Phosphodiesterase 3 inhibition mitigates sepsis progression in a rodent sepsis model

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, disrupts intracellular messengers, such as cyclic nucleotides cAMP and cGMP, contributing to high mortality.

To investigate the impact of phosphodiesterase 3 (PDE3) inhibition by cilostazol on cyclic nucleotide levels and sepsis outcomes, focusing on cardiovascular, hemodynamic, inflammatory, and survival parameters using an experimental sepsis model.

Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP) surgery, while controls underwent a sham operation. Cilostazol (15 mg/kg, gavage) or vehicle was administered six hours post-CLP. Cardiovascular, inflammatory and organ damage or dysfunction parameters were evaluated within 24 h after CLP, alongside monitoring survival rates over 120 h.

Septic animals exhibited high disease severity scores, hypotension, tachycardia, impaired renal and muscular blood flow response, vascular hyporesponsiveness, systemic inflammation and high mortality. Sepsis reduced plasma cGMP in plasma and heart tissue without impacting cAMP, PDE3A expression or even its phosphorylated status at Ser³¹². However, PDE3 inhibition in sepsis increased cAMP in plasma and skeletal muscle tissue, improved renal blood flow, reduced systemic and tissue inflammation, plasma lactate, and, to some extent, improved vascular responsiveness to vasoconstrictors. In the heart, PDE3 inhibition reduced NOS2 content; however, it caused injury due to cardiac overload. When combined with antibiotics, cilostazol reduced the risk of mortality from early-onset sepsis.

Based on findings, we postulate that PDE3 inhibition may help prevent sepsis progression to septic shock by modulating cAMP levels, offering potential cellular benefits for sepsis management.