PDE5 Inhibitor Tadalafil Attenuates Liver Sinusoid Endothelial Cell Dysfunction in Rat Hepatic Ischemia-Reperfusion Injury by Reducing Platelet-Secreted NO and Suppressing LSEC Pyroptosis
Abstract
Background: Hepatic ischemia-reperfusion (I/R) injury, an inexorable event after liver surgery, is associated with circulating platelet activation and aggregation. Phosphodiesterase 5 inhibitor (PDE5i) is a promising option for treating organ I/R injury. Therefore, this study investigated the underlying mechanism of PDE5i in hepatic I/R injury. Methods: Rats received tadalafil pre-treatment (a PDE5i; 5 mg/kg/day) and underwent hepatic I/R modeling. The impact of tadalafil against liver injury was assessed by measuring the nitric oxide (NO) content as well as the levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), followed by histological analysis and TdT-mediated dUTP nick end labeling (TUNEL) assay. The liver sinusoid endothelial cells (LSECs) isolated from normal rats were pre-treated with tadalafil (100 nM) and co-cultured with platelets obtained from hepatic I/R rats. Additionally, cell viability, lactate dehydrogenase (LDH) activity, and degree of pyroptosis were evaluated using Western blot analysis in in vitro experimental settings. Results: Tadalafil protected rats against hepatic I/R by reducing serum levels of AST and ALT and attenuating liver tissue damage, cell apoptosis, and NO content ( p < 0.01). Tadalafil inhibited the secretion of NO by platelets in hepatic I/R-induced rats ( p < 0.001). Furthermore, it enhanced cellular viability and decreased LDH activity and pyroptosis of LSECs in platelets derived from hepatic I/R rats (…
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