Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil.
Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil.
Chem Biol Interact. 2014 Sep 5;220:1-11. doi: 10.1016/j.cbi.2014.05.020. Epub 2014 Jun 6.
The purpose of the present work was to verify if tadalafil affects hepatic glucose output, one of the primary targets of cAMP, in the isolated perfused rat liver. No effects on glycogen catabolism and oxygen uptake were found under basal conditions for tadalafil concentrations in the range between 0.25 and 10 μM. However, tadalafil had a clear and time-dependent inhibitory effect on the cAMP- and glucagon-stimulated glucose release. Constant infusion of tadalafil in the range between 0.25 and 10 μM eventually abolished 100% of the stimulatory action of those effectors. The tadalafil concentrations producing half-maximal rates of inhibition of the cAMP and glucagon stimulated glycogenolysis were 0.46±0.04 and 1.07±0.16 μM, respectively. These concentrations are close to the plasma peak concentrations in patients after ingestion of 20 mg tadalafil. The drug also diminished the activity of glycogen phosphorylase a and increased the activities of glucose 6-phosphatase, glucokinase, pyruvate kinase and glucose 6-phosphate dehydrogenase. These actions occurred only in the cellular environment. Tadalafil did not affect binding of cAMP to protein kinase A. Diminution of cAMP-stimulated glucose output is the opposite of what can be expected from a phosphodiesterase inhibition, the most common effect attributed to tadalafil. Diminution of glucose output by tadalafil can be attributed (a) to an interference with glycogen phosphorylase stimulation and (b) to an increased futile cycling of glucose 6-phosphate and glucose with a concomitant increased flow of hexose units into cellular metabolic pathways. The effects described in the present work may prove to represent important side effects of tadalafil.
本研究旨在验证他达拉非是否会影响肝糖输出，肝糖输出是 cAMP 的主要作用靶点之一，在离体灌流大鼠肝中进行。在 0.25 至 10 μM 的范围内，他达拉非对基础状态下的糖原分解和耗氧量没有影响。然而，他达拉非对 cAMP 和胰高血糖素刺激的葡萄糖释放有明显的、时间依赖性的抑制作用。在 0.25 至 10 μM 的范围内持续输注他达拉非最终使这些效应物的刺激作用完全被抑制。产生半最大抑制率的他达拉非浓度分别为 0.46±0.04 和 1.07±0.16 μM，可抑制 cAMP 和胰高血糖素刺激的糖原分解。这些浓度接近患者口服 20mg 他达拉非后的血浆峰值浓度。该药物还降低了磷酸化酶 a 的活性，并增加了葡萄糖 6-磷酸酶、葡萄糖激酶、丙酮酸激酶和葡萄糖 6-磷酸脱氢酶的活性。这些作用仅发生在细胞环境中。他达拉非不影响 cAMP 与蛋白激酶 A 的结合。cAMP 刺激的葡萄糖输出减少与磷酸二酯酶抑制作用相反，磷酸二酯酶抑制作用是他达拉非最常见的作用。他达拉非对葡萄糖输出的抑制作用可归因于（a）对磷酸化酶刺激的干扰，以及（b）葡萄糖 6-磷酸和葡萄糖的无效循环增加，同时伴有更多的己糖单位进入细胞代谢途径。本研究中描述的作用可能被证明是他达拉非的重要副作用。
