ADENOSINE FORMATION & METABOLISM IN HYPOXIA

在含氧量正常的心脏中，大部分腺苷（AR）由AMP形成， 被AR激酶（AK）再磷酸化，一些被腺苷脱氨基 脱氨酶（ADA），而很少的AR释放。 肌苷（Inosine，HR） 由AMP脱氨酶的产物IMP形成，并降解为 次黄嘌呤（HX）、黄嘌呤（X）和尿酸（UA）。 由于高 AMP-腺苷代谢循环的活性， 与对照组相比，从含氧量正常的心脏释放（0.07 nmol/min/g） IR、HX、X和UA（1.1、0.4、0.2、1.4 nmol/min/g）。中的作用 用离体豚鼠研究了缺氧时的代谢循环 心中 用~（31）P核磁共振和冠状动脉造影测定细胞内游离AMP 通过HPLC测定静脉嘌呤释放; 碘杀结核菌素和EHNA。 游离腺苷酸浓度与血浆腺苷酸浓度呈线性关系， （200-3000 nmol/L），ADA期间AR净形成（AMPAR）和HR释放 封锁（IMPVR）。 令人惊讶的是，AR发布量增长了几倍， AR形成。 切换到40%O2增加了游离AMP和AR的形成 4倍，而胞质AR和AR释放上升20倍。 虽然95% O2仅释放6%的AR形成，该分数增加到22% 已经在40% O2下，表明AR抢救减少。 选择性进行酶 阻断表明通过AK的通量从AR的85%下降到35 缺氧形成。 数学模型分析表明， 这种酶活性的降低是由于AK活性的抑制 基础水平的6%。 数据显示a）AMP底物 浓度直接控制5 '-核苷酸酶的AR形成， 最可能的是通过AMP脱氨酶的通量，和B）缺氧减少 AK活性，将心肌AR从嘌呤补救分流至静脉 release. 由于AMP-腺苷的正常高周转率 代谢周期，缺氧诱导的AK抑制导致 游离AMP的微小变化放大为AR的大幅上升。 这种机制在高灵敏度的传感器中起着重要作用。 心脏AR系统受损的氧合。

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.