Fluorofenidone enhances cardiac contractility by stimulating CICR and Ca1.2.

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 Ca homeostasis, and activity of voltage-gated Ca channels. Remarkably, AKF-PD enhanced the percentage of cell shortening and rates of both contraction and relaxation by nearly 100%. A stimulus in Ca-induced Ca release (CICR) most likely accounts for these effects because AKF-PD also increased the magnitude of electrically evoked Ca transients. Of note, the compound did not alter the peak value of caffeine-elicited Ca transients, indicating stimulation of CICR at constant sarcoplasmic reticulum Ca load. Since CICR is triggered by the entry of Ca through Ca1.2 (I), a possible effect on these Ca channels was also investigated. AKF-PD increased the magnitude of both I and maximal macroscopic Ca conductance (G) by about 50%. However, no differences were found in either voltage dependence of inactivation or the amount of maximal immobilization-resistant charge movement (Q). Thus, the effect on I could be explained by a higher channel's open probability (P) rather than a greater abundance of channel proteins. Additional data indicate that AKF-PD reduces the rate of Ca extrusion in the presence of caffeine, suggesting inhibition of the Na/Ca exchanger. Overall, these results indicate that AKF-PD upregulates the P of Ca1.2 and then sequentially enhances I, CICR, and contractility. Therefore, the novel compound is also a candidate to be tested in cardiac disease models.