ADENOSINE FORMATION & METABOLISM IN HYPOXIA

在常氧心脏，大部分腺苷(AR)由AMP形成 被AR激酶(AK)重新磷酸化，一些被腺苷脱氨基 脱氨酶(ADA)，同时释放少量AR。肌苷(HR)也是 由AMP脱氨酶的产物IMP形成，可降解为 次黄嘌呤(HX)、黄嘌呤(X)和尿酸(UA)。由于高企 AMP-腺苷代谢循环的活性很小，AR是 从常氧心脏释放(0.07nmol/min/g)与 IR、HX、X和UA(1.1、0.4、0.2、1.4nmol/min/g)。这一点的作用 离体豚鼠低氧时代谢循环的研究 红心。用~(31)P核磁共振和冠脉造影测定胞浆游离AMP 高效液相色谱静脉释放嘌呤；选择性阻断AK和ADA 碘-结核杀菌素和埃赫纳。游离AMP与游离AMP呈线性关系 (200~3000nmol/L)、AR净形成(AMPAR)和HR释放 封锁(IMPHR)。令人惊讶的是，AR发布增长了几倍以上 阿尔编队。改用40%O2可增加游离AMP和AR的形成 4倍，胞质AR和AR释放增加20倍。而在95% O2只释放了6%的AR，这一比例增加到了22% 已经处于40%的氧气中，显示AR回收减少。选择性酶 阻断表明，通过AK的流量从AR的85%下降到35% 在低氧条件下形成。数学模型分析表明， 这种酶活性的下降是由于AK活性的抑制 至基础水平的6%。数据显示a)AMP衬底 浓度通过5‘-核苷酸酶直接控制AR的形成 最有可能通过AMP脱氨酶的流量和b)低氧减少 AK活性，将心肌AR从嘌呤回收分流到静脉 放手。因为AMP-腺苷的正常高周转率 代谢循环，低氧诱导的AK抑制导致 放大后游离AMP变化较大，AR上升较大。 这一机制在生物多样性的高敏感性中起着重要作用。 心脏AR系统对氧合受损的影响。

In the normoxic heart, most of the adenosine (AR) formed from AMP is rephosphorylated by AR kinase (AK), some is deaminated by adenosine deaminase (ADA) while little AR is released. Inosine (HR) is also formed from IMP, the product of AMP deaminase, and is degraded to hypoxanthine (HX), xanthine (X) and uric acid (UA). Due to the high activity of the AMP-adenosine metabolic cycle very little AR is released (0.07 nmol/min/g) from the normoxic heart when compared to IR, HX, X and UA (1.1, 0.4, 0.2, 1.4 nmol/min/g.). The role of this metabolic cycle in hypoxia was investigated in isolated guinea pig hearts. Free cytosolic AMP was determined by 31P NMRand coronary venous purine release by HPLC; AK and ADA were selectively blocked by iodotubercidin and EHNA. There was a linear relation between free AMP (200-3000 nmol/L), net AR formation (AMPAR) and HR release during ADA blockade (IMPHR). Surprisingly AR release rose several-fold more than AR formation. Switching to 40% O2 increased free AMP and AR formation 4-fold, while cytosolic AR and AR release rose 20-fold. While at 95% O2 only 6% of AR formed were released, this fraction increased to 22% already at 40% O2 demonstrating reduced AR salvage. Selective enzyme blockade indicated that flux through AK decreased from 85 to 35% of AR formation in hypoxia. Mathematical model analysis demonstrated that this decrease in enzyme activity was due to inhibition of AK activity to 6% of basal levels. The data show a) that AMP substrate concentration directly controls AR formation by 5'-nucleotidase and most likely flux through AMP deaminase and b) tha t hypoxia decreases AK activity, shunting myocardial AR from purine salvage to venous release. Because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of AK causes the amplification of small changes in free AMP into a major rise in AR. This mechanism plays an important role in the high sensitivity of the cardiac AR system to impaired oxygenation.