Abstract 330: Kinin B1r Inhibitor Prevents Sepsis-induced Cardiac Dysfunction And Promotes Survival In Mice

Abstract

Introduction: Hyperpermeability of the microvascular barrier and the resulting capillary leakage are hallmarks of sepsis. B1R has been proposed to be a therapeutic target for sepsis-induced microvascular hyperpermeability and multiorgan failure. However, its direct role in regulating of cardiac function during severe sepsis remains poorly characterized. Hypothesis: We hypothesized that B1R inhibition can protect against sepsis-induced cardiac dysfunction and improve survival. Methods and Results: To address the hypothesis, we pre-treated mice with either vehicle (control) or a specific B1R antagonist B6929via subcutaneous injection then subjected them to 40% cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Serum levels of IL-6 and TNFα increased significantly within 4 hours post-CLP in the controls. However, B1R antagonist treatment abolished CLP-induced expressions of IL-6 and TNFα by 70% and 30%, respectively. B1R antagonist also protected mice from sepsis-induced organ failure—as highlighted by the lowered increase in MSS score over the 24-h post-CLP—resulting in significant improvement in survival rate (P<0.05). In-vivo cardiac vascular permeability assessed using the Miles assay further demonstrated that B1R inhibition prevented sepsis-induced cardiac microvascular leakage and edema. Similar improvements were also observed in the liver and kidney. Further study revealed an early cardioprotective effect of B1R inhibitor, as evidenced by the improvement of EF%, FS%, and cardiac output in mice treated with B1R antagonist + CLP vs. CLP alone (p<0.01) from the echocardiogram analyses at 4-6 hours following CLP. Furthermore, mitochondrial H 2 O 2 measurement of the freshly isolated cardiac mitochondria from septic mice also showed that B1R inhibition partially abolished the production of H 2 O 2 . The opening of mPTP was also reduced with B1Ri treatment. Taken together, these findings indicated improvement in cardiac mitochondrial function following B1R inhibitor treatment. Conclusions: Our findings provide novel insights into the pathogenesis of sepsis-induced cardiac mitochondrial dysfunction and heart failure. Inhibition of B1R may be a novel therapeutic strategy for sepsis-associated cardiovascular disease.