Ganguli S, Sterman B, Harris P S, Sinha M K, Banach W J
Metabolism. 1984 Sep;33(9):845-52. doi: 10.1016/0026-0495(84)90113-6.
We previously demonstrated that treatment with indomethacin in vivo significantly blunted the glucagon-induced glycemic response in the rat. This prostaglandin synthetase (cyclo-oxygenase) inhibitor also accentuated the evanescent effect of glucagon on hepatic glucose output in the intact, anesthetized rat. In this report, we present evidence that impairment of glucagon action in the rat liver by indomethacin is mediated through its inhibitory effect on both cAMP-dependent and cAMP-independent hepatic protein kinase. Indomethacin treatment did not have a measurable effect on any of the other components of the glucagon transducer system. Furthermore, infusion with glucagon for two hours that maintained plasma glucagon values at high physiological levels significantly reduced hepatic cAMP-dependent protein kinase activity without altering its Km. Glucagon infusion also down-regulated its own hepatic receptors and glucagon-stimulated cAMP production; prostaglandin E1-stimulated cAMP production was not affected. We concluded that prostaglandins may play a role in the regulation of hepatic protein kinases involved in the glucagon-stimulated glycogenolytic response and that glucagon-induced down-regulation extends at least to the hepatic protein kinases. However, a direct effect of indomethacin or protein kinase and the adenylate cyclase complex cannot be ruled out.
我们先前证明，体内用吲哚美辛治疗可显著减弱大鼠体内胰高血糖素诱导的血糖反应。这种前列腺素合成酶（环氧化酶）抑制剂还增强了胰高血糖素对完整麻醉大鼠肝脏葡萄糖输出的短暂作用。在本报告中，我们提供证据表明，吲哚美辛对大鼠肝脏中胰高血糖素作用的损害是通过其对cAMP依赖性和cAMP非依赖性肝脏蛋白激酶的抑制作用介导的。吲哚美辛治疗对胰高血糖素转导系统的任何其他成分均无显著影响。此外，输注胰高血糖素两小时，使血浆胰高血糖素值维持在高生理水平，可显著降低肝脏cAMP依赖性蛋白激酶活性，而不改变其Km值。胰高血糖素输注还下调了其自身的肝脏受体以及胰高血糖素刺激的cAMP生成；前列腺素E1刺激的cAMP生成不受影响。我们得出结论，前列腺素可能在参与胰高血糖素刺激的糖原分解反应的肝脏蛋白激酶调节中起作用，并且胰高血糖素诱导的下调至少延伸至肝脏蛋白激酶。然而，不能排除吲哚美辛或蛋白激酶与腺苷酸环化酶复合物的直接作用。
