion, because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of adenosine kinase causes the amplification of small changes in free AMP into a major rise in adenosine. This mechanism plays an important role in the high sensitivity of the cardiac adenosine system to impaired oxygenation.