Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response and Increases Survival in a Murine Model of Endotoxic Shock

INTRODUCTION: Urotensin II (UII) is a potent vasoactive peptide activating the G protein-coupled receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation and cardiac function during endotoxic shock. METHODS: C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6 and 9 hours (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. RESULTS: Urantide treatment improved survival (88.9% vs 30% on day 6, p < 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2485 [2280-2751] pg/ml vs 3330 [3119-3680] pg/ml, p < 0.01) at H6, in IL-3 (1.0 [0.40-2.0] pg/ml vs 5.8 [3.0-7.7] pg/ml, p < 0.01), and IL-1β (651 [491-1135] pg/ml vs 1601 [906-3010] pg/ml, p < 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9-1.9] vs 3.2 [2.3-4], p < 0.01) and kidney (0.3 [0.3-0.4] vs 0.6 [0.5-1.1], p < 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5-38.9] vs 12.0 [8.7-17.6] %, p < 0.01 and cardiac output: 30.3 [25.9-39.8] vs 15.1 [13.0-16.9] ml/min, p < 0.0001). CONCLUSION: These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients.