Depre C, Gaussin V, Ponchaut S, Fischer Y, Vanoverschelde J L, Hue L
Hormone and Metabolic Research Unit, Louvain University Medical School, Brussels, Belgium.
Am J Physiol. 1998 May;274(5):H1443-9. doi: 10.1152/ajpheart.1998.274.5.H1443.
Guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of nitric oxide (NO), regulates myocardial contractility. It is not known whether this effect is accompanied by a change in heart metabolism. We report here the effects of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), a cGMP analog, on regulatory steps of glucose metabolism in isolated working rat hearts perfused with glucose as the substrate. When glucose uptake was stimulated by increasing the workload, addition of the cGMP analog totally suppressed this stimulation and accelerated net glycogen breakdown. 8-BrcGMP did not affect pyruvate dehydrogenase activity but activated acetyl-CoA carboxylase, the enzyme that produces malonyl-CoA, an inhibitor of long-chain fatty acid oxidation. To test whether glucose metabolism could also be affected by altering the intracellular concentration of cGMP, we perfused hearts with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, or with S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. Perfusion with L-NAME decreased cGMP and increased glucose uptake by 30%, whereas perfusion with SNAP resulted in opposite effects. None of these conditions affected adenosine 3',5'-cyclic monophosphate concentration. Limitation of glucose uptake by SNAP or 8-BrcGMP decreased heart work, and this was reversed by adding alternative oxidizable substrates (pyruvate, beta-hydroxybutyrate) together with glucose. Therefore, increased NO production decreases myocardial glucose utilization and limits heart work. This effect is mediated by cGMP, which is thus endowed with both physiological and metabolic properties.
鸟苷 3',5'-环磷酸（cGMP）作为一氧化氮（NO）的第二信使，可调节心肌收缩力。目前尚不清楚这种作用是否伴随着心脏代谢的变化。我们在此报告 cGMP 类似物 8-溴鸟苷 3',5'-环磷酸（8-BrcGMP）对以葡萄糖为底物灌注的离体工作大鼠心脏中葡萄糖代谢调节步骤的影响。当通过增加工作量刺激葡萄糖摄取时，添加 cGMP 类似物完全抑制了这种刺激并加速了糖原的净分解。8-BrcGMP 不影响丙酮酸脱氢酶活性，但激活了乙酰辅酶 A 羧化酶，该酶产生丙二酰辅酶 A，丙二酰辅酶 A 是长链脂肪酸氧化的抑制剂。为了测试改变细胞内 cGMP 浓度是否也会影响葡萄糖代谢，我们用 NO 合酶抑制剂 NG-硝基-L-精氨酸甲酯（L-NAME）或 NO 供体 S-亚硝基-N-乙酰青霉胺（SNAP）灌注心脏。用 L-NAME 灌注可降低 cGMP 并使葡萄糖摄取增加 30%，而用 SNAP 灌注则产生相反的效果。这些情况均未影响腺苷 3',5'-环磷酸的浓度。SNAP 或 8-BrcGMP 对葡萄糖摄取的限制降低了心脏的工作能力，而通过添加可氧化的替代底物（丙酮酸、β-羟基丁酸）与葡萄糖一起可逆转这种情况。因此，NO 生成增加会降低心肌葡萄糖利用并限制心脏工作能力。这种作用由 cGMP 介导，因此 cGMP 兼具生理和代谢特性。
