Discovery of the synergy between sulindac and NO expands the application of NSAIDs in cardiac complications.

Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The in vitro screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives in vivo, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.