STIMULATION OF GLYCOGENOLYSIS BY ADENINE-NUCLEOTIDES IN THE PERFUSED-RAT-LIVER
STIMULATION OF GLYCOGENOLYSIS BY ADENINE-NUCLEOTIDES IN THE PERFUSED-RAT-LIVER
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DOI：
10.1042/bj2370773
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发表时间：
1986-08-01
影响因子：
4.1
通讯作者：
OLSON, MS
中科院分区：
文献类型：
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作者：
BUXTON, DB;ROBERTSON, SM;OLSON, MS
将腺嘌呤核苷酸和腺苷输注到灌注的大鼠肝脏中导致肝糖原分解的刺激、流出物灌注液[3-羟基丁酸]/[乙酰乙酸]比率的短暂增加以及门静脉压力的增加。在用含有50μM-Ca2+的缓冲液灌注的肝脏中，在用腺嘌呤核苷酸或腺苷刺激肝脏时观察到Ca2+的瞬时流出。 ADP 是最有效的核苷酸，在低至 0.15 μM 的浓度下刺激葡萄糖输出，在大约 10 μM 时具有最大刺激的一半。 1μM，而ATP的效力稍差，半最大刺激需要4μM-ATP。 AMP和腺苷的效果要差得多，提供半最大刺激的剂量分别为40和20μM。非水解 ATP 类似物在促进肝脏代谢变化方面的效果远低于 ATP。 ITP、GTP 和 GDP 引起的肝脏代谢变化与 ATP 相似，但效力比 ATP 低 10-20 倍。在以低(7μM)Ca2+灌注的肝脏中，在ATP之前输注去氧肾上腺素使肝脏对ATP的反应脱敏。在这种低 Ca2+ 灌注的肝脏中重复输注 ATP 会导致 ATP 反应的同源脱敏，并且还会使随后的 Ca2+ 依赖性对去氧肾上腺素的反应脱敏。去氧肾上腺素输注后短暂输注Ca 2+ (1.25 mM)恢复了随后对ATP的反应，表明在用含有7μM-Ca 2+ 的缓冲液灌注期间，ATP和去氧肾上腺素消耗同一池内Ca 2+ ，其可以在细胞外Ca 2+ 存在的情况下快速补充。冻夹肝组织中环AMP的测量表明，腺苷(150μM)显着增加肝环AMP，而ATP(15μM)则没有作用。结论是ATP和ADP通过P2-嘌呤能受体通过类似于肝组织的α-肾上腺素能刺激的Ca 2+ 依赖性机制刺激肝糖原分解。然而，腺苷通过 P1-嘌呤受体刺激糖原分解和/或摄取到细胞中，至少部分通过涉及环 AMP 增加的机制。此外，肝脏对腺嘌呤核苷酸的反应可能对调节生理和病理生理状态下的肝脏葡萄糖输出具有重要意义。
Infusion of adenine nucleotides and adenosine into perfused rat livers resulted in stimulation of hepatic glycogenolysis, transient increases in the effluent perfusate [3-hydroxybutyrate]/[acetoacetate] ratio, and increased portal vein pressure. In livers perfused with buffer containing 50 .mu.M-Ca2+, transient efflux of Ca2+ was seen on stimulation of the liver with adenine nucleotides or adenosine. ADP was the most potent of the nucleotides, stimulating glucose output at concentrations as low as 0.15 .mu.M, with half-maximal stimulation at approx. 1 .mu.M, and ATP was slightly less potent, half-maximal stimulation requiring 4 .mu.M-ATP. AMP and adenosine were much less effective, doses giving half-maximal stimulation being 40 and 20 .mu.M respectively. Non-hydrolyzed ATP analogues were much less effective than ATP in promoting changes in hepatic metabolism. ITP, GTP and GDP caused similar changes in hepatic metabolism to ATP, but were 10-20 times less potent than ATP. In livers perfused at low (7 .mu.M) Ca2+, infusion of phenylephrine before ATP desensitized hepatic responses to ATP. Repeated infusions of ATP in such low-Ca2+-perfused livers caused homologous desensitization of ATP responses, and also desensitized subsequent Ca2+-dependent responses to phenylephrine. A short infusion of Ca2+ (1.25 mM) after phenylephrine infusion restored subsequent responses to ATP, indicating that, during perfusion with buffer containing 7 .mu.M-Ca2+, ATP and phenylephrine deplete the same pool of intracellular Ca2+, which can be rapidly replenished in the presence of extracellular Ca2+. Measurement of cyclic AMP in freeze-clamped liver tissue demonstrated that adenosine (150 .mu.M) significantly increased hepatic cyclic AMP, whereas ATP (15 .mu.M) was without effect. It is concluded that ATP and ADP stimulate hepatic glycogenolysis via P2-purinergic receptors, through a Ca2+-dependent mechanism similar to that in .alpha.-adrenergic stimulation of hepatic tissue. However, adenosine stimulates glycogenolysis via P1-purinoreceptors and/or uptake into the cell, at least partially through a mechanism involving increase in cyclic AMP. Further, the hepatic response to adenine nucleotides may be significant in regulating hepatic glucose output in physiological and pathophysiological states.