Abstract：
Fluorofenidone (AKF-PD) is a novel pyridone derivative that inhibits fibrosis and inflammation in many tissues. Accordingly, it has been effective in disease models, such as liver failure, nephropathy, and pulmonary fibrosis. However, its potential role in cardiac physiology and pathology has yet to be elucidated. Thus, this paper investigated a possible functional impact of AKF-PD on adult rat cardiac myocytes. Cells were kept in culture for 1-2 days under either control conditions or the presence of AKF-PD (500 μM). They were next examined concerning cell contractility, intracellular Ca2+ homeostasis, and activity of voltage-gated Ca2+ channels. Remarkably, AKF-PD enhanced the percentage of cell shortening and rates of both contraction and relaxation by nearly 100%. A stimulus in Ca2+-induced Ca2+ release (CICR) most likely accounts for these effects because AKF-PD also increased the magnitude of electrically evoked Ca2+ transients. Of note, the compound did not alter the peak value of caffeine-elicited Ca2+ transients, indicating stimulation of CICR at constant sarcoplasmic reticulum Ca2+ load. Since CICR is triggered by the entry of Ca2+ through CaV1.2 (ICa), a possible effect on these Ca2+ channels was also investigated. AKF-PD increased the magnitude of both ICa and maximal macroscopic Ca2+ conductance (Gmax) by about 50%. However, no differences were found in either voltage dependence of inactivation or the amount of maximal immobilization-resistant charge movement (Qmax). Thus, the effect on ICa could be explained by a higher channel\'s open probability (Po) rather than a greater abundance of channel proteins. Additional data indicate that AKF-PD reduces the rate of Ca2+ extrusion in the presence of caffeine, suggesting inhibition of the Na/Ca exchanger. Overall, these results indicate that AKF-PD upregulates the Po of CaV1.2 and then sequentially enhances ICa, CICR, and contractility. Therefore, the novel compound is also a candidate to be tested in cardiac disease models.
摘要：
氟菲尼酮（AKF-PD）是一种新型吡啶酮衍生物，可抑制许多组织中的纤维化和炎症。因此，它在疾病模型中有效，比如肝功能衰竭,肾病，和肺纤维化。然而,其在心脏生理学和病理学中的潜在作用尚未阐明。因此，本文研究了AKF-PD对成年大鼠心肌细胞的功能影响。在对照条件或存在AKF-PD(500μM)的情况下,将细胞保持培养1-2天。他们接下来就细胞收缩性进行了检查，细胞内Ca2+稳态，和电压门控Ca2+通道的活性。值得注意的是,AKF-PD将细胞缩短的百分比以及收缩和松弛的速率提高了近100%。Ca2诱导的Ca2释放（CICR）中的刺激最有可能解释这些作用，因为AKF-PD也增加了电诱发的Ca2瞬变的幅度。值得注意的是，该化合物没有改变咖啡因引起的Ca2+瞬变的峰值，指示在恒定的肌浆网Ca2负荷下刺激CICR。SinceCICR是由Ca2+通过CaV1.2(ICa)进入触发的，还研究了对这些Ca2+通道的可能影响。AKF-PD使ICa和最大宏观Ca2电导（Gmax）的幅度增加了约50％。然而,在失活的电压依赖性或最大固定抗性电荷移动量（Qmax）方面均未发现差异。因此，对ICa的影响可以用更高的通道开放概率（Po）来解释，而不是更丰富的通道蛋白。其他数据表明，AKF-PD降低了在咖啡因存在下Ca2+挤出的速率，表明Na/Ca交换剂的抑制作用。总的来说,这些结果表明，AKF-PD上调CaV1.2的Po，然后依次增强ICa，CICR,和收缩性。因此,这种新型化合物也是在心脏病模型中进行测试的候选化合物。
